patho combine by halim seman

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Pathology Diseases of the Oral Cavity Reema Al-Safadi Thurayya Hawari Tuesday, 25/10/2011

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‫بسم هللا الرحمن الرحيم‬ Today we will start talking about the oral cavity. The oral cavity is the orifice to the GIT as well as transports air to the respiratory tract. What surrounds the oral cavity?? The lips extraorally, the buccal mucosa intraorally bilateral, the tongue in the floor and at the top there lies the soft and the hard palate. What are the alveolar processes?? They are the part of the maxilla or mandible that contains the teeth. The soft tissue surrounding the teeth is called gingiva, when the teeth are extracted they will have an alternative name "alveolar mucosa" The oral cavity is surrounded by stratified squamous epithelium.

Here we have in the picture, para-keratinized epithelium since we have piknotic nuclei in the keratin, most of the lining of the oral cavity is of the para-keratinzed type not the ortho-keratinzed. Most of the lining of the oral cavity is keratinized

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We will classify the keratinization (or the mucosa) into: - Keratinized - Non-keratinized When we say non-keratinized, we mean that the keratinization is relatively less keratinized than other areas. Keratinized

Non-keratized

Hard palate Gingiva Dorsum of the tongue

Buccal mucosa Labial mucosa Soft palate Sublingual surface of the tongue Floor of the mouth

We have minor salivary glands everywhere around the oral cavity except in (keratinized part): 1- Dorsum of the tongue of anterior two thirds **(The posterior one third has von Ebnar salivary glands)** 2- Anterior part of the hard palate 3- Gingiva One of the findings in the oral cavity>> fordyces granules which are the yellowish granules on the buccal mucosa, at the junction of the vermilion border with labial mucosa; they are ectopic sebaceous glands, they are called ectopic because their location is abnormal, as usually they are associated with normally hair but here inside the oral cavity we have no hair. Why do they occur here?? May be as a result of some displacement during embryogenesis but the real cause isnâ&#x20AC;&#x2122;t known.

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These sebaceous glands are not found in all human beings since they are developmental changes, mostly found on the buccal mucosa. Like any other mucosa of GIT, there's lymphoid tissue inside the oral cavity called MALT (mucosa associated lymphoid tissue) found in mucosa or they can form collections. Here in this picture, on the posterior lateral border of the tongue (the arrow on the pic) we have what’s called foliate papilla which is a type of papilla found in the tongue and it’s a part of the Waldeyer's ring (adenoid, tonsils, foliate)

Waldeyer's ring: is an anatomical term describing the lymphoid tissue ring located in the pharynx and to the back of the oral cavity. The ring consists of (from superior to inferior):    

Pharyngeal tonsil (also known as 'adenoids' when infected). Tubal tonsil (where Eustachian tube opens in the nasopharynx). Palatine tonsils (commonly called "the tonsils" in the vernacular, less commonly termed "faucial tonsils"). Lingual tonsils.

Clinical note regarding foliate papillae: sometimes during tonsillitis these papillae swell & enlarge and they occur bilaterally. Some patients may come complaining about them thinking they have lesions on their posterior lateral surface of the tongue.

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Now we will shift into the diseases of the oral cavity. These diseases may be developmental diseases (anomalies), sometimes they are considered deviation from normal rather than specific diseases which require treatment. Examples of these:

Developmental anomalies The cleft lip and cleft palate, macroglossia and Branchial cleft lip. Now regarding the cleft lip & palate, here there's incomplete fusion during embryogenesis between processes which is a developmental change. 1- Cleft Lip: It may be mild, may be only cleft lip in the soft tissue, or in the soft tissues and alveolar process of anterior part, complete cleft lip reaching the nose, it may be unilateral or bilateral.

2-Palate: bifid uvula (mild, best prognosis, minor form). When the bone is included, there will be communication between the oral cavity and nasal cavity, and here it must be repaired, require obturator, as well as surgical treatment. It may be unilateral and complete cleft lip reaching the anterior part Or bilateral & complete. ***obturator: A palatal obturator is a prosthesis that totally occludes an opening such as an orinasal fistula (in the roof of the mouth). They are similar to dental retainers,**** |Page5

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3-Macroglossia: is like Downe syndrome patients they have enlarged tongue however, macroglossia is not always developmental it may be secondary to: A) B) C) D)

tumors in tongue, lymphangioma, hemangioma, secondary to amyloidosis (deposits of proteins in the tongue) causing the size of the tongue to increase. E) secondary to loss of teeth, when the patients' teeth are extracted, the tongue hypertrophies as to fill the spaces of the teeth which has been extracted. ***therefore, we can conclude that macroglossia can be either developmental or secondary to tumors and lesions.

4-Branchial cleft cysts: Are lining epithelium surrounded by lymphoid tissue. Etiology: the epithelium may be entrapped within the lymph nodes in the cervical region, later on the epithelium makes a cyst within the |Page6

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lymph node, so it appears as lymphoepithelial cyst (branchial cleft cyst); We may ask why branchial cleft cyst occur in this area particularly?? May be because of the entrapment of epithelium occurs here in the cervical lymph node, therefore appear as branchial cleft cyst The other etiology: it's remnant of the branchial arches.

Now we'll start talking about inflammatory lesions and infectious diseases of the oral cavity :

Recurrent aphthous ulceration (Recurrent aphthous stomatitis): Etiology: is not 100% known the most likely accepted theory is autoimmune ALTERATION, where the T-CELLS are fighting the basal or basement membrane in the oral cavity in a way or another, has 3 subtypes: 1) Minor: small size, less than 10 in number, doesnâ&#x20AC;&#x2122;t heal with scar, pts stay free of ulceration for long period of time. (The most mild between the three types) 2) Major: large size, heals with scar 3) Herpitifrom: hundreds in no., may or may not heal with scar. We differentiate between them according to the size, number and healing process. Shallow fibrin coated like any ulcer, whitish or yellowish coat surrounded by erythema, usually less 1 cm in diameter however, herpitiform it's pinpointed 2cm in diameter. Apthous ulceration are extremely common having a prevalence of 70%, in the JORDANIAN population, most common variant is the minor. |Page7

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Ulcers appear especially during stress periods (exams) , hormonal changes in females, medications as corticosteroids ,broad spectrum antibiotic has slight role (not always), HIV patients, renal transplantation, fever, pregnancy and any condition which cause alteration of the immune system. All of these cause slight suppression of the immune system, therefore increasing frequency of minor apthous ulceration. Itâ&#x20AC;&#x2122;s small in size but very distressing, painful and annoying. Since apthous ulceration is an immune mediated disease, hypersensitivity plays role here, patients having hypersensitivity to certain types of food like: Tomatoes, white cheese and chocolate. Some micronutrients including folic acid, B12, iron are important for the integrity of the oral cavity and oral mucosa so any deficiency may increase the rate of ulceration. Inflammatory bowel diseases: such as crohn's disease, ulcerative colitis It's also related to BehĂ§et syndrome BehĂ§et syndrome: is a rare immune-mediated systemic vasculitis that often presents with mucous membrane ulceration and ocular involvements. As a systemic disease, it can also involve visceral organs such as the gastrointestinal tract, pulmonary, musculoskeletal, and neurological systems. This syndrome can be fatal, due to ruptured vascular aneurysms, or severe neurological complications. -wikiAsma's question: "if the immune system is suppressed by medications how come it will be hyperfuctioning causing apthous ulcers?" It's related to T-cells themselves (they are malfunctioning) attacking the oral cavity; how these medications affect the immune system it's not really clear. |Page8

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Itâ&#x20AC;&#x2122;s not an AUTOIMMUNE disease, unlike pemphigus and pemphigoid which produce autoantibodies directed against specific antigens in oral mucosa, if pts take corticosteroids the process of the disease will be controlled as autoantibodies will decrease while in apthous ulceration we DONâ&#x20AC;&#x2122;T HAVE AUTOANTIBODIES, it's the T-cells themselves attacking the mucosa whether the patient takes corticosteroids or not the T-CELLS are going to attack the mucosa, IT'S alteration of the immune system *** Here the DR said to delete the word suppression and replace it by alteration of immune system*** For example: if we have cross reactivity against certain bacterial antigens which mimics antigen in the basement membrane, T-cells are going to attack the oral mucosa. Inflammatory bowel diseases have an increased rate of opthous ulcers ; the reason isn't clear but may be due to malabsorption of micronutrients ( Fe, folic acid, B12) which are responsible for the integrity of oral mucosa. Ulcers IN GENEARAL are self limiting, heals in 10-14 days unless it is major it requires month to heal leaving a scar and has high recurrence.

Infections of the oral cavity We have viral, bacterial & fungal infections Viral infections>> there's herpes simplex virus which is the most common viral infection affecting the oral cavity, type 1&2. Type 1 is more common than 2 in the oral cavity, herpes family usually have primary infections and secondary infections. For the primary infection of the herpes simplex , it's asymptomatic most of the time >>> SUBCLINICAL (that's why it's written in red color in the slides). Sometimes the primary infection is severe, causing acute primary herpetic gingivostomatitis. It's acute since it's an acute problem, it's |Page9

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gingivostomatitis because it involves the gingiva where ulcers appear on it as well as ulceration of the rest of the oral cavity. Here we have perioral vesicles and later on ulceration and crusting

The tongue as well has ulcer. If I want to know if the patient has primary acute herpetic gingivostomatitis, I check the tongue and gingiva since they are important structures and locations, being infected in primary acute herpetic gingivostomatitis since they are KERATINIZED. How to differentiate between herpetic gingivostomatitis and apthous? Apthous ulers infect non-keratinized areas of the oral cavity but the primary herpes infect keratinized (dorsum of tongue and gingiva) as well as non- keratinized areas. Recurrent or reactivation of the herpes occurs as herpes labialis. Note: being infected with herpes virus, you can infect others who donâ&#x20AC;&#x2122;t have this virus to induce primary or secondary infection, however, you can never infect a person and induce herpes labialis (which is a secondary infection), having herpes labialis is an indication for having the virus latent in the trigeminal ganglion.

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Summary of the above: Pt A (INFECTED WITH HERPES)>> pt B(non- exposed) shows gingivomostomatitis then it's primary infection , and this show that A infected B WHILE: Pt A (INFECTED WITH HERPES)>>pt B shows herpes labialis indicates that he's not been infected by pt A, he had latent herpes previously in trigeminal ganglion and it has been reactivated. (You can infect person to induce primary infection but never the secondary) Herpes labialis>>> vesicles appear on the branches of the trigeminal nerve, and most common location is the lip, usually UNILATERAL not bilateral. Triggering factors causing reactivation of herpes virus, leading to herpes labialis: 1) sun exposure 2) trauma to the lip 3) Stress (suppression or alteration of the immune system) So the virus replicates and will travel down along the sensory nerves of the trigeminal nerve to induce herpes labialis. Histologically: The virus enters the epithelial cells, it replicates using the cell's nucleus and cytoplasm, here we have enlarged nucleus with fragmented chromatin (tznak cell). In pemphigus we have tznak cell also, but these two cells are totally different. | P a g e 11

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Tznack cell in herpes labialis>> is a virally infected epithelial cell, with enlarged nucleus, swollen appearance and deeply eosinophilic cytoplasm. Then will rupture and spread the virus to the surrounding cells forming a vesicle (a space of ruptured cells), edema will leak into this space and form these vesicles. How can we treat herpes labialis???? We ask the patient to take acyclovir (antiviral) to place it immediately on the area where numbness can be felt, before rupturing of the vesicles, if the vesicle ruptures acyclovir seems to be useless and it will take 10-14 days to heal. The virus may give extensive recurrence INTRAORALLY instead of localized>> (like herpes labialis), if the patient is immune compromised or having HIV. this is the appearance of extensive recurrence on the PALATE & GINGIVA **KERATINIZED LOCATIONS ONLY INTRAORALLY**

Recurrent infection in herpes simplex have two locations; intraorally and extraorally. - Extraorally>>> junction between vermilion border and skin of the lips , unilateral - Intraorally>> gingiva and hard palate(keratinized), unilateral & not painful.

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Now the fungal infections of the oral cavity: One of the most common fungal infections of the oral cavity is the CANDIDIASIS Candidiasis has at least 4 subtypes the most common one is the thrush.

Concentrate on sloughed off, as leukoplakia can't be sloughed off.

Thrush: soft white plaques that can be SLOUGHED OFF leaving red bleeding base, Thrush can be found on: Palate Tongue Buccal mucosa Thrush most common among (individuals whom immune system not well functioning):   

Children Elderly Pregnancy

Candida causing the thrush is found in the oral cavity as normal flora up to 40%-60% especially on the dorsum of the tongue. When does the Candida cause infection?? When there's suppression of the immune system or alteration of the oral environment itself. Salivation is very important to wash the Candida, if the salivation decrease this will allow the Candida to replicate and cause infection, especially after certain medications which lower saliva production rate.

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Thrush is common in: 1) Anemic pts. 2) Diabetes mellitus (immune compromised). 3) Use of antibiotics, since there's a balance between bacteria and Candida, if normal flora bacteria decrease, this gives the opportunity to Candida to replicate. 4) HIV pts(immune compromised). Etiology of thrush (opportunistic infection): Hyphae are the etiologic factor of Candidiasis ONLY penetrate superficial layer of epithelium secrete substances causing inflammatory response.

Spores ARE NOT the pathologic agents, we all have Candida spores, if we take smear of the oral cavity we find spores!

Candida has two morphological appearances; Hyphae and spores. Hyphae>> the one causing disease Immune compromised having the disease: infection is severe, widely spread and doesnâ&#x20AC;&#x2122;t respond to normal treatments. In HIV patients, there's Kaposi sarcoma, which is vascular endothelial malignant tumor, rarely metastasize, found in 25 % of HIV patients may be related to human herpes virus 8.

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Hairy leukoplakia: found in HIV patients and immune , compromised patients induced by Epstein bar virus (EBV) , which is human herpes virus 5, has primary and secondary infections, hairy leukoplakia is considered as a secondary infection. There are vertical folds on the lateral surface of the tongue. If biopsy is taken, certain histopathologic changes indicates infection with EBV

Although leukoplakia is a premalignant state, but here hairy leukoplakia ISNâ&#x20AC;&#x2122;T premalignant

In hairy leukoplakia: ď&#x201A;ˇ ď&#x201A;ˇ

Excessive keratinization. Increase thickness of the epithelium (acanthosis).

Leukoplakia: premalignant state. A white patch in the oral cavity which CAN'T be removed by scrapping And can't be attributed to any other cause, not traumatic in origin, not due to thermal injury, or sharp tooth or cusp. | P a g e 15

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Thrush>> white plaque can be sloughed off. Leukoplakia>>white patch CANT be sloughed off

In the picture above, we see a white patch which is leukoplakia, here it's questionable since some may say that it's near the tooth and may have occurred due to friction, therefore, we can't be sure, however, in this case there's white patch on floor of the tongue, therefore, we can't say that this is due to friction from teeth since they donâ&#x20AC;&#x2122;t reach this area they are in the ventral surface of the mouth making us confident that this is leukoplakia.

The only cause which can be related to leukoplakia is SMOKING!! LEUKOPLAKIA: is a clinical term!! You can't use the term microscopically If you face a question in the exam, saying that what are the histopatholigic features of this disease showing this and that, and one of the choices is (leukoplakia) THIS IS WRONG!!! Since it's a clinical term UNLESS you can't find any reasonable choice then you can choose leukoplakia. This is the floor of the mouth having white patch (leukoplakia)

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These blue structures are varicosities which are age-related (dilated vein) Here we have a white patch which is nonhomogenous and not smooth leukoplakia ,reddish areas in between Student: how can we differentiate between homogenous and nonhemogenous leukoplakia?? Homogenous has smooth surface, no nodular or red areas. Microscopically(LEUKOPLAKIA): We see hyperkeratosis which is completely normal, Or hyperkeratosis with mild dysplasia, Or hyperkeratosis with moderate or severe dysplsia; carcinoma in situ, Or sqaumous cell carcinoma BUT ONLY 3-6% OF LEUKOPLAKIA TRANSFROM TO SQAMOUS CELL CARINOMA

Erythroplakia: This is erythroplakia Red velvety areas which may remain level with or slightly depressed in relation to surrounding mucosa. Can't be attributed to any specific cause.

Hyperkeratosis is less frequent; red color is due to intense inflammation and vascular congestion. Greater tendency for epithelial cell atypia and marked dysplasia than leukoplakia. | P a g e 17

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Higher risk (50%) of malignant transformation to sqaumous cell carcinoma while in leukoplakia it was (3-6%) Erythroleukoplakia: speckled leukoplakia; mixture of erythroplakia and leukoplakia The greater the red component involved, the higher rate of malignant transformation. **higher transformation risk than leukoplakia**

Tumors Most common Malignant Tumors of the Oral Cavity: ***Squamous Cell Carcinoma*** M>F Most common affected areas: 1-Floor of the mouth 2-ventral of the tongue 3-soft palate 4-posterior lateral part of the tongue

Etiology of squamous cell carcinoma: 1- Tobacco: smoking, smokeless tobacco(chewing gum containing tobacco). 2- Protracted irritation (e.g. dentures?). 3- Chronic dental & oral infections, broken tooth or broken filling causing chronic irritation to buccal mucosa. 4- Sunlight- lip cancer. 5- Heat. | P a g e 18

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6- Alcohol. 7- Epithelial atrophy, because it allows toxins to enter easily 8- HPV. When we have tobacco& alcohol they have synergistic effect, Alcohol acts as a solvent for toxic material of the tobacco therefore, these toxic material are pooled in the floor of the mouth, that's why the most common locations are the floor of the mouth and ventral and lateral of the tongue. ***The Dr said that this slide is easy and you can read it by yourself, so I copied it: Clinical and Histopathological Features: Plaque, mucosal thickening or ulcer. Invasive &/or in situ carcinoma; well differentiated to undifferentiated. Spread to local LN (submandibular, high jugularâ&#x20AC;Ś). Px: depends on location (e.g. lip), grade, stage.50% lead to death in 5 years; overall 5 YS without LN metastasis is 40% after chemotherapy & radiotherapy, and 20% with LN metastasis.

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1- normal mucosa, keratin forms a thin layer. 2- hyperkeratosis, thick layer of keratin, epithelium is still normal and organized. 3- disorganization of epithelium, dysplasia. 4- dysplasia extending to full thickness>> carcinoma in situ. 5- dysplasia invading underlying connective tissue >> squamous cell carcinoma. "Knowledge is knowing that a tomatoe is a fruit, Wisdom is not putting it in a fruit salad" "But if you judge a fish on its ability to climb a tree, it will live its whole life believing it is stupid." Einstein's quote reminds us to think twice before measuring ourselves (and others) against inappropriate standards. Everyone has a different ability or particular "genius." Often, comparing yourself to someone else's abilities might mean overlooking what it is you are naturally more suited towards doing. In other words, stop being a fish trying to climb a tree and embrace your fishiness. The point: We're not all made to be theoretical physicists. Aim for what you're good at, work hard for what you want, and don't beat yourself up when you can't do everything perfectly.

FINALLY, I WOULD LIKE TO THANK SAMA GROUP FOR THEIR CONTINUOUS HARD WORK AND WISH U THE BEST EACH AND EVERYONE OF U GOD BLESS U ALL ď &#x160; DONE BY: THURAYYA HAWARI

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Pathology Diseases of Salivary Glands & Esophagus I

Ismaâ&#x20AC;&#x2122;eel Matalqa Bassam Al-Hasson Wednesday, 26/10/2011

Pathology lecture #2 Wednesday, 26/10/2011 Done By: Bassam Al-Hasson

Note about the lecture: - Anything between brackets “[]” or in boxes are additional notes from me, book, or the NET. - The lecture includes everything you don’t need the slide while studying it.

Today inshallah we are going to continue discussing some of the remaining part of the last lecture about oral pathology. I think you left with the salivary gland pathology so we will continue the remaining quickly and we will switch to discuss different aspects of the pathology of esophagus and next lecture we will continue with the stomach.

SALIVARY GLANDS So this is just quickly to have like an overview of the different diseases or pathology affecting the salivary glands, and you will see here like any other organ in the body some sort of inflammations, tumors and some other diseases.  Inflammation o Viral sialadenitis: which is caused mainly by different viruses and we see one example of that later. o Bacterial sialadenitis. o Autoimmune sialadenitis: it's an important disease of pathology because it leads to some other syndromes and sometimes it might be associated with other manifestations. o Sialolithiasis: which mean the formation of stones in the salivary glands mainly in the ducts of the salivary glands. It's like a stone which we have in the gallbladder. We call it as Sialolithiasis and lithiasis from stone formation.

 Tumors There are benign tumors and malignant tumors. And there are about 32 types of benign and malignant salivary gland tumors it's very extensive list, these are the most important examples of benign and malignant tumors . o Benign » Pleomorhpic adnoma (mixed tumor): The most common type of benign tumors. » Warthin’s tumor o Malignant » Carcinoma ex-pleomorphic adenoma: which means those cases of carcinoma which arise in the background of Pleomorphic adenoma (benign). Although most of the carcinoma's actually arise de-novo which means not in the background of the pre-existing benign condition . » Mucoepidermoid carcinoma » Adenoid cystic carcinoma .  Mickulicz’s syndrome

VIRAL SIALADENITIS:  The most common cause is mumps (‫ )النكاف‬which is usually affecting [swelling of] the parotid glands, in an epidemic usually sort of transmission.  70% are bilateral, 20% unilateral and 10% others.  Mumps is an acute contagious childhood disease and you know it spreads very quickly among the children.  It's a Paramyxovirus, acquired by respiratory droplets.  Usually self-limited. You know usually we don't give any medication for mumps. If there is fever or pyrxia you can give him some sort of antipyretic medication we call it compresors other than that we give antiviral.  May lead to complications, which are commoner in adults. 3

o Pancreatitis. o Orchitis: which is re-inflammation of the testis, it’s usually unilateral. If it’s so sever it may leads to infertility later during adult life by affecting the germ cells within the seminoprostatic tubules but this is very rarely. o CNS inflammation: are rare but might be very serious. AUTOIMMUNE SIALADENITIS

A good example of what's called autoimmune Sialadenitis or autoimmune parotitis is Sjögren syndrome:  It's inflammation of salivary glands & mucus-secreting glands of nasal mucosa (resulting in dry mouth or xerostomia) and lacrimal glands (resulting in dry eyes or keratoconjunctivitis), so these are the manifestation of such syndrome. Note : dry eyes ....... xerophthalmia 

90% are females; parotid enlargement in 50%

 May be primary or secondary (60%) to other autoimmune disease (RA, SLE, polymyositis).  It's characterized by lymphocytic infiltration of the parotid gland with variable degree of fibrosis.  We do some sort of autoimmune anti-body panels like: o RF: rheumatoid factor. o ANAs (AntiNuclear Antibodies) might be +ve [usually] or –ve o Anti-ribonucleoprotein SS-A & SS-B Abs. 

They have High risk to develop lymphomas. Those cases of Sjögren syndrome or autoimmune Sialadenitis also in consistent with some other sort of autoimmune disease might increase the risk of development of lymphomas. o So if this happens in the parotid gland it might lead to lymphoma of the parotid gland.

SIALOLITHIASIS & NONSPECIFIC SIALADENITIS:  Might from of bacterial origin.  Secondary to ductal obstruction by stones (sialolithiasis) in major excretory duct (especially in submandibular)  It's usually unilateral.  Pathogenesis: may have impacted food debris or edema (due to inflammation) around the orifice following injury.  And this will lead to ductal dilatation, periductal inflammation and superimposed by bacterial invasion & suppuration.  Predisposing factor: o History of major surgery at salivary glands. o Dehydration. o Long-term phenothiazine treatment: phenothiazines are known to cause some sort of dryness of the secretion of either the salivary gland secretion or other digestive secretion so this might dispose to some degree of stone formation. # Phenothiazine:Phenothiazine is an organic compound that occurs in various antipsychtic and antihistaminic drugs.

TUMORS: Just briefly now for the tumors as I said there are many types of these tumors we just need to know at least two examples of these tumors.  There are relatively uncommon only 2% of tumors in humans.  80% of tumors occur in parotid gland. o You know there are different types of salivary glands we have parotid, sublingual, submandibular etc. And there are some minor salivary glands which are present in the palate, we have major and minor salivary glands tumors.

 They have usually equal male to female ratio, all ages and peak incidence in elderly with (6th - 7th decade)  Most of the parotid tumors are benign (up 80%) and only 50% in the submaxillary tumors. o As the size of the salivary gland become smaller, the chances of malignancy increases. o So if you have a tumor in the minor salivary glands the chances that this would be a malignant tumor is higher than a benign o A tumor in the major salivary glands like in the parotids , the chance to be a benign are much higher than to be a malignant one. .  So they have wide histological variations as I said there are some benign and some malignant ones and the examples as we just mentioned. PLEOMORPHIC ADENOMA (mixed tumor)  The most common tumor represent about (70% - 80%) of salivary glands tumors.  Slowly growing well-demarcated, mostly arising from superficial parotid.  Pathology: it's mixed or pleomorphic because we have two components 1)Epithelial component and 2)Myxoid stromal (mesenchymal) component. So it has a heterogeneous histology with epithelial elements, myxoid stroma, often containing chondroid foci and rarely it might contains some bone.  They also have recurrence rate, 10% of cases might recur after surgery.  Malignant transformation might occur and again the chances are higher in the smaller glands rather in the larger glands which means the chances of transformation for example: o 40% in submandibular. o It's less than 15% in the parotid gland.

enlargement of the mandibulojagular angle

And this is a typical example of pleomorphic adenoma.

The tumor

Normal salivary gland

This is the consistency of the tumor . You can see the hemorrhage and the cut surface

This is the typical appearance. You can see a normal salivary gland and the tumor. Also you can see myxoid background and epithelial component 7

WARTHIN’S TUMOR  It's old name is papillary cystadenoma lymphomatosum and this is no longer used. o This name describes pathological appearance because its composed of cystic spaces which are lined by tall columnar epithelial cells and over lined abundant lymphoid tissue.  Benign  Slowly growing tumor.  5-10% of all parotid tumors it's extremely rare in other salivary glands.  Histogenesis: vestigial embryonic remnants of branchial cleft origin. o We have branchial cleft which transforms during the embryonic life to different structure in the head and neck so if you are left with some remnants within the parotid tissue this might give rise to such tumor.  They are benign and they are cured by surgical resection.

lymphoid tissue cystic spaces

And this is a typical example of WARTHIN’S TUMOR. You can see cystic spaces lined by these columnar epithelial and underlined the lymphoid tissue. 8

MICKULICZ’S SYNDROME  It’s a combination of salivary and lacrimal glands enlargement with xerostomia.  Causes: o Leukemia/lymphoma o Sarcoidosis o Sjögren syndrome. So we will talk about the digestive system and we just finished the salivary glands which are the accessory organs of the digestive system. The digestive system or alimentary tract in some sort of anatomical sequence consists of:         

Oral cavity (including salivary glands) Esophagus Stomach Small intestine Colon Appendix Liver Biliary tract Pancreas

!

I should emphasaize here at this point the anatomy and histology are very crucial in understanding any pathological process because we will be discussing some diseases that are purely anatomic abnormalities and some of them of course they have other etiologies but you need to understand the histology behind this like when we see the peptic ulcer disease, when we discuss the stomach. !

THE ESOPHAGUS o Esophagus: is a mechanical tube connecting the pharynx to the stomach. o You will see that most of problems we dealing with esophagus is mechanical.  Congenital anatomic disorders: o Agenesis: it means the total failure of development of that organ. So esophageal agenesis is the absence of the esophagus. o Atresia: means constricted. The esophagus becomes fibrotic and there narrowing of the lumen. o Fistula: is also congenital mal-development where there are two organs linked to each other by a fistula tract which is abnormal » Example: the esophagus could be connected by a fistula to the trachea we call it tracheo-esophageal fistula and we have different types of tracheo-esophageal fistulas. o Stenosis.  Acquired anatomic/motor disorders » Stenosis. » Webs & Rings. » HH= hiatus hernia. » Achalasia. And we will discuss them one by one.  Inflammations The most important inflammatory condition of the esophagus is the esophagitis and in particular we will discuss what we call it reflux esophagitis. What's reflux esophagitis? It's abnormal because the esophagus is created in a way that it should clear the flow in one direction and there should be no reflux and we will have different mechanism that we will discuss later.  Barrett’s esophagus:

Very interesting disease which is known to be pre-neoplastic (premalignant) which means if left untreated or without follow-up this will progress to cancer. It’s called Barret after one of the famous surgeons who describe this entity in the 1950s and because he is a surgeon not a pathologist he didn't understand exactly the pathology. So the pathologists later discover that Barrett describe it by non logical thinking because initially he thought that in Barrett's esophagus is a kind of shortening of the esophagus that will lead to pulling the stomach up to the thoracic wall but later on the pathologists clarified this in a scientific way that this is a metaplastic process rather than a congenital one and there are some risk factors for that.  Vascular diseases  Tumors We will elaborate on that later. CLINICAL FEATURES OF DISEASES OF THE ESOPHAGUS Now whatever is the disease of the esophagus, usually all disorders of the esophagous share limited number of symptoms and signs all of them related to some esophageal disorder.  Dysphagia: difficulty in swallowing, so he can’t perform the task of sollowing in normal circumstances and its related to: o Deranged esophageal motor function. o Mechanical: narrowing or obstruction of lumen.  Heartburn: (‫)الحرقة‬: is a very common symptom, retrosternal burning pain and it's mainly due to regurgitation of the gastric fluid.  Hematemesis: vomiting of blood.

 Melena: blood in the stool. When there is massive bleeding in sort of loss of blood whether from esophagus, stomach or upper parts of the duodenum (Upper GI bleeding). o It's an altered blood, which has been altered by acids, alkali and by all sort secretions to become altered and we call it melena. o It's a tarry looking feces. o It might be related to severe inflammation, ulceration or laceration and we will see different causes for each one. o Usually we divide the GI tract into lower GI and upper GI our anatomic landmark to divide this is a ligament in the second part of the duodenum [ligament of Treitz].  So when it's in small amount leading to vomiting of this blood we call it hematemesis.  When this blood in massive amount it will be secreted and emptied to the small intestine so this will be called as melena which is a blood in the stool.  Respiratory symptoms: like dyspnea, cough, aspiration o Aspiration happens as we will see in some congenital abnormality, if you regurgitate some of gastric content back to the esophagus this might go back to the trachea and this will lead to aspiration and different respiratory symptoms. CONGENITAL ANATOMIC DISORDERS :  They Present at birth with vomiting, aspiration (pneumonia, asphyxia), gastric distention.  Agenesis: absence of esophagus. It’s very rare and off course incompatible with life unless it’s corrected directly after birth.  Atresia: failure of development of a segment of esophagus, which is replaced by a thin non-canalized cord (absence of lumen) with formation of upper & lower pouches; associated with tracheo-esophageal fistula.

 Stenosis: developmental defect resulting in partial obstruction or narrowing of the esophageal lumen. Off course in all these situations and conditions we need urgent medical and surgical intervention

Fistula: communication with trachea

‫؟‬A student ask what’s asphyxia? DR had translated as ‫إختناق‬ WiKi says: is a condition of severely deficient supply of oxygen to the body that arises from being unable to breathe normally.

?

ACQUIRED ANATOMIC DISORDERS

 Underline cases of Stenosis: » caustic strictures: stricture which follow ingestion of some chemicals (caustic). It’s common in children, they could drink hydrochloric acid that will cause some sort of ulceration and caustic injury that leading to fibrosis and stenosis. » post-surgical (fibrosis) » Inflammatory » Tumours » Autoimmune diseases (e.g. Scleroderma: might cause functional stenosis).  Webs & Rings: » Congenital Mucosal webs: mucosa protruding inside the esophagus. » Rings: mucosal and submucosal concentric ring which partially occluding the esophagus. Both cause partially obstruct or narrowing the lumen of esophagus.  Diverticula: Outpouching of the esophageal wall.

Segment of the stomach herniated above the diaphragm

Close to the diaphragm

These are different examples of congenital and acquired conditions we’ll take about them in details later.

One of the important diseases of oesophagus Hiatus Hernia (‫)فتق الحجاب الحاجز‬:  There are many people severing from variable degree of hiatus hernia. And there are too many who actually have hiatus hernia but have never been diagnosed by endoscopy.  Protrusion of a dilated sac-like segment of stomach above the diaphragm. Such as protrusion through the esophagus hiatus [is a hole in the diaphragm through which the esophagus passes].  Underline cause: Separation of the diaphragmatic crura (layers of muscles which form the diaphragm). 15

 Incidence: 1-20% of adults. It’s probably more common in Jordan because of high incidence of obesity and increase with age  Mostly asymptomatic.  If they are symptomatic they will present with heartburn & regurgitation of gastric juices in 9% of cases due to LES incompetence.  It’s very position related if you bend forward these might elevated the manifestation of HH because this will facilitated the regurgitation of gastric juices. o Symptoms are accentuated by positions favoring reflux.  Patients with severe reflux esophagitis usually have HH; however, HH & reflux are not the same condition. o They are two different conditions you might get reflux esophagitis in the absence of HH or vice versa but usually if have HH you will have reflux esophagitis as well. o

‫؟‬Why?

Because LES is incompetence, due this abnormal mechanical function so the chances for the gastric contents to reflux upward is more likely.

?

 It has 2 anatomic patterns: o Sliding (axial): 95% of cases; bell-shaped dilation; due to congenital short esophagus, strictures, spasm or long-standing fibrous scarring of esophagus, resulting in traction on stomach. o Paraesophageal (non-axial or rolling): segement of cardiac stomach dissects alongside esophagus through a defect. May follow traumatic rupture of diaphragm; may strangulate and infarct. This is less common (5% of cases) but more serious because it could lead to infarction [by applying pressure on blood vessels and blocking them] that may lead to chest perforation.

ACHALASIA  ACHLASIA: a Latin word. o A: none and Chalasia: relax. o So it means failure to relax of the esophagus, i.e., incomplete relaxation of LES in response to swallowing.  Usually the mechanic of swallowing you take the food fragmented, formed a bolus and you will swallow it through the esophagus to stomach then LES relax. If this mechanical [LES relaxation] failed it will producing functional obstruction above the sphincter and such continuous of obstruction will lead to dilation of more proximal esophagus.  Complain: progressive dysphagia to liquids and solid food, nocturnal regurgitation & aspiration of undigested food and off course aspiration pneumonia. o

‫؟‬Why they will sever form nocturnal regurgitation? Its dysfunctional sphincter so it’s neither relaxes nor closes properly. So When they lie down during sleep , this position will allow regurgitation

of food through this abnormal sphincter. ?  Abnormal manometric studies (During endoscopy we measure manometric studies (pressure study)): aperistalsis (absence of movement), partial relaxation of LES and increased basal tone of LES.  Pathology: deranged innervation of LES [is innervated by both parasympathetic(vagus)& sympathetic; however, the vagus is essential for reflex relaxation of LES]; absent myenteric ganglia in the body of esophagus. Depend on the severity of the disease the muscle might be normal, hypertrophic, or because of continuous dilatation in advanced stages this might lead to thining of the muscles. And because of dilatation and long standing contact between the food and mucosa these might lead to mucosal inflammation, ulcer or fibrosis as secondary consequences of the disease.  Two main types: o Primary (sporadic): Commoner, Unknown cause might be autoimmune or previous viral infection but nothing has been conformed so far as an exact cause. o Secondary: 17

» Chaga’s disease: Tryponosoma cruzi infection (parasite) causing destruction of myenteric plexus ganglion cells in the GIT & ureter; leading to megaduodenum, megacolon or megaureter. » Diabetes (Autonomic neuropathy): vagus nerve injury. 

!

Esophageal squamous cell carcinoma will arises in 5% of cases usually

younger

age

than

patients

without

this

disease.

!

LACERATIONS (Mallory-Weiss syndrome)  It’s mechanical injury.  Longitudinal tears at the esophago-gastric junction. o At esophago-gastric junction we have anatomical and histological junctions and it located just below the diaphragm. o What is important for us is the histological part which sort of junction between squamous epithelium and columnar epithelium and you should remember that the columnar epithelium of the stomach goes in zigzag line at the junction.  Encountered mainly in alcoholics, after bout of severe retching or vomiting. o You know alcoholic people tend to vomit and retch. So such mechanical irritation will lead to tear the mucosa at that site  Underline Pathogenesis: inadequate relaxation of LES muscle during vomiting  May occur in patients without history of vomiting.  HH is found in 75% of patients with MWS.  Linear irregular lacerations, few mm to cm in length.  Involve mainly mucosa or sometimes it might extend deeply to penetrate & perforate wall in severe conditions.

 It’s one of the main cases of massive hemetemesis in 5-10% of all cases; however, the majority doesn’t cause profuse bleeding.

Shiny (squamous) epithelium of esophagus

Columnar epithelium of stomach

Some degree of zigzag lining

LACERATION

VARICES:  It’s one of the fatal conditions of the esophagus. Occurs around the gastro esophageal junction.  The main cause is portal hypertension [portal pressure gradient of 10 mmHg or greater, the normal pressure is 9 mmHg].  Increase in portal pressure will lead to formation of portal-systemic collateral bypass channels. o This collateral channels happens in 4 anatomic sites within the body and you should know them of course because these are the portosystemic anastomosis sites and each one of them has some sort 19

manifestation and diseases. 1)One of these collateral or shunts is the cause of esophageal varices. 2) haemorrhoids. 3) retroperitoneal space. 4) falciform ligament of the liver [I got them for the net because I couldn’t hear what the dr said.. Sorry!!]  Collateral veins will develop in the region of lower esophagus when portal flow is diverted through the coronary veins of stomach into the plexus of esophageal submucosal veins into azygous veins. It’s bypassing of the normal flow of blood because portal hypertension. o Such diverted through the coronary veins of stomach into the plexus of esophageal submucosal veins into azygous veins we call it varices.  Most common cause of portal hypertension is liver cirrhosis.  Rare causes: o Portal vein thrombosis. o Hepatic vein thrombosis (Budd-Chiari syndrome). o Pylephlebitis. o Tumor compression or invasion into major portal radicals.

Esophagus

dilated tortuous sub-mucosal veins

Stomach VARICES (‫)دوالي المريء‬  Esophageal varices represented as dilated tortuous sub-mucosal veins.

 Tortuous dilated veins directly beneath mucosa or in periesophageal tissue. Overlying mucosa may be normal or eroded & inflammed; with or without thrombosis.  It could cause massive upper GI bleeding.  Asymptomatic until they rupture when massive hemetemesis results; rupture may be spontaneous or secondary to vomiting.  Hemorrhage rarely subsides spontaneously.  40% die after 1st episode  70% of the survivors will re-bleed within 1 year.  Mortality rate: 40%. o As you see the mortality rate is very high with varices so it should be corrected and if you can, you should treat the underline causes if it’s possible.  Develops in 2/3 of cirrhotic patients.  Accounts for 50% of deaths in liver cirrhosis.  Treatment Therapeutic endoscopy is considered the mainstay of urgent treatment They are now a new methods of treatment esophageal varices: o Sclerotherapy: Inject the vein with specific material that cause them to thrombosis and this will decrease the possibility to bleed. o Balloon Tamponade: Use special type of balloons and that compress the varices and preventing them from rupture. o Surgical Technique: such as banding to prevent there complications.

!

Banding is a medical procedure which uses elastic bands for constriction. Banding may be used to tie off blood vessels in order to stop bleeding WiKi!

THE END

Done By:

Bassam Al-Hasson Special thanks to my friend Faisal Helmi, for helping me in this lecture. Also 2 all my friends specially Wasem, 3â&#x20AC;&#x2122;ayth, Shlool, Qusai, Qudsi, Hassan, Abo shehabz, Abo sameer (9sa7eb alshalah :P)

10/59 3/17 30

Pathology Diseases of Esophagus II Ismaâ&#x20AC;&#x2122;eel Matalqa Salah Al-Gharaibeh Wednesday, 26/10/2011 24/10/2011

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Wednesday , 26-10-2011 Pathology lecture 3 Done by : Salah Al-Gharaibeh.

ESOPHAGITIS Esophagitis is a generic name which means inflammation of the esophageal mucosa , there are many causes of this condition: 1. Reflex of gastric content which is the most important cause, it causes what we call reflex esophagitis. -There are other causes which account for a lesser degree of esophagitis these include: 2. ingestion of irritants like alcohol, corrosive acids, alkali, excessive hot fluids like tea and heavy smoking. 3. Bacteremia (bacterial esophagitis) and viremia(viral esophagitis) are also possible causes of esophagitis either by direct infection of the esophageal wall or contiguous structures. The most common viruses causing esophagitis are Herpes Simplex Virus and Cytomegalovirus which effect mainly immunocompromised patients (diabetics, HIV patients, and patients undergoing chemotherapy or cytotoxic therapy). 4.Fungal infections (candidiasis,mucormycosis, aspergillosis) which also effect immunocompromised patients. 5.Systemic desquamative skin diseases (pemphigoid). The esophagus is lined with squamous epithelium just like the outer skin, so any systemic disease that affects the skin can also affect the esophagus. So diseases like pemphigus vulgaris and pemphigoid bullous diseases in general affect both the outer skin and the esophagus. Note that these diseases can be very severe and they have a high mortality rate.

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6.Graft-versus-host disease.(GVHD), which is a reaction that occurs between the host and the graft in a transplantation procedure. Thatâ&#x20AC;&#x2122;s why we make sure that we have a matching donor with the least possible HLA incompatibility to reduce the risk of rejection and the risk of developing GVHD. GVHD can affect the skin or the gastrointestinal tract in the form of esophagitis. 7. Radiation, cytotoxic therapy, and uremia, are also possible causes. As we said reflux of gastric content to the esophagus is the most important and commonest cause of esophagitis, it causes what we call reflux esophagitis which is also known as gastroesophageal reflux disease (GORD), or (GERD). ---Pathogenesis of GORD: >>Frequent and protracted reflux due to incompetence of the lower esophageal sphincter (LES) and decreased efficacy of other antireflux mechanisms, which are: the diaphragm, the cardio-esophageal angle (an angle made by the esophagus when it enters the abdomen, or the junction between the esophagus and the cardiac part of the stomach), and the pressure on the intraabdominal esophagus. >>Disordered esophageal motility: gastric contents will remain in contact with the mucosa for a longer time. This means we will have elevated acid peptic levels of regurgitated fluid, duodenal bile acids, lysolecithin and, gastric acids in contact with the esophageal mucosa which will lead to irritation of the mucosa and then inflammation then the development of reflux esophagitis. NOTE: biliary secretions are as harmful as gastric secretions. Biliary secretions are secreted into the duodenum and sometimes people might develop duodenal reflux into the stomach (causing what we call reflux gastropathies) and then reflux to the esophagus so we will have biliary secretions in the esophagus causing esophagitis. Recent studies have shown that biliary secretions are even more harmful and have more potential to cause Barrettâ&#x20AC;&#x2122;s esophagus (explained later) than gastric contents themselves. |Page3

>>impaired reparative capacity of the esophageal mucosa will lead to continuous inflammation and with time we will have mucosal injury and then ulceration. ---Clinical Staging of reflux esophagitis: >>depends on the severity and on the length of the esophagus thatâ&#x20AC;&#x2122;s effected by the disease. >> This staging process is done endoscopicly (evaluating the GROSS appearance). >>We have stage 1,2,3 and when the disease is so severe we call that stage 4, which is a very terrible disease and cannot be tolerated. ---Predisposing factors of reflux esophagitis: 1.Fat, chocolate, alcohol, smokingâ&#x20AC;Ś..etc. after having a fatty meal there is some sort of indigestion leading to some regurgitation of gastric fluid especially if you lie down on your back after eating that meal. 2.Hiatal hernia, because of the mechanical abnormality that effects the lower esophageal sphincter and the junction itself. 3.Pregnancy, because of the increased pressure. 4.Drugs, which effect the lower esophageal sphincter like : Thiazines and Phenothiazines. * ---Consequences of the reflux: >>if the reflux is occasional (only after certain meals) then there are no consequences. >>if the reflux is recurrent and persistent this will lead to inflammation and continuous inflammation will lead to ulceration and that might lead to bleeding causing some degree of hematemesis after a while there will be some reparative and healing changes which will lead to fibrosis and fibrosis leads to stricture which might lead to dysphagia. With such continuous turnover (damage,inflammation,ulceration + regeneration) too much regeneration will increase the chance of having a "faulty |Page4

regeneration" and faulty regeneration might lead to metaplasia, continuous metaplasia (Barrett's esophagus) will lead to dysplasia and then carcinoma. >Taking into consideration the high incidence of reflux esophagitis and the very low incidence of barrett's esophagus you will realize that the previously mentioned sequence (Refluxď&#x192; metaplasia) is very unlikely to happen and it is not the usual scenario. ---Pathological findings in esophagitis: >> Depends on the cause, duration, severity, and stage. >>Hyperemia, edema, wall thickening, pseudomembrane formation, necrosis, and ulceration. >>Fibrosis and stricture formation may follow. **the previous two are characteristic of reflux esophagitis, the next are specific for candidal and viral esophagitis.** >>Candidal esophagitis: gray-white inflammatory pseudomembranes. >>Viral esophagitis: it is very important from a cytological or a histological point of view to see the intranuclear inclusions caused by the cytomegalovirus or herpes simplex virus. >>In reflux esophagitis the "histological hallmark" is to see esophageal mucosal hyperplasia (epithelial hyperplasia)+ basal layer (lower zone) hyperplasia and thickening, these reflect the high turnover of the epithelium. Also the presence of intraepithelial eosinophils and or polymorphonuclear cells (PMN's). NOTE: the presence of eosinophils within the epithelium is crucial for the diagnosis of reflux esophagitis, even if we see epithelial and basal hyperplasia and leukocytic infiltrate in a biopsy, which are characteristic of reflux esophagitis we still like to see eosinophils to confirm the diagnosis. ---why do we have eosinophils? |Page5

>> it is sort of a reactive mechanism between the mucosa and the content of the refluxed material (gastric fluid, or bile) somewhat like a "hypersensitivity" reaction. (so it's not actually a hypersensitivity reaction). **Pic. In slide #56**

BARRETT'S ESOPHAGUS (premalignant lesions of the esophagus) >>it is a condition in which a gastric or intestinal type of mucosa lines the distal part of the esophagus above the lower esophageal sphincter (actually above the histological gastroesophageal junction). >>it is considered metaplasia in which the normal squamous epithelium of the esophagus is replaced by columnar or glandular epithelium. >>most cases are acquired and are present in adults, rarely seen in children. >>originally people thought it was a congenital disease but this is not very valid ,it is an acquired metaplastic disease and the main cause as we mentioned before is reflux esophagitis. |Page6

>>Complication of long standing reflux  inflammation of squamous epi.ulcerationrepair re-epithelization ingrowth of pluripotent stem cells differentiation into intestinal or gastric epithelium. Generally we say that the normal squamous epithelium changes into glandular epithelium which could be glandular that resembles the intestinal type or glandular that resembles the gastric type. If it was the glandular intestinal type then we will have Goblet cells, if goblet cells are not present then it is the gastric type. When it comes to classifying barrett's esophagus we have two schools: 1. The American School, which necessitates the presence of glandular epithelium AND goblet cells to call it Barrett’s esophagus. If the goblet cells were not present they don’t call it Barrett’s they call it glandular epithelium in the lower esophagus (with a comment for further followup). 2. The British School, it is enough to see only glandular epithelium to call it Barrett’s, -of course it is better to see the goblet cells- but if only glandular epithelium is present and the doctor who performed the endoscopy is telling you that the biopsy was for sure taken from a level ABOVE the gastroesophageal junction (37 cm) then we can call it barrett's esophagus. >>so basically Barrett’s esophagus is the presence of metaplastic glandular epithelium above the gastroesophageal junction. >> a new theory suggests that biliary secretions are the main cause or the main driving force of metaplasia rather than the acid secretions, why is that? In the digestive system as a whole when a regenerative process or a metaplastic process takes place it usually happens to protect against the forces or the injuries that take action within that environment. Let’s say that biliary secretions are causing damage in the esophagus, Normally the biliary secretions are secreted into the duodenum which is lined by intestinal epithelium so in order to protect the esophagus from these secretions a change from squamous epithelium to intestinal epithelium |Page7

should take place because that intestinal epithelium is the normal environment for the biliary secretions. **Pic. In slide #58**

>> The picture above: this is a normal gastroesophageal junction you can see the demarcation between the esophageal stratified squamous epithelium and the gastric simple columnar epithelium. This is referred to as the histological gastroesophageal junction in which the zigzag pattern is seen.

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**Pic. In slide #59**

The picture above: the normal junction (anatomical junction) should be next to the arrow, but as you can see in the lower segment of the esophagus: the gastric epithelium (columnar) has replaced the squamous epithelium; therefore the junction is elevated about 5cm. this is a typical example of barrett's esophagus. >> another name for this esophagus is CLO (COLOUMNAR LINED ESOPHAGUS). **Pic. In slide #60**

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The picture above: this is an endoscopy as you can see again the columnar epithelium is going upwards replacing the shiny squamous epithelium. **Pic. In slide #61**

This is a histological picture: you can see that the squamous epithelium is interrupted by the columnar epithelium, you can also see some goblet cells. Again this is a CLO or a barrett's esophagus.

---Clinical symptoms : >>dysphagia, retrosternal pain, hematemesis, melena. ---Secondary complications: 1.Barrett's ulcers. 2.strictures. 3.dysplasia. 4.adenocarcinoma, which is the main worry or the main fear, 8-10% of patients develop Carcinoma (patients with Barrettâ&#x20AC;&#x2122;s esophagus have 30100X higher risk than general population to develop adenocarcinoma).

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>> Barrett’s esophagus is the only recognized precursor of esophageal adenocarcinoma . >>which is more common, squamous cell carcinoma or adenocarcinoma of the esophagus? in western countries adenocarcinoma is becoming the more common type because Barrett’s is more common over there, but in other countries like Jordan squamous cell carcinoma is still the more common type that might be due to the diet or the lifestyle… >>in the past most of the adenocarcinomas that were found at the gastroesophageal junction were in their advanced stages in which there was involvement of the junction itself, the esophagus, and the stomach, and most of these tumors were referred to as gastric adenocarcinomas. But currently due to the advanced endoscopic techniques we can detect Barrett’s esophagus in early stages and then detecting the adenocarcinomas at that junction earlier, so there is a relative increase in the incidence of adenocarcinoma in the lower part of the esophagus. And that’s why adenocarcinoma is becoming the more common type in the western countries (because it is actually being detected before it involves the whole esophagus and the stomach.) >>however there are some endemic areas where there is an increased risk for squamous cell carcinoma of the esophagus, for example some countries which have a high consumption of pickles and "smoked\salted fishes" (couldn’t hear).

TUMORS >>Benign tumors are rare: leiomyoma is the most common, and is usually small, asymptomatic and discovered incidentally. >>Malignant tumors: Esophageal cancer is the 7th most common tumor in humans. >>More common in males (M:F=3:1) | P a g e 11

>>Great variation in geographic distribution >>Commonest types: Squamous cell carcinoma and adenocarcinoma. ---Squamous cell carcinoma: >>80-85% of esophageal cancers (this statistic is related to our region as mentioned before). >>10% of all GIT cancers; higher contribution to mortality (asymptomatic with late diagnosis), the symptoms of mild reflux esophagitis are more or less similar to the symptoms of esophageal carcinomas so these carcinomas may be under diagnosed or overlooked for a long time and then they will come to the attention of the clinician in their late stages and by that time they will be very advanced involving other structures and there will be lymph node metastasis, thatâ&#x20AC;&#x2122;s why they are associated with high mortality (this can be true for esophageal carcinomas in general). >>Patients: most patients are adults >50 yrs; M>F >>Higher incidence in certain countries (Iran, China..) >>Higher incidence in blacks than whites (especially in American blacks) >>Etiology & pathogenesis: multifactorial with environmental & dietary factors acting synergistically. **pic from slide #65**

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An example of squamous cell carcinoma.

Endoscopic example of squamous cell carcinoma. Associated factors: (Risk factors) 1) Dietary: >>Fungal contamination of food (Aspergillus), thatâ&#x20AC;&#x2122;s why there is a higher incidence in some countries more than others, because of the ways they use to preserve and store their food. >>High content of nitrites/nitrosamines., in countries which use salted fish in their cooking. >>Deficiency of vitamins (A, C, riboflavin, thiamin, ..) >>Deficiency of trace metals (zinc, molybdenum) 2) Esophageal disease: achalasia, reflux esophagitis , strictures, Plummer-Vinson syndrome 3) Lifestyle: Alcohol & tobacco abuse 4) Racial or genetic predisposition: blacks; celiac disease, Tylosis, (these diseases increase the risk for squ.cell.CA)... 5) HPV (human pappiloma virus ) in squamous cell carcinoma, this is a possible factor because it is the main cause of cervical cancer and the

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cervix is lined by squamous epithelium just like the esophagus, and some squamous cell carcinomas of the esophagus tested positive for HPV. 6) p16/INK4 tumor suppressor gene & EGF (epidermal growth factor) receptor abnormalities. p53 mutations in 50%. These are some molecular alterations and abnormalities present in SCC.

---Pathology of SCC: >>50% in mid 1/3; 30% in lower 1/3; 20% in upper 1/3 >>Starts as in situ lesion which is a full thickness dysplasia of the squamous epithelium; thickening of mucosa >>Polypoid fungating (60%); ulcer (25%); diffuse (15%) >>Grade: Most are well to moderately differentiated >>Stage (depends on the size of the tumor and the lymph nodes involvement): I (<5 cm), II (>5 cm; resectable LN), III (>10 cm; extension to adjacent tissue; inoperable); IV (perforation; metastasis)

---Clinical features: >>symptoms are gradual & late; include dysphagia, extreme weight loss, aspiration, hemorrhage & sepsis. >>treatment (Rx): surgery & radiotherapy >>Mortality rate (Px): 70% die within 1 yr; 5 yrs survival 5-10% (very high mortality rate due to the late discovery of the tumor) **pic on slide #69**

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In this histological picure you can see the full thickness dysplasia of epithelium and invasion of the underlying stroma.

This picture shows the steps of carcinoma in general which might start as esophagitis or irritation then there is metaplasia (barrett's esophagus) this might become dysplastic and this dysplasia might lead to carcinoma and in this example it is adenocarcinoma.

---ADENOCARCINOMA: >>5-10% of esophageal cancers; rising incidence (still increasing, in some references it says that 60-70% of esophageal cancers are adenocarcinomas). >>Middle or lower third; may extend to stomach >>Vast majority arise from Barrettâ&#x20AC;&#x2122;s esophagus >>Most are adults >40 yrs; M:F=5:1; v. rare in blacks >>Mass or nodular elevation of mucosa; frequently multicentric (you might have different islands of barrett's epithelium and the tumor will develop from these different islands, so you will have a multifocal tumor). >>Histologic types: intestinal, diffuse (signet cell) or adenosquamous (sometimes you will have a mix between adeno and squamous and when this happens you might think of double etiologic factors ). >>Grade: most are moderately to poorly differentiated >>Stage: similar to squamous cell carcinoma

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>>c/o: progressive dysphagia; long standing symptoms **pic from slide#72**

This is an adenocarcinoma arising in a Barrettâ&#x20AC;&#x2122;s esophagus, as you can see there are many tumors (a big one in the center). **pic from slide#73**

This is dysplasia, actually there is some intestinal metaplasia with dysplasia, which has progressed into adenocarcinoma. **pic from slide#74**

| P a g e 16

>>This is the stomach, we have different parts of the stomach : cardia, fundus, body, and pylorus. The stomach is one of the main secretory organs of the digestive system, it secretes secretions that aid in the secondary digestive stage (the first being in the oral mucosa). As you can see the fundus has special types of cells that secrete specific secretions: -*Prietal cellsacid

*chief cells-->pepsin

>>The cardia is mainly composed of mucous cells which secrete mucous secretions! >>in the antrum we have mucous cells that resemble those of the cardia in addition we have G-cells which secrete gastrin. Similar things are present in the pylorus. >>we have to know the histology of the stomach and what each part is composed of and then we have to what each parts secretes and then we have to know the physiological function of these secretions. For example: Parasympathetic stimulationgastrin secretion(Gcells)acid secretion(parietal cells) >>this is very important in order to understand the pathogenesis of gastritis and peptic ulcer disease. >>the doctor mentioned how in the 1980's they used to treat peptic ulcer disease by a surgical procedure known as highly selective vagotomy which involves the cutting of the nerve endings supplying the antrum to reduce the stimulation of the antrum and that will lead to the reduction of gastrin secretion which will ultimately lead to overall reduction of acid secretion in the stomach. At that time infection was not considered as a cause of peptic ulcer disease and when they discovered that infection (bacteria=helicobacter pylori ) is a possible cause it was a revolution in gastrinology and it changed the strategy of treatment of peptic ulcer disease, so instead of highly selective vagotomies (which we don’t see any more) and antrectomies | P a g e 17

(which is removal of the distal part of the stomach; antrum, also known as distal gastrectomy, also not seen any more) we use simple antibiotics.

Done by : Salah Al-Gharaibeh Good Luck ď &#x160;

| P a g e 18

14 / 59 4 / 17 35

Pathology Gastritis Isma'eel Matalqa Marwa Al-Nairat Thursday, 27/10/2011

Dear colleagues please refer to slides while you are studying this lecture, and I put some information from hayat archive to clarify some points. Enjoyyyy..... :) Let's start our lecture by remembering the anatomy and histology of the stomach. What are the contents of gastric juice? 1-Pepsin 2- Acid 3-Mucus 4-Other secretions

The stomach is divided into four major anatomic regions: 1- CARDIA the Cardiac and Pylorus are composed of mucous cells mainly 2- FUNDUS contains mainly Parietal cells (produce the acid) and Chief cells (produce pepsin) 3- BODY made mainly of Parietal gland component 4- ANTRUM we will find that it is composed from non-parietal glands which are the mucous cells and the G-cells (that produce the gastrin)

from Hayat archive : The cardiac and antrum are lined mainly by mucin-secreting foveolar cells that form small glands. The well-developed glands of the body and fundus also contain chief cells that produce and secrete digestive enzymes such as pepsin. The parietal cells also: secrete IF â&#x20AC;&#x201C; Intrinsic Factor â&#x20AC;&#x201C; requires for B12 absorption.

We said last lecture that the main function of the G cell in the antrum is to stimulate the secretion of the acid from the body cells â&#x20AC;Ś.keep this in mind because itâ&#x20AC;&#x2122;s important in pathophysiology of the peptic duodenum ulceration. The bulk of the acid secreting cells (parietal cells) are present in the body. Chief cells secrete the pepsin and you know the function and the importance of the pepsin in the digestion process within the stomach. And here just to remind you again the mucosa, muscularis mucosa, submucosa and muscularis propria. Mucosa of the stomach is composed of _ fovealar component (compartment) and _ glandular compartment this glandular compartment contains these secreting cells (parietal cells, mucus cells, G cells) G cells are some sort of a type of neuroendocrine cells and that's why they exert their sort of hormone-like action from the antrum on the body secreting cells. And we said that they are different from part to part. The body type usually you have these parietal cells. In the antrum, you donâ&#x20AC;&#x2122;t have these parietal cells and therefore they look more eosinophilic in the body. There are more mucus-like in the antrum and in the cardiac.

DISEASES OF THE STOMACH

 Congenital anomalies – Diaphragmatic hernia & pyloric stenosis  Inflammations – Gastritis – Acute erosions & ulcerations – Peptic ulcer  Tumors – Polyps – Adenocarcinoma – Lymphoma

CONGENITAL ANOMALIES OF THE STOMACH DIAPHRAGMATIC HERNIA These are the CONGENITAL ANOMALIES OF THE STOMACH to start with: - It's weakness or partial-to-total absence of a region of the diaphragm (or any defect in the diaphragm), away from the foramen hiatus permitting abdominal contents to herniate into the thorax. - Defect does not involve the hiatal orifice (vs. HH) and this is to compare with hiatus hernia. - Hernia wall often be composed of peritoneum & and pleura. So as result of that Portion of stomach, small intestine or liver or any abdominal content may protrude from the abdomen to the thorax (into hernial pouch). And you can imagine what this could lead to or cause. Of course that depends on size of the hernia; if it is so large, this might lead to acute respiratory distress in newborn because of the compression in their lungs. If it is small, this might be asymptomatic.

-Rare condition and the main protocol of treatment is the surgery once they are discovered after delivery or appear later on. PYLORIC STENOSIS

Do you know what the difference between familial and inherited is?

It is another congenital anomalies and it’s a Familial condition. -It is quite common 1:300-900 live births might have this pyloric stenosis so it’s rather common; M:F=3:1

When we say familial, this means that this kind of the disease runs in the family, because there is more incidence of this kind of disease in a specific family. Now we don’t exactly know what is the exact gene responsible for this, it might be more than one gene or it might be multifactorial (some gene or other molecular abnormalities or chromosomal etc..) but because it runs in sort of specific families we call it familial.

-The Pathology presents with hypertrophy & hyperplasia of circular muscle of muscularis propria of pylorus and this leads to thickening and then narrowing of the lumen leading to mucosal edema and inflammation. Actually in the infants, they look like grain of olive (‫ )زي حبة الزيتونة‬at pylorus on the epigastria area. Some sort of small mass which is obvious and becomes more obvious with visible peristalsis and there is firm ovoid palpable mass in abdomen.

When we say this is a genetic disease, this means we know exactly the defect, the genes involved and the kind of abnormalities involved in that gene whether it’s abnormal protein production, or if it’s cytogenetic, does it have any relationship with deletions or translocations ... -So, Pyloric Stenosis is a Familial condition and it has multifactorial inheritance.

-So they will complain of regurgitation because of obstruction & persistent projectile vomiting is very characteristic (so if a newborn child came to you and after awhile he presented with projectile very strong vomiting )‫ ((زي المقذوفات‬this is because of obstruction of the back pressure. - Usually appear in 2nd-3rd week of life.

-The treatment is very easy; they use Pyloromyotomy; which is an incision; they open and incise the muscularis propria to release the obstruction and then repair it, so it’s a very simple sort of surgery. 5

INFLAMMATIONS OF THE STOMACH GASTRITIS Inflammation of gastric mucosa is gastritis and Gastritis again is a general name. When we say gastritis, this does not mean it’s specific for helicobacter gastritis or others. It’s general. Any cause of inflammation, irritation or erosion of gastric mucosa we call it gastritis

And we will see that there are different causes and different classifications of gastritis. -It is an Overused term and underdiagnosed condition: It is overused because we use it a lot and used in the clinical practice more than its actual presence (HAYAT). For example, if someone complains of some abdominal pain, dyspepsia, indigestion, etc, we will say he has gastritis. Now to confirm the diagnosis of gastritis, we need to do an endoscopy and biopsy. And that's why it is underdiagnosed because we would have large number of cases of genuine gastritis without conformation, and they will just pass without treatment or sort of spontaneous recovery, etc. If we take 100 students in this hall, how many do you expect to have helicobacter in their stomach? About 75 will have H.pylori microorganism in their stomach. But is everybody complaining of any symptoms or signs? At least we will see that out of those 75 persons, 10 to 15 of them will have some sort of symptoms of gastritis. The remaining it might be silent or it might be aggravated in some point. This is some sort of natural history of gastritis with its causes.

From hayat: Underdiagnosed : because not every single patient suffering of actual gastritis and is having the actual inflammation will undergo endoscopy and get a biopsy – because to do a proper diagnosis of gastritis , we need to do endoscopy and biopsy , and of course not all patients suffering of gastritis symptoms will undergo that 6

How do we classify them???

Mainly we classify them into: 1) Acute gastritis: it’s not common and there are specific causes for it we will say it later. 2) Chronic gastritis - more common and represent most cases - prevalence exceeds 50% in adults >50 yrs - usually asymptomatic or cause few symptoms like (upper abdominal discomfort, nausea and vomiting) We call these (upper abdominal discomfort, nausea and vomiting) non-specific symptoms. It means they do not indicate a specific disease or diagnosis. There are different causes of this chronic gastritis; the most important of these and the main cause is Helicobacter pylori.

Does Helicobacter pylori infection present as acute gastritis? Usually not, but in initial infection -usually in early childhood- some of these H.pylori present with acute gastritis with some sort of acute symptoms, and most of these infections (H.pylori) are acquired during childhood. The other causes are: » Autoimmune (atrophic) gastritis which has an autoimmune etiology » Hypertrophic gastritis (gastropathy) » Granulomatous gastritis; eosinophilic gastritis So all of these are some sort of specific types of chronic gastritis, and the most important of these is H. Pylori.

ACUTE GASTRITIS Acute mucosal inflammation, usually of transient nature May be accompanied by hemorrhage & erosions

Pathology: spectrum of severity from acute simple gastritis to acute hemorrhagic gastritis, or acute erosive gastritis, or acute stress gastritis & this might lead also to perforated acute ulcer. The Pathogenesis in general is poorly understood but it is multifactorial and it’s mainly due to the loss of balance between the gastric acidity and mucosal resistant. - Back to physiology, there are different mechanisms within the stomach to resist or to accommodate the gastric acidity. The acid secreted and the gastric juices can digest meat. If you eat meat, the first step of digestion of the meat is in the stomach by gastric acidity. - If gastric acidity has the ability to digest the meat, it would have the same ability to digest the stomach itself! . ‫يعني المعدة يمكن تهضم حالها‬ - So to prevent this, there are some other mechanisms which we call them normal preventive mechanisms within the stomach. - Now if you have more acid output by stimulation of acid secretion by H+ backdiffusion, or you have decreased bicarbonate buffer production -which is one of protective mechanisms; because we know that the stomach secretes bicarbonate buffer and mucus-, so when there is any sort of increase acidity or loss of these protective mechanisms; like reduced mucosal blood flow, mucosal cell disruption or direct epithelial damage, this will lead to acute gastritis.

And this is an example of acute hemorrhagic gastritis and this leads to ulceration and erosions and destruction of gastric mucosa.

So what are the risk factors of acute gastritis? They are frequently associated with the following: Heavy use of NSAIDs, especially aspirin (up to 25%) NSAIDs is one of the good medications because it’s discovery has made our life easier because it’s an anti-inflammatory, antipyretic and we use it to relieve pain, but on the other hand it causes a lot of harm to our body especially our digestive tract, and if you take NSAIDs, it causes what we call drug induced injury in the whole digestive tract 8

from the mouth until the anus in the form of erosion, ulceration, and some other diseases; sometimes they lead to formation of what we call diaphragm disease of small intestine, perforation, acute gastritis, esophagitisâ&#x20AC;Ś etc. The problem they are really accessible; they are over the shelf drugs; you can get them from any pharmacy without any prescription and because of that these problems are very serious and we have to take control over them. From Hayat achieve: NSAIDS are considered as the main cause of acute gastritis In the book , 25% of RA-rheumatoid arthritis- patients using aspirin , develop acute gastritis .and the risk of gastric bleeding from NSAIDS is dose related , thus increasing the likehood of this complication in patients require longterm use of such drugs. How? The idea is that aspirin , and other NSAIDS - Nonsteroidal anti-inflammatory drugs â&#x20AC;&#x201C; inhibit the COX enzyme, cyclooxygenase, and when this COX is inhibited this leads to decrease in the prostaglandin production , and as we know prostaglandins are important for the blood flow to the stomach and the protection against the acid secretion.

Other risk factors of acute gastritis: -Excessive alcohol consumption -Heavy smoking -Severe stress, e.g. trauma, burns, surgery -Ischemia and shock are important because they reduce the blood flow. The continuous and adequate blood flow to the stomach is one of the preventive mechanisms to get rid of hydrogen ions which are the cause of the acidity.

So any decrease of the blood flow, any cause of hypovolemia, shock or reduce in the blood flow, these will lead to gastritis. -Suicidal attempts with acids/alkali. -Mechanical trauma: sometimes those who are unable to eat, they put what we call nasogastric tube (NG tube) for suction of the secretion for those patients in ICU. This tube itself might cause injury so patients who have post-gastrectomy, postsurgery, chemotherapy, uremia and systemic infection; all of these are possible causes of acute gastritis.

Uremia: condition of blood poisoning due to the retention of toxic elements that are usually excreted in the urine.

Of course this will increase if we lose the balance, or if we lose the efficiency of our preventive mechanisms in the stomach itself.

So, clinical features depend on the severity: might be asymptomatic or variable epigastric pain, nausea, vomiting, hemetemesis (particularly alcoholics because of other added risk factors), melena & fatal blood loss. So this is for acute gastritis in general. A student asks a question: Why is it nasogastric not orogastric tube?! Dr answers: Not to obstruct the mouth and it’s easier to insert. Anatomically, when you insert it from the nose it will be guided down to the esophagus. Another student asks a question about the factors if they can cause chronic gastritis or not …. and the Dr said: Some of them can cause a chronic gastritis, but in general they are the main causes of acute gastritis.

What is this??? -This our star! This is H. pylori microorganism. -This organism is curved gram negative bacteria and they have coma shape or seagull shape ‫ طائر النورس‬it presents as we see 10

here at the surface epithelium or within the gland in the lumen of the gland or crypts of the stomach. The H.pylori which is seen here is a G-ve curved, rod shaped bacteria, that as we can see, can be present within -It wasthediscovered and. Robin Warren. crypts or onby theBarry surfaceMarshall of the mucosa HAYAT

They have discovered it

accidently in 1980s.

And one of them I think Marshall; they didnâ&#x20AC;&#x2122;t believe him that this microorganism causes peptic ulcer disease. So he did an experiment; do you know what did he do?? He ingested H. pylori and got peptic ulcer just to convince the scientists that is what is going on! The Dr said: I like to read the old historical medical books and actually I find very similar organisms have been drawn by a polish physician back to the 1911. He took gastric juice and under the microscope he was trying to just draw down what is there and some of these were H. pylori. It was exactly curved. So H. pylori is an old microorganism but it was discovered in 1980s. That dramatically revolutionized our concept about peptic ulcer disease and made changes in management of peptic ulcer disease. Now we are treating them by antibiotics instead of surgery. This will lead us to talk about: CHRONIC HELICOBACTER PYLORI GASTRITIS o Commonest form of gastritis o H. pylori is a widespread noninvasive curved gram -ve rod, which is present in gastric mucosal surface of 50% of adult more than 50 yrs old. But in some studies in Jordan, they found that about 75% of the population have the H. pylori in their stomach. o Infection more likely to be acquired in childhood o Most infected individuals have gastritis but are asymptomatic That means 75% of you have H. pylori. If we take a biopsy for all of them, we will find quite significant number of those have chronic inflammation in their stomach with some activity with H. pylori which are characteristic of helicobacter pylori associated chronic gastritis and only 10-20% of them will have symptoms.

o Pathogenesis: Directly by bacterial enzymes & toxins, and indirectly by recruitment of polymorphonuclear (PMNs) which release noxious chemicals either by direct damage or by stimulation of other inflammatory cells like neutrophils to produce and release some other cytokines and chemicals leading to the effect of the injury. o Appearance: Hyperemic edematous gastric mucosa (how) The histology for that is lymphocytic and the plasma cells infiltrate in lamina propria, chronic inflammation (lymphocytes, histiocytes, plasma cells within the lamina with some activity). The more H. pylori the more pathogenicity; and we will see later there are different genotypes of H. pylori. I will not talk about this microorganism a lot because it should be covered by microbiology lectures. We have different genotypes of H. pylori and their virulence (the pathogenicity) depends on their genotypes and there are some genotypes which are more virulent and more pathogenic than the others, and this explains why some of you have symptoms and others do not have symptoms; it depends on the genotype that is affecting you. These genotypes have relationship with the substances released by bacteria and this may lead to cryptitis, active inflammation, crypt abscess and lymphoid cell proliferation. When it is not treated, it’s like a continuous inflammation leading to more accumulation and more lymphoid cells within the stomach. Normally and histologically, how much does the stomach contain lymphocytes? We know in colon and small intestine we have lymphoid follicles and lymphoid cells within the lamina propria. But how much are you allowed to have lymphoid cells within the stomach? None! It should be none or very little. The normal stomach does not contain any lymphoid cells as part of their normal histology, so such continuous irritation and aggregation of lymphoid cells will lead to the formation of acquired lymphoid tissue and we call this MALT (mucosa associated lymphoid tissue). Now this MALT when it’s progressive and continue to be irritated and with high turnover of inflammation, it becomes MALT lymphoma. Some people call it MALToma and this is wrong! There is nothing called maltoma; when we say –oma, it’s benign and lymphoma is not benign. 12

But in this context in the stomach, it might reflect the benign behavior if it is low grade MALT lymphoma. So this means H. pylori so far can cause lymphoma and chronic gastritis which will lead to peptic ulcer disease and you will see also it might lead to carcinoma, so H. pylori causes all of these. You can imagine the benefit that we achieved from the discovery of this microorganism and the management protocols of this microorganism. We can prevent against all of these and that’s why the incidence of gastric carcinoma and lymphoma has been dramatically decreased over the last 20 years because of the new protocols of treatment of these microorganisms. So, clinical features are variable. Now, what is the treatment? We have different regimens of treatment. These regimens could be triple, quadruples, or 5 drugs regimens; it depends. But at least it should contain anti-acid drugs and antibiotics; these at least should be part of the treatment. You will take it in pharmacology.  Px: Relapses are associated with reappearance of H. pylori; peptic ulcer disease is one of the consequences and causes gastric lymphoma and gastric carcinoma. So this is the histology of chronic gastritis; presence of chronic inflammation, presence of some sort of activity (neutrophilic infiltration we call it “activity”). And the other thing that we should look at in the context of chronic gastritis is the degree of atrophy. What is atrophy? Loss of glandular component. And you can see here the glandular component has dropped and this is the degree of atrophy. Now because of the turnover, the inflammation , and the activation, we will get some degree of goblets. We call the Goblets in the gastric glands “intestinal metaplasia” and the intestinal metapalsia are the precursors of adenocarcinoma of the stomach. And this intestinal metaplasia later will develop dysplasia and dysplasia becomes carcinoma. 13

And this is how the gastric carcinoma-intestinal type develops. The intestinal type is more or less or almost exclusively related to H. pylori infection in the stomach. From our book: Intestinal metaplasia refers to replacement gastric epithelium with columnar and goblet cells of intestinal variety. This is significant because gastrointestinal type carcinoma seems to arise from dysplasia of this metaplastic epithelium. We have 2 types; as we will see later: 1) The intestinal type 2) The diffuse type So again it’s a spectrum: Chronic gastritis >Atrophy >intestinal metaplasia >dysplasia >carcinoma Chronic gastritis> lymphoid follicle formation >MALT formation> MALT lymphoma

Diseases Associated with Helicobacter pylori Infection

Disease

Association

Chronic gastritis Peptic ulcer disease Gastric carcinoma Gastric MALT lymphoma*

Strong causal association Strong causal association Strong causal association Definitive etiologic role

So what is the clinical significance of Helicobacter associated chronic gastritis? This summarizes what we have said already   Most common cause of chronic gastritis and peptic ulcer disease.  Long term risk for gastric carcinoma (5 fold risk), gastric atrophy, intestinal metaplasia, and dysplasia role.  Long term risk for gastric MALT-lymphoma.  The biggest question is there any possible prophylactic vaccines in the future? Possible of course  and this is one of the hot areas in research now. 14

It’s so common and prevalence; in some countries, almost 100% of population is H.pylori positive; so if we find a way to develop a vaccine, this means we will prevent the humanity from all these diseases and complications. A student asks a question: Why when we have inflammation and regeneration, it leads to intestinal metaplasia in the stomach? Maybe reflux is one of the possibilities. When you have H. pylori microorganism, it will lead to destruction of parietal cells and this is especially in the body. In H. pylori infection, we have what we call bodypredominant or antrum-predominant H. pylori gastritis. If it was mainly affecting the parietal cells, this means we will have lower acidity. Now what will be the appropriate way to accommodate lower acidity? Intestinal. A student asks: if it is lower acidity, why is the treatment by decreasing the acidity? Dr answer: not always, it depends; if it is antrum-predominant H pylori, this will lead to 2 things: activation of G-cells and gastrin level, and gastrin will act on the preserved body with their parietal and there will be increase in the acid output, so increase acidity in this condition. So, in chronic gastritis, you might get normal acidity, high acidity or low acidity depending on the site affected. That's why I told you, you need to understand the histology and the physiology of the different compartments of the stomach. It depends which area is affected more or predominantly affected. CHRONIC AUTOIMMUNE GASTRITIS It’s another kind of chronic gastritis and it’s important. o Extensive multifocal atrophy and that’s why we call it (atrophic gastritis) o Endemic in some parts of the world, e.g. Japan The best endoscopists in the world are Japanese and they can identify small tumors as small as 0.5mm in the stomach by the endoscopy, because of the high prevalence of gastric carcinoma in Japan and this is because that autoimmune gastritis or atrophic gastritis are common there. o Pathogenesis: 15

â&#x20AC;&#x201C; Autoantibodies to gastric glands parietal cells which will lead to gland destruction & mucosal atrophy and loss of the parietal cells; such loss of parietal cells leads to decrease acidity and decrease in intrinsic factor. IF production is important for the absorption of B12 in the terminal ileum, and decrease in vitamin B12 leads to megaloblastic anemia. Such combination of autoimmune gastritis and megaloblastic anemia we call it pernicious anemia. From our Book The autoimmune injury leads to gland destruction and mucosal atrophy with concomitant loss of acid and intrinsic factor production. The resultant deficiency of intrinsic factor leads to pernicious anemia. This form of gastritis is seen in Scandinavia in association with other autoimmune disorder such as Hashimoto thyroiditis and Addison disease.

In pathology, they are mainly targeting the parietal cells, and the body eventually will lose all the parietal cells, so the body will later look like the antrum (it will become antrum-like). And that's why we are so skeptical about these situations to exactly know from where the endoscopic took the biopsy; because if it is from the body and what I see is antrumlike mucosa, this means I should raise the possibility for autoimmune gastritis because it is an atrophic condition. So we will have gland loss, atrophy & intestinal metaplasia then intestinal metaplasia again undergoing dysplasia and then carcinoma. Intestinal metaplasia > dysplasia of metaplastic epithelium > carcinoma

o If severe parietal cell loss: hypo- or achlorhydria which means very low acidity & hypergastrinemia (because itâ&#x20AC;&#x2122;s trying to replace this low acidity so more gastrin secretion but no parietal cells to act). o So there is 2 - 4% risk of developing gastric carcinomain these cases.

HYPEPTROPHIC GASTRITIS 16

o It is another group of chronic gastritis. It’s uncommon condition characterized by enlargement of rugal folds of gastric mucosa. o Three main variants: – Menetrier’s disease: rare idiopathic disease; may be asymptomatic or produces pain, nausea, vomiting & bleeding and it’s characterized as protein-losing gastroenteropathy (very prominent folds) – Hypersecretory gastropathy: associated with hyperplasia of parietal and chief cells … (they are hyperplastic: increase in number). – Gastric gland hyperplasia: secondary to excessive gastrin secretion by a gastrinoma (it’s a tumor of gastrin producing cells) and leads to the Zollinger-Ellison syndrome. From the net: Zollinger-Ellison syndrome is a condition in which there is increased production of the hormone gastrin. Usually, a small tumor (gastrinoma) in the pancreas or small intestine produces the high levels of gastrin in the blood. o The importance of this group that they radiologically or endoscopically may mimic carcinoma because of thickening hypertrophy and hyperplasia.

GASTRIC EROSIONS & ULCERATIONS  Erosion: loss of superficial epithelium of mucosa – May heal within days  Ulcer: breach in the mucosa, which extends through the muscularis mucosa into the submucosa or deeper – Needs longer time to heal  Main types: – Acute gastric erosions & ulcerations – Peptic ulcers

Refer to slide 94: Just before we go to the peptic ulcer disease, what do we mean by gastric erosion and what do we mean by gastric ulceration? Erosion is the loss of superficial epithelium of the mucosa alone, and this will heal within days, whereas ulcer is breach in the mucosa which extends down through the muscularis mucosa into the submucosa or even deeper. And of course when this is so deep, this ulcer 17

needs weeks and months, 2 years or even longer than that to heal; and that's why these ulcers sometimes don't heal at all. Actually and at some points, if they are not healing or not responding, you might go and do surgery to excite this ulcer because it is very painful. Ulcer in the stomach is a very painful situation; main types: 1. acute gastric erosion and ulceration (almost all causes of acute gastritis will lead to ulceration and erosion). 2. Peptic ulcerations. This will lead us to discuss different clinical and pathological aspects of peptic ulcer, and we already have known most of these factors, and we talked about the pathogenesis more or less when we talked about some factors and about the importance of H. Pylori. At this point, you should know that for gastric peptic ulcer (of course when we say peptic ulcer, an ulcer induced by Pepsin ď&#x192; and that's why it is peptic), so for those ulcers occurring in the stomach the majority of them are related to H. pylori microorganism more than 75-90% or even more. For those Duodenal Peptic Ulceration, how many of them are related to H. pylori?

100% All duodenal peptic ulcerations are related to H. pylori infection or related to helicobacter associated with chronic gastritis

And next time I want one of you to tell me what is the pathogenesis of duodenal ulceration in the context of chronic gastritis? Why in the chronic gastritis due to H. pylori, why do we have duodenal peptic ulceration?? And why all of them are related to that?

The risk of duodenal ulcer is enhanced by infection with pro-inflammatory H. pylori. Progressive damage to the duodenum promotes gastric metaplasia, resulting in sites for H. pylori growth and more inflammation. This cycle results in an increasing inability of the duodenal bulb to neutralize acid entering from the stomach until changes in duodenal bulb structure and function are sufficient for an ulcer to develop. 18 < from net > â&#x20AC;Śâ&#x20AC;Ś.

It is more obvious in the next lecture. You should understand the host defence mechanisms of the stomach to protect against the high acidity (please refer to slides, or you can find them in the beginning of the next lecture). And that was the end of our long lecture,, ya36eeko l-3afyeh!!! Done by: Marwa Mohammed AL Nairat "You were the one who made things different, you were the one who took me in. You were the one thing I could count on, above all, you were my friend Tom Petty

Big thanks for my sisters Asma, Enass, Mai, and Sana

Sorry for any mistake .. Nobody is perfect ;D GOOD LUCK 19

15 / 59 5 / 17 20

Pathology Peptic Ulcer Isma'eel Matalqa Zeina Majthoub Sunday, 30/10/2011

Peptic Ulcer

Today, we are going to continue with the peptic ulcer disease, and I have already asked you last time to remember some sort of physiology and host defense mechanisms against the acidity of the stomach, and you can read about it from Guyton and pathology books. Back to peptic ulcer disease and keeping in mind the story that I told you regarding the peptic ulcer disease and the discovery of H pylori microorganism which has actually revolutionized our concept about peptic ulcer disease, and the management protocols of peptic ulcer disease and in the coming pharmacology lectures Dr Qasim will talk about modalities of treatment of peptic ulcer disease and different regimens and protocols for the treatment of such diseases. Peptic ulcer disease is a chronic lesion most often solitary lesions that occur in any part in the GIT exposed to aggressive action of acid-peptic juices and that’s why it’s called peptic ulcer disease, because of the exposure to the acid-peptic juices which are secreted from the stomach. As you note here, it might occur at any part of GIT: stomach, esophagus, duodenum, and it could be in the terminal ileum in specific conditions; y3ni where you have some ectopic secretion of acid peptic juices, this will lead to ulceration of the nearby or adjacent mucosa. We will see a condition in the small intestine called meckel's diverticulum; in meckel's diverticulum which occurs in the terminal part of the ileum, there’s out pouching “diverticulum” which is lined by gastric mucosa and this gastric mucosa will secrete peptic juices and the action of these peptic juices will be exerted on the adjacent mucosa leading to peptic ulcer disease of small intestine, so it can occur there. 98% of these peptic ulcers will occur either in the duodenum or in the stomach with a ratio of 4:1 (duodenum:stomach), so it’s more common in the duodenum than the stomach. It’s more common in the industrialized countries; 1-2% of population has active disease. In autopsy studies, 6-14% of men will have evidence of peptic ulcer disease in autopsy which is a post-mortem examination for people who die in hospital. And in some countries, post-mortem examination is mandatory for everybody who dies in the hospital or at home; they should perform autopsy, so they do some studies in autopsies which reflect sometimes the general incidence of different findings, and it’s 2-6% in women. It’s a remitting and relapsing lesion; remission means become inactive, relapse become active, so active-inactive phase, so it always has this course of disease. Mostly occurs in middle-aged to older adults. 1

Pathogenesis We can’t say it’s unclear; we have now some sort of insights, and there are two key facts: 1)

Mucosal exposure to gastric acids and pepsin is a requisite and the famous saying in surgery and medicine “NO acid….NO ulcer” so we need the action of the acid to lead to ulceration. 2)

Strong causal relation between the peptic ulcer disease and the H pylori microorganism.

So, impaired host defense mechanisms play an essential role in gastric ulcer; and we know that the host defense mechanisms that prevent the stomach from auto-digestion or protect the mucosa of the stomach from the action of the acidic juices are the following mechanisms: Surface epithelial mucus secretion. Bicarbonate secretion into mucus (buffered environment). Apical surface membrane transport of acid & pepsin. Rapid epithelial regenerative capacity of the mucosa. Mucosal blood flow (to remove back-diffused H+ which causes the acidity so removing H+ leads to decrease the acidity). Mucosal elaboration of prostaglandins. The relation between prostaglandin and NSAIDs is that NSAIDs will inhibit the release and elaboration of prostaglandin, so we’ll lose one of the important host defense mechanisms to protect against acid action, and that’s why those people who are taking NSAIDs are at a higher risk to develop peptic ulcer.

Why the peptic ulcer occurs more in the duodenum not in the stomach? We’ll talk about this later.

“Talking about the figure above” So, this is the normal situation where you have the damaging forces which are the 1)gastric acidity and 2)peptic enzyme; these are the normal damaging effect, and these are the host defense mechanisms (defensive forces) which are mentioned above. Now if we have injury in one of these factors, this will lead to imbalance between damaging forces and normal host defense, if one of them increases, this will lead to decrease in the other, so if you have sort of further damaging effects or forces like H pylori infection -and we’ll talk now how H pylori infection leads to ulceration- or NSAID, Aspirin, cigarettes, alcohol, gastric hyperacidity, duodenal–gastric reflux; all of these lead to increase damage or impaired defense, and we said that the blood flow is important; so if we have ischemia or shock, this will decrease the blood flow; if we have surgery or anything delaying the gastric emptying, this will leave the stomach with a longer time exposed to acidic juices, and if we have some other host factors related or inherent factors in the mucosa, this will lead to some sort of impairment and eventually this will lead to peptic ulceration. And you will see here the ulcer is ulcer; which means mucosa reaching the sub-mucosa, and this is different from erosion. If you look to the ulcer, there will be 1) necrotic debris, there is 2) tissue granulation and 3) nonspecific acute inflammation and underneath this there is 4) fibrosis and these are the 4 layers of any ulcer. How is the peptic ulcer associated with alcohol? Alcohol is not very well understood, but alcohol could exert some direct damaging effect on the epithelium of the stomach and sometimes it's related to decreasing the blood flow to the stomach.

Now talking about H pylori, what are the mechanisms by which H pylori leads to peptic ulceration? And we know there are different genotypes with different pathogenicity leading to such ulceration. They secrete urease, protease, and phospholipase. By releasing urease, for example, the urease will convert the urea to ammonia, and the ammonia is basic so it’s less acidic, so the pH will increase (urease will create less acidic environment with a higher pH with less acidity). Protease will affect the proteins. Such infection will attract more neutrophils and these neutrophlis will produce myeloperoxidase which produces the hypochlorus acid. Remember, in inflammation, the hypochloride and the hypochlorus are secreted by leukocytes. And monochloramine, in the presence of ammonia which is released due to the urease action, will take the ammonia and lead to release of the monochloramine. There's some sort of colonization and more direct damage to mucosal epithelial cells and the lamina propria endothelial cells by the release of bacterial enzymes and other factors like the lipopolysacharidase. Such damage will lead to leakage of tissue nutrients into the surface to sustain the bacilli “nutrients go into the lumen and this is to sustain the survival of bacilli”. And by the release of platelet activating factor PAF by the bacteria, this will lead to thrombotic occlusion in blood vessels and this will lead to ischemia; decrease the blood flow to that area. Now with all these mechanisms leading in a way or another to creating the environment of damaging of either the mucosa or decreasing the efficiency of the host defense mechanisms, only 10-20% of infected individuals will develop peptic ulcer disease; not all of them will develop it. There are other factors associated with peptic ulcer disease other than H pylori; we said that H pylori are the main factor associated with peptic ulcer. Other factors have been associated with PUD:  Zollinger-Ellison syndrome: excess gastrin secretion by tumor leading to excess acid production (gastrin will activate the parietal cells to secrete more acid). These tumors might be located in the duodenum, small intestine, pancreas which will lead to neuro-endocrine tumors.  Chronic use of NSAIDs & aspirin suppresses mucosal PG synthesis “there are other mechanisms by which the NSAIDs lead to peptic ulcer; at least other 3 mechanism and this is your HW “.

And this is the solution ^_^: 1) Increase secretion of hydrochloride acid. 2) Reduce bicarbonate. 3) Reduce mucus production. 4) Reduce glutathaion synthesis, which is a free-radical scavenger. 5) Also, may penetrate the gut mucosal cells. ”Robbins”  Cigarette smoking: impairs mucosal blood flow & healing.  Alcohol: unproven direct effect. Alcoholic cirrhosis: there are some other conditions and one of these is the cirrhosis and parahyperthyrodisim and other conditions which make the patient more exposed to ulceration especially the duodenal ulceration.  Repeated use of high doses of corticosteroids; it has similar action to NSAID.  Personality & psychological stress: in the past, this used to be one of the most important factors; the person who had a lot of stress or people who have personality type A (who need everything to be optimum and right); those people were believed to have a higher risk to develop peptic ulcer. This is a fact but not that important as it used to be in the past, so in the past people who had peptic ulcer disease we asked to take sedatives, tranquilizers, or just to change the life habits as part of treatment. Peptic ulcer is usually round sharply punched out craters and this is in comparison with malignant ulcers which aren’t punched out (we will talk about these later). The size is variable; it might be 1 cm up to 4 cm. Sites: –

Duodenum: anterior & posterior walls of first part

–

Stomach: lesser curvature

Associated chronic gastritis (in duodenal ulceration 85-100%; it’s actually 100% more or less. In gastric ulceration 70-75%) Histology: 4 zones: –

1) base of thin necrotic fibrinoid debris

–

2) active nonspecific inflammation, underlined by

–

3) granulation tissue &

–

4) fibrous collagenous scar

With healing, crater fills with granulation tissue, with re-epithelialization from margins, nearly restoring normal architecture with a fibrous scar remaining; so if we have restoration, we will have fibrous tissue in that area and scarring.

This is an example of peptic ulcer. It’s punched out to some extent, clear looking and shiny, and this is because of the action of acid. It has debris and fibrin. This is in comparison with the malignant ulcer, and this is an important gross appearance that the endoscopist or the pathologist uses to differentiate by gross rather than histology.

Now, back to our question: what’s the pathogenesis of duodenal ulceration in peptic ulcer disease?

CR-na answered: when you say duodenal ulcer, 100% of the cases are associated with H pylori, but the association of stomach problem is 10-15% of the cases, because the H pylori will attack special cells in antrum called D cells which produce somatostatin that has an inhibitory mechanism for acid secretion, so there will be a reflex or a positive feedback mechanism leading to increase in acid secretion, so the gastric emptying increases and the acids secretion increases; there is no inhibition for them “somatostatin is destroyed by D cell” and this causes duodenal ulcer mainly.

Dr commented: H pylori grows only in the stomach “the only place where H pylori grows and sustain its survival is the stomach“; it needs this kind of environment with its secretion to survive. In normal circumstances, it can’t grow in the duodenum; only in the stomach. When the H pylori infection is body predominant, this will lead by the direct effect of either direct damage or the secretion of other cytokines by leukocytes and other proteases and lipopolysacharidases >> this will lead to loss of parietal cells, and this will lead to decrease the acid. 6

Now when it is antrum predominant, I have preservation of the parietal cell mass, so the amount of inflammation is less; this will lead to activation of G cells or loss of the inhibitory mechanism; so more G cells, more activation of the parietal cells. This will lead to increase acids secretion so we have more acidity; this more acidic juice will go to the duodenum, and the duodenum has some sort of capacity to accommodate the acidic juices; but when it’s more than its capability, this will lead to damage, and therefore erosion and damage to duodenal mucosa. So the duodenum tries to accommodate this new environment by a metaplastic process which leads to gastric metaplasia of the duodenum, so we will have gastric mucosa in the first part of the duodenum. So, now it’s easy for H pylori to colonize the duodenum, and this is the only way that H pylori colonizes the duodenum causing damaging effect, inflammation, erosion, and ulceration; this is the pathogenesis of duodenal ulceration in the context of H pylori infection. So, it’s a step of high acid output  damage to the first part of the duodenum  gastric metaplasia  colonization of H pylori  ulceration.

about having H pylori in the body? In the body, it’s less likely to produce more acidic juices and it’ll be less likely to develop duodenal ulceration because it’s less acidic, so it’ll not lead to gastric metaplasia and will not lead to H pylori colonization.

Clinical feature of peptic ulcer 

Chronic remitting and relapsing disease.



The main complain is gastric pain and it can be so severe, it worsens at night, after meals due to increase in acid secretion and may be relieved by alkalis or food “in the past, they used to say that any patient with peptic ulcer should avoid this list of food or drinks, for example, they should avoid cooked tomato and any spicy food, and should eat, for example, milk, b6a6a maslo8a, rez masloo8 ….etc” making their life more miserable! Now, this is proved to be not really clinically right, now if you have peptic ulcer disease, the doctor tells you to eat whatever you think it’s appropriate for you, and you feel comfortable with. Some people drink milk and they are discomforted; they get epigastric pain. Sometimes people eat “8layet bandoora w ma fe 3ndo $e” so it’s up to the patient to decide what to eat and not to eat.



It could be associated with vomiting, nausea, bloating, belching, and weight loss. 7

Complications of peptic ulcer –

Hemorrhage: it’s the most common complication. In the past, many patients used to come with upper GIT bleeding in the emergency department, it can be minimal bleeding or so massive that it can’t be controlled medically, and in this case they go to surgery of gastrectomy to stop bleeding.

–

Perforation: uncommon but serious; it will lead to peritonitis.

–

Pyloric channel obstruction: rare; because the healing process might lead to fibrosis in the distal part of the stomach in the antrum or pylorus, and this will cause pyloric channel obstruction. These complications were common in the seventies and eighties; not seen now “perforation and pyloric channel obstruction“.

–

Malignant “transformation”: gastric ulcers NOT the duodenal ulcer. Duodenal ulcers don’t transform to malignant, but the gastric ones might transform into malignancy.

Pyloric obstruction has specific signs; when you examine the abdomen, you can hear fluid in the stomach and it has some physical signs, but we don’t see it anymore.

Treatment How do we treat peptic ulcer? In the past, it was surgical; they did distal gastrectomy, vagotomy and selective vagotomy, then highly selective vagotomy to cut the nerve endings. At the moment, the main treatment of peptic ulcer disease is medical and very rarely we use the surgical approach except in some emergency cases with bleeding. Medical treatment will be covered by pharmacology, but it is different regimens which consist of 2 antibiotics plus a proton pump inhibitor or antacid or antihistamine, it’s taken as three drugs or four and sometimes five drugs, and there are a first line drugs and second line drugs each by specific medications.

Now to compare between gastric ulcer and duodenal ulcer (reading from the table) GASTRIC ULCER

DUODENAL ULCER

 M:F= 1.5-2:1

 M:F=3:1

 Genetics plays no role

 Genetics play important role

 Low-to-normal acid output

 Higher acid output

 Major cause: decreased mucosal resistance against acid & pepsin

 Major cause: Exposure of mucosa to excessive amounts of acid & pepsin

 H. pylori present in 70%

 H. pylori present in all cases

 Pain within 30 min. after meal, not relieved by eating Associated with malignant “transformation

 Pain 1.5-3 hrs after meal, relieved by ingestion of milk or food  Malignant transformation is unknown

 M:F= 1.5-2:1

 M:F=3:1

About pain, clinically, they try to discriminate between duodenal ulcer and gastric ulcer on the characteristic of the pain; that was in the past, now it’s not that much valid. They used to say if you have pain within 30 minutes after meal and not relieved by eating, this is more likely to be gastric. But if the pain is 3 hours after meal and relieved by ingestion of milk or food, this is more likely duodenal (this is just to neutralize the acid and increase the acidity and therefore try to minimize the exposure of the duodenum to acidic juice). It makes sense, it’s logical, but actually it’s not accurate.

Acute Gastric Ulcer We talked about ulceration and about acute gastritis and we said we’ll elaborate a little bit more on the acute ulcer. Acute stress erosions & ulcers: focal gastric mucosal defects that develop acutely after severe stress: –

shock 9

–

extensive burns (Curling’s ulcers)

–

Severe trauma, including major surgery, sepsis...

–

Conditions with increased intracranial pressure, e.g. hemorrhage, trauma, surgery, tumor (Cushing’s ulcers).

Pathogenesis: Gastric acid hypersecretion which will lead to systemic acidosis and this will exacerbate the effect of acid on the stomach, so anybody who comes with extensive burns we give him prophylactic like antacid “IV antihistamine” to protect against gastric ulceration. Vagal stimulation, gastric mucosal hypoxia because of hypovolemia or the shock, exogenous ulcerogenic agents (alcohol, smoking, caffeine, aspirin..) may potentiate the appearance of stress ulcers. They are very acute ulcers and usually they are multiple, hemorrhagic, small ulcers which is more typical of these conditions.

And this an example of acute ulceration of stomach; this might be related to drugs like aspirin or NSAIDs, it might be gastritis with ulceration in cases of shock, in surgeries, after trauma …etc

About peptic ulcer and gastritis We said that peptic ulcer disease is due to chronic exposure to pepsin and acid “remitting and relapsing disease” and they are more related to H pylori, but acute gastritis are acute and have different pathogenesis.

Why doesn't the duodenal ulcer transform into malignancy? It’s not reported as a consequence, we could have duodenal carcinomas but not related to chronic peptic ulcer disease. 10

The Dr asked if we are mastering chronic gastritis now; if anyone asks you, can you treat chronic gastritis?? Until now we can diagnose chronic gastritis or peptic ulcer disease and after the pharmacology probably you might be able to give some prescriptions! “Alla Ysm3 mnk ”

H pylorus has a strong association with chronic gastritis, peptic ulcer, carcinomas and lymphomas; a student asked, is there any sort of sequence which develops before the other? No, there is no specific sequence or reasons why some patients might develop lymphoma and others develop carcinoma, it depends on host factors, the host factors are variable from one individual to other, and we will see later there are some genetic factors which might enhance and potentiate the effect of H pylori infection to develop carcinoma. This week we had a case of 19 years old patient presented with obstruction in his ureter, He was thought to have pelviuretric junction obstruction “junction between the pelvis and the ureter “and because of this obstruction he developed stones, So they insert a double J catheter to relieve the obstruction and let these stones drain out, Accidently, they found a mass in his bladder and they took a biopsy from that and sent it to pathology lab and we didn’t find bladder carcinomas or tumor, actually we found a signet ring carcinoma, and we know signet ring carcinoma occurs more commonly in the stomach -although might happen very rarely primary in the bladder-, so this is metastatic from the stomach and eventually this patient develops signet ring carcinoma with wide spread metastasis to the bladder, around the ureter, to the lymph nodes and everywhere causing obstruction. And we’ll see later that signet ring carcinomas of the stomach are actually not related to H pylori; they are more related to genetic factors rather than H pylori infection which are the diffuse type of gastric carcinoma.

Why do we have duodenal ulcerations more than gastric ulcerations in the context of peptic ulcer? Because the majority of peptic ulcer more antral predominant gastritis than pangastritis or body predominant gastritis, they tend to go more to the antrum, and the density of H pylori infection is more in the antrum by statistics.

The End Done by: Zeina Majthoub 11

16 / 59 6 / 17 25

Pathology Stomach Tumors Isma'eel Matalqa Samah Rjoub Sunday, 30/10/2011

‫بسم هللا الرحمن الرحيم‬ The date: 30-10-2011. The lecture: pathology/stomach tumors. The doctor: Ismae’el matalgah. Done by: Samah Rjoub.

The gastric tumors: Introduction: we have benign and malignant tumors. When we examine the histological aspect of the stomach we can find that it is made of different components, and these components are the origins that are going to give-rise to different gastric tumors. And here are some examples of the origin and the tumors that it gives-rise to it: 1- Epithelium of the mucosa; it gives rise to carcinoma “malignant” or polyps “benign”. 2- Blood vessels; it gives rise to vascular tumors such as Angiomas “benign” or it could gives-rise to Angiosarcomas “malignant”. 3- Fat will give-rise to lipoma “benign”. 4- Mesenchymal elements such as smooth muscle cells will give-rise to Leiomyoma “benign” and Leiomyosarcoma “malignant”. 5- “Cajal cell” is a type of interstitial cell found in the gastrointestinal tract that serves as a pacemaker which creates the basal electrical rhythm leading to contraction of the smooth muscle (peristalsis & Segmentation). And theses cells are the origin of specific tumors that are known as “Gastrointestinal stromal tumors” and its abbreviation is “GIST”. These tumors “GIST” could be either benign, border-line which means intermediate or it could be malignant within a specific criteria. Nowadays we can see that these tumors become more prevalence as a diagnosis than the past; as we have discovered a specific marker for theses tumors which is “CD117”, which indicates the origin of the tumor which is the “Cajal cell”.

Gastric tumors

 Benign gastric tumors are more common than malignant tumors, but infrequently cause clinical problems and we know them just accidently; reported in 5-25% of autopsies. That means that most of those who have benign tumors are going to live there whole life without even know that they have problems and without any symptom and we just know that they had have benign tumors when we do autopsy.

 benign tumors: 1- Polyps 2- GI Stromal tumors (GIST): spindle cell “Cajal-cell” tumors 3- Lipomas, hemangiomas, granular cell tumors, heterotopic pancreatic rests and sometimes we can get ectopic pancreatic tissue within the stomach and it may cause some kind of clinical manifestation and it occurs ass a mass or a small nodule in the mucosa  malignant tumors: 1234-

Carcinomas Lymphomas Sarcomas (malignant GI stromal tumors) Very very very rarely we can have melanoma

This is an example of polyps; which is the hyperplastic or inflammatory polyp and we can see the hyperplasia in the epithelium and some of the inflammatory cells in the stroma or lamina propria, so this is how polyps look like; it is a benign gastric tumor that protrudes above the level of gastric mucosa.

This is how the polyp looks like grossly it is a protrusion above the level of the gastric mucosa and it has a hyperplasia in the epithelium and inflammation in the stroma or lamina propria.

GASTRIC CARCINOMA  Approximately 90% of gastric malignant tumors, that means the majority of the gastric malignant tumors are represented by gastric carcinomas followed by gastric lymphomas and then the other malignant tumors such as the malignant “GIST” and others.  The have Variable geographic distribution such as in Japan where we have high prevalence of gastric carcinoma.  It represents 3% of all cancers.  It has a dismally poor prognosis: 5 yrs survival is just 5% to 15%. That those who have gastric carcinoma and can survive for 5 yrs are just 5% to 15% and the rest of the patients can’t do so, and they will die in less than 5 yrs, so it is really a bad tumor. But the prognosis is still a dependant factor which depends on the time of the detection, if you do detect it in early stage as Japanese do, you will have a good prognosis and more patients will survive for long time that could

reach up to (20 to 30) yrs if we do complete excision of these tumors and just before they begin to metastasize.

ď Ž We have two main Histological types of gastric carcinoma: 1) Intestinal type; which mainly due to intestinal metaplasia that is most related to H.pylori . 2) Gastric diffuse type: non H.pylori related.

Risk factors (for intestinal type) of gastric carcinoma: 1- Diet: nitrites, smoked & pickled food, salty foods 2- Gastric disease: H. pylori which will cause intestinal metaplasia, â&#x20AC;&#x153;the most related risk factorâ&#x20AC;?.

3- Altered anatomy: post-subtotal gastrectomy which will lead to Biliary reflux or duodenogastric reflux is a condition that occurs when biliary fluid flows upward (refluxes) from the duodenum into the stomach and esophagus and this will lead to intestinal metaplasia and this will propagate intestinal gastric carcinoma.

Here are some of the risk factors that cause Gastric carcinoma in general:

1234-

Slightly increased risk with blood group A Family history of gastric cancer Hereditary nonpolyposis colon cancer syndrome Familial gastric carcinoma syndrome (E-cadherin mutation), E-cadherin gene is a tumor suppressor gene.

This is a malignant ulcer which represents Ulcirative gastric carcinoma. This ulcer is large with irregular, heaped-up margins and it is neither shiny nor clean ulcer. There is extensive excavation of the gastric mucosa which may extend to be necrotic ulcer.

Now we will have some information in order to dedifferentiate between “intestinal type” and “gastric diffuse type” of gastric carcinoma. INTESTINAL TYPE

DIFFUSE TYPE

 Arise from gastric mucous cells that have undergone intestinal metaplasia

 Arise de novo from native gastric mucous cells without undergone intestinal metaplasia.

 Proliferation of well formed glands

 Proliferation of “signet-ring” cells

 Expanding growth

 Infiltrative growth which will lead to a sort of gross appearance ofstomach known as linitis plastic"‫ "كيس بالستيك‬as the infiltration growth will take place in the submucosa layer leaving the stomach as a leather bag.

 Well or moderately differentiated  Poorly differentiated  Associated with risk factors

 Undefined risk factors , it may be genetics or familial

 Usually >50 yrs; M>F

 Usually <50 yrs; M=F

 Decreasing in frequency

 Increasing in frequency

About the last point we see decreasing in frequency in intestinal type as a result of well development of treatment of H.pylori which is the main cause of it, so it is a relative association between the decrease in intestinal type and increase in gastric diffuse type "‫"بالنسبة لبعض‬

Intestinal type

Gastric diffuse type

This is an example of intestinal type in which we see the gland formation by the malignant cells that are invade the muscular wall of the stomach.

This is the gastric diffuse type in which we see signet-ring tumor cells. It is known as signetring as we have cells filled with mucin that are going to push the nucleus peripheral and it will look like ‫خواتم الحجاج‬

The sites of the gastric carcinomas: 12345-

: Pylorus & antrum 50-60% cardia 25% body & fundus 15-25% lesser curvature 40% greater curvature 12%

 Gross appearance: » 1) Exophytic » 2) Flat or depressed (focal effacement of mucosa or linitis plastica) » 3) Excavated (ulcer-like)

Histology: or the histological spectrum of the development of the tumor: the development will be as a sequences manner and it will be as the following “it is specially seen in the intestinal type”: 12345-

Back ground of chronic gastritis Metaplasia Dysplasia Carcinoma in situ Gastric carcinoma

 Depth of invasion (stage): 1- Early gastric carcinoma: confined to mucosa & submucosa regardless of LN status. In Japanese they detect this stage and going to inject normal saline solution in the submucosa leading to separation of the mucosa from the submucosa and then they do excision of the mucosa and by that we can end up the progression of the tumor but this done just when the mucosa is the only site of the tumor that we still in early-early stage. Early gastric carcinoma is generally asymptomatic; usually discovered by endoscopy while screening persons at high risk; excellent prognosis

2- Advanced gastric carcinoma: extended beyond submucosa .Advanced carcinoma may be asymptomatic; may cause abdominal discomfort, weight loss, or obstructive symptoms; dismal prognosis.

The gastric carcinoma whether it is early stage or advanced it may spread to regional & distant lymph nodes; earliest lymph node metastasis may be to supraclavicular (Virchow’s LN). This may be the only manifestation sometimes in which we will have an enlargement in the LN which is present supra-clavicularly and this LN is known as “Virchow’s LN).

 Krukenberg tumor: it is a malignant tumor in both ovaries that arise from intraperitoneal spread of gastric carcinoma to both ovaries.

***.‫ ولكن المهم هو أال تتوقف‬،‫ال يهم أنك تمشي ببطء‬ ‫كونفوشيوس‬

GASTRIC LYMPHOMA

**Lymphoma in general is divided to nodal( lymphoma which arise in lymph node) and extra nodal lymphoma ( any lymphoma arise out side lymph node Ex. MALT in general , GIT ,thyroid ,salivary gland, ovary or in kidney ).

***by definition primary extra nodal is diagnosis in absent of nodal involvement .

* stomach might be involve by lymphoma as part of nodal lymphoma( wide spread nodal lymphoma with involvement of gastric mucosa = secondary to nodal lymphoma ) *However what we are interested in is here is PRIMARY LYMPHOMA IN STOMACH So it May be primary or secondary * Gastric lymphoma GL represent 5% of all gastric malignacies * Classification similar to nodal lymphoma; most common type of primary GL is B-cell type more specific is MALT lymphoma which is equivalent to marginal zone lymphoma of node. """ SO MARGINAL ZONE LYMPHOMA IN lymph node IN nodular lymphoma IS CALLED MALT LYMPHOMA""". *Stomach is the most common site of extranodal lymphomas (20%) dr focus on it a lot! *Patients: middle aged & elderly; clinical features depend on type, grade and stage of lymphoma ( dr said not imp) there is no specific presentation for lymphoma to differentiate it from Peptic ulcer disese or carcinoma or chronic gastritis so thatâ&#x20AC;&#x2122;s why why differentiate GL late ď &#x152;. *MALT (mucosa-associated lymphoid tissue) lymphomas (MALToma) are most common lymphoma in stomach as extra nodel : it is low grade, limited to mucosa or submucosa . ** and what characterize it is lymphoepithelia lesions ( where neoplastic lymph cells are attacking the glands so intermental toghather and we can highlight them by cytokeratin stain or leukocyte antigen stains and see how these neoplastic cells attacking the glandular epithelium , we call these lymphoepithelia because it is combination of lymphoid cells and epithelium of glands) * hypothesized to be related to H. pylori gastritis, with chronic antigenic stimulation giving rise to one or more clones of lymphoid cells 12

*In lamina propria we have some sort of diffuse lymphoid proliferation occupying lamina propira then attacking glands and the overlying superficial epithelium and this might lead to ulcer or erosion or mass or other presentation! ***The nice thing about this is the treatment by antibiotic ! it is the ONLY lymphoma which is treated by antibiotic , because H.pylori is the cause and by antibiotics you eradicate it ( if it is low grade)* But in high grade we do surgery first "gastrostomy" then chemotherapy (thatâ&#x20AC;&#x2122;s important because sometime if u had lymphoma and u give chemotherapy before surgery the wall of stomach is so weak and might lead to perforation of stomach )

This is an example of diffuse proliferation centrocyte lines incubing lamina propria causing lymphoepithulim lesion.

Of course there are other gastric tumor, what is important of these is carcinoid tumor* *** CARCINOID TUMORS : Tumors of neuroendocrine cells, which are widely distributed cells of epithelial stem cell origin capable of producing a variety of bioactive compounds , and it is associated with chronic autoimmune gastritis ( which associated with neuroendocine hyperplasia) . *** GIST: Gastro- intestinal stromal tumor arising from interstitial cells of cajal and lead to malignant( in the past called leiomyoblastoma because they were thinking it is arise from smooth muscle but thatâ&#x20AC;&#x2122;s wrong it is from interstitial cells of cajal ) , bening or border line . 13

SMALL & LARGE INTESTINES

***We have some Developmental anomalies like : Atresia, stenosis, Meckel’s diverticulum(do something like peptic ulcer in terminal ileum) , malrotation *Hirschsprung’s disease( one of congenital anomalies lead to chronic constipation in infants ) *Vascular disorders *Inflammatory & diarrheal diseases : most of diarrheal diseases caused by viruses * *Enterocolitis, malabsorption syndromes *Idiopathic inflammatory bowel diseases : this is important and we have 2 types: Crohn’s disease, ulcerative colitis. *Colonic diverticular diseases *Tumors. Here histological pic: villi and microvilli on surface and brush border cells that secret brush border enzymes , and they are important in absorption and ingestion. Main function of these villi to icrease surface area Normal villi : crypt ratio is 3-2:1

**If you lose the villi by any destructive process like inflammatory, mechanical, infection or surgery will lead to decrease surface for absorption and this will lead to mal-absorption.

* here in contrast of stomach the lamina propria normally contain inflammatory cells like lymphocyte , histiocyte and sometimes plasma cells and if there is inflammation what happened actually is increase in this amount of content because it is already there. *There is preserve relationship btw crypts and muscularis mucosa and only alter in chronic inflammatory diseases not acute . * later you will see in crypts in colon almost touching muscularis mucusa.

This is colon , there is no villi but more surface epithilum and Crypts is touching muscularis mucus and they are regular and rounded and no angulations. this is normal colon and normal content of inflammatory cells in lamina propria

THE END :‫ سمعت رسول هللا صلى هللا عليه وسلم يقول‬:‫عن أنس بن مالك رضي هللا عنه قال‬ ‫ "يا ابن آدم إنك ما دعوتني ورجوتني غفرت لك على ما كان فيك وال أبالى‬:‫قال هللا تعالى‬ ‫يا ابن آدم لو بلغت ذنوبك عنان السماء ثم استغفرتني غفرت لك وال أبالى‬ ‫يا ابن آدم إنك لو أتيتني بقراب األ ر طاايا ثم لقيتني ال ترر بي يياا ألتيتك بقراباا مغفر"" روا الترمي‬ ‫ ( ما من أيام أعظم وال احب إلى هللا العمل فيهن من‬: ‫روى اإلمام أحمد رحمه هللا عن ابن عمر رضي هللا عنهما عن النبي صلى هللا عليه وسلم قال‬ ‫هذه األيام العشر فأكثروا فيهن من التهليل والتكبير والتحميد ) وروى ابن حبان رحمه هللا في صحيحه عن جابر رضي هللا عنه عن النبي صلى هللا‬ ‫( أفضل األيام يوم عرفة‬:‫)عليه وسلم قال‬. )= . ‫**** عيد اضحى مبار‬

24/59

7/17 15

Pathology Diseases of the Intestine I (Malapsorption)

Ismael Matalqah Ahmed Al-Zu'bi Wednesday, 2/11/2011 24/10/2011

Pathology Lec7 Dr-Ismael Matalqah Ahmed Al-Zu'bi Wednesday 2, Nov, 2011 Last time, we were just having an overview on the main pathology and main diseases of the small intestine, and probably you remember some sort of the important histological features that we have elaborated on regarding the small and large intestines; and the relationship between the crypts and the villi, and the importance of the villas architecture in preserving the surface of absorption, and for the colon we emphasize the importance of the architectural relationship and the density of the crypts, and we talked about some chronic inflammatory wall diseases that will lead to loss of such density then destruction of the crypts, and the presence of inflammatory cells between the crypts and the muscularis mucosa which is a histological feature which remarks the chronic inflammatory wall disease.

Developmental Anomalies of the small intestine: 

We have already mentioned the possibilities of Atresia or Stenosis which involve a segment of the bowel, which might happen throughout the GIT, whether in the esophagus or the small intestine …etc.



Duplication is a well-formed saccular structure which may or may not communicate with bowel lumen.



Meckel’s diverticulum is the most common congenital anomaly of the small intestine, it is the Failure of involution of the omphalomesenteric duct; you know during the embryonic life, there is a duct connecting between the umbilicus and the bowel through the mesentery, this duct involutes during the embryonic life, such failure of complete involution of the duct will lead to the formation of this diverticulum, so it is Blind-ended tubular protrusion, it is usually less than 6 cm in length.The most common site is the ileum,within 2 feet of the cecum (about 60 cm from the ileocecal valve).

The importance about this that it is lined by heterotopic gastric mucosa in about 50% of the cases, and that is why these diverticulum might present with bleeding and pain, rarely they might contain heterotopic pancreatic tissue, and this pancreatic tissue might be a source of insulin and other hormones or secretions, sometimes these heterotopic tissue whether it is gastric or pancreatic might undergo malignant transformation, and we might have some sort of ectopic tumors at that site. It is not uncommon, it is preventing good proportion of normal population, not all the cases actually are discovered unless there is some sort if symptoms, and quite significant number of them are asymptomatic. So some of these are discovered accidentally during intraabdominal operations for other causes (appendix .... etc), sometimes because this(terminal ileum) is very close to the appendix, this might be mistaken as appendix, so it is very important to clarify the anatomic relationship, and of course if they find it accidentally they will check it out and repair the small intestine. 

Omphalocele is a defect in periumbilical abdominal wall, resulting in a membranous sac; +/- intestinal herniation.

Meckelâ&#x20AC;&#x2122;s diverticulum: there is out-pouching of the small intestine out of the wall.

Meckelâ&#x20AC;&#x2122;s diverticulum: here the small intestine has been opened, you can see the small intestinal mucosa, and you can see more hemorrhagic mucosa (this might contain some gastric or pancreatic mucosa), and this gastric mucosa will secrete acid and pepsin, and these will drain down leading peptic ulceration of the adjacent small intestinal mucosa, this is one of the rare examples of the peptic ulcers occurring outside the stomach and the duodenum.

Omphalocele: you can see a huge herniation of the intra-abdominal contents including the intestine, and this represents intra-uterine fetal death. 2

MALROTATION: Malrotation is another congenital anomaly in which the developing cecum fails to descend to its definitive adult position in the right lower quadrant (the normal anatomical position), the cecum may be found anywhere in the abdomen. This might be asymptomatic, and this might cause clinical problems since it is not fixed in its right anatomical position, this might lead to volvulus. And here we have a clinical problem; the misdiagnosis of acute appendicitis; it might be a problem, so if we do not know that this patient that his bowel (cecum) is malrotated, and this patient has light left lower quadrant pain, we will be excluding appendicitis, because this is not the right position for it, so this might be mis-interpreted as something else non-specific colitis or colonic diverticular diseases, and the patient might be treated symptomatically without operation, and if you fail to treat acute appendicitis, you will end by perforation then peritonitis, and peritonitis is a life-threatening condition which might lead to death.

HIRSCHSPRUNG’S DISEASE: It is another congenital anomaly; it has another name "congenital mega colon ", and the name describes the disease, because the colon becomes functionally obstructed in its distal part, and this will lead to dilatation of the colon proximal to it. It is defined as the Failure of development of Meissner’s & Auerbach’s plexuses ( meissner's plexus is present in the submucosa, and auerbach's plexus is intramural within the muscle "muscularis propria/muscularis externa" , due to arrest in migration of neural crest-derived cells along GIT. So such failure in development of these ganglions ( meissner and auerbach ) are lacking at anorectal junction & distal colon, causing functional obstruction and progressive distension (mega colon) of the innervated colon proximal to the affected segment; now the ganglion cells are part of the parasympathetic system, they are important in the innervations of the colon and the peristaltic movement of the colon, when these ganglion cells are absent, this will lead to dysfunction of the colon and inappropriate peristalsis, then we will have functional obstruction in those areas where the ganglion cells are lacking, usually in this disease the ganglion cells are absent in the distal part of the colon ( the rectum and part of the sigmoid colon), so the segment of the aganglionic is variable, sometimes it is a short segment, and sometimes it is a long segment. The presentation of patients with this disease: they present with constipation, usually after birth, weeks or month after birth they present with prolonged or chronic constipation, so in 20% of patients, a longer segment is aganglionic. It is not uncommon, one out of 5000-8000 live births, it is more common in males than in females, M:F = 4:1. It may be associated with other congenital anomalies like: hydrocephalus, VSD "ventricular septum defect", Meckel’s diverticulum … etc. So the surgeon will resects the constricted part, the make anastamosis between the innervated (normal) part and the remaining part of the rectum, which we have to make sure that it is innervated, so the surgeon usually takes biopsy, and it should be full thickness mucosa (because as we said the ganglions are present in then submucosa and the muscularis), in order to be sure that the ganglions are present.

As pathologist to confirm hirschsprung's disease, we do up to 100 histological levels in the full thickness mucosa, to be sure that the ganglions are present.

SM Hirschsprung's disease: here you can "M" mucosa, "MM" muscularis mucosa and "SM"submucosa; and here in the submucosa we can find the ganglion cells as the black arrow indicates.

Hirschsprung's disease: we have two segments; narrowed and dilated segments, the narrowed one is the diseased one, and the dilated is the normal one.

So the presence of these ganglion cells >>> Normal "no disease" . And the absence of them>>> the disease is present.

Hirschsprung's disease: we have two segments; narrowed and dilated segments, the narrowed one is the diseased one, and the dilated is the normal one.

Clinical symptoms: Delayed passage of meconium, one of the earliest signs that indicates hirschsprung's disease, the first stool passage after delivery we call it meconium, it is a greenish stained stool (dark green to black), it is greenish because the baby in the intrauterine life ingests the amniotic fluid, when the muconium passes, that means the bowel functions properly, then vomiting in about 48-72 hours which is a sign of obstruction, and then obstructive constipation. These symptoms might take longer than this; it depends on the severity, the length of the anglionic segment.

Complications: When we have a patient with this disease, we should put in consideration that the patient might develop colitis and perforation, and because of the continuous obstruction, and because the large bowel is the major site for electrolytes and fluid absorption and secretion, this will lead to electrolyte and fluid disturbances, and that will affect the life of the infant because he is so fragile. Diagnosis: We need full thickness biopsy of nondistended bowel segment. As for the treatment it is done by surgical procedure.

Now let's move to the DIARRHEAL

DISORDERS:

As you know diarrhea is an increase in the stool mass; frequency or fluidity. It indicates abnormal bowel movement. The daily stool production is in average 250 gm (this is the minimal level), and this usually contains about 70-95% of water. Dysentery is defined as low volume painful bloody diarrhea, we don't have increase in the mass of the stool, and it is caused by bacterial infection like shigella. The classification of diarrheal disorders is according to the pathophysiology of the diarrhea, because there are many causes of diarrhea:  Secretory diarrhea: direct or enterotoxin-mediated damage to surface epithelium. This will lead to secretory diarrhea because of the extravasation of the fluid from the epithelium, lymphatics, blood vessels … etc into the lumen.  Osmotic diarrhea: this depends on the osmotic forces of the luminal solutes, of course if the oncotic pressure or the osmotic forces is decreased in the bowel (mucosa), the oncotic pressure increases in the inside of the lumen, so the fluids instead of being re-absorbed, they will be secreted into the lumen.  Exudative diarrhea: destruction of epithelial layer.  Malabsorption diarrhea: unabsorbed nutrients & fats (inability to absorb fats and other nutrients), because of some other defects.  Deranged motility: this maybe functional or mechanical, so it is a decreased intestinal retention time, or decreased motility (in WIKI : hypermotility, which is increased motility. From another source: slow intestinal transit (decreased motility) may lead to a secretory diarrhea by promoting bacterial overgrowth in the small intestine).

Malabsorption syndroms: Here you may ask a Question: why is it called syndrome not disease??!! Because we have different causes intermixed with each other for the malabsorption to be developed, and it affects more or less all the systems in our bodies.

Malabsorption is a suboptimal absorption of different nutrients, electrolytes &/or water as a result of disturbance in intraluminal digestion, or absorption, or terminal digestion --we said in the small intestine we have brush borders on the surface of the epithelium, and these brush borders are so important for the intraluminal digestion, so any abnormality in these brush borders will prevent the secretion of the digestive enzymes (glycosidases digest carbohydrates as an example), and this will affect the digestion leading to malabsorption-- &/or transepithelial transport of the nutrients. Digestion of food occurs mostly in stomach & small intestine, while absorption occurs mostly in duodenum & jejunum and other parts of the ileum. Malabsorption may be caused by a variety of diseases. Diagnosis: Small intestinal biopsy is an important diagnostic tool: may show characteristic findings, normal or nonspecific changes, it is important, and when we say small intestinal biopsy, this should be distal to the first part of the duodenum; the first part of the duodenum is part of the small intestine, but it is not appropriate to asses any malabsorption disease, and the reason for this: it is exposed to the destructive action of the gastric acids, so most of the time it (first part of the duodenum) shows abnormality. So it should be taken from the second part of the duodenum and distal to it, and sometimes if we expect a certain disease, we may take it from the terminal ileum. Sometimes the result might be normal, but normal is good as abnormal, this will lead us to exclude specific diseases at least. It is more widely used nowadays as a tool for diagnosis because of the easy accessibility of the small intestine by the endoscopy technique. Complications: Weight loss, anorexia, abdominal distension, muscle wasting and steatorrhea (passage of abnormally bulky, frothy, greasy)‫ (شحمة‬, yellow or gray stools). Bulky: because there is no absorption. Greasy and yellow: because it contains high content of fat. Sometimes when somebody is seeking attention and there is a malabsorption; one of the questions the physician asks him: what about your bowel motion? How frequent do you pass stool? What is the nature of the stool? Is it bulky, greasy? He may ask what do you mean by greasy? The physician answers: is it difficult to flush it? The difficulty in flushing it indicates that there is a high content of fat, because it has not been absorbed in the small intestine (jejunum), so this is steatorrhea. Why do we have muscle wasting? Because we are losing protein, protein is important for muscles, and this is the main source of protein (absorption of protein from the diet) for the muscle to keep its mass, so we will have muscle wasting.

General consequences of MALABSORPTION:  Anemia: iron, pyridoxine, folate or vit. B12 deficiency, because all of them are malabsobed in the small intestine. If it is not controlled, it may lead to cardiac failure.



Bleeding: vitamin K deficiency, vitamin K is produced in the liver, vitamin K and fatsoluble vitamins (A,D,E,K) need fat for their absorption. And you know vitamin K is essential and crucial for coagulation and clotting, so if you are not absorbing sufficient amount of vitamin K, you will suffer from bleeding (coagulation defects). Osteopenia (decrease in the mass of the bone) & tetany "the Dr said that it is similar to rickets, but it is in adults but that is wrong, it is not called tetany, it is called osteomalacia, but tetany and rickets have the same cause which is Vitamin D, Mg and Ca deficiency" (Tetany is a case of involuntary muscle convulsion, or it is a medical sign consisting of the involuntary contraction of muscles, which may be caused by disease or other conditions that increase the action potential frequency): because of vitamin D deficiency and Ca and Mg deficiency. Amenorrhea, impotence, infertitlity: generalized malnutrition.

Amenorrhea: is the absence of a menstrual period in a woman of reproductive age. Impotence: is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance. Infertility: inability of a couple to become pregnant (regardless of cause) after 1 year of unprotected sexual intercourse (using no birth control methods).

     

Hyperparathyroidism: it is secondary to Ca & vitamin D deficiency. Purpura & petechiae: vitamin K deficiency. (correct it in the slides) Edema: protein deficiency. Dermatitis & hyperkeratosis: vit A, Zn, eFA (essential fatty acid), niacin deficiency. Mucositis: multiple vitamin deficiencies. Peripheral neuropathy: vit A & B12 deficiency.

We classify MALABSORPTION syndrome according to the pathophysiology: 

Defective intraluminal digestion: (causes)  as you know the intraluminal digestion occurs in the presence of pancreatic juices, so deficiency in those pancreatic juices will lead pancreatic insufficiency, and then defective intaluminal digestion.  Zollinger-Ellison syndrome; here we have increase in the gastrin production, gastrin will increase the acidity. Hyperacidity might affect the intraluminal digestion in the small intestine, because we need the optimum PH for the intraluminal digestion.  Defective bile secretion due to biliary obstruction.  Hepatic or ileal dysfunction.  Bacterial overgrowth.

 Mucosal cell abnormalities: (causes) lactose intolerence, bacterial overgrowth, abetalipoproteinemia.

 Reduced small intestine surface: (causes) we need surface for digestion, if we lose part of the surface due to surgery (short-gut syndrome)—as you know the length of the small intestine is 6 meters, if 3 meters has been resected surgically for any reason ischemia or whatever—then we do not have enough surface for digestion and absorption. There are other inflammatory diseases Celiac disease, chron's disease, which lead to destruction of the villas and crypts architecture, then reducing the surface area for digestion and absorption.  Lymphatic obstruction: (causes) lymphoma, tuberculosis. You know that the lymphatic drainage is very important for the fat absorption.  Infection: like enteritis, tropical sprue, Whipple’s disease.  Iatrogenic: surgeries (removing part of the small intestine), drug induced; one of the most important drugs that will lead to destruction of small intestinal mucosa (erosion and ulceration) are the NSAID's (Non-Steroidal Anti-Inflammatory Drugs) . Someone asked about the Iatrogenic diseases: they are disease that caused by the patient him/herself or by the physician, as a result of management (surgery, medical treatment). Going back to the pancreatic

insufficiency:

as we said it is a major cause of defective intraluminal digestion. Causes: Chronic pancreatitis, Cystic fibrosis. The main presentation: diarrhea, steatorrhea. Later on we will talk about chronic pancreatitis in details, and we will elaborate a little bit on cystic fibrosis )‫(التليف الكيسي‬, and in Jordan there are so many patients with cystic fibrosis, it is one of the diseases lead to morbidity and mortality, the majority die early in their twenties, and they need very special care.

THE END Finally, I just wanna thank my friend Muhammad AL-dawod for his help :D

‫اللهم وفقنا أجمعين‬ 8

25/59 8/17 20

Pathology Diseases of the Intestine II (Inflamatory bowel diseases)

Isma'eel Matalqa Omar Bataineh Wednesday, 2/11/2011

Pathology Lecture 8 Done by: Omar Bataineh Wednesday , 2/11/ 2011

The lecture includes everything you don’t need the slide while studying it.

The bacterial overgrowth You know that the small & large intestine are normally colonized by bacteria which we call them normal flora, and this normal flora is very well balanced. Inside our small intestine & between the small & large intestine any shift in this balance will be a bacterial overgrowth… there are other causes of bacterial overgrowth , we will talk about it... Normally we ingest loads of bacteria in daily bases as a food or fluid or other things that we ingest... but because of our immunological system in small & large intestine characterized by the presence of lymphoid cells within the lamina propria in the intestine, thus keeping the balance between the antigenecity of these bacteria & the immune response of the intestine. If an over-reacting of immune response happened to the organisms & bacteria, this will be so harmful because it will lead to other manifestations like inflammatory conditions like inflammatory bone disease. So if a pathologic colonization of jejunal lumen by an abnormally large population of aerobic or anaerobic organisms qualitatively similar to those present in the colon... an imbalance occur there between the sorts of normal flora in the small intestine, this will lead to impairment of the intra-luminal digestion & damaging of the epithelium in the proximal small intestine leading to malabsorption. This Occurs in patients with: –

Intestinal luminal stasis: strictures, fistula, blind loops or pouches I mean the people who have anatomically abnormal small intestine that cause stasis of food & nutrients leading to bacterial overgrowth.

–

Post-operative states associated with inadequate gastric acidity

The acidity of the stomach is important because it kills the microorganisms & it keeps the balance of micro flora so prevent the overgrowth. So hypoacidity will lead to overgrowth of some other bacteria. –

Immunological deficiencies

–

Mucosal disease of small intestine either due to mechanic or other disease or cause.

LACTOSE INTOLERANCE  Deficiency of lactase is mostly acquired (Lactase is one of the brush border enzymes; it breaks the lactose into glucose & galactose)  Lactase deficiency result in > Lactose cannot be broken down to glucose & galactose; unabsorbed lactose exerts an osmotic pull leading to watery diarrhea & malabsorption.  Familial inborn error of metabolism: presents at birth with initiation of milk feeding with explosive watery frothy stools & abdominal distension  In adults, occurs with bacterial and viral gastroenteritis & other GIT disorders

Milk is one of the most important sources of lactose, so people with deficiency of lactase when they drink milk they will have abdominal distention especially in newborn immediately after bottle feed so it’s a sign of lactose intolerance. In adults this deficiency is usually acquired & happens after an episode of enterocolitis.

 Dx (diagnosis): intestinal biopsy is normal; breath hydrogen testing by gas chromatography that is a machine used for detect this type of deficiency.

CELIAC SPRUE It’s one of the most important causes of malabsorption syndrome. The other name for it is Gluten-sensitive enteropathy. It’s hypersensitivity to gluten. Gluten is the component of wheat & related grains (oat, barley & rye), Gluten contains water insoluble gliadin peptides. Because it’s insoluble the main function of this gliadin peptide is to make the dough sticky.

Pathology: When hypersensitive patients are exposed to gluten, large numbers of B cells & plasma cells accumulate in the lamina propria, resulting in epithelial damage & total flattening of villi. So it’s a type of hypersensitivity reaction. Such sensitivity makes them produce more lymphoid which stimulate other T lymphocytes. Although the main lymphoid in the lamina propria is B cells but the cells that destruct the epithelium & the villus structure is the T lymphocytes. So this is what we call intra-epithelial lympocytosis. Normally the surface epithelium of the villus contains (5-15) intra-epithelial lymphocytes per 100 epithelial cells. Upon this hypersensitivity & stimulation the number of these T lymphocytes will increase. In this disease the cut of point is variable from ethnic group to other ethnic group; for example: In Ireland there should be more than 30 intra-epithelial lymphocytes per 100 epithelial cells to call it abnormal. In Jordan we need 20 to call it abnormal. So anything above the 20 is abnormal & has the potential to lead to manifestation of celiac disease. The incidence: (1:2000-3000) in white Europeans; familial & viral links. But in some countries like southern island (Doblin) is (1:200). In Jordan it’s about (1:1000). So it’s not uncommon, it’s there & around us. So we have to use histological or clinical criteria to diagnose it. Presentation: It ranges from infancy to mid-adulthood; diarrhea and malnutrition. They have features of malabsorption like anemia. One of the earliest manifestations of this disease in children is what we call failure to thrive (failure of growth). The celiac disease is an important cause of this failure to thrive so if we have a child with failure to thrive the first thing to do is to exclude the celiac disease. PX (Prognosis): Increased risk of developing malignancies. Of course the other consequence of that is increasing the risk of other malignancy, and we will talk about the malignancies that develop as a consequence of celiac disease if not treated.

How do we treat gluten hypersensitivity? Rx (Treatment): Gluten-free diet We don’t have any medication to treat celiac disease and this is the difficult thing about this type of disease, we don’t have medication so we don’t have anything to treat with. The only thing that you can offer now is Gluten free diet, and that means that the child won’t eat (bread, 4

biscuit, chocolate, cake) and anything that contain Gluten which is a very wide list of food. Countries like Europe, it’s much easier because earlier they have a lot of Celiac disease patients , so any supermarket you go or any big store you will find a corner for celiac disease patients (Gluten-free) . in our country it’s not that easy, so it’s very difficult for the parents, and you can imagine the miserable life for parents (that they should hide all the food that contain Gluten and to keep out all these foods from their child), so if he is on Gluten-free diets he will be ok, but if he eat any food that contains gluten he will relax and he will get diarrhea, malabsorption and rabies.

This normal villus architecture and normal crypt ratio 3:1 and there’s no destruction or anything .now, if you look at the surface epithelium here you see black dots, these are T lymphocytes (intra-epithelium phosphate to charge T lymphocytes)most of lymphocytes are T lymphocytes and the average of these is ( 5-15:100 ) epithelial cell .

This is endoscopic appearance of celiac disease and called (mosaic appearance), so the histology is very important.

This is a classic example of celiac disease , and thereâ&#x20AC;&#x2122;s almost complete loss of villus architecture and the surface epithelium is crowded by these intra-epithelial lymphocytes , in early phase we donâ&#x20AC;&#x2122;t have this , we have increased intra-epithelial lymphocytes in the earliest manifestation ,earlier we have something like this with preserved villus architecture .

but when count the intra-epithelial lymphocytes we found it (30-40) this might present the earliest sign of celiac disease , and we call this the silent celiac disease or sometimes we call it latent , therefore celiac disease is like iceberg phenomena (iceberg :a mountain covered with ice) so under the iceberg thereâ&#x20AC;&#x2122;s patients which are : -silent (they have the manifestation but not the full histology) - latent (they have the genetic for it and they have the liability to develop it at any time in their life, if not early life might be late in adult and we call them the adult presentation in celiac disease. the majority is during childhood but there is cases that develop it in adult. so you can develop celiac disease at any stage of your life.

Now, the adult presentation of celiac disease later in life is worrying because it might be the early manifestation of lymphoma. So, it presents with Enteropathy-Associated T-cell Lymphoma (EATL), so you have to be more careful about this.

This is to show you the increase intraepithelial lymphocytosis .there are some villi, we might have total villus atrophy of the villi or partial villus atrophy or prolonging of the villi, we have variable histological pictures of the celiac disease.

In the past, diagnosing the patient with celiac disease was by endoscopy and biopsy from the 2nd part of the jejunum. Biopsy >>histological changes >>villus atrophy >>this’s celiac disease Now, for the last 15 years they have found some serological markers (serum antibodies) which are very helpful in diagnosing celiac disease. they changed our concept about H.pylori ,peptic ulcer disease and celiac disease and that’s why the incidence of celiac disease is now increasing because of these markers now we diagnose more and more of these celiac diseases , especially those silent (that doesn’t mean they don’t have clinical presentation but usually it’s interpreted as something else ). SERUM ANTIBODEIS: 1- Antigliadin antibody. 2- Antiendomysial antibody. 3- Anti-tissue transglutaminase antibodies. They are very important and you can do any one of them but the best is to do the combination of them.

The incidence: In the past it was (1:5000), now they are doing a lot of studies on blood donors in blood bank and that’s how they actually found that the incidence is more than it was previously and found that this serological markers exist in a huge number of population. and if you found a positive marker it’s better to take histology to confirm it, but at least these are excellent for screening & following up the patient. If you started the patient -a kid for example-on a gluten-free diet, it is easier to use these serological markers to monitor his commitment to this diet than to take a biopsy each time. If these serological markers were increased (positive results), then he is not committed to his gluten-free diet. 

What are the complications of Celiac Disease? 1- Malignancy : - T cell lymphoma, these lymphocytes, because of the extra activation of these intraepithelial T lymphocytes, at some point they will be mutated and become

neoplastic and develop what we call Enteropathy-Associated T-cell Lymphoma (EATL). Patients with celiac disease have a higher incidence of developing Adenocarcinoma of small intestine & Squamous cell carcinoma of esophagus. Some patients may improve on Gluten-free diet and some donâ&#x20AC;&#x2122;t, these who are unresponsive to gluten-free diet are said to have Refractory Sprue. This condition is hard to treat and patients are given steroids to reduce their hypersensitivity reactions toward gluten. These patients who are predisposed to the malignancies we talked about in most cases.

* Refractory sprue (RS) is a complex autoimmune disorder much like the more common celiac sprue but, unlike celiac sprue, it is resistant or unresponsive to six months of treatment with a strict gluten-free diet.* -

ď&#x201A;ˇ

Ulceration and stricture of small intestine.

Treatment: -

Gluten-free diet, & sometimes we may take some steroids. Here, just to show you the antigliadin, antiendomysial & anti-tissue transglutaminase antibodies. You can see that the consistency (positivity) of these markers help us to diagnose or to confirm the diagnosis.

Some theories say that Celiac disease may be due to a viral infection causing the hypersensitivity reaction; of course it has a familial distribution which means that the chance of the patientâ&#x20AC;&#x2122;s first degree relative (sibling) to have Celiac disease is (15-30%). 8

That’s why screening of families & first degree relatives became a standard with Celiac disease cases. One of the research areas to treat this disease, is to develop a sort of hyposensitization, if we give the patients bolus injection of a gliadin-containing peptide (vaccine), this will make them hyposensitized reducing their chance to develop Gluten-sensitive enteropathy (Celiac disease). Other research area concerns genetically modified food (GMF), in this method you modify the genes of wheat, to produce wheat without gliadin. If they could identify the viral link to this disease, it will be very helpful because you will be able to vaccine against a specific virus which is much easier than hyposensitization of a patient.

Tropical Sprue: Which is a celiac-like disease occurring almost exclusively in the tropics, it has an infectious etiology, but no definite microorganism has been identified. The manifestation of the sprue is malabsorption like Celiac Disease, it follows an acute diarrheal infection, the only difference here is that we can treat them with broad spectrum antibiotics and sometimes they are self-limiting. Pathology: minimal to severe diffuse enteritis with villous flattening, but here, you don’t see much intraepithelial lymphocytosis, and that’s where the biopsy is helpful for differentiation. Taking history here is very important, to know if the patient has been to countries known to have these tropical sprue.

Whipple’s Disease: It is also infectious, caused by the (gram +ve actinomycetes) Tropheryma whipelii contained in macrophages. It is a systemic rare infection which involves the intestine, CNS & joints. That’s why patients (males 30-50 years) will complain of lymphadenopathy, polyarthritis and other CNS symptoms. We treat them by antibiotics. This is the typical appearance of Whipple’s disease where you see the lamina propria in the small intestine is replaced by macrophages with minimal inflammation, and if you do PAS 9

stain, it will stain the cytoplasmic contents of these macrophages which are the causative microorganisms (Tropheryma whipelii).

Abetalipoproteinemia: It is a rare autosomal recessive inborn error of metabolism, with inability to synthesize apoproteins required for export of lipoproteins from mucosal cells. Normally, free fatty acids and monoglycerides enter absorptive cells and are normally reesterified but cannot be synthesized into chylomicrons. To eserify those to chylomicrons you need apoproteins, if apoproteins are deficient, then fatty acids will accumulate resulting in mucosal cells vacuolated with lipid inclusions in their cytoplasm. This will lead to severe hypolipidemia (decreased mainly in chylomicron, VLDL, LDL because they are mainly affected by the apoprotein deficiency). Typical complication of diarrhea, steatorrhea, & failure to thrive. Peripheral blood picture can be useful, where you find RBCs showing characteristic burr cells (acanthocytosis). RBCs having irregular cell membrane, because lipids are important components of the plasma membrane.

Giardia lamblia: It is the worldâ&#x20AC;&#x2122;s most prevalent pathogenic gut protozoan. The asymptomatic carrier state is common. Trophozoites live in duodenum & give rise to infective cysts that are shed into the stools. Spread by fecal contaminated water. Parasites attach to small intestinal mucosa but do not invade the mucosa. Pathology: Intestinal villi are usually normal, or it might be blunted with a mixed inflammatory cell infiltrate in lamina propria. -

malabsorptive diarrhea 10

The main diagnostic tool is to identify this trophozoyte (Giardia lamblia), so we take the duodenal mucosa biopsy and they will be present on the surface epithelium. You treat them by antibiotics, and they are pear-shaped trophozoites, so it is very easy to identify them when they are present in the duodenal biopsies.

The end Done by: D.O.B Special thx to people who helped me... - Abdulla Masaâ&#x20AC;&#x2122;deh (MEETA MEETA ;) ) -Mohammad Rusan (you are very example ;) ) -Ibrahim Migdady (Actions are by intentions ;) ) -the Unknown Soldier D (meema3a ;) )

History does not repeat itself, but people insist on stupidity.. Know your enemy.. Thank you Omar for your effort ď &#x160; - SAMA Group

30 / 59 9 / 17 30

Pathology Ischemic Bowel Disease Isma'eel Matalqa Noor Al-Momani & Tamara Shoter Sunday, 13/11/2011

|Page1

‫بسم هللا الرمحن الرحمي‬ ’’ Adha Mubarak Everyone’’ 

Last time we stopped at ischemic bowel disease and we grouped diseases of small and large intestines, we discussed the malabsorption and its causes and the effect of celiac disease, gluten hypersensitivity. We tried to classify diarrheal disorders according to their etiology and pathogenesis (some of these causes are the infectious ones that will be discussed in microbiology) while today we will talk about some of the ischemic diseases and the inflammatory bowel disease.

Ischemic bowel disease: -"Ischemic bowel disease" Is a generic name for any ischemic insult of the small and large intestine in general, and sometimes they can use other names interchangeably with this as "Mesenteric ischemia" -and it is obvious why they named it like that because of ischemic insults & because of the obstruction of the vascular or the blood supply through the mesentery as we know where the blood vessels pass within the intestines. So,,,,

1) it involves small &/ or large intestines depending on the particular vessels involved whether it’s the celiac or superior and inferior mesenteric arteries .

*We should know what they supply...

The celiac artery supplies oxygenated blood to the liver, stomach, abdominal esophagus, spleen and the superior half of both the duodenum and the pancreas. Wiki

**Superior mesenteric artery: supplies the intestine from the lower part of the duodenum through two-thirds of the transverse colon, as well as pancreas. **Inferior mesenteric artery : supplies the large intestine from the left colic (or splenic) flexure to the upper part of the rectum, which includes the descending colon, the sigmoid colon, and upper part of the rectum |Page2 Wiki..

Why is it important to know what they supply?

2) Usually elderly patients are involved: And they usually suffer from other chronic diseases (like cardiovascular diseases or heart problems in general, Hypertension, and Diabetics as they have atherosclerosis).

* For those with hypertension we give them antihypertensive drugs and they might become hypotensive *so sometimes hypertensive patients might undergo hypotensive Rebounds because of certain drugs which may lead to hypoperfusion.

3) It could be acute (sudden) or insidious and sometimes abdominal pain is long standing and chronic. So the presentation is variable depending on the severity and blood vessels that are involved.

Causes of ischemic bowel disease: -Arterial thrombosis: the formation of thrombus on the back ground of atherosclerosis leading to the obstruction of the lumen of the blood vessel.

-Arterial embolism:

where we have short fragment of this thrombus into distant

sites like cardiac vegetations, sometimes post-myocardial infarction and lead to showering of small thrombo-emboli through the coronaries and these thrombo-emboli will spread through the circulation so they may go and obstruct one of the main blood vessels (either celiac or superior & inferior mesenteric arteries in this case) it might also obstruct the kidney (renal artery) which will lead to renal failure, or obstructing other blood supply to vital organs.

-Venous thrombosis: in hypercoagulable states. - Nonocclusive ischemia: heart failure and hyotension, shock (hypovolemic shock or due to loss of blood because of trauma, bleeding and massive hematurea)

|Page3

-Miscellaneous: - Radiation (radiation will lead to fibrosis ď&#x192; occlusion of the pedicles of blood vessels ď&#x192; might lead to ISCHEMIA), - Volvulus (twisting of the bowel around itself- the dr said around its pedicle I think) - Herniation (entrapment of the intestine in the hernia content leading to ischemia) and these are due to impairment of blood supply. -Volvulus + herniation are mechanical causes

Types of ischemic bowel diseases: Are divided into 3 main categories according to the severity f the injury:

Mucosal infarction where it involves only mucosa.

2) Mural infarction "hemorrhagic gastroenteropathy" and usually due to: hypoperfusion (hypotension for ex. Hypovolemic shock) damaging only the inner layer of the GIT (mucosa, submucosa, part of the muscularis propria) and it can be multifocal or continuous lesions depending on the blood vessels that are affected, there will be hemorhage, edema & ulceration and because of these partial circumstances we can find intact serosa (part of the wall will be intact) and to some extent they can be treated without leading to perforation and peritonitis. 3) Transmural intestinal infarction (full thickness infarction): The whole wall is infracted, it is a dark red hemorrhagic segment of variable length, ischemia starts in mucosa and extends outwards with edema, hemorrhage necrosis, mucosal sloughing followed by gangrene and perforation and the most severe complication is perforation and peritonitis also the mortality rate is very high.

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This is just to summarize, as you can see this is the mucosal infarction with only mucosal involvement, then the mural where the mucosa, submucosa. Then there is the transmural where is the full thickness is involved.

This is an example of red large gangrenous, more or less transmural infarction or ischemic necrosis.

This is mucosal sloughing and hemorrhage which is mucosa ulceration.

|Page5

Clinical presentation: Transmural lesions usually present with: sudden abdominal pain, bloody diarrhea, shock. Mural and Mucosal have late presentation of abdominal pain or distention or sometimes bleeding, gradual pain or discomfort so it's very variable.

Diagnosis: To diagnose IBD we need high index suspicion in the appropriate setting. What does high index suspicion mean?? It means to keep your threshold LOW because if you keep it high you will miss all the cases of course. You need to keep your threshold as low as possible to diagnose or to get the clinical impression of ischemic colitis or ischemic bowel disease because if you do a wrong diagnosis of ischemia and prove that it's not ischemic you are not going to lose a lot ya3ny even if you did laparotomy and found that it is not ischemia it is something else probably diverticulitis you are not going to lose that much .BUT if you miss a case of ischemic bowel disease you might lose your patient and he will die as a result especially if the diagnosis was late.

** Remember that transmural infarction has high mortality rate (nearly90%) largely due to delay in diagnosis ** Sometimes the patient comes to the ER complaining about abdominal pain, so the physician might say ok he has a little bleeding could be hemorrhoids.. ok not hemorrhoids , probably infectious ,could be diverticulitis and so this can take hours and hours without making an action leading to delay in the diagnosis, thatâ&#x20AC;&#x2122;s why we need to be sharp and take prompt actions if you have a suspicion do what you have to do

Mucosal and mural may not be fatal if causes of hypoperfusion are corrected, y3ni you can have patient who has abdominal pain, bleeding... etc you examine him to find that he is hypotensive blood pressure is probably 80/50 suspecting ischemic heart disease so these are the right settings. We can correct the underlying cause, we can give him fluids to raise his pressure and he will improve after that. A student asked a question and I couldn't hear what he said but the dr commented: you will have necrosis, tissue damage of course you will have blood so if there was venous obstruction it will impair blood drainage and this also will cause ischemia!!

|Page6

Now we come to:

ANGIODYSPLASIA: It is another vascular disorder. Angiodysplasia means dysplasia of the blood vessels which means something neoplastic which wrong so it is: misnomer; not a premaleganant lesion.

-tortuous dilation of submucosal & mucosal blood vessels, mostly in cecum and right colon in elderly patients and these blood vessels might rupture and bleed especially if somebody has constipation, mucosal injury or sloughingď&#x192; this will expose blood vessels and they will rupture and bleed and they account for 20% of lower GIT bleeding. The Dr: remember when we talked about causes of upper GIT bleeding? we said that the most important cause is esophageal varices

*tortuous: varicose vein or varicose blood vessel or tortuous dilated bood vessels if it is in the right colon we call it angiodysplasia

- It is difficult to diagnose , because if you do radiological investigation by barium enema radiology it will appear normal.

-it is visible by endoscopy or specifically angiography( to inject blood vessels like the superior mesenteric artery for example) and then we do radiographical tests and you will see these tortuous blood vessels in the right colon so it is the only confirmative diagnostic way. Sometimes even by endoscopy we can't see angiodysplasia. -They might present as isolated lesions or part of systemic disorders like OSLER-WEBERRENDU syndrome & CREST syndrome. And these are syndromes which might be associated with angiodysplasia as part of their manifestation.

You can see here mucosa, submucosa and tortuous blood vessels

|Page7

So if there was ulceration they will be very close to the mucosa and any ulceration or erosion of the mucosa will become exposed and will bleed and you can lose a lot of blood within minutes.

Hemorrhoids:

**They are dilated varices (piles) of anal and peri anal submucosal venous plexuses. *Common in adults > 50 yrs and the setting of persistingly elevated venous pressure within the hemorrhoidal plexus. *predisposing factors that will increase hemorrhoid plexus pressure: pregnancy (increase intra abdominal pressure), chronic constipation( with strain) and portal hypertension. Q: remember when we talked about sites of portal system anastomosis?? The dr said that he will ask about them in the exam so I copied them from wiki 1) oesophageal branches of left gastric veinwith oesophageal veins, 2) superior rectal vein with middle and inferior rectal veins, 3) paraumbilical veins withsubcutaneous veins of anterior abdominal wall, 4) retroperitoneal veins with venous branches of veins of the colon and barearea of the liver, and 5) a patent ductus venosus connecting left branch of portal vein to inferior vena cava (rare)

Pathology: it is thin-walled dilated blood vessels covered by anal mucosa

We classify hemorrhoid into Internal: (Above dentate line) and external (below dentate line) From hayat dentate line is: (pectinate line, anocutaneous line, anorectal junction) is a line which divides the upper 2/3rds and lower 1/3rd of the anal canal.]] Which is between the

rectum and anus. *Usually they are asymptomatic. *They might be protrusion and itching. |Page8

*Ulceration and they might bleed, usually in upper GI bleeding to some extent it is altered blood while in hemorrhoid this bleeds FRESH BLOOD. *The most irritating symptom -in addition to being itchy is- thrombosis and sever pain. Now these are dilated veins and they can get thrombosed (thrombus inside it) and this can be very painful. In case that happened we should open it and remove or evacuste the thrombus or to do banding. -Internal hemorrhoids trapped by the anal sphincter and we call it "prolapse", with sudden pain, edema or strangulation.

Treatment: depends on the severity, sometimes you might start by medical treatments and varicose veins will disappear, but if they persistent and not reversible you can perform surgery(there are different types of surgeries for these hemorrhoids) .

Idiopathic inflammatory bowel disease: This is a very important group of GI disease in general because it is NOT UNCOMMON. We call it idiopathic because it is of an unknown cause ( we don't know the exact underlying cause) although we have some hypothesis but still we are not sure. There are 2 types: crhon's disease and ulcerative colitis.

)‫خريش‬ ُّ ‫التقريح الت‬ ُّ ‫(الهتاب الامعاء‬ CD&UC: are chronic and relapsing disorder of unknown cause which are characterized with extensive bowel inflammation, tissue injury and mucosal destruction. **They are remitting- relapsing disorders and these remitting periods can be achieved by medical treatments or sometimes spontaneously and this is their natural course depending on the severity. So they are chronic, remitting, relapsing inflammatory lesions of the intestine. **They present with intermittent bloody diarrhea and they become bloody due to ulcerations (sometimes non bloody and sometimes watery diarrhea), pain and malabsorption ( if it involves small intestine) and the crohn's is the one that involves the small intestine and large intestine while UC only large intestine.

|Page9

And the suggested etiologies (uncertain hypothesis): 1) Genetic predisposition: just recently they identified certain genes on chromosome 16 called "INFALAMTORY BOWEL DISEASE 1" and they found strong relationship with HLA-DR that is why sometimes it runs in a familial way ( you will find it more in some families). 2) Abnormal mucosal structure: variation in the mucosal structure in the contents and the distribution of lymphoid cells within the mucosa. We have big number of microbes in the food we eat, but in case of CD they don’t stimulate antigenic stimulation as they are supposed to as there will be some balance between antigenic stimulation and immunological rx…when there is disturbance in that imbalance that will lead to abnormal activity One of the theories that

there are inherence of mucosal structure which are predisposed or ore liable to such injuries or loss of the equilibrium between antigenic stimulation and the immunological rx.

Studies of inflammatory bowel disease focus on infections. For ex. Later we will find that CD has something different that is not found in UC which is GRANULOMA (50-60% of CD cases). And the causes of granuloma are multiple one of them is Mycobacterium TB and there are other mycobacterial species. Researchers were able to identify certain mycobacterial strains in granuloma.so they proposed a theory that CD is caused by mycobaceria that was found in certain types of milk in the UK.

)…

3) Infectious: - In CD GRANULOMA (50-60% of CD cases), it could be due to mycobacterium species infection. - It could be could be viral: like mumps, measles. - It could be related to vaccines, like MMR. Infectious causes have active hypothesis*

4) Abnormal host immunoreactivity: over reaction this will lead to inflammatory response (release of IL-2, IL-10, TNF, interluken relapsing factor (IL-R). From hayat: causes of granuloma (which is a type of chronic inflammation) could be due to mycobacterial, fungal or parasitic infections and sometimes it could be due to autoimmune reactions.

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Now about UC & CD: They have common features *Chronic recurrent inflammation (relapsing-remitting disease; on & off disease) *No definite cause is identified *May have extra-intestinal (systemic) manifestations; so it`s more or less like a syndrome rather than a disease..

The integration of clinical, radiological, pathological findings are essential for diagnosis of CD & UC. You cannot diagnose any IBD without the clinical, radiological, pathological, microbiological and endoscopic findings. Something called "multidisplinary approach of diagnosis". And there is something called MDT meeting: all doctors gather in a meeting and discuss the case they have until they end up with a diagnosis, this is very important because this is a disease for life and itâ&#x20AC;&#x2122;s a stigmata for the patient so we shouldn't tell patients they have IBD without being sure as this disease can affect the patient's social and marriage life. *Histological features may be identical, particularly with small biopsies. * In 10-30% of cases distinction between CD&UC cannot be made and that is why we sometimes we use indeterminate case of IBD. So we have a third type of the IBD which is the indeterminate.

Crohn's disease: * Has other names: terminal ileitis, regional enteritis *It's a systemic disease with predominant GI involvement **CD might involve any part of GIT from the mouth to the anus where as UC involves the large intestine (colon) only (the 1st difference between the 2 diseases) ď&#x192; Associated immune extra-intestinal manifestations (iritis, uveitis, polyarthritis in joints, erythema nodosum in skin, hepatic pericholangitis in liver , sclerosing cholangitis in urethra too.) it can happen in both CD&UC with variable incidence between the two. - At any age and peaks at 2nd-3rd &7th-8th decades * It may have Insidious or sudden onset of symptoms which may remit spontaneously or with therapy, the disease may subside without treatment but the treatment here is to control the disease. | P a g e 11

* Marked weight loss & malabsorption (because of small intestinal involvement) on the other hand we don't have any malabsorptive features in UC because it doesn't involve the small intestine. * Complications: fistulas, abdominal abscesses & peritonitis, stricture and obstruction, bleeding. ~fistulas (mainly in crohn's they DONâ&#x20AC;&#x2122;T occur in UC)~ ~abdominal abscess more likely in crhon's~ ~stricture and obstruction, fibrosis are more likely in crohn's, why?? Because crohn's is transmural (mucosa, submucosa, muscularis externa and sometimes serosa) inflammatory process and this might lead to fibrosis and thereforeď&#x192; stricture. Whereas ulcerative colitis involves the mucosa that is why it leads to bleeding because of mucosal sloughing and because it is continuous, and causes distention it might lead to perforation. ** Cancer: negligible or no increased risk for cancer whereas UC has significant increased risk for cancer & dysplasia (3rd difference).

This is what we call creeping of the fat (arrows). Because CD is transmural the fat will try to protect the wall from perforation which is more or less a feature of crohn's diseas.

Creeping of fat could happen in UC but it is much more likely to be seen in CD.

| P a g e 12

Here we can see endoscopic pictures and we can see crohn's ulceration, they might have pseudopolyps

Specific lesions called "skip lesions" are characteristic of crohn's disease (so this is another difference) in ulcerative colitis it's usually continuous. Skip lesion=Not continuous as you will find hemorrhagic areas and healthy areas.

This is exactly what it looks like:

| P a g e 13

* The Cobble stone appearance results from both actions of ulceration 'Erosion of mucosa which is in between' and the healthy-looking regenerating mucosa (i.e. it results from deep, longitudinal ulcerations interlaced with intervening normal mucosa). * Pseudopolyps formation (Because of ulceration and regeneration of the mucosa) is a complication of Crohn's disease. Again, it's a transmural inflammation, and you see that the inflammatory process affects all the layers from mucosa to serosa but of course if you take a biopsy, you are going to get a portion of this mucosa, not the whole thing, and they are only resections so it's hard to differentiate between them. And we have also the tracts formation in the histology of CD. If you see Granuloma then this is Crohn's disease. ** But not all cases of Crohn's disease you'll be able to find granuloma (Only in 50%-60% of the cases you will be to see granuloma). Again, granuloma in lamina propria is a diagnostic feature of Crohan's disease. It's important to distinguish between ulcerative colitis and Crohan's disease. So, first step is to make the diagnosis of an inflammatory bowel disease, next step is to differentiate between the previous two diseases. Why is that important? Because there are many differences between the medical and the surgical approaches.

On the other hand:

Ulcerative colitis : It`s an Ulcero-inflammatory disease of the colon, limited to mucosa & submucosa (Mainly mucosa). It starts in rectum & extends proximally in a continuous fashion. Again, it's a Systemic disease, may be associated with polyarthritis, ankylosing spondylitis (HLA-B27+), uveitis, liver (pericholangitis & PSC) & skin involvement. Patients: Any age; peak 20-25 yrs Chronic relapsing & remitting disease; MORE bloody stool. -Complications: severe diarrhea & electrolyte disturbances, massive hemorrhage, toxic megacolon, rupture. -Cancer: depends on duration & extent of disease â&#x20AC;&#x201C; The cancer risk depends on the duration and the extension of the disease, usually there are some sort of mathematical calculations taken into consideration; duration of the disease, involvement of the segmentsâ&#x20AC;Śetc to predict the likelihood of developing cancer. Note: Ulcerative Colitis >> Continuous involvement of the mucosa.

| P a g e 14

Here is the rectum, we have severe ulcerative colitis and as we said before the whole mucosa is involved continuously. You can see the sharp demarcation where it stopped.

The important histological features of all inflammatory bowl diseases are: 1) crypt (gland) loss due to the continuous destruction. 2) Distortion of the crypt's architecture, usually crypts maintain monotamous relationship between each other and between the surface epithleum and the submuscularis layer. Loss of architecture is very important to distinguish between inflammatory bowl diseases and the infectious ones (Here in infectious colitis we have gland destruction, abscess formation but no architecture loss). You can see:* inflammantory cells between the glands and muscularis mucosa (There are spaces).

*Now, the features of chronicity are: 1. Gland loss 2. Basal cell plasmacytosis. 3. Loss of the architecture and paneth cell metaplasia. Normally we find paneth cells in the small intestine up to the right colon ,after the hepatic flexure you don't see paneth cell, if you see any paneth cells distal to the hepatic flexure that will be a sign of chronicity (Remember, we don't see granulomas). Also, the glands will be irregular, destroyed, branching, angulated â&#x20AC;Ś.etc

| P a g e 15

This is crypt abscess (Neutrophils within the crypts). Lamina contains an increased number of chronic inflammatory cells and neurtophils. Also, there's surface epithelium destruction and neutrophilic infiltration.

**This is what we call a toxic megacolon, it's dilated, huge, distended and it's black. This must be surgically treated.

INFLAMMATORY BOWEL DISEASE: CROHNâ&#x20AC;&#x2122;S DISEASE Incidence: 1-3/100,000. whites, Jews Small intestine 40%; small & large intestine 30%; large intestine 30%. Skip lesions Granulomas 40-60%. Deep linear ulcers. Cobblestone appearance Strictures: early Fissures, sinuses & fistulas

ULCERATIVE COLITIS Incidence : 4-6/100,000 Whites. Rectum/rectosigmoid 80% extending proxi-mally; pan-colitis 10%. mainly Large . Continous involvement No Granuloma Superficial ulcers. Pseudopolyps Strictures: late/rare No

| P a g e 16

MICROSCOPIC FEATURES CROHNâ&#x20AC;&#x2122;S DISEASE Inflammation, ulceration & chronic mucosal changes and submucosal. Deep ulcers with transmural involvement Wall thickening Granuloma +/Marked lymphoid reaction Marked serositis Fistulas and sinuses Moderate-marked fibrosis

ULCERATIVE COLITIS Inflammation, ulceration & chronic mucosal changes Ulcers with mostly mucosal involvement Wall is usually thin No granulomas Mild lymphoid reaction No or mild serositis No fistulas or sinuses Mild firbosis

Dysplasia: Patients who have Crohn's disease or ulcerative colitis suffer a lot. However, patients with ulcerative colitis are afraid of dysplasia which might arise in multiples areas and this will make it difficult to detect. Risk of dysplasia is the highest in pancolitis, it also correlates with the duration of the disease (Increase by 1% per year after diagnosis). Colonscopy follow-up with biopsies is used to detect dysplasia, we do frequent endoscopes every year or six months, we see the severity of the disease and compare it to the previous status by histology, endoscopyâ&#x20AC;Śetc. Also, we take random samples to exclude dysplasia and malignancy.

The End

| P a g e 17

34/59 10/17 35

Pathology Diverticular Disease Ismaâ&#x20AC;&#x2122;eel Matalqa Ghaith Al-Hourani E 14/11/2011 Monday,

Ghaith Al-Hourani 14/11/2011 Pathology of Small & Large Intestine

‫بسم هللا الرحمن الرحيم‬

Diverticular Disease As you know diverticuolosis or diverticulum is a blind pouch leading off the alimentary tract (GIT), lined by mucosa, communicating with gut lumen. Note: Zinker Diverticulosis – esophagus &Meckel’s Diverticulosis – Colon.

Diverticulosis or Diverticular disease in the colon – acquired mostly , except for some congenital diverticuli examples’ like Meckel’s Diverticulum – may arise anywhere in the GIT but colon is the most common site. Sometimes you get diverticulosis in the small intestine but this is rather an exception. Again, diverticulosis is the loss of a sort of balance between the strength of the wall and the peristalsis movement or any increase in the intra-luminal pressure. So if there is any kind of weakness in the wall of the colon this will lead to defects at the site of blood entry usually leading to diveticulosis or forming of these out-pouches. Recall that Marfan’s Syndrome is a defect in elastin – loss of elastin- which leads to weakness in walls, in blood vessels and in other segments, this also can lead to diverticulosis. So, They are 2 main factors : 1) Increased peristalsis and intra-luminal pressure in cases of long standing constipation for example, hard stools due to low-fiber diet will result in

exaggerated peristaltic contractions (aggressive peristalsis). So, there is some sort of functional and even mechanical causes leading to exaggeration of peristalsis movement. 2) weakness in the wall of the bowel.

â&#x20AC;&#x153;Such increase in the pressure and in the peristalsis accompanied with some weakness in the wall of the bowel will lead to variable degrees of diverticulosis.â&#x20AC;?

Gross : Out-pouching of the mucosa Histology : We can see the mucosa outside the surface of the bowel and the out-pouching. wall, inside the mesentery .

Colonic Diverticulosis Pathology:Colonic diverticulosis is common in West. In some studies it is declared that 50% of adults above the age of 50 or 60 years have degree of

diverticulosis. It is common in autopsy cases, whenever we perform autopsy in elderly you will find some degree of diverticulosis. And this is mainly related to those who have low-fiber diets like those who eat junk food and this is a part of westernization in food habits ( high fat content, low fiber content, etc. ) which exaggerate peristalsis and intra-luminal pressure leading to diverticulosis. Usually they are small and multiple but we can attain a large size. Sigmoid colon is the most common site accounting for 95% of diverticulosis, it might happen in the right colon. Grossly : Prominent taeniae coli & circular muscle bundles due to muscular hypertrophy; out-pouching may be visible from serosal surface (you can see it from outside ).

Histologically : sacs with thin wall made of mucosa & submucosa surrounded by fat or intact peritoneum.

Clinical Features: Usually asymptomatic “ specially if they are mild”.  They might present with intermittent cramping or continuous left

lower quadrant pain with sensation of incomplete emptying of rectum “ this is a very common finding, that whenever a patient of diverticulosis goes to the toilet to open his bowel he feels that he didn’t complete “. 

Complications : 1. Severe inflammation (Diverticulitis ) -> Perforation -> Peritonitis. symptoms : tenderness, fever.

The out-pouching sacs ( diverticulum ) might get infected either by infectious agents or other agents leading to diverticulitis ( acute inflammation of diverticular disease ).

2. If diverticulitis continues it will lead to Peridiverticulitis, and might lead to perforation, abscess or fistula. 3. Although in most of the cases it might be asymptomatic, some might lead to serious complications; fistula formation, bleeding .

ď Ž

For those who have diverticular disease or suspected clinically, usually we advise them to take High-fiber diet, if any complication happens ; then we need to perform surgery (and by that case most of the cases might be part of the sigmoid or part of the rectum ).

Bowel Obstruction Pathology:This Leads us to the causes of bowel obstruction; Mechanical mainly or functional. Firstly, The bowel is a tube with lumen and wall, So, Obstruction may be in the lumen, In the wall or may be outside the whole

lumen or the whole tube (extramural). Q) What are the possible causes of mechanical obstruction of the bowel? By imagining the possible causes it could be something luminal, may be a tumor in the wall or something from outside, so, there are different causes of bowel obstruction.

 So, bowel obstruction may occur at any level, but is more frequent in small intestine than the large one, and the reason is obvious, it is

narrower. It can be acute or chronic as a presentation, acute for example if there is acute ulcer. And chronic when it needs some sort of time to develop.  Clinical features: abdominal

distension (+/- pain) , followed

by vomiting (more likely in small intestinal obstruction), then

constipation.  They may present at birth, during infancy, childhood or adulthood (depending on the cause), we will talk about the causes later.  As we said It may be in the lumen, wall or extramural (outside the lumen).  Tumors and infarction account for 10-15% of small bowel obstruction but mechanical causes such as Hernias, intestinal adhesions, intussusception, and volvulus account for 80% of cases.

Look at this picture, you can see herniation, intestinal Adhesions, intussusception, volvulus.

Classification: Mechanical: – Congenital: Strictures, atresias, bands, imperforate anus, meconium in cystic fibrosis. – Infants: hernias, intussusceptions. – Adults: hernias, adhesions, tumors, inflammatory strictures (like inflammatory bowel disease), obstructive gallstones (gallstones are formed in the gallbladder and they are small enough to pass from the neck of the gallbladder to the cystic duct and then to the common bile duct and may pass to the small intestine and cause some degree of obstruction), fecaliths (“Fecal + lith for stone”, So it’s hard solid stool), foreign bodies, volvulus .

 Functional: – Paralytic ileus: it is failure of the intestines to return their peristalses after surgery. Before surgery we put the patient on NPO (nil per oral) which means nothing per mouth, and on IV fluids for 1-2 days before surgery that the stomach and the intestines will be empty. After having the surgery, we put him on NPO for 3-4 days, this will lead to paralysis due to laziness, and that’s why the patient will be told to eat step by step until they check for the presence of peristalsis in the intestine. Sometimes it takes more time than expected and may not return its ability to peristalsis back.

Caused by: electrolyte imbalance, neural injury, or reflex

atony secondary to peritonitis.

–

bowel infarction (ischemia)  No peristalses  leading to Bowel obstruction.

– Myopathies & Neuropathies (e.g. Hirschsprung’s). “don’t mixed up : if a surgery had these outcomes, Electrolyte imbalance, Neural injury, peritonitis causing Reflex Atony these will lead to Paralytic Ilues a functional causative of bowel obstruction. Bowel infarction, Myoand Neuro- pathies are also causatives of bowel obstruction functionally.”

a) Hernias: “Weakness or defect in the wall of peritoneal cavity with

protrusion of a serosa-lined sac of peritoneum”. Possible sites for herniation: Inguinal & femoral canals, umbilicus & surgical

scars.Segments of viscera may protrude & become entrapped, mostly in inguinal hernias. If small bowel is involved, partial or complete obstruction of its lumen may follow. Incarceration (‫س ْجن‬ َ (: permenant trapping of hernial sac contents due to

venous stasis & edema ( meaning that they stuck within the hernia sac ).

Strangulation ) ‫ ( َح ْجز‬: Venous & arterial supply to entrapped viscus is compromised leading to infarction or gangrene.

* Treatment of hernia depends on the size of the hernia[ Diameter ] ; if it’s narrow and I have a protrusion , It’ll be difficult to get reduced back .

b) Intestinal Adhesions: Due to localized or generalized peritonitis secondary to Surgical

procedures, Infections or Endometriosis in women “ the presence of endometrial tissue outside the uterine cavity ”. This endometrial tissue might shed and bleed fibrosis  adhesion. If it resolves  it will leave some sort of scarring and fibrosis  leading to adhesions. Intestinal adhesions are rarely due to congenital fibrous bands, especially in small intestine. They may result in intestinal obstruction, incarceration and

strangulation in these fibrous bands. Fibrous bridges which develop between bowel segments creating closed loops through which viscera may slide & become entrapped (internal hernias; loops herniated into each other) Y3ne these fibrous bands may act like hernia, will surround segments and lead to obstruction. So, fibrosis will constrict and narrow the lumen more and more from inside.

c) Intussusception:

Intussusceptum Intussuscepiens

Uncommon disorder where a segment of small intestine, constricted by a wave of peristalsis, suddenly becomes telescoped into the immediately distal segment of bowel (meaning segment inside segment because of the wave of peristalsis, and of course itâ&#x20AC;&#x2122;s because of an underlying pathology). Intussusceptum: trapped bowel segment. Intussuscipiens: bowel segment which envelops it ( = receiving that intussusceptum ). â&#x20AC;&#x153; Intussuscipiens envelops intussusceptumâ&#x20AC;?

Mostly in infants & children of unknown pathogenesis. In adults, an intra-luminal tumor may act as a point of attraction ( we call it leading point ), pulling along a segment of bowel. this leading point with peristalsis causes this sort of Intussusception, and pull along a segment of bowel. They can cause intestinal obstruction and Intestinal infarction due to trapping of mesenteric blood vessels. This is very characteristic for children ; the child comes with severe sudden onset of pain ; having tender abdomen , and we notice that he passes jelly like stool ( this jelly is because of some bleeding that happened earlier ).

VOLVULUS: Complete twisting of a loop of bowel around its mesenteric base of attachment.Mostly in small intestine, large intestine especially sigmoid and cecum and other structures (e.g. ovary) may be involved. Q: Why sigmoid and cecum? Because they are more free in movement than the other parts ( intra-peritoneal ). Volvuli will lead to: “Check the picture in pg.5 or 6 to relate these complications easily “ 1. Constriction of venous outflow and/or arterial supply. 2. Intestinal obstruction and infarction ( all blood vessels close ). 3. Uncommon disorder, occurring in all ages when an intestinal segment becomes longer and the mesentary narrower. *May be caused by colon malrotation and peritoneal bands.

TUMORS

A very common cause of obstruction that it’s the first thing to think of when having obstruction, especially in elderly. Colonic tumors are

much more common than small intestinal ones’. Tumors may arise from any layer of GIT wall, mucosa, submucosa, muscularis or serosa; however most often from mucosa ( “of epithelial origin” ), So, most of intestine tumors are Carcinomas. In the epithelium or mucosa carcinoma occur (most common). In submucosa if you remember there’s a group of tumors called GIST

( “gastrointestinal stromal tumor” ) that can be benign or malignant. Sometimes you may have tumors arising from adipose tissue; lipomas or atypical lipomas. Also, you may have vascular or smooth muscle tumors like leiomyomas or leiomyosarcomas. The majorities are benign; however, colonic cancers are major causes of morbidity and mortality in the population which it’s an interest to learn about colorectal cancer. For example, if you take the Jordanian population, it’s the most common cancer in males, and comes after breast cancer in females. “For clarification, The majority are benign, stands for the number of benign tumors that can invade the GIT which is greater than the malignant ones’; cancers”

Clinical presentation:– May be asymptomatic, incident discovery. – It may present with Blood

per rectum or/and anemia.

A kind of investigation for an elderly patient if he comes with unexplained anemia is doing occultive blood test (test for the presence of blood in stool), if you find blood (there’s bleeding) at this age then it should be a tumor unless proven otherwise. In case of having high suspicion you should do some radiology or colonoscopy to see what is underling there.

“May be the use of elderly patient is that unexplained anemia is common at their age or because colonic tumors are common at their age “. – It causes Bowel

obstruction in some cases.

Classification: Benign: – Stromal tumors (GIST). in submucosa – Hyperplastic and Adenomatous Polyps. – Lipomas.  Malignant: – Adenocarcinoma. the most common – Carcinoid tumors. ( If you remember we have taken them previously when we talked about the stomach; Neuroendocrine tumors, Carcinoid tumors ).

– Lymphoma. – Sarcoma. *In some parts of the colon more specifically in the anus or in the anorectal junction we can get melanomas.

Carcinoid tumors Pathology:They are tumors of neuroendocrine cells, which are widely distributed cells of epithelial stem cell origin capable of producing

a variety of bioactive compounds. If you remember in autoimmune Gastritis we had this subject. Based on the bioactive compounds carcinoid tumors secrete, they may produce multiple compounds or a predominant product, causing a clinical syndrome such as gastrinoma, insulinoma and others.

Carcinoid tumors arise in the GI tract, and may arise in other organs like the lung, the biliary tree & the pancreas. 50%,2% of small intestinal and colonic tumors are carcinoid, respectively. So, it’s more common to get carcinoid tumors in small intestine than carcinomas, and more likely to get lymphomas than carcinomas in small intestine. “So, generally speaking, In the small intestine, Lymphomas are more common than carcinoids which is more common than carcinomas”.

Affects any age, with peak incidence in the 6th decade ( 50 – 59

years). Carcinoids are well differentiated tumors that are

potentially malignant tumors and may metastasize.

For more clarification we classify neuroendocrine tumors into well differentiated carcinoid tumors which behave in a benign way but in some occasions they metastasize, and the only evidence of malignant potential is the presence of metastasis.

This is extra, said by the doctor Depending on their differentiation, there are also atypical carcinoids which are less differentiated and the less differentiated neuroendocrine carcinomas ).

Clinical Features:-

 Sites: Appendix (an important site) > Small intestine (ileum) > Rectum > Stomach > Colon. A one important thing we look for in appendectomy specimens is carcinoid because it is the most common site for carcinoid tumors, Usually in the apex of appendix.



Most are asymptomatic particularly the appendix but may cause local symptoms like angulation or obstrcution of

small

intestine.  May secrete some compounds that produce a variety of endocrinopathies like Zollinger-Ellison syndrome, Cushing’s syndrome excissive release of steroids or hyperinsulinism excessive insulin secretion.

 Carcinoid syndrome: Occurs in 1% of patients, 20% of those with widespread metastasis, mainly due to serotonin secretion [ vasoactive, one of the earliest cytokines to be secreted in acute inflammation ]. Which leads to vasomotor

disturbances since it is a vasodilator, intestinal hypermotility, hepatomegaly and if long standing it might be associated with systemic fibrosis. The collection of these symptoms is called carcinoid

syndrome. And we donâ&#x20AC;&#x2122;t call it carcinoid syndrome unless it shows metastasis in the liver.

Grossly: Usually small tumors, rarely >3 cm, forming an intramural or

submucosal yellow-tan firm elevation or polypoid lesion.

Histologically : Monomorphous population of cells all cells looking alike with scant granular cytoplasm fine and small dots of chromatin &

round nuclei. Neoplastic cells form islands, nests, strands or glands. Intact or ulcerated overlying mucosa.

â&#x20AC;&#x153;Salt and pepper pattern â&#x20AC;&#x153; left

This is a specimen of carcinoid tumor presented under electron microscopy, showing

neuroendocrine granules present in the cytoplasm and neurosecretory glands which secrete those compounds (the neuroendocrine granules ). Electron microscopy simplifies differentiation.

right

â&#x20AC;&#x201C; May be multicentric especially in stomach and ileum. â&#x20AC;&#x201C; May be localized or have local spread and/or metastasis to lymph nodes or more distant sites, particularly liver, so, liver is a favorite site for metastasis for this tumor.

A Comparison Remember in carcinomas we have prominent nuclei but in carcinoid tumors we have salt and pepper pattern.

The Clinical Behavior:-

The clinical behavior is difficult to predict from histological features. Generally, it depends on the size of the tumor, if it's more than 2 cm and invading more than 50% of the wall thickness, we have poor prognosis, and the site, appendiceal & rectal carcinoids almost never metastasize, they are less likely to behave in a malignant fashion. The 5 years survival rate is excellent 90%. The 5 years survival rate for small intestinal tumors with liver metastasis is 50%. This widespread disease usually causes death if spread all over the body.

Adenocarcinoma “of small intestine” Adenocarcinomas in small intestine arise in the duodenum including ampulla of Vater; the 2 most common sites of Adenocarcinoma. A group of malignancies we call the Ampullary and the Pre-Ampullary tumors. “Ampulla of vater is where the common bile duct enters the duodenum in its distal part.” It’s a polypoid fungating tumor ( polypoid : having the shape of a polyp, fungating : growing rapidly like a fungus )

encircling pattern .

a napkin-ring

In its early stages, it’s asymptomatic, However, if it progressed more and more it will lead to obstruction and to obstructive jaundice ( “ jaundice caused by a blocked bile duct “ )

Signs & symptoms:

Usually appear late.

Appear when a tumor has already penetrated the bowel wall into the mesentery, other bowel segments, spread to lymph nodes, metastasized to the liver or more widely. The symptoms of abdominal obstruction are; pain, nausea,

vomiting and weight loss appearing late in the course. If there is more obstruction especially in the ampulla of vater this will lead to obstructive jaundice. The 5 years survival with wide en bloc excision is about 70%. It depends on the stage of the tumor whether still localized to the wall or had invaded the nearby eg. Pancreas; at this stage prognosis is poor.

POLYPS Polyps are either benign or adenomatous ( premalignant) .

The next lecture will be probably the last lecture of the GIS. We will discuss different types of the polyps, colorectal carcinoma and we might have an early introduction to liver and some of its anatomy and histology.

And finally,

-Qudsi , Hasan , Nuwedir , Qusai and for honesty Asim Eyadeh ;) - for help, teslam hal edain.

Mohammad Shlool , Wassim Jalab , Faisal Helmi , Bassam Al- Hassoun , Big & Little Abu Shihabz , Imad Hussein , Tariq Al-Kurdi , Obadah Al-Ali , Mohammad Abu-Taleb , Saa’d Al-Deen Mohammad , Bassem Abu-Zahra , Ahmad Zou’bi , Mohammad Smadi , Hisham Al-Qadi , Anan Al-Qudah , Hareth Sharadgah , Fadel Freihat , Mohammad Shatnawi , Khalid Awad , Khalil AlKhalifa, Mohammad Hailat && Tarek Hammouri " َ ‫ " َور ٌد إذا َو َر َد البحير َة شاربًا َو َردَ الفراتَ زئيرُه و النيل‬.

-‫ رحمه هللا‬-‫قال عمر بن عبدالعزيز‬ ] .‫[ أُنثروا القمح على رؤوس الجبال حتى ال يقال جاع طيرٌ في بالد المسلمين‬

‫الحمدهلل‬

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Pathology Intestinal Tumors Husam Telfah Ahmad Al-Khatib Wednesday, 16/11/2011 24/10/2011

Page 1 of 18

Intestinal Tumors Pathology # 11

16-11-2011

Ahmad Al-Khatib

Before starting the Dr said that he will give us this lecture but the questions will be written by Dr.Ismail, so the slides are so importer. Though I but all things in the slides in this lecture with some additional notes from Dr.ismail and other sources. So sami allah w ebda2 :P

POLYPS  Polyp: is a tumorous mass protruding into the lumen of the gut; may be pedunculated or sessile.  Pedunculated: means that the mass attaches to the mucosa by a stalk, so usually the size of attachment is small depending on the size on the stalk which usually very small.  Sessile: the mass will be in direct contact with the mucosa, and the base of it is larger than the pedunculated polyps  so it is easier to excise the pedunculated polyps than the sessile one. - Usually the surgery of removing polyps done by endoscope or colonoscopy.  Types of Polyps: 1- Non-neoplastic polyps: - About 90% of polyps. - Formed as a result of abnormal mucosal maturation, inflammation or disturbance in architecture. Page 2 of 18

- Here w will find a normal epithelial lining these polyps. - These masses are benign and don’t carry any risk for malignant transformation  so we don’t need follow up for the patient. - Types: a) Hyperplastic Polyps. b) Hamartomatous Polyps. c) Inflammatory Polyps. 2- Neoplastic polyps: - Formed as a result of epithelial proliferation and dysplasia, so they have some sort of malignant transformation. - Example: Adenoamtous Polyps.

Hyperplastic Plyps: just normal epithelium, the only difference may be the size of the crypts which become taller but still normal epithelium. Adenoma: the color will be basophilic because once there is dysplasias there will be more DNA, so it will be more basophilic not like the normal one which appear pink in color (esinophilic). Pedunculated adenoma: we can see the stalk (arrowed), usually we cut these polyps from the top of the stalk to minimize the risk of bleeding

4 3

Villous: usually the base is larger, so we excite from the area between the upward arrows.

Page 3 of 18

Hyperpalstic Polyps

 Majority of polyps.  Sites: Usually in the colon but it can affect other areas in the gut, but >50% of cases are Rectosigmoid colon.  There is increase risk of having these polyps with age.  Appearance: Most are small <5 mm, nipple-like protrusion which can be multiple or single.  Pathology:  Histologically it consists of abundant crypts lined by well-differentiated goblet or absorptive epithelial cells, separated by scant lamina propria.  Usually these polyps are asymptomatic because they are small, but they can have some sort of bleeding of mucus production which can be seen in the rectum.  They carry no malignant potential, but there is a type of these polyps called Sessile Serrated Adenoma which can bs a source of colorectal carcinoma  {these adenoma located on the right side of the colon – Robbins}.

Page 4 of 18

1 1

This pic indicates abnormal situation. - The lamina propria is normal (arrowed). - but the glands in the colon normally their lining is strait like a circle but here the lining is papillary, and this appearance we call it Serrated, that is why it is abnormal, and it indicates abnormal maturation. - We don’t have any sort of dysplasia because the nuclei are basally located and the goblet cells are present.

Hamartomatous Polyps  The prototype of these polyps is Juvenile Polyps.  These polyps are hamartomatous proliferation of lamina propria surrounding cystically dilated glands, unlike hyperplastic polyps where we have less lamina propria {with the presence of muscle fibers or strands of muscles. And that is why we called them “Hamartomatous” – Dr.Ismail}.  Usually they look a little bit larger.  We call this tumor Juvenile because it present in children.  Once we find this tumor in adult we call it Retention Polyps.  Usually the lesions are large in children (1-3 cm), but smaller in adult. These lesions will be as single rounded or lobulated lesions with or without stalk.  Presentation: bleeding per rectum; stalk may twist and undergo painful infarction due to the cut of blood supply and this infarction will be painful. Once the polyps become infracted it can be sloughs off and we can see them in the feces.  No malignant potential. Page 5 of 18

 The other type of hamartomatous polyps is Peutz-Jeghers polyps:  It present in a syndrome called Peutz-Jeghers syndrome: it is an autosomal dominant syndrome characterized by GIT polyps, melanotic mucosal and cutaneous pigmentation around lips, oral mucosa, face, genitalia & palmar surfaces of hands.  Sites: in stomach (25%), colon (30%) and small intestine (100%).  Appearance: large peduculated lobulated polyps.  Pathology: branching framework of connective tissue & smooth muscle intersecting between the crypts in large polyps.  These polyps have no malignant potential, but PJS patients have increased risk of developing carcinoma of pancreas, breast, lung, ovary & uterus.

This is the appearance of the PJP, we have large polyps with prominent lamina propria and smooth muscles

* Here we finished the non-neoplastic polyps *

Page 6 of 18

* Concerning the Neoplastic Polyps:

Hamartomatous Polyps  By definition adenoma means: Dysplasia  so any polyp with dysplastic epithelial we call it adenoma.  Vast majority of adenomas arise in colon, but we could have adenoma in other parts of GIT like: stomach, small intestine or esophagus.  Mechanism: epithelial proliferation and dysplasia, which may range from mild to carcinoma in situ (which will be without invasion).  Variable in size; pedunculated or sessile.  We classify them according to the appearance into: 1) Tubular Adenoma  which compose only from crypts or gland forming only tubules. {The most common – Robbins} 2) Villous Adenoma  it will form finger like projections “villous like”. {Account for just 1% of cases – Robbins} 3) Tubulovillous Adenoma  composes of both villous and tubules, the villous component is less that 50% of the total surface area of the polyps. {5-10% of cases – Robbins}  Risk of malignant transformation depends on: 1) Size of the polyps: if the polyps are Some people say that villous bigger that will increase the risk of adenoma carries a higher risk than malignant transformation. tubular adenoma to go into  <1 cm (v. rare); 1-2 cm (10%); >2 malignant transformation. And some cm (45%). say that it just a matter of size.

2) Histological architecture: proportion of villous component. 3) Severity of dysplasia. Page 7 of 18

This a low power view, we can notice the bluish color, and this is a Pedunculated polyp and we have both the tubule and the villous so it is a Tubulovillous Adenoma . - Robbins: fibrovascular stalk covered by normal colonic mucosa and a head that contains abundant dysplastic glands.

# Here we can compare between dysplastic epithelium from normal one.

This focus here indicates the normal epithelium; we can see normal concentration of goblet cells.

This is a dysplastic one, we have less goblet cells and the nuclei and are not basally located, there is a stratification, the arrowed black donâ&#x20AC;&#x2122;t are mitotic figure.

Page 8 of 18

This is a Villous Adenoma

Dysplastic Epithelium, we have 1- Less concentration of goblet cells. 2- Nuclei are not basally located they are some sort of stratification and they are more basophilic.

Normal Epithelium, we have 1- normal concentration of goblet cells. 2- Nuclei are basally located.

Page 9 of 18

 Tubulovillous adenoma: 5-10% of adenomatous polyps; mixture of tubular & villous (20-50%) areas; intermediate in frequency of having a stalk, size, degree of dysplasia & risk of carcinoma.  Clinical features: 20-30% are <40 yrs; 50% after 60.  Small polyps usually asymptomatic.  If we have some sort of ulceration that will lead to Occult bleeding, anemia, hypoproteinemia & hypokalemia.  If these polyps are big they might cause intestinal obstruction or biliary obstruction.  Treatment:  Most are cured by adequate endoscopic excision.  Prognosis:  Annual endoscopic follow-up, because they carry a high risk for malignant transformation. Tubular Adenoma

Villous Adenoma

>85% of adenomas

1% of adenomas

Majority are in distal colon, 50% in rectosigmoid.

75% in Rectum & rectosigmoid, followed by cecum & ascending colon

Most are small (few-2 mm) with stalk (2cm)

Sessile ranging from 1-10cm (most are 1-3 cm)

Histology shows neoplastic epithelium forming glands & tubules

Histology shows neoplastic cells forming villi (>50% villous)

Variable degrees of dysplasia to CIS

Carcinoma in situ in 10%

Invasive carcinoma is rare

Invasive carcinoma can be detected in 30% of cases

Page 10 of 18

The Last types of polyps are considered as Sporadic polyps, now we will talk about another type which:

FAMILIAL POLYPOSIS SYNDROMES  Familial means that they happened in the same family, we have 4-types: 1) Familial adenomatous Polyposis (FAP):  Rare autosomal dominant trait.  Diagnosis: we need at least 100 polyps to be present in the colon to call it FAP, but usually the average is 1000 polyps !!!  Most of cases these polyps are tubular.  The underlying genetic defect is present in APC gene {Adenomatous polyposis coli} which is located in chromosome 5q21, this gene is a Tumor Suppressor Gene.  The problem in this syndrome is carrying a risk of colon cancer in 100% of cases at age 30.  Treatment: Prophylactic colectomy (we remove the whole colon).

This is exactly what you see in Familial polyposis syndrome; polyps of all sizes and shapes and of all types carpeting and replacing all of the Mucosa of the colon.

Page 11 of 18

2) Gardner’s Syndrome:  Here we have the polyps plus extra GI manifestation which are: - Osteomas - Epidermal cysts. - Fibromatosis. - Thyroid Cancer … etc. 3) Turcot’s Syndrome:  In addition to the polyps we have CNS tumors (Gliomas). 4)

Lynch’s Syndrome:

 Also called: Hereditary nopolyposis colorectal cancer (HNPCC).  Here the number of polyps is less than 100 and the risk for cancer is not 100% it is about 70%, and this syndrome can affect the whole GIT not just the colon.  Autosomal dominant syndrome characterized by an increased risk of colorectal cancer and extra-intestinal cancer, particularly endometrial carcinoma.  Multiple recurrent colorectal adenomatous polyps which present ar an early age.  Mutations in any of 4 genes (MSH2, MLH1, PMS1 & PMS2) involved in DNA repair, located in chromosomes 2, 3 & 7, resulting in microsatellite instability.  Colonic carcinoma is typically located proximal to splenic flexure usually the right side, often multiple, mucinous, not arising in preexisting adenomas and a sort of lymphocytic infiltrate.

Microsatellite instability (MSI) is a condition manifested by damaged DNA due to defects in the normal DNA repair process.[1] Sections of DNA called microsatellites, which consist of asequence of repeating units of 1-6 base pairs in length, become unstable and can shorten or lengthen. Microsatellites are also known as simple sequence repeats (SSRs) - WIKI.

Page 12 of 18

Tumor which is: Mucinous + on the right side of colon + sort of lymphocytic infiltrate = Microsatellite instability In the FAP: the adenocarcinoma arises just from the polyp. In the HNPCC: arises from the normal mucosa or from the polyp.

COLORE‫‏‬CTAL ADENOCARCINOMA  More than 98% of colonic malignancies.  Second most common cancer.  Peak incidence 60-70 yrs; <20% before age of 50 yrs.  Wide geographic variation in incidence; more frequent in Western industrialized nations.  Environmental dietary factors have been implicated: 1- Low un-absorbable vegetable fiber content. 2- High refined carbohydrate content. 3- High fat content. 4- Low protective micronutrients content (vit. A, C & E).  Almost always arise in adenomatous polyps.  Majority are sporadic; 1-3% in patients with FAP or IBD.  Mostly single; location is shifting to the right colon.  In Proximal colon the mass is fungating polypoid tumors and big due to the late presentation which give the mass the time to become big before producing the symptoms. Page 13 of 18

 In Distal colon the mass is annular encircling tumors (napkin-ring).  Tumors penetrate colonic wall layer into serosal surface.  Histology range from well differentiated to undifferentiated; may be mucinsecreting.  Symptoms: - Asymptomatic for years. - If the cancer is in the right side we will have: fatigue, weakness and irondeficiency anemia. - If it is in the left side we will have: occult bleeding, change in bowel habit (like: diarrhea and constipation) and discomfort.  Diagnosis:  we need Physical examination, X-ray, endoscopy and biopsy.

# THE ADENOMA-CARCINOMA SEQUENCE:  Cumulative alterations in the genome lead to progressive increase size, dysplasia & invasive potential.  “Multi-hit” concept for colon cancer carcinogenesis: 1- First Hit: germline {means it can be transmitted to the success generation} or somatic mutations of cancer suppressor genes i.e. APC & mismatch repair genes. 2- Second Hit: Methylation abnormalities & inactivation of of normal alleles of APC & mismatch repair genes. 3- Other Proto-oncogene mutation like: K-RAS at 12q12. 4- Homozygous loss of additional cancer suppressor genes, e.g. DCC at 18q21 and p53 at 17p13. 5- Additional mutations of many genes will occur in carcinoma.

Page 14 of 18

# This diagram show the sequence of adenoma â&#x20AC;&#x201C; carcinoma. # Here we have over expression of COX-2 (cyclooxygenase) which might play a role, so that some people say that daily tablet of Aspirin can protect you from development of adenocarcinoma because it inhibit the COX â&#x20AC;&#x201C; pathway.

This is a carcinoma in the cecum which at least 5cm. This exophytic tumor will not cause any symptoms unless there is anemia because it is in an occult place, so there will not be any obstruction or constipation

Page 15 of 18

This is a mass in the distal colon which has heaped-up edges and an ulcerated central portion. This mass might produce constipation because it is in the distal colon.

The white arrows identify mucosal polyps

This how the tumor look under the microscope. We can see dysplastic glands surrounded by desmoplastic stroma.

Page 16 of 18

# Staging is very important for tumors because it determines the prognosis. # TIS: once the tumor is present just in the mucosa, this means it is non-invasive or what we call it Carcinoma in Situ. # T1: once the tumor crosses the mascularis mucosa it becomes invasive. # T2: if the tumor reaches the Mascularis Properia. # T3: if the tumor invades the whole wall into the serosa. Definition of Invasion in GIT depends on where the tumor extended. - If it cross the mascularis mucosa  invasive. - If it in mucosa  non-invasive or carcinoma in situ.

Modified Dukes’ (Astler-Coller) Staging System

TUMOR HISTOLOGIC FEATURES STAGE

5-YEAR SURVIVAL

Limited to mucosa

100%

Extending to muscularis propria but not penetrating thru it; uninvolved LN Penetrating thru muscularis propria; uninvolved LN Extending into muscularis propria but not penetrating thru it; involved LN Penetrating thru muscularis propria; involved LN Distant metastasis

67%

B2 C1 C2 D

54% 43% 22% Very low Page 17 of 18

INTESTINAL LYMPHOMA  Usually it is a type of Non-Hodgkin lymphoma (MALT type or Diffuse larg B-cell type or …).  The GIT is the most common extranodal location of lymphomas.  May be primary or secondary.  Primary GI lymphoma: no evidence of liver, spleen or bone marrow involvement at diagnosis.  Adults, M=F, stomach>small intestine>colon.  Classification similar to nodal lymphomas: MALTomas, large cell lymphoma, … etc.  Nonspecific symptoms.  Treatment:  Surgery, chemo- and radiotherapy.  Prognosis:  Better than nodal lymphomas.

The END

ِ ِ ِ ‫كر‬ ِ ِ ‫ب ال َْعالَ ِمين‬ ّ ‫ْح ْم ُد للّه َر‬ ّ َ َ ّ‫ُس ْب َحا َن َرب‬ َ ‫ين * َوال‬ َ ‫ب الْع ّزة َع ّما يَص ُفو َن * َو َسالَ ٌم َعلَ َى ال ُْم ْر َسل‬  Your Brother: Ahmad Al-Khatib  ‫ال تنسوا تقبيل أقدام أمهاتكم يا من ببرهم إله الكون اوصانا – رضائهم سر توفيقنا – وحبهم‬ ‫ومض إيماننا‬ ُ

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Pathology Cholestasis & Cirrhosis Hussam Telfah Omar Shunnar Wednesday, 16/11/2011 24/10/2011

In the name of allah Patho. Lecture # 12: Introduction to Liver Diseases Wednesday, 16-11-2011 We will talk today about the liver diseases in general, and before that I will revise the histology of the liver with you, in order to understand the diseases. [Slides 2-4] When talking about liver histology, we should consider 2 aspects of it. The first one is the lobular histology, where we have a hexagonal shape for the hepatic lobule, and we have also the acini which are 6 in each lobule.

Each lobule has 3 different areas around the central hepatic vein, so for each acinus it will be divided into the 3 areas according to the distance from the hepatic triad [hepatic artery, portal vein, and bile duct]. The blood supply into these lobules comes mainly from the portal vein that brings about 80% of the blood supply and the remaining blood come from the hepatic artery. The blood comes from both these vessels and go into the central vein that collects the blood and then take it into the inferior vena cava and then the heart, thus making the direction from outside to inside (according to the hepatocyte). The areas that are next to the portal triad will be well oxygenated, because they are closer to the blood suppliers, while areas near the central vein will be less oxygenated, and thus more susceptible to injuries and necrosis. On the lobular scheme, we will have the 3 areas named (area 1-periportal, area 2-midzonal, and area 3centrilobular) with area 1 next to the hepatic triad directly. The acinar scheme is the best one that describes the liver functionally; however, the lobular scheme describes it histologically, because you can easily distinguish the lobules on a histological slide.

Histology of the Liver [Slides 5-7] Usually the hepatocytes are arranged into plates; with the thickness in each plate is only one cell. When we see a 2cell thick plate in an adult, this mean there is an abnormality, but that is not the case in children where we can normally find 2-cell thick plates. These hepatocytes in each plate are connected to each other mainly through a duct called (bile canaliculi) that moves the bile from a hepatocyte into another. In slide # 6 you can see sinusoids around the hepatocytes plate, and in these sinusoids you can see the blood that comes from the portal vein and the hepatic artery. These sinusoids are lined with epithelia, and between these epithelia and the hepatocytes there is a space that has some cells responsible for the production and activation of the fibroblasts, so it plays role in the hepatic fibrosis and cirrhosis process. Also we can see next to the hepatocytes some macrophages that are called Kupffer Cells, and these help in the process of phagocyting of any foreign material that comes to the liver. Note : this space is called space of disse and the cells are called stellate cello r ito cells .

On the naked eye aspect of the histology, we can see the portal triad and the central vein easily. In the real life, this portal triad is not actually a triad (3 structures), because sometimes you can see more than that number, due to the presence of more than one hepatic artery or bile duct passing from the same place. This triad is surrounded by some fibrous tissue to protect it, and this tissue is mainly collagen. The central vein actually is a tribute from the hepatic vein, and collects the blood from the hepatic parenchyma. The blood will come from the hepatic triad , centrally to the central vein. Now we are done with this small histological introduction, and we will move to the next subject which is the pathology of the liver.

Diseases of the Liver 1-Hepatic Injury: any insult to the liver will lead to the liver reacting to this injury and undergoing several mechanisms and appearances. 2- Many liver diseases lead to the appearance of Jaundice and Cholestasis [yellowish discoloration of the skin and sclera]. 3-Hepatic Failure: sometime the liver stops functioning. The liver is one of the most important organs in the body because there happens most of the metabolism in the body, so any failure in its function will be a serious case. 4- Cirrhosis. 5- Inflammatory Diseases: infectious and non-infectious; hepatitis and abscesses.

6-Drug and toxin-related diseases: the main one is alcohol. 7- Genetic or inborn errors of metabolism: Hemochromatosis (iron), Wilsonâ&#x20AC;&#x2122;s disease (copper), neonatal hepatitis & Reyeâ&#x20AC;&#x2122;s syndrome [which is connected to the aspirin use]. 8-Intrahepatic biliary tract disease: PBC, PSC;

â&#x20AC;˘

tumors, and circulatory diseases.

Histological patterns of hepatic injury: 1-Degenration: it is a reversible cell injury that results in swelling and ballooning of the hepatocyte. There are 2 types of ballooning: the foamy ballooning, and the feathery ballooning of liver which means the presence of bilirubin inside the hepatocyte. 2-Inflammation: either acute or chronic hepatitis. And the hepatitis here doesn't rely on the type of inflammatory cells to be called acute or chronic. We just refer to the time of the inflammation: if it is less than 6 months then it is acute, while on the other side if it is more than 6 months then it is chronic hepatitis. The inflammation can be affecting only the hepatic triad, or it can involve sometime the hepatic lobules too.

3-Necrosis: this can be either coagulative or lytic. Depending on the severity of the diseases, this necrosis can be submassive or massive. Councilman Bodies are nothing but apoptotic hepatocytes, or eosinophilic hepatocytes. The necrosis can be divided according to the location into: centrilobular, focal (single), peace-meal (it affects the liver gradually, one peace at a time), bridging (between 2 portal areas, one portal and one central or 2 central areas). 4-Regeneration: the liver can easily regenerate after destruction. The liver has massive ability to regenerate after massive destruction or removal, even if half of it is gone! This is the reason why you can donate half of your liver while you are alive, and the remaining half will compensate for the missed half and regenerate to have a full liver again soon. 5-Fibrosis: if regeneration fails, the fibrosis will take place either portally, centrally, or bridging between both. Note : bridging fibrosis (portal-portal, portal-central ,central-central). 6-Cirrhosis: it is a fibrosis of the liver tissue, accompanied by regenerative nodules with abnormal appearance, such as multi-plate hepatocytes. 7- Ductular Reaction: any injury to the biliary ducts will cause proliferation of the biliary tracts and ducts. 8

8- Steatosis: it is accumulation of fat tissue inside the liver, which is not a normal condition. This can happen after any injury to the liver, and can be seen easily and more common in the western countries where they consume alcohol a lot. It can be either macro vacuoles, that are present in the hepatocytes and push the nucleous into the periphery, or micro- and these are small and present in the hepatocytes preserving the place of the nucleous.

9-Hepatocyte Swelling: this is simply the increased size of the hepatocytes due to presence of fluids inside it. Looking at a histological slide of it, we cannot see the sinusoids around the hepatocytes, because the enlarged cells took its place. The main reason for such swelling is a defect in the Na-K pump in the membrane of the cells.

Necrosis: 1-Coagulative Necrosis: in this type of necrosis, the architecture of the cells is preserved, but we cannot see the nucleus in them because it will stain pink like the cytoplasm. 2-Councilman's bodies: these are simply dead hepatocytes that underwent apoptosis. 3-Lytic Necrosis: here the cells have ruptured after severe swelling of them.

Physiology of the liver What we care about here is the metabolism of the bilirubin. So the source of it from the beginning is the RBCs. When RBCs become old they will be apoptosised in the liver, and heme will be out of them there. Being in the liver, they will face the macrophages that have many enzymes inside it. The first one is called Heme Oxygenase that will turn them into biliverdin. This biliverdin will then be reduced through another enzyme called Biliverdin Reductase into Bilirubin. The next step is the process in which one bilirubin molecule will come together and be conjugated with two or one glucoronic acid molecules by the action of UDP (Uridine Di-Phosphate) to make Bilirubin Glucuronides (in wiki the enzyme is called UDPglucuronosyltransferas). The main difference between the

conjugated and non-conjugated bilirubin is that the conjugated ones are water-soluble. These bilirubin glucoronides will be then secreted with the bile into the intestines. Going down in the intestine, we have another enzyme called beta-glucoronidase that will break them into a molecule called urobilinogen that does not have any color. Next, there will be absorption of the molecules in the intestine and they will be excreted then through the kidneys.

Jaundice: Jaundice is the appearance of yellowish discoloration on either the skin or the sclera of eyes (aka icterus); due to increased concentration of the bilirubin in the blood (> 2 mg/dl) [the average value is 1.2 mg/dl]. This increase happens when there is a disruption of the equilibrium between bilirubin production and clearance. This can happen in many cases like: excessive production, mainly in hemolytic anemia and hemolytic cases and hematoma ; reduced hepatocellular uptake; impaired conjugation that happens in a lot of diseases; decreased hepatocellular excretion; and impaired bile flow that happens mainly due to bile stones that block the ducts. Kernicterus is the accumulation of bilirubin in the brain, and this happens with the unconjugated type only, because it can cross the blood brain barrier easily. 11

We have 2 types of the bilirubin: the first one is the conjugated one (direct bilirubin), and the other is the unconjugated one (indirect bilirubin). We call them direct and indirect because in the lab we can measure the conjugated type directly, while the unconjugated type is measured in-directly from the total and the direct bilirubin. (un-conjugated = total-conjugated).

Liver Function test: To check if the liver is functioning well, we do some tests to check the levels of many molecules that are metabolized and produced by the liver. These tests include the following: Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Lactate Dehydrogenase (LDH), Serum Bilirubin, Alkaline Phosphatase, Gamma-Glutamyl transpeptidase, Albumin, Prothrombin time, Ammonia, and Aminopyrine. [The bold underlined ones are the important ones] Note : not all these to check the function , some tests are used to check integrity and excretory functions.

Cholestasis: It is the systemic retention of bilirubin and any other solutes in the bile salts, which result from either intrahepatic or extrahepatic causes, or from biliary duct obstruction. The clinical findings of cholestasis will be jaundice, pruritis, xanthomas, and malabsorbtion of the vitamins that need the bile salts to be absorbed. As for the lab findings, you will notice elevated bilirubin, alkaline phosphatase, and lipids.

On biopsy, you will notice bile pigment accumulation, foamy degeneration, bile duct distension & proliferation, bile lakes, portal tract fibrosis, cholangitis & cholangiolitis. And as I said in the beginning, it can be either intrahepatic or extrahepatic. Accumulation of bile pigment within hepatic parenchyma will be caused, and thus the cells will swell and undergo foamy degeneration. After biliary tree obstruction, the ducts will proliferate and enlarge in size also. All of these things will lead to necrosis of the hepatocytes, bile lakes, and fibrosis. This accumulation can be in the parenchyma in the hepatocytes, bile canaliculi, kupffer cells, or apoptotic cells. In the portal tract, the accumulation can be in any part of the hepatic triad. You can see in slides 21-22 histological slides showing the accumulation of bilirubin in the hepatocytes.

Question: What is the Difference between jaundice and Cholestasis?? Answer: Jaundice is a symptom, cholestatis is a disease!

Neonatal Cholestasis It is a prolonged conjugated hyperbilirubinemia in the newborns, caused mainly by Extrahepatic Biliary Atresia (EHBA) or Hepatitis. We should differentiate between the 2 causes when we want to treat the disease, because EHBA is treated by surgery, while the hepatitis is treated medically. Both of these causes will lead, if left untreated, to permanent liver damage that cannot be compensated. The causes of the disease can be: neonatal infections such as CMV or UTIs; toxins like drugs or parenteral food; 15

metabolic diseases especially AAT deficiency and galactosemia; miscellaneous like shocks, hypo perfusion, or Alagille's syndrome; or many times it will be idiopathic hepatitis. Note : alagille’s leads to a paucity of the bile ducts …. Less bile ducts. The clinical presentations of the disease are usually jaundice, black urine, or light stools. Most cases of the disease will be caused after: primary idiopathic hepatitis, EHBA, and AAT deficiency. And as I said before, we should always differentiate between the different types because each has different treatment. And to help in the diagnosis and differentiation of the cause, a liver biopsy is always recommended.

I hope I didn't have any mistake in this lecture; forgive me if I had some  Sorry for being late, but I did not receive the recording before Saturday afternoon.

Omar Shunnar 16

50/59 13/17 25

Pathology Hepatic & Alchohol liver disease Hussam Telfah Malik Al-Houranie Monday, 21/11/2011

ok guys, about the lecture: the doctor did copy-paste all slides of the PowerPoint presentation (who attended knows that) and he just added some extra words for elaboration. I’m sorry for any mistake and here it is … Clinical syndromes related to Liver We can see lots of symptoms in patients with liver diseases, here are some specific symptoms accompanied with severe hepatic dysfunction: 1- Jaundice and cholestasis; we talked about these condition in the last lecture. 2- hypoalbuminemia : low albumin in the blood because the factory - liver - lost its function. 3- Hyperammonemia , Hypoglycemia; which is secondary to liver injury. 4- Palmar erythema, Spider angiomas , Hypogonadism and Gynecomastia ; those symptoms are usually secondary to estrogen retention due to defect in estrogen metabolism. The first two conditions are found in male and female while the last two conditions are found in male patients. 5- Weight loss due to less energy production, and muscles wasting due to less protein metabolism. This is explained later: *One of the main complication of liver cirrhosis is what we call “portal hypertension” and portal hypertension will lead to ascites, splenomegaly, Hemorrhoids and Caput medusae (paraumbilical skin)* Some of the life threatening complications: 1-hepatic failure: associated with coagulopathy , hepatic encephalopathy and hepato-renal syndrome. 2- Portal hypertension: mainly due to liver cirrhosis leading to esophageal varices which might rupture and lead to severe bleeding with high mortality rate. 3- Malignancy with chronic disease; hepato-cellular carcinoma.

Hepatic failure

it’s simply when the liver when it can’t function normally and usually it’s due to progressive disease; so once there are long standing liver diseases whether it’s due to infection or metabolic disorder or other conditions, after a while the liver will lose it’s normal function. sometimes hepatic failure can happen suddenly once there is severe hepatic destruction or necrosis secondary to infection or drug intoxication leading to acute hepatic failure. the patient will suffer from hepatic failure only when 80-90 % of normal liver function capacity is lost; because the liver has a good regeneration ability and it’s able to compensate the damage.

Causes of hepatic failure : 1- Chronic liver disease : and usually its final outcome is liver cirrhosis 2- Massive hepatic necrosis (acute failure with 2-3 weeks): due to fulminant (sudden) viral hepatitis, drugs & chemical toxicity (acetaminophen, halothane, Rifampicin, INH (isoniazid), (Monoamine oxidase inhibitors) “MOI class” of antidepressants, CCl4, Amanita mushroom toxins). 3- Hepatic dysfunction without overt (clear) necrosis: the liver by histology looks normal but it doesn’t work or function normally; caused by Reye’s syndrome, tetracycline toxicity, acute fatty liver of pregnancy and other conditions. Most cases of hepatic failure are due to overwhelming viral hepatitis and alcoholic liver disease, Symptoms may occur within days, with or without prior history of liver disease, and hepatic failure may lead to other organs failure (respiratory & renal) as we have hepatorenal and hepato-pulmonary syndromes.

Patients suffer from chronic liver disease might have some stressful conditions which may lead to sudden onset of hepatic failure:

1- GI bleeding: this will produce more ammonia and more toxic material and this will contribute in the development of hepatic failure syndrome. 2- Acute infections, which is also not easy to treat in patrients with liver disease !! 3- Electrolyte disturbances, which can lead to sudden appearance of hepatic failure, and these patients have to be under controlled; they don’t take proteins, their Na & other electrolytes intake is parametered and so on. 4- Major surgery, heart failure, shock and any other major incidence can predispose to hepatic failure.

• Treatment: not satisfactory especially if hepatic failure developed after suffering from chronic Liver disease because the liver is already chattered and has no reserve, so any incidence of the above mentioned means development of Hepatic failure !! obviously here the only solution is Liver Transplantation. • Prognosis: 80% mortality rate. However, if the liver had acute failure and it had some chance of cellular regeneration, there would be some chance of escaping death o.O but acute episodes of hepatic failure can undoubtedly demand Liver Transplantation. Now complications of Hepatic Failure: 1- HEPATIC ENCEPHALOPATHY •

A metabolic disorder of CNS & neuromuscular system associated with severe loss of hepatocellular function & portosystemic shunting (regarding portosystemic shunting: when we have portal hypertension, blood will start to escape going to liver and it will go directly through systemic circulation to the heart without getting detoxified carrying all metabolic wastes and toxic substances which could be very dangerous especially on the brain.

•

The brain is exposed to an altered metabolic environment (Ammonia is the major compound here which impairs neuronal function & promotes generalized brain edema. (we advise these patients not to take proteins bcz proteins metabolic tract produces Ammonia)

•

Patients exhibit a wide range of disturbances of consciousness: subtle behavioral changes, confusion, stupor, deep coma & death. (here as you see stupor is after feeling confusion and before the coma).

•

Other neurologic signs: Rigidity, hyperreflexia, EEG changes, seizures, asterixis (asterixis appears also with CO2 retention like in respiratory failure) Minor morphologic changes in brain, I mean if we took some specimen of the brain you won’t find that much, only edema maybe ?!

•

Asterixis wiki (also called the flapping tremor, or liver flap) is a tremor of the wrist when the wrist is extended (dorsiflexion) while extending you hands. > doc: associated with encephalopathy. > wiki also: it can be a feature of Wilson disesae.

2- Hepato-Renal Syndrome *The kidney here is normal with no defects but not functioning well* •

•

Development of renal failure in patients with severe liver disease, without presence of intrinsic morphologic or functional causes in the kidney (meaning that if you take a specimen out of the kidney it would look normal) Before diagnosing this syndrome we have to exclude other causes of such renal failure using certain images and certain investigations and others, because if we have a known cause of renal failure it would be easier to treat obviously, such causes are cases of concomitant damage to liver & kidneys and acute tubular necrosis secondary to circulatory collapse. Pathogenesis:

due to generalized vascular constriction & decreased renal blood flow. We actually have multiple mechanisms for this syndrome. • Manifestations: decrease in urine output is the first thing observed by any person who realized having this syndrome, However the kidney will have the ability to concentrate the urine: it will Hyperosmolar & concentrated urine, with very low proteins & low [Na+]; this will lead to retention of Na+ in the circulation. • Lab findings: Increased blood urea and creatinine. *We have the LIFT (liver function tests): phosphatase concentration and others.and we have the KIFT (kidney function tests): urea, creatinine, Na+, K+* • Prognosis: in case it’s a manageable or mild situation it would persist for months, also it may hasten death !

3- Cirrhosis “Irreversible & Diffuse” •

•

Irreversible end stage of chronic liver disease, which leads to parenchymal injury and fibrosis and by definition the disease should be diffuse (involving the whole liver), for example if we have fibrosis in one focus on the liver we don’t call it Cirrhosis, it’s just fibrosis or nodular or whatever but not Cirrhosis. 3 histological features: 1) Bridging fibrous septa (either portal-portal, portal-central or central-central) 2) Disruption of entire liver architecture: we don’t find the portal tract and the central veins as they should be normally ! 3) Parenchymal nodules: these regenerative nodules appear as a compensation by the liver to this process (cirrhosis), however these are abnormal structurally. They are divided to micro- and macronodules depending on the size.

Etiology: • •

• • • • •

Viral hepatitis: one of the commonest causes specifically type B & C, nowadays in Europe it’s Hepatitis C the commonest one. Alcoholic liver disease (alcohol): we actually have two types; we have the Alcoholic & the Nonalcoholic liver disease which both can cause Cirrhosis. Biliary diseases. Autoimmune diseases. Inherited and metabolic ( Hemochromatosis, Wilson’s disease, a1antitrypsin deficiency…) Drugs & Toxins. Cryptogenic cirrhosis 10-15% (unidentified causes).

It really depends on the area you live in, I mean we have: Western countries South-East Asia Our country

alcohol hepatitis B cryptogenic (unknown)

Pathogenesis: •

Progressive fibrosis with collagen types I & III deposited in all portions of lobule, these are produced by the “Ito cell”. collagen types I & III are normally present around the portal tract and the central veins, and we have type IV normally between the hepatocytes, ok, so once we have injury to the live collagen types I, III, V & VI will be deposited in liver cells causing fibrosis and eventually cirrhosis. • Collagen synthesis & deposition is stimulated by: – Chronic inflammation & cytokine production (TNF, IL-1) – Cytokine production by endogenous liver cells – Disruption of extracellular matrix

– Direct stimulation of Ito cells by toxins •

This is accompanied by alterations in sinusoidal endothelial cells, normally we have kind of pores in-between these epithelial cells so that can solutes & substances can cross in & out the liver cells, but when we have fibrosis these pores will be closed and no more transportation.

•

This also will Result in severe disruption of blood flow & impaired diffusion of solutes & proteins just secondary to the fibrosis.

* Once there is cirrhotic process the number of Ito cells (stellate cells) will increase and proliferate becoming myofibroblasts. * More collagen type I , III, V & VI will be produced, cytokines also will be produced heavily helping in the production of Fibrous tissue. * The hepatocytes will lose it’s microvilli and some of them will just die by apoptosis. This diagram shows the steps & cytokines associated with the process

Two types:

•

Micronodular cirrhosis nodules & scars of uniform size, so they are usually of the same size, however sometimes when you look by the naked eye on the liver you might not be able to distinguish if it’s a cirrhotic liver or not, so in such cases you need to have a histological specimen for confirmation.

•

Macronodular cirrhosis nodules & scars of variable size, and can be appreciated by the naked eye.

Here you can see an example of cirrhotic liver most likely of alcoholic cause, you can see this granular surface is just small nodules (this is mostly a microNodular cirrhosis).

(this & the next picture will look better on the soft copy)

If we take a histological look at this liver, in Masson's trichrome stain, in this stain the fibrous tissue will be stained blue, ok, and so you can see all this fibrous tissue between the hepatocytes (called peri-cellular fibrosis) in this liver, and it’s very characteristic for cirrhotic liver caused by alcohol.

•

Clinical features of cirrhosis: – May be asymptomatic: in the compensated liver disease, however when the disease become decompensated then symptoms and problems will start to appear: Nonspecific symptoms: – malaise, anorexia, weight loss, weakness. More specific symptoms: – Jaundice, Ascites, peripheral edema. in Blood Liver function testing we will find these have increased: serum transaminases / bilirubin / alkaline phosphatase –

Decreased serum protein (globulins, albumin, C.F.) and Hb.

In more Advanced disease: frank debilitation: no movement what so ever, just attached to the bed. Finally the patient will develop Hepatic failure Prevention is much better for this disease because it has a very poor prognosis.

• Prognosis: depending on the stage of the disease and how active it is, and usually the patient will end by death due to: – Progressive hepatic failure – Portal hypertension – Hepatocellular carcinoma *Nowadays we have a very good vaccines against the viruses causing liver cirrhosis which is a big advantage*

Portal Hypertension:

• •

It means increased resistance to portal blood flow. Causes: – I. Pre-hepatic: • Portal vein thrombosis. • Massive Splenomegaly with increased splenic vein blood flow which will increase the portal pressure. – II. Hepatic: • Cirrhosis (most of cases)

– III. Post-hepatic: • • •

Severe right-sided heart failure Constrictive pericarditis Hepatic vein outflow obstruction

All these three will cause obstruction and increased blood back flow volume and hypertension, so ultimately portosystemic anastomosis vessels in their known locations will suffer mostly, and we will have the portal-systemic shunt.

Liver Cirrhosis causing Portal Hypertension Liver Cirrhosis will lead to Portal Hypertension as you know, and it will be done by these mechanisms: 1) Increased resistance to portal blood flow in sinusoids 2) Compression of central veins by perivenular fibrosis & expanding parenchymal nodules 3) Anastomosis between arterial & portal systems in fibrous bands by imposing arterial pressure on the normally low pressure portal venous system. •

Consequences: – 1) Ascites (accumulation of fluid in the peritoneal cavity) – 2)Portosystemic venous shunts (mentioned before) – 3) Congestive Splenomegaly by the big blood flow through splenic vein leading to enlargement of spleen. – 4) Hepatic encephalopathy (when Liver failure occurs).

Here we have a diagram (slide 20) showing major findings in liver disease: hepatic encephalopathy malnutrition skin spider angiomata esophageal varices splenomegaly caput medusa hemorrhoids testicular atrophy lymphatic ascitis

Ascitis: •

It is Excess serous-type fluid in the abdominal (peritoneal) cavity, this fluid contains: 1) Albumin & solutes 2) some mesothelial cells & mononuclear leukocytes 3) Neutrophils which is of coarse secondary infection

•

Hydrothorax: usually when the ascitis is severe there will be fluid going through the trans-diaphragmatic pores (wasn’t heard clear) into the pleural cavity most likely on the right side.

•

Pathogenesis: – Sinusoidal hypertension: increased hydrostatic pressure (blood vessels >> interstitial space >> peritoneal cavity) & hypoalbuminemia – Leakage of hepatic lymph into peritoneal cavity – Renal retention of sodium & water secondary to hyperaldosteronism

It’s really confusing which mechanism will develop but usually the all happen at the same time and the patient will suffer many complications. (here the doctor answered some Q and said: I will not ask you about it (it was the hyperaldosteronism)).

Port-Systemic Shunts: • •

Bypasses develop wherever the systemic & portal circulation share capillary beds Sites: – Rectum. (hemorrhoids) especially with elderly patients suspicious of having liver disease. – Cardio-esophageal junction (varices) commonest and most emergent situation, it needs immediate therapy with what we call “sclerotic therapy” here we make the vessels fibrotic by injection, ok.

– Falciform ligament of liver inducing periumbilical & abdominal wall distention, something we call “Caput medusae”. (caput medusa is just descriptive term; caput (Head) & medusa (snake), so it means snakes coming out of a central head, the head here is the Umbilicus and the snakes are the dilated veins radiating from the umbilicus)

*Sclerotherapy: Injecting the unwanted veins with a sclerosing solution causes the target vein to immediately shrink, and then dissolve over a period of weeks as the body naturally absorbs the treated vein, taking only about 10 minutes to perform. it is preferred over laser for eliminating large spider veins (telangiectasiae) and smaller varicose leg veins. Unlike a laser, the sclerosing solution additionally closes the "feeder veins" under the skin that are causing the spider veins to form, thereby making a recurrence of the spider veins in the treated area less likely !! (wiki)* Splenomegaly: Happens secondary to the portal hypertension through splenic vein dilatation and increased flow. •

we can have Congestive splenomegaly, which is dangerous.

•

May be massive, if it’s massive enough it will lead to Hypersplenism”

•

Hypersplenism: which means removal of excessive amounts of one or more of the formed blood elements leading to 1 of the following: – Anemia (RBCs destruction) – Leukopenia (WBCs destruction) – Thrombocytopenia or even pancytopenia (platelets destruction)

The End I want to thank my friend el DON for his help (kolhen 10 dagayeg 5ef 3a 7alak $way). wel $okor wa9el la 7amootta, d’eeb, $ardoog, 3oday, anoos w 7amzeh !! and I wish u all a great system.

51 / 59 14 / 17 20

Pathology LIVER (Infections and Inflammatory Disorders) Hussam Telfah Noor Abu-Farsakh, Mai Mazin, Dima Bani-Eisa Tuesday, 22/11/2011

Pathology - Lecture 13 Tuesday, 22-11-2011

Liver (Infections and Inflammatory disorders)

In this lecture we'll continue the topic about the liver diseases; we'll talk about the infections and the inflammatory disorders affecting the liver. â&#x20AC;˘

Pathways (The way the microorganisms can get into the liver): -

Arterial supply: from any systemic spread of the infection whether it's from the respiratory tract, bladder or anywhere from which the microorganism can get to the liver through the circulation or the arterial supply

Portal vein: from any infection in the GI or the portal area

Ascending infection in the biliary tract, gall bladder, hepatobiliary system

Direct liver invasion from a nearby infection: any organ nearby the liver, like the diaphragm or the stomach; in case there's an abscess or something like that the infection can get directly into the liver

Open or penetrating injury: this carries a high risk of infection to the liver

In all of them, we might give prophylactics (antibiotics or antiviral treatment) if there's a high risk of infection.

â&#x20AC;˘ Responsible Organisms: -

Bacterial: Staphylococcal bacteremia (from the skin or any other sources), salmonellosis, miliary TB (sometimes can involve the liver extensively)

Viral: infectious mononucleosis (EBV: Epstein barr virus), CMV (Cytomegalovirus) especially infect children

Protozoal: malaria, amebiasis (can lead to liver abscess), Echinococcus Granulosus (the causative agent for Hydatid disease)

VIRAL HEPATITIS  We have general viruses that affect the liver and other organs: • • • • • • •

EBV CMV HSV Arbovirus (Yellow fever) Rubella Adenovirus Enterovirus

 And we have: Hepatotropic (Hepatitis) viruses -which affect only the liver-: A, B, C, D, E, G G virus is non pathogenic at the moment (causes no harm).

CLINICAL SYNDROMES OF VIRAL HEPATITIS (Ways of presentation of viral infection): 1. Asymptomatic acute infection (just the infection happens and goes without causing any symptoms) 2. Acute hepatitis (the duration is less than 6 months) 3. Chronic hepatitis (persistent, more than 6 months) 4. Chronic carrier state (patients have the causative agent in their blood but still they are not affected by the disease and they are infectious to the others) 5. Fulminant hepatitis (acute hepatic failure, the loss of function is severe, carries a high mortality rate)

1. ASYMPTOMATIC INFECTION -

Only diagnosed by serology. Sometimes the patient presents to the hospital for different reasons and when you do the lab workup, by incident, you'll find that liver enzymes are raised, then you do the serology and you'll find something (the Dr. meant positive result).

So, diagnosed just incidentally or by serology but the patient usually is completely asymptomatic. -

Comes and goes without sequelae of infection

2. CARRIER STATE Sometimes can be asymptomatic and sometimes symptomatic but the typical carrier state should be asymptomatic and with no adverse effects to the liver. However, in the carrier state, the causative agent or part of the causative agent is still present. 3

Asymptomatic vs. Carrier The asymptomatic: The first manifestation after the infection has gone: usually there will be no antigens in the blood. All the viral (DNA) surface material is gone because there are antibodies against those antigens so the antibodies from the body will eliminate any viral particle and patients will be cured from the disease. Carrier: There will be specific viral antigens that are still present in the blood. The antibodies against these specific antigens are not present. But in this case only one antigen is there and other antigens are not there (the example will clarify this point). For example: -

In hepatitis B the antigens are the surface antigen, core antigen & E antigen.

In the active infection all of them are present. Normally, antibodies after a certain period of time will neutralize the antigens and destruct them.

The scenario in the carrier state:

HBeA â&#x20AC;&#x201C;ve Anti-HBeA +ve (see how the antibodies neutralize the antigens) Surface Ag +ve (if the disease is cured it should be â&#x20AC;&#x201C;ve) Anti-HBsAg not present or in low titer Remember: it's mentioned above that only one gene remains on the blood and here it's the surface antigen. -

Surface antigen is present in the blood. It's not capable of producing the disease to the carrier but still this can infect the others -although the infectivity rate is very low-

The problem in HBsAg is that sometimes (rarely) it can produce active disease but usually -in the following years the patient goes on- there will be a sort of clearance of this material. So HBV usually do not develop active disease. Sometimes when patients develop the active disease, some people describe it as an indolent infection and not a carrier state.

Where does the carrier stage happen usually? a) 90-95% of early life infections through the vertical transmission during the birth So in areas where the Hepatitis B is endemic (South East Asia), many women get infected by the HBV and during the birth this virus will be transmitted to the child. 90-95% of the children affected by the HB will be carriers rather than to develop the disease itself. In our country hepatitis is not endemic so the carrier state is not that common. b) Individuals with impaired immunity for a reason or another sometimes can develop the carrier state From the slides: c) 1-10% of infections in adulthood And all (a, b & c) is regarding HBV as mentioned in the slides, because as you'll see below: it's the one known for its carrier state. The carrier stays carrier all his life? No, year after year there's a chance that the body will clear itself from this antigen this (this carrier shouldn't develop the disease like HIV). â&#x20AC;˘ HCV: there's a percentage that some of them can be carrier From the slides: 0.2-0.6% carrier state in USA â&#x20AC;˘

HDV: also there's a small percentage of being carriers for the HDV. BUT: The most common and well known example is HBV. HBV is highly contagious (infectious) even 0.1 ml of blood can transmit the disease. Not like the HIV, more infectious than the HIV.

3. ACUTE HEPATITIS It's divided into four phases: 1) Incubation period: asymptomatic and the peak infectivity, attributed to the presence of circulating infectious viral particles, occurs during the last asymptomatic and early days of acute symptoms. Of course, the incubation period is different according to the virus; we have A, B, C, D and E. 2) Symptomatic pre-icteric (before the appearance of jaundice) state: nonspecific constitutional symptoms: malaise, general fatigability (most common, especially after activity), nausea, loss of appetite, weight loss, fever, headache, muscle and joint aches, vomiting, diarrhea. About 10% of patients with acute hepatitis B develop a serum sickness-like syndrome consisting of fever, rash and arthralgia, attributed to circulating immune complexes. 5

3) Symptomatic icteric (once the jaundice appears) state: surprisingly, as jaundice appears and patients enter the icteric phase, other symptoms begin to abate. Here we have Jaundice which is caused by conjugated hyperbilirubinemia and hence is accompanied by dark-olored urine, light-colored stools due to the cholestasis and pruritis due to the retention of bile salts. This phase is usual in adults (but not in children) infected with HAV but is absent in half the cases involving HBV and is absent in most cases of HCV infection. 4) Convalescence: within few weeks-months where the jaundice and most of the other systemic symptoms clear.

Histology of acute hepatitis:  Ballooning degeneration: diffuse swelling.  Cholestasis and bile plugs in canaliculi.  Steatosis: fatty change is mild and is unusual except with HCV infection. But bear in mind that we see fatty change in alcoholism which can present with acute hepatitis, so we need to aware of this and correlate the histology with the clinical findings - Remember that!  Hepatocyte necrosis: take two forms: - Dropped out cells surrounded by macrophages - Apoptotic cells (Councilman Bodies)  Kupffer cell hypertrophy & hyperplasia.  Portal tracts infiltration by inflammatory cells (not neutrophils, they are usually lymphocytes) with spill over to parenchyma to cause necrosis of the periportal hepatocytes or piecemeal necrosis (interface hepatitis) – Remember that! Much of these can be found also in the chronic hepatitis and, as we said, the diagnosis depends on the period whether less than 6 months (acute) or more than 6 months (chronic), y3ni it's clinically.

This is a portal tract here, and we can see the inflammation extending to the parenchyma, so this is interface hepatitis. And also we can see some apoptotic and eosinophilic cells. 6

Here we can see swollen cells undergoing ballooning degeneration causing disturbance in the architecture. Always once you look at any biopsy and see the normal histology is disturbed, think about acute hepatitis. In chronic hepatitis, the architecture is apparent, but here because all the cells are swollen; it's difficult to identify the sinusoids between the cell plates.

4. CHRONIC HEPATITIS It is usually symptomatic and the patient might have jaundice and might suffer from. And there is biochemical or serological evidence of active disease for more than 6 months. So the patient will have the AST and the ALT and sometimes the alkaline phosphatase are high for more than 6 months. The histology will be nearly the same of what we saw in the acute phase; sometimes the changes in the parenchyma are a little bit less, and sometimes the feathery degeneration is not that obvious. And sometimes there is fibrosis, so once there is fibrosis, it usually indicates a chronic status (but sometimes we find fibrosis in acute statuses). So once there is fibrosis, and you take a liver biopsy, youâ&#x20AC;&#x2122;ll describe the features of inflammation, and there is a great extend of the inflammation. And both; the inflammation and the fibrosis are divided into strata; mild, moderate and severe. So the more the severe the fibrosis is, the more is the liability to develop cirrhosis. The causes of chronic hepatitis The hepatitis viruses, but not all of them lead to a chronic status. For example, hepatitis A doesnâ&#x20AC;&#x2122;t go into a chronic state (always acute), however, it can lead to a fulminant hepatitis. But hepatitis C is the opposite; it rarely produces acute hepatitis and usually the presentation is a chronic hepatitis.

Wilsonâ&#x20AC;&#x2122;s disease is the same thing, usually it is a chronic disease, however, it can present sometimes as acute or fulminant hepatitis. Alpha 1-AT deficiency, alcoholism, drugs and autoimmunity can also lead to chronic hepatitis. The etiology rather than histologic pattern is the single most important factor determining the probability of developing progressive chronic hepatitis. So if we have hepatitis C, then usually we have a high tendency to go into a chronic stage and cirrhosis. As we said, the characteristic features of hepatitis C are the state of steatosis (fatty change), and the other feature is the lymphoid follicle (the arrow), and sometimes we find a germinal center within these follicles and then they will look just like the secondary or the activated lymphoid follicle. So the presence of such lymphoid follicles plus the steatosis is very suggestive of chronic hepatitis due to hepatitis C viral infection. **The primary lymphoid follicles are always devoid of a germinal center, while the secondary lymphoid follicles contain a germinal center and it is present in the activated lymph nodes (secondary to an infection). In the autoimmune diseases it is the same; we can find lymphoid follicles with an activated germinal center with adequate or abundant plasma cells, and sometimes eosinophiles if there is a drug element. The following is just a schematic diagram that shows the changes that can be seen in both; the acute and the chronic statuses. And this fibrosis is usually present in the chronic rather than the acute stage (but sometimes we find fibrosis in the acute hepatitis).

If we take a biopsy from a liver infected with hepatitis B virus, weâ&#x20AC;&#x2122;ll have what we call the ground-glass appearance of the cytoplasm. The hepatocytes will have a pink, glassy, or a homogenous appearance. And this is due to the surface antigen particles of hepatitis B.

In the lab, we have specific antibodies against the surface antigen of HBV. So when we want to detect this antigen, we react it with its specific antibodies, and then they will produce the brown color (the arrows) to indicate the positive result. And this is very specific for the hepatitis B antigen.

The histology of chronic hepatitis: All these things may appear in both; the acute and the chronic. The fibrosis is more in the chronic. The bile duct epithelial proliferation is more in the chronic, but also can be found in the acute state. The cirrhosis is more in the chronic. The lab findings: persistent increase in all these things: PT, AST, ALT, bilirubin, ALK. The clinical features: are highly variable and not specific. The prognosis: is variable, and it depends on the cause.

All of these are possibilities for the HBV infection: -

The subclinical disease, or the asymptomatic and it usually leads to recovery. The Acute hepatitis, it may recover, or may go into the fulminate hepatitis. The healthy carrier.

Persistent infection, here there is still a chance for recovery. But once the patient goes into the chronic hepatitis stage, then it is a continuous process, and the prognosis depends on the activity of the disease. The problem with the chronic hepatitis is that about (20-50)% will go to cirrhosis, and after the cirrhosis we may have a hepatocellular carcinoma which may lead to death! And this is how the hepatitis virus can cause cancer; it should go through the cirrhotic stage. We have now some drugs (the interferons) that can alter the progression of the disease and prolong the life of the patient. For the hepatitis C infection: -

Almost 85% of cases will go into the chronic stage. The fulminant hepatitis is very rare (negligible). The resolution is only in 15%.

So, the HCV is a BIG problem especially in blood donation. The portal inflammation in the chronic hepatitis can be mild, moderate and severe. And it is usually composed of lymphocytes.

5. FULMINANT HEPATITIS It is just a hepatic insufficiency that progresses from onset of symptoms to hepatic encephalopathy or hepatic failure within 2-3 weeks, or up to 3 months which is in this case called “subacute hepatic necrosis” or “subfulminant hepatic disease”.

Causes: Most of these cases are due to viral hepatitis infections: A, B, D and E. And sometimes it is caused by drugs or chemicals like: paracetamol, INH, monoamine oxidase inhibitors (MOI), antidepressants, halothane, and methyl dopa. And rarely the fulminant presentation can be due to hepatic vein obstruction, Wilson’s disease, malignancy, autoimmune hepatitis, and pregnancy. The clinical features: Sometimes the liver can be completely normal, but in most cases there is a massive necrosis of the hepatocytes, and variable degrees of inflammation.

You’ll see jaundice, fetor hepaticus (ammonia..), and stigmata of chronic liver disease. Prognosis: The mortality is very high and it depends on the cause and on the severity. **We usually grade the fulminanat hepatitis according to the encephalopathy; we have grades 1 to 4 encephalopathy. Grades 1 and 2 carry a better prognosis, whereas grades 3 and 4 carry a very bad prognosis. Transplantation may sometimes be the solution, but some people might live even without transplantation. But once there is no hope for recovery, then the solution is transplantation. **Transplantation is not a permanent solution because the transplanted organ will be attacked by antibodies, but it prolongs the patient’s life; and that’s why it is a good solution. This is the gross feature of the fulminant hepatitis; usually the capsule will be wrinkled not smooth, and sometimes we find sort of red hemorrhages on the surface. And sometimes the weight is very low to the liver; it is below the normal weight.

In the histology we see a massive necrosis; usually a severe inflammation between these liver cells and the portal areas.

This is the central vein (the vertical arrow), and hepatocytes should be present here, but we don’t find hepatocytes here because they are necrotic. All these inflammatory cells destructing the hepatocytes, and the macrophages are engulfing the dead hepatocytes. So this is called collapsing necrosis; the lobules are collapsed because there is no acini, no structures, and no sinusoids. And these things (the horizontal arrows) are the proliferating bile ductules.

The End 11

54/59 15/17 25

Pathology Inflammatory & metabolic disorders of the liver

Hussam Telfah Yousef Odeh Wednesday, 23-11-2011

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Pathology lecture 15 Wednesday, 23-11-2011 Done by: Yousef Odeh -------------------------------------------------------------------------------------------------------------------------

Inflammatory & metabolic disorders of the liver

Autoimmune hepatitis  Usually, it’s a form of chronic hepatitis of variable severity, histologically, it’s indistinguishable from chronic viral hepatitis..  Generally, autoimmune diseases are more common in females; so accordingly, this disease more common in females, so there’s a female predominance in 70% cases.  There’s no serologic viral markers; once you do workup to the patient, the hepatitis viral antigens (B,E,C,A,..) are negative, but, you’ll find that serum IgGs are elevated more than 2.5 g/dl, these things are distinguished from the lab easily, so just measured in the serum.  We have also increase in the titer of autoantibodies in the serum in 80% of the cases, so there’s what we call anti nuclear antibody, also we have anti smooth muscle antibody, liver kidney microsomal antibodies and anti-soluble liver/pancreas antigen.  All these things can be measured in the lab, and for clinical situation, they divide autoimmune hepatitis into several subtypes; type 1, type 2 (2A, 2B), type 3, depending on the type of the autoantibody present in the serum PREDOMINANTLY (so, this doesn’t mean that we don’t have another antibodies), SO,  If there’s more antinuclear antibody then it’s type 1, more common the western countries  If it’s liver kidney microsomal antibodies then it’s type 2 (which can be divided into A & B), more common here in our area.  Patients with immune hepatitis usually complain of other immunologic disorders or autoimmune diseases so other forms of autoimmune diseases can be present in 60% of cases, like rheumatoid arthritis, UC, SjÖgren syndrome.  The most common tissue antigen types are HLA-B3, HLA-B8, HLA-DR3 or HLADR4.  Overall risk for cirrhosis is 5% Treatment: good response to immunosuppressive therapy; [remember in the previous lecture that the main treatment of viral hepatitis is anti-viral treatment Page 1 of 13

(interferons) with or without steroids.] but here, the main drug is the immunosuppressive drugs with or without interferons depends on the type and the presentation of the disease.  Some studies, they found that one of the types (maybe 2B) has a sort of relation to hepatitis C, so in this type, they give as well, interferon alpha.  Histologically, there’s portal inflammation, abundant numerous plasma cells in the portal tract.  So, chronic inflammation + abundant plasma cell + negative serology of viral antigens then we think of autoimmune hepatitis or drug-induced hepatitis (we exclude it by taking the history). So the drugs is the differential diagnosis for any chronic hepatitis.

Alcohol-liver disease  It’s the prototype of toxin-induced liver diseases:  Alcohol is the fifth leading cause of death in the U.S which is usually related to car accidents or automobile accidents or liver cirrhosis.  Alcohol has many adverse effects on 1liver, 2GIT (ulcers, gastritis), 3CNS (peripheral neuropathy & Wernicke-Korsakaff syndrome secondary to thiamine deficiency, cerebral atrophy, cerebellar degeneration), 4CVS (cardiomyopathy, hypertension, HDL), 5pancreas (pancreatitis), 6pregnancy (fetal alcohol syndrome)  We have 3 forms of alcoholic liver disease; so once there’s alcoholic exposure, it’s like a clinical syndrome or presentation so the patient might have: 1) Hepatic steatosis 2) Alcoholic hepatitis, chronic hepatitis. 3) Alcoholic cirrhosis <We’ll discuss each one of them later>  Pathogenesis of alcohol-liver disease: - Mechanisms of Alcohol-induced hepatocellular steatosis: so alcohol will affect fat & lipid metabolism and the ultimate result will be increased in the level of lipids within hepatocytes, and why the fat is accumulated in the hepatocytes is explained as enzymatic malfunctioning that will lead to: 1- Generation of excess NADH by alcohol dehydrogenase & acetaldehyde dehydrogenase leading to increased lipid biosynthesis. 2- Impaired assembly & secretion of lipoproteins. 3- Increased peripheral catabolism of fat.

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- Mechanisms of alcohol-induced hepatocellular damage; either directly or by certain mechanisms, like: 1- Induction of cytochrome P-450 (usually it’s responsible for metabolism of many drugs, so sometimes, if you give any drug in its inactive form then this drug in the liver -by induction of P450- will be transformed into its active metabolite. Alcohol also known that it promotes the function of this cytochrome so once there’s inactive drug in the presence of alcohol, this means that more drug will be transferred into its active metabolite. So if the active drug is more than the therapeutic concentration then it will lead to toxicity so then you need to take in consideration to adjust the dose of the drugs that are taken specially the drugs that are metabolized in the liver. 2- Generation of free radicals. 3- Direct effect on microtubular & mitochondrial function & membrane fluidity. 4- Acetaldehyde induces lipid peroxidation & acetaldehyde-protein adducts formation, further disrupting cytoskelatal & membrane function. - Mechanisms of alcohol-induced fibrosis:  Multifactorial and poorly understood - Other mechanisms:  Indirectly by Malnutrition (so alcoholic usually eat less food cuz they depend mainly on alcohol so they have poor nutrition so the vitamins will be deficient. (The most common vitamin is thiamin).  Impaired digestive function (chronic gastric & intestinal mucosal damage & pancreatitis) It’s thought that drinking red wine in moderation might be protective against IHD. The problem is in piggish drinking, drinking lots of alcohol in a short time. (‫ بشراهة‬،‫ )شره‬ this is known in parties. They said that piggish drinking is more severe than chronic drinking in moderate amounts.

Now, talking about the 3 forms of alcohol liver disease:

First: hepatic steatosis So, the main thing we see secondary to alcohol is accumulation of the fat within the liver, or what so called steatosis or fatty change.

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 2 histologic types: 1- Microvesicular  multiple droplets within the cytoplasm but still the nucleus is centrally located. 2- Macrovesicular  one big droplet that displaces the nucleus to the periphery. <These 2 terms are just descriptive terms & not specific to certain causes>  The way that fatty change progressives: it starts around the central vein (centrilobular) and later it will extend to the rest of the lobule (panlobular)  The liver become Large (reach up to 4-6 kg) and usually it look soft yellow (instead of brown) and once you cut the liver, it looks greasy; so it’s easy to diagnose it by naked eye.  This fat change is completely reversible once the person stops alcohol, and there should be no fibrosis cuz usually fibrosis is an irreversible process. <If there’s fibrosis, then if you stop drinking, the fibrosis still constant, and once you continue drinking, the fibrosis will be more> <So fatty change is reversible (at early stages) & fibrosis is irreversible (late stages> Now the other syndrome is alcohol hepatitis.

Second: alcoholic hepatitis  Acute hepatitis injury, so the main features are swelling (ballooning; due to accumulation of fat & water) & degeneration & necrosis.  Now, what’s specific for alcohol is what so called steatotic hepatitis; this means that there’s fatty liver & acute inflammation.  Also, there’s what so called Mallory bodies; they are part of the cytoplasm (cytokeratin intermediate filaments), they just come together and form this Mallory bodies. Page 4 of 13

>> Also, In the slides  Mallory bodies: characteristic eosinophilic cytoplasmic inclusions. So this is the fat droplet within the hepatocytes, these are the nuclei, these pink condensations (arrows) within the cytoplasm are Mallory bodies. They are specific for alcohol but they are not pathognomic.  Also, we’ll find infiltration by Neutrophils. They can be found in the parenchyma  Fibrosis can be present: surrounding the central vein or the hepatocytes, sinusoidal & perivenular.

This is a closer view for one cell, so all these condenastions are the Mallory bodies. Again, they are eosinophilic inclusions secondary to clumping of cytokeratin intermediate filamnetns.

Again here, this (arrow) is a Mallory body, and see the focus (arrowhead) that represents lymphocytes and macrophages surrounding a dead hepatocytes so this focal necrosis. It’s not easy to see the necrotic cells of the liver, sometimes, if we see this collection of lymphocytes, this indicate that a hepatocyte was there but now, it’s engulfed by inflammatory cells. So the presence of lymphocytic cells or inflammation without identifying necrotic cells this means that there’s focal cell Third: necrosis.liver cirrhosis Page 5 of 13

 The final and irreversible stage  We see granular clumpy liver cirrhosis >>

secondary to

 Histologically, we use a stain called massotrichome stain that stains the fibrous tissue blue & you can see the sinosiodal fibrosis >> all this doesn’t mean cirrhosis >> cirrhosis definition is different. But this can present before the stage of cirrhosis, or at the cirrhotic stage but seeing this field by its own doesn’t mean that it’s a cirrhotic liver, it’s just fibrosis, cuz cirrhosis has stages from 1-6 (1normal, 6-full cirrhotic picture). So fibrosis once it’s extensive, in the portal centre with nodule formation >> this is cirrhosis but fibrosis alone doesn’t mean cirrhosis.  So, Initially, the liver is yellow-tan, fatty & enlarged then it becomes brown, shrunken & non-fatty  In the end stage, cirrhotic liver secondary to alcohol, we’ll lose steatosis. But it’s difficult to know what’s the cause of liver cirrhosis cuz all of them look the same.  Fibrous septa become thicker & extend through sinusoids  Regenerative nodules with entrapped hepatocytes  Features characteristic of alcohol disappear at the cirrhotic stage.

Another picture with granular, cirrhotic liver and this is the full picture of cirrhosis.

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And this is masson-trichome stain, again, all the blue stuff is a fibrous tissue, and all these nodules are abnormal, with regard to the architecture.

 Clinical features of alcoholic liver disease:  Hepatic steatosis: - Fatty change, usually asymptomatic and sometimes with mild alteration or increase of the serum bilirubin and alkaline phosphatase. - Once we do the AST:ALT ratio, it will be more than 2 or less than 1 or more than 1, there is certain indications; - if it is less than 1then it is non-alcohol & if it is more than 2 then it is alcohol.  -

Alcoholic hepatitis: More symptomatic, nonspecific symptoms; vomiting fever. Minimal to severe manifestations Increase in Serum bilirubin, alkaline phosphatase, and also we have leukocytosis (WBCs)

 Alcoholic cirrhosis: Similar to other forms of cirrhosis whatever the cause is.  Prognosis of alcoholic liver disease:  Variable outcome depending on the severity, drinking and the histological changes.  5 years survival approaches 90% in abstainers who are free of jaundice, ascites, or hematemesis, but drops to 50-60% in those who continue to drink.  Immediate causes of death:1) Hepatic failure 2) Massive GI hemorrhage 3) Intercurrent infection 4) Hepato-renal syndrome 5) Hepatocellular carcinoma  There is something called acute fatty liver -we don’t have it in the west- its scenario is usually in adult persons, usually alcoholic, and usually with poor Page 7 of 13

nutrition, and usually come from venge drinking; keep drinking until he dies :/,, usually what cause the death what’s called alcoholic ketoacidosis, in this disease we have ketosis and acidosis and type 1 diabetes and this is the most cause of death in the west.  This diagram describes all the outcomes that we have discussed.

        

Nonalcoholic fatty liver disease  More common in our areas than alcoholic liver disease.  First described in 1980, present as fatty liver and Steatosis which is called Nonalcoholic Steato-hepatitis (NASH), so we have ASH & NASH.  We see this nonalcoholic fatty liver disease in type 2 diabetic patients, in obese patients and patients with Dyslipidemia, all these three together with insulin resistance and hypertension are known as syndrome X or metabolic syndrome.  The Progression from steatosis to NASH and from NASH to cirrhosis seems to be low, but it is present, i.e. the presence of NASH is not benign but sometimes might lead to cirrhosis, and this NASH is one of the causes for cryptogenic cirrhosis in 10-15%.  The clinical symptoms variable. Page 8 of 13

 AST:ALT >> less than 1, in contrast to alcoholic which is more than 2 to 2.5.  Now, people come to clinic with all these liver enzymes and u do biopsy and the biopsy shows fatty liver so how we can differentiate between alcoholic and Nonalcoholic?? By the ratio.  So fatty change NOT only in alcohol, other causes might lead to fatty change; Nonalcoholic, hepatitis C Virus also can lead to fatty change. Y3ne msh etha shoft wa7d 3ndo fatty change tro7 ts2alo enta bt36eha wela ma bt36eha mashe ;)  Treatment: is by reducing the weight and control the diabetes.  Histology: fatty change similar to alcoholic, once we do Masson-trichrome stain, we see the same thing; sinusoidal fibrosis and then perisinusoidal fibrosis, so it looks the same as alcoholic, we find Mallory bodies & leukocyte infiltration so it’s the same in ASH, so it is difficult to differentiate if it is alcohol related or non alcohol related.          

Hereditary hemochromatosis  It is a genetic disorder, characterized by accumulation of iron in tissues such as the liver, pancreas, heart & skin.  The typical picture is liver, pancreas & skin. The skin become hyperpigmented, the pancreas will stop producing insulin and the liver will accumulate irons and then fibrosis and then cirrhosis.  There are different forms of this genetic disorder, the most common form autosomal recessive and caused by mutation of what is called HFE gene.  We have secondary hemochromatosis, it’s better to call it hemosiderosis > it is secondary to blood overload, if the patient suffer from hemolytic anemia or Page 9 of 13

thalasemia, so these patients have a high frequent of blood transfusion and this will develop hemosiderosis but it isn’t a hereditary hemochromatosis.  Clinical features: Cirrhosis, Diabetes and skin pigmentation  Treatment: by regular phlebotomy.  Phlebotomy: is the donation of blood, so the patient will go to the lab and every time they take from him 500 ml of blood each time so these things in acute phase done weekly or twice weekly, but when the iron level within normal, it is done once every 3 months and it is cheap, there are other drugs that chelate iron but they are rather expensive but this (phlebotomy) cheap and easy to do.  It is familial so if there is suspicion for this disease in families or if the iron was high and discovered incidentally for whatever the reason is, so these patients will go this genetic counsel and they will do this frequent phlebotomy in order to prevent cirrhosis from happening so phlebotomy is used as treatment and preventable method in individuals with this genetic alteration, the genetic alteration might be homozygote or heterozygote and even so, the heterozygote patients suffer from a milder form of iron metabolism.  It is charactarized in the liver biopsy by accumulation of these golden granules in the parenchyma and in the kupffer cells.  Once we do the Prussion blue stain these iron particles so they’ll become blue

Wilson disease  It is a rare metabolic disease.  It is autosomal recessive (AR) and defect in copper metabolism so we have accumulation of toxic levels of copper in liver, brain and eyes.  Genetic defect: mutation in ATP7B gene on chromosome 13. Page 10 of 13

 Morphology: Liver  fatty change, acute hepatitis, chronic hepatitis, massive liver necrosis, cirrhosis, as u see the same presentation and morphology but the cause is different. Brain  basal ganglia. Eyes  Kayser-Fleischer rings in the cornea of the eyes.  Histologically, we use the rhodamine stain that stains the copper red. And there is another stain which stain the copper associated with proteins.

AAT (Alpha1 Antitrypsin Deficiency)  AR, characterized by Low serum level of protease inhibitor (A1AT). >> The function of A1AT is the inhibition of proteases released at sites of inflammation.  Liver diseases secondary to this accumulation of proteases, and pulmonary emphysema.  Liver injury: cholestasis, hepatocyte necrosis, chronic hepatitis and cirrhosis.  In patients with emphysema usually we advice them to stop smoking, sometimes we give them replacement therapy for this protease inhibitor.  Difficult to treat, sometimes they use liver transplant.  The stain in A1AT deficiency is PAS stain, it will stain these globules pink. These globules are just folded and acumulated in the liver. So, remmeber: 1) Prussian blue in iron 2) Rhodamine  red in copper 3) Orcein black in copper associated protein 4) PAS pink in A1AT

Reye’s syndrome    

Rare disease. Fatty liver with encephalopathy. Children, younger than 4 years 3-4 days after viral illness. Symptoms are variable: Vomiting, irritability Page 11 of 13

 Death in 25 %.  Pathogenesis: generalized loss of mitochondrial function.  It’s a prototype of what’s called mitochondrial hepatopathies, it is associated with aspirin intake during any viral illnesses, so it is advice not to give aspirin in children who suppose for viral infection.  Morphology: in the Liver we have: microvesicular steatosis, in the electron microscope (EM) shows mitochondrial enlargement and lucency (y3ne absorb less rays in X-ray), so the mitochondria will be swollen and abnormal. In the Brain: edema. Heart, skeletal muscle and kidneys may show fatty change and mitochondrial abnormalities but they are much much stable than that of the liver.

NOW, IT’S

DONE  Hamza Bani-Younes… thank U  Done by: Abo Abdulrahman Yousef Ahmad Odeh

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55/59 16/17 25

Pathology Diseases of extrahepatic Biliary Tract Hussam telfah Ibrahim Miqdady Wednesday, 23-11-2011

Pathology (16) Thursday 23/11

Diseases of Intrahepatic Biliary Tract:Secondary Biliary Cirrhosis:•

• •

Might be caused by Extrahepatic cholelithiasis (Gallstones in the cystic duct, hepatic duct, common bile duct. The commonest is in the common bile duct), Malignancies (might lead to obstruction in the common bile duct) and Strictures (narrowing of the bile duct, secondary to fibrosis, inflammation, or vasculitis) If treated before the cirrhotic or fibrotic stage it would be reversible. (if there is cirrhosis or fibrosis, the changes are not reversible) Morphology: yellow-green liver (because of the cholestasis and bile accumulation), fibrosis in a Jigsaw-like pattern (like a Jigsaw puzzle), prominent ductular proliferation at the interface of fibrous septa, cholestatic features and bile inspissation (thickening of the bile).

This is what we mean by ductular proliferation at the fibrous septa. All these small things (in the picture to the right) represent the ductular proliferation, this is not adenocarcinoma. In this power it is difficult to know if this is adenocarcinoma or not, but once you go to the low power and see the full picture, you see that these things are only within the fibrous septa.

Primary Biliary Cirrhosis:• • • • •

• • •

•

Chronic progressive and often fatal cholestatic liver disease. (if untreated it progresses to cirrhotic stage). Usually the cause is idiopathic or secondary to immunity. Destruction of intrahepatic bile ducts, portal inflammation and scarring. (the main pathology is in the portal tract) 90% have high titers of antimitochondrial antibodies against specific domains of mitochondrial acid dehydrogenase enzymes. Morphology: - First it is focal (if you take a liver biopsy you might miss it) and variable disease showing different degrees of severity. - dense portal inflammation including eosinophils and noncaseating granulomas. around the bile duct in the portal tract. If it progresses it will cause End-stage cirrhosis. Affects middle aged women (m:f = 6:1), peak 40-50 yrs. Pruritus then jaundice. High alkaline phosphatase and cholesterol levels. (remember that the ALT and the AST are usually high in paranchymal diseases, while the alkaline phosphatase is more specific to the biliary tract). Cholesterol levels increase because the bile salts are mandatory for the metabolism of lipids. Associated extrahepatic conditions: Sicca complex (dryness of the mucous membranes-wiki), scleroderma, thyroiditis, RA, ciliac disease, and other autoimmune diseases. 2

This is a picture that represents one of the portal tracts, you can see the lymphocyte infiltrate, you can also see the bile duct in the center, part of the bile duct is invaded by this inflammatory complex. There're also epithiloid macrophages. So this is a granuloma attacking the bile duct. This picture is very characteristic of primary biliary cirrhosis.

Treatment: we have some drugs in the market, but once its in its end stage, the treatment is not effective.

Primary Sclerosing Cholangitis:•

• • •

Chronic cholestatic disease characterized by progressive fibrosis and destruction of extrahepatic and large intrahepatic bile ducts (so it takes place in the hepatic duct, cystic duct, common bile duct, and the bile ducts present within the portal tracts). Immunologically mediated: ANA (anti-nuclear antibodies) , Antismooth muscle antibodies, RF and atypical p-ANCA. Morphology: fibrosing cholangitis of bile ducts, onion skin appearance (layering of the fibrous tissue around the bile duct, remember we also have this appearance in Ewing's sarcoma). M:F 2:1, 3rd to 5th decades, 70% of the patients are associated with ulcerative colitis. But only 4% of UC patients might develop Primary Sclerosing Cholangitis.

This is a section from the portal tract. You can see the inflammatory cells and the onion skin appearance; concentric layers of fibrosis around the bile duct.

Now done with the Diseases of Intrahepatic Biliary Tract.

Circulatory Disorders: • • •

•

They might cause Passive congestion and centrilobular necrosis. Right sided heart failure: causes Congestion of centrilobular area. Left sided failure sudden with shock causes centrilobular necrosis (nutmeg liver grossly). Remember that the areas the farthest from the portal areas (zone 3) are the most expected to develop ischemia and necrosis. Cardiac cirrhosis. (it is an old term that presents in the books, nowadays it is rare but usually these patients do not develop cirrhosis.)

>> Cardiac cirrhosis (congestive hepatopathy) includes a spectrum of hepatic derangements that occur in the setting of right-sided heart failure. Clinically, the signs and symptoms of congestive heart failure (CHF) dominate the disorder. Unlike cirrhosis caused by chronic alcohol use or viral hepatitis, the effect of cardiac cirrhosis on overall prognosis has not been clearly established. As a result, treatment is aimed at managing the underlying heart failure. - medscape

Here to the right you can see the nutmeg appearance of the liver.

Here you can see the necrosis in the center of the lobule. (it is coagulative type of necrosis).

# The other disease associated with the circulatory disorders is the (Budd-Chiari Syndrome). Where the symptoms are hepatomegaly, weight gain, ascites and abdominal pain. The causes are either Idiopathic , or secondary to thrombotic conditions in the hepatic vein (or one of it's main branches). Notice that in this case, the thrombi must be in the vein only, meaning that the blood is able to come but not able to leave. The arteries are not affected, but the vein is blocked by a thrombus.

Tumors and tumor-like conditions of liver and biliary tract:•

Classification of liver tumors: - Benign • Non-neoplastic: Cysts (simple, congenital, choledochal, or a part of systemic polycystic diseases), focal nodular hyperplasia • Neoplastic: hemangioma (very common benign tumor in the liver that is discovered incidentally on CT scans done for other purposes), adenoma. - Malignant • Primary: Hepatoblastoma (young childhood), Hepatocellular carcinoma, Cholangiocarcinoma. • Secondary: Metastatic malignant tumours. (the liver is a very preferred site for metastases especially from the lung).

Secondary tumors are far more common than the primary. They are usually from the colon, breast, lung and pancreas (or any cancer). As in the lung, the metastatic tumor is characterized by typically multiple nodules, but can be solitary (e.g. renal cell carcinoma). Once there's a solitary metastases, we can remove the metastatic nodule by surgery, otherwise it'd be difficult to remove all the metastatic nodules by surgery, so you usually give chemotherapy. These secondary tumors can be asymptomatic even if extensive (discovered by CT scans either incidentally, or for staging purposes; if the patient presents for rectal bleeding for example and there's adenocarcinoma of the rectum, you do these scans for staging and you find metastatic nodules in the liver secondary to this primary rectal tumor). The Symptoms and signs include: jaundice, hepatomegaly, and abnormal liver enzymes. If we have pancreatic metastases to the liver, it is contraindicated to do resection of the pancreatic tumor.

You can see here the yellow spots representing metastatic tumors in the liver.

One of the benign lesions is called :

Focal Nodular Hyperplasia • • • • • • •

Solitary (most cases) or can be multiple. Well demarcated poorly encapsulated mass up to many centimeters in diameter. Background liver is normal. (the liver is not cirrhotic) Typically, we have central stellate scar with radiating fibrous septa. (By CT scan or imaging) Lymphocytic infiltrate in the fibrous septa. Normal hepatocytes with thickened plates (instead of one-cell plates sometimes we have twocell plates). Related to long term use of anabolic hormones and contraceptive pills.

This is a resected nodule, you can see here the central scar and the surrounding liver parenchyma, and the fibrous septa.

The central area is sclerotic (fibrotic) and the septa traverses between the liver parenchyma, and the dense material out there is just inflammatory cells.

I know you are wishing that this remains a blank page to be counted as a studied one. I won't ruin it for you ď &#x160; now flip the page.

Now another neoplastic benign tumor :-

Hepatic Adenoma (Liver cell Adenoma):• •

Mostly in young women with history of oral contaceptive pills (OCP) use. Well-demarcated yellow-tan frequently bile-stained nodule(s), often located beneath capsule, usually small in size but may reach up to 30 cm.

•

Histology: sheets & cords of cells that resemble normal hepatocytes with minimal pleomorphism. Portal tracts absent. (Liver parenchyma without the portal tract, the central vein is not affected).

• Clinical significance: 1) Misdiagnosed as hepatocellular carcinoma. 2) May rupture & cause serious intra-abdominal hemorrhage (especially during pregnancy). (If this adenoma is subcapsular and large, and during pregnancy lady stops taking the OCP, there is a risk for rupture and bleeding into the peritoneal cavity until death). • May regress on discontinuance of OCPs, rarely undergoes malignant transformation. (Transformation might occur if it is on the background of Glycogen Storage Disease, or there is a sort of mutation in the B-Catenin gene). However, usually we do not see this transformation.

This's a resected adenoma (to your left), and this's how it looks under the microscope (to your right). You can see the prominent central venules, and this explains the liability to bleed. And usually there is no portal tract.

PRIMARY MALIGNANT TUMORS:• • • • •

Hepatocellular carcinoma (Hepatoma ; a misnomer). Cholangiocarcinoma. Tumors of mixed cell types (Hepatocellular carcinoma with Cholangiocarcinoma at the same time). Hepatoblastoma. – Aggressive tumor of children. Angiosarcoma. – Association with exposure to vinyl chloride, arsenic & Thorotrast ( Thorotrast is a suspension containing particles of the radioactive compound thorium dioxide, used as a contrast medium in the X-rays – wiki).

•

Primary lymphomas, sarcomas, ... etc.

So starting with the first one :-

# Hepatocellular Carcinoma (HCC): • • •

• • •

Malignant tumor arising from hepatocytes. Wide variation in geographic distribution (more in south-east Asia and Africa). The causes differ from an area to another. Chronic HBV carrier state increases the risk by 200 folds. (the doctor says that this 'carrier' should not be put here, what we mean here is the active chronic HBV disease, not the actual carrier state). HCC is frequently associated with cirrhosis, especially after chronic hepatitis due to viruses or other metabolic causes. M:F ratio ranges from 3:1 to 8:1; and usually in adulthood. Pathogenesis: several factors are – Viruses: HBV, HCV. – Chemicals: alcohol, food hepatocarcinogens (e.g. Aspergillus flavus aflatoxins B1; these are common in south-east Asia and Africa). – Chronic liver disease that might lead to transformation into HCC.

The HBV link: – Hepatitis B virus genome does not contain any oncogenic sequences, & there is no selective site of integration of viral DNA into the host genome. – Repeated cycles of cell death & regeneration leads to accumulation of mutations & genomic instability. – HBV genome encodes the X-protein; a transcriptional activator of many genes which may disrupt normal growth control by activating host cell proto-oncogenes. – HBV proteins bind & inactivate p53‫(‏‬a tumor suppressor gene).

This is a normal liver at one side, it is not cirrhotic, and at the other side this is the bigger mass (you can see them easily with colors), there is the satellite nodule which is typical of HCC. The color might be sometimes yellowish–greenish depending on the content of the bilirubin. 8

- It might you take to a small biopsy from the liver, it is not that straight forward to diagnose the malignancy, but we depend on the architecture, if it is rosetting (not sure about this word) this is abnormal, if the thickness of the cell plate is more than 1, this is abnormal, if the mitotic figures are easily found then this is also abnormal. If dysplasia is present, this is …. abnormal. So you take all these factors together plus the imaging and the history to diagnose it as cancer.

Cancer here is on the background of a cirrhotic liver (to the right). While to the left here it is arising in a normal liver, usually there's vascular invasion increasing the metastasis.

(There're some other pictures in the slide but the doctor either skipped them, or talked about them very quickly that I couldn't understand which for which. I know you are not checking them anyway but just felt like telling you, go check them if you want.) Literally form the slides:PATHOLOGYOF HEPATOCELLULAR CARCINOMA:• Unifocal, multifocal or diffusely infiltrative tumor involving entire liver. • Cirrhosis of surrounding liver parenchyma is frequently present. • Strong propensity for invasion of vascular channels. HISTOPATHOLOGY OF HEPATOCELLULAR CARCINOMA:• Range from well- differentiated to anaplastic. • Neoplastic cells of well-differentiated tumors resemble hepatocytes & may show intracytoplasmic bile globules. 9

There's a variant of this HCC:-

# Fibrolamellar carcinoma • • • •

Variant of HCC. Young adults. Fibrous bands crossing between the tumor cells. Better prognosis because it is nodular, well-circumscribed and resectable by surgery. This is how it looks grossly (to the right), there is a scar. It looks like the Focal Nodular Hyperplasia. So you need differential diagnosis. To the left, you can see all the fibrous tissue intersectingbetween the hepatocytes randomly.

CLINICAL FEATURES‫‏‬OF PRIMARY HEPATIC CARCINOMA:• •

•

• •

Asymptomatic hepatomegaly. Patients with cirrhosis: – Rapid increase in liver size. – Sudden worsening of ascites. – Appearance of bloody ascites. – Fever & pain. In the Lab: alpha-fetoprotein: nonspecific tumor marker; if >1000 ng/ml it is highly suggestive of HCC. (where the marker for adenocarcinoma of the colon is CEA (Carcino- Embryogenic Antigen) and can be used for follow up). Prognosis is grim. Death within 6 months - 1 year due to: 1) Severe cachexia, 2) GI bleeding, 3) liver failure & 4) tumor rupture. Treatment: Complete surgical resection. (depends whether it is on the left/right lobe, which segment is affected … ). So it is not that easy, especially if the tumor arises on the background of a cirrhotic liver.

# CHOLANGIOCARCINOMA:• • • •

Malignant epithelial neoplasms of bile duct origin. (here the histology is adenocarcinoma). Less common than hepatocellular carcinoma. Not associated with etiologic factors related to HCC. Etiology: – Majority of cases are not associated with any known risk factor. – Radiologic contrast material: Thorostrast exposure. – Parasites in some parts of south-east Asia. – Opisthorchis sinensis (a parasite) infestation of biliary tract – Primary sclerosing cholangitis. – Intrahepatic (the bile duct within the portal tract) and extrahepatic (80-90% ; the hepatic duct and the common bile duct). 10

# In the hepatoma (HCC), the color was yellowish-greenish, and once you feel the tumor, it is soft. While in here, the color is white, and feels firm and hard, because it is all fibrotic. If the tumor is located between the right and left hepatic ducts this is called the Klatskin tumor.

Literally from the slides:-

Pathology of the cholangiocarcinoma: • • • •

Usually single tumor with a firm gritty consistency (because of the fibrosis). May be located in liver or biliary tree. Papillary, intraductal or diffuse. Klatskin tumor: present in the junction of the right and left hepatic ducts.

Histopathology of the cholangiocarcinoma:• • •

•

Usually well- differentiated, forming glands and tubular structures. (just like adenocarcinoma) Desmoplastic stroma (desmoplasia means fibrosis secondary to tumor). Bile pigment not present. (because the bile is produced then only transmitted via the bile ducts, so the ducts are only transmitters, not producers). May mimic metastatic adenocarcinoma.

How to differentiate between Adenocarcinoma, Choalngiocarcinoma, and Metastatic Carcinoma? (the doctor was displaying a picture and asking if we can differentiate depending on that picture only)

- No we can't. We should know the clinical scenario of the patient, if there is a tumor in the pancreas, then it is most likely a secondary tumor (metastatic). If the CT scan showed negative imaging of other tumors in other organs, then this is a primary tumor (Cholangiocarcinoma), because all other adenocarcinomas will look the same, sometimes you can’t tell the difference.

TUMORS OF THE BILIARY TRACT Carcinoma of the extrahepatic ducts: # If the carcinoma arises in the ampulla of vater, it is called Periampullary carcinoma (whether it is a Chalangiocarcinoma or Pancreatic carcinoma you can't tell the different, so we just call them periampullary carcinomas or periamplullary adencarcinomas). # The jaundice is the single alarming symptom to the patient, and it usually indicates a sort of advanced disease. But it's better to present with jaundice rather than not to present with this symptom, because the jaundice is an earlier stage to other complications. The Alkaline Phosphatase, the aminases, and the prothrombin time will always increase to –sometimes- liver cirrhosis. Diagnosis: we usually do endoscopy, CT scan, and retrograde endoscopy (through the ampulla of vater retrogradely to explore the bile duct). Prognosis: if the tumor is within the lumen of the bile duct, the symptoms will appear early, here the tumor is usually of a small size, and at this time this is your only chance to treat the patient by doing whipple's operation (we excise the pancreas, the duodenum, and a part of the stomach; even if the tumor is small). You need to be very aggressive to treat such adenocarcinoma, because the prognosis is very bad. And it doesn’t respond very well to chemotherapy.

(Again I'll copy the slides, some of the points are discussed above, some are not).: CARCINOMA OF THE EXTRAHEPATIC DUCTS:• • • • • • • • • • • • • •

Cholangiocarcinoma arising in extrahepatic ducts. Insidious behaviour, producing painless progressive jaundice. Older individuals, more in males. Periampullary carcinomas: arising in immediate vicinity of Ampula of Vater. At time of diagnosis, these tumors tend to be small in size. Most are firm nodules within bile duct wall. Some are diffusely infiltrative lesions. A few are papillary polypoid lesions. Adencarcinomas. Squamous features are uncommon. Jaundice, light stools, nausea, vomiting. Hepatomegaly & palpable gall bladder. Elevated alk. phosphatase & transaminases, PT… Dx: endoscopy. Px: despite small size, most are not surgically resectable at time of diagnosis.

GALLBLADDER CARCINOMA:(the doctor mentioned only two points about this; it presents late, and it usually carries a bad prognosis. Oh and he said it happens in the gallbladder  so here are the slides again:- ) • • • • • • • • • •

Commonest extrahepatic biliary tract cancer. Slightly commoner in women; peak 7th decade. Due to recurrent trauma and inflammation: usually associated with stones; pyogenic or parasitic. Pathology: Infiltrating or fungating growth pattern. Most are adenocarcinoma; 5% have squamous differentiation; minority are carcinoid tumors. At diagnosis, most have invaded liver, +/- cystic & biliary ducts, portahepatic LN. Seeding to peritoneum, GIT, and lungs. Insidious symptoms similar to cholelithiasis. If obstruction develops early: early Dx & Rx. Px: dismal. 5 year survival: 1%.

--------------------------------------- The end --------------------------------------Done by : Ibrahim Miqdady

Not an inside joke, I swear.

58/59 17/17 15

Pathology Diseases of Exocrine Pancres Hussam Telfah Yazan Mousa Thursday, 24/11/2011

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Wednesday, November 23rd, 2011 Pathology: Diseases of Exocrine Pancres Please note that I have only written what the doctor mentioned in the lecture. You can find the additional details in the powerpoint slides.

So we finished the liver and extrahepatic ducts, now we will go to the pancreas. It is 20 cm in length, weight is 60-140 gm. Two types histologically: Exocrine: Ducts surrounded by acinus. Produces [Trypsin, chemotrypsin, aminopeptidase, amylase]. Endocrine: Islets of Langerhans. Produces Insulin, Glucagon. ď ś Anatomy & Embryology Pancreas is a retroperitoneal organ; it is very difficult to reach in operations. Most people have just one pancreatic duct called the Duct of Wirsung (functional - carries pancreatic enzymes). However, some have an additional accessory pancreatic duct also called the Duct of Santorini (nonfunctional), which connects straight to the duodenum at the minor duodenal papilla. As you can remember in embryology, there are the dorsal and ventral buds which undergo rotation and fuse. The ventral mainly forms the head; dorsal forms the body and tail. The duct of the dorsal part (accessory pancreatic duct / Santorini) opens independently into the duodenum, while that of the ventral part (pancreatic duct / Wirsung) opens with the common bileduct. Sometimes the fusion between the two buds fails, and only the ventral opens into the Ampulla of Vater. The main duct of the pancreas will empty through the minor sphincter which is much smaller than the ampulla of vater. Once this congenital anomaly is present, it is more common to develop chronic pancreatitis.

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 Congenital anomalies Agenesis:-

Complete pancreatic absence. Usually associated with diverse severe malformations that are incompatible with life. IPF1 gene mutation.

Divisum:- [Mentioned Above]

Most common anomaly. Failure of fusion of the dorsal and ventral buds.

Annular Pancreas: -

Pancreatic head will surround the duodenum, this might lead to narrowing of the lumen of the duodenum / obstruction.

Aberrant (ectopic) pancreas:-

It is very rare, the doctor stated that he had seen it only once in his life; it could be a massive ectopic pancreas causing obstruction to the stomach. If we take a biopsy from the stomach, Meckel’s diverticulum or duodenum, sometimes we find focal pancreatic tissue in the submucosa. Asymptomatic usually, but with enzyme synthesis would be symptomatic.

Congenital Cyst:-

Part of a systemic polycystic disease involving the liver, kidneys, and other organs.  Cystic Fibrosis (CF)

It is the most common lethal genetic disease worldwide (1 in 2000-2500 live births). It is autosomal recessive. Features include viscous mucous secretions that lead to blockage of airways and pancreatic ducts, responsible for: 1) Recurrent chronic pulmonary infections. 2) Pancreatic insufficiency: The mucus will not be able to run down to the duodenum so there will be fatty malabsorption in the pancreas. 3) Sterility in males: Absence of Vas Deferens. 4) Infertility in females: Can get pregnant using IVF(In-vitro fertilization), 85% infertile. Diagnosis:-

The method we use in KAUH is to measure the NaCl in sweat (sweat test). If it is more than 40-50 mmol/L  suggestive of CF. [Normal ≈ 25 mmol/L]

Pathognesis:- Primary defect in transport of Cl_ across the lining epithelia of the duct. The cAMPdependent Cl_ channels (CF transmembrane conductance regulator [CFTR]) are defective. Gene is present on chromosome 7 with up to 300 mutations. Pathology:-

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Mucus accumulation, duct dilation & plugging, exocrine atrophy secondary to pressure by the accumulated mucus. Islets are usually spared. Ducts can be converted into cysts secondary to the increased intraluminar pressure. Surround stromi might become fibrotic. Malabsorption secondary to the absence of enzymes (particulary fat). Sometimes there is squamous metaplasia of the ducts.

Other presentation include Meconium ileus and pulmonary problems. Meconium is the greenish yellow stool of an early infant. Meconium Ileus: failure to produce meconium due to constipation / obstruction. Secondary infection due to inability to clear the mucus. Note: Mucus (noun), Mucous (adj) Treatment:- Gene therapy is effective.

 Acute Pancreatitis (AP) Diseases of the pancreas are classified into benign, neoplastic. Non-neoplastic is inflammatory  classified into acute and chronic. You should know a rough outline of these classifications for next year’s clinical rotations. Inflammation of the pancreas is almost always associated with acinar cell injury. (Acini secrete the enzymes and the ducts carries them) Etiologic factors:-

Alcohol and gall stones. Other causes include mechanical obstruction secondary to tumors or slough / biliary sludge. Parasite accumulation may obstruct the lumen. Drugs like the thiazides, antidiuretics, azathioprine and estrogens. Infections like Mumps, Cocksackie virus, Mycoplasma pneumonia may produce injury due to their virulence. Metabolic disorders; hypertriglyceridemia, hyperparathyroidism and other hypercalcemic states. Ischemic causes / trauma and mutations as well.

Pathology:-

Necrosis, edema, fat necrosis (destruction of fat secondary to the spillage of enzymes). We see necrosis, hemorrhage, neutrophilic inflammation in the pancreas and peritoneum; after a while if the case subsides down we might get a pseudocyst containing fluid produced from necrosed tissue. Pseudocyst:

Looks like a cyst but without epithelial lining.

  Red areas represent hemorrhagic pancreatitis. Yellow areas represent the fat necrosis of the pancreas.

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If we take a microscopical section. This is viable pancreatic tissue as well as necrotic area, and all is this white stuff is necrotic fat. The little red dots are dilated ducts or vasculature.  

How can we tell if this is necrotic or viable fat? The edges will be eosinophilic and nuclei will be absent. Once again if the nuclei are present, it is viable tissue. If nuclei are absent  necrotic. Pathogenesis:Autodigestion of pancreatic tissue by activated pancreatic enzymes. Trypsin plays a major role. It activates other proenzymes like proelastase, prophospholipase. Coverts prekallikrein to kallikrein, and activates the Hageman factor. Mechanisms of Pancreatic enzyme activation: 1) Pancreatic duct obstruction; edema, impaired blood flow, ischemia. 2) Primary acinar cell injury; causes include drugs, alcohol, infection  release proenzymes, hydrolases. 3) Defective intracellular transport of proenzymes within acinar cells. All these three mechanisms lead to acinar cell injury and enzyme activation which in turn cause lesions and lead to AP:

Clinical features:-

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Mainly abdominal pain, it is your job as a doctor to tell which organ is responsible by taking history, physical examinations, blood work etc. Pain radiating to the back.

Severity depends on how the organ is affected. Sometimes if the organ is diseased very severely the mode of presentation might be by a shock status. Hemorrhage, and release of vasodilatory agents, prostaglandins, bradikinins etc. A very high mortality rate is associated with severe cases (20-40%). Testing amylase is very important.  serum amylase and lipase;  Ca;  bilirubin,  glucose and glycosuria are all indicators. Calcium decreases because if you have pancreatic necrosis, the Ca will be deposited in the necrotic tissue  dystrophic calcification. Glucose is only affected if it has spread to the Islets of Langerhands as well. CT scan:-

It is possible to see inflammation and pseudocysts.

Death is due to:

1) shock, 2) secondary abdominal sepsis, 3) adult respiratory distress syndrome. So it is something very crucial to diagnose AP.

Treatment:-

Basicly supportive therapy, to prevent the intake by mouth. IV fluids to treat infection etc. There is no specific treatment for AP, just wait and observe.  Chronic Pancreatitis (CP)

If the stage of acute pancreatitis has gone away, but the process is repeating itself again and again, this might lead to CP. Fibrosis plays a crucial role here, and it is irreversible. Presentation is the same as before (abdominal pain and so on). Enzyme concentrations might be marginally elevated, which causes gall stones. Mechanisms are the same as AP; ductal obstruction or toxic injury or radical production etc. – all play a role in the pathogenesis. Pathology:-

The organ is hard because of the fibrosis. Ducts are dilated and you can also find calcification. If you do an X-ray to patient which CP, sometimes you might see the pancreas is occupied by a calcified mass. Formation of pseudocysts can also be present.

Clinical features:-

Attacks of pain or may be silent.

Diagnosis can be clinically, lab and CT – similar to AP. Prognosis:- Chronic disabling disease due to its major complications. Sometimes if it is severe enough it might lead to pancreatic insufficiency, fibrosis and diabetes mellitus. You can administer Insulin; enzymes can be given orally. The problem is that this process is very very very painful, the patient might form an addiction to morphine for example. Therefore the best treatment would be complete resection of the pancreas. You can see this histological slide. This is a dilated duct, all the surround is fibrotic tissue. If the disease isn’t very severe, the Islets might be spared like the situation below. But there are no acini, so there

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will be production or secretion of digestive enzymes. So this is CP:

A diagram of AP and CP and their related consequences is shown below:

 Neoplasms We have three things to remember in pancreatic cystic neoplasms: 1) Serous cystadenoma;

usually benign (adenoma).

2) Mucinous cystic neoplasms;

can be benign, borderline or malignant. If it is malignant we call it mucinous cystic adenocarcinoma. Affects women mainly (95%).

3) Intraductal papillary mucinousneoplasm;

solitary nodule in the head, usually in males.

Pancreatic Carcinoma Is a malignant epithelial neoplasm in exocrine portions (ducts + acini). Once you tell a patient that he has pancreatic adenocarcinoma, that is the end – consider it the end of his life; there is no treatment whatsoever. You can try operating on him, but it won’t be of much benefit. The problem is that the presentation is with jaundice (obstruction), so you can do the major operation – called the Whipple procedure – which is removal of the pancreas, part of the duodenum, part of the stomach and part of the gall bladder. It is a very painful, very sad way of death. The operation may last from 6 to 12 hours, it is not at all easy. It is the 4th most frequent cause of death from cancer. Pancreatic is not as common as lung or breast but it is the 4th most common. It has an increasing incidence in the West, peaks around 60 years of age, 7|Page

cause is unknown, they say it is more common in smokers (like bladder tumors). Location is in the head of the pancreas, which is better theoretically (not practically) beacause it produces obstructive symptoms and jaundice. The body and tail are usually silent and present only in very advanced disease. It involved the whole pancreas (head, neck, tail) in 20% of cases. The doctor stated that every time he saw a case of pancreatic adenocarcinoma, there was always lymph node metastasis! You can administer chemotherapy treatment maybe, but in 6 months – 1 year maximum the patient would have passed. It has a very bad prognosis. So by the likes of it what Steve Jobs had was not pancreatic adecarcinoma. Pathogenesis:-

As we discussed for the chronic cancer – dysplasia pathway is the same thing here. Grading includes 1A, 1B, 2 and 3 – these are like mild to moderate to severe dysplasia, and these stages are acccompanied by mutations (p16 gene, p53), or activation of the K-RAS oncogene.

Characterized by gritty gray hard masses, secondary to the extensive fibrosis. Adenocarcinomas as we said is the most common type. Head of pancreas causes bile duct obstruction  jaundice. Lymph node and liver metastasis is common, if it is very extensive it might reach the lungs or bones. Appearance is difficult to see, but its much easier to feel the hardening due to accumulation of fibrotic tissue. If there is neutrophil infiltration in the lumen of the gland then this will be a malignant duct. Tumor markers include CEA (like colon), and also CA19-9. They are non-specific but usually raised. For example the marker for the liver is the Alpha-Fetoprotein (AFP), in the colon there’s the CEA as we said, in the ovary it is CA-125. Prognosis is said to be 1 year, and 5 year survival rate is less than 5%; it seems that Steve Jobs was part of that 5%. On the same note, according to Wikipedia - Jobs had stated that he had a rare, far less aggressive type of pancreatic cancer known as islet cell neuroendocrine tumor. The End From Steve Jobs Stanford Commencement Speech 2005: "I have looked in the mirror every morning and asked myself: "If today were the last day of my life, would I want to do what I am about to do today?" And whenever the answer has been "No" for too many days in a row, I know I need to change something."

Done by Yazan Mousa 8|Page