LIVER PATHOLOGY by IHC001

Liver Pathology Judy Wyatt

LP1 66F Childs A cirrhosis. Hepatitis C positive. Tumour in right liver

HCC

LP1 • Insufficient background liver for comment here - include comment on background liver if possible i.e. cirrhotic or not. • Moderately differentiated- cells clearly resemble hepatocytes. • If very well-differentiated – diagnosis of HCC vs. dysplastic nodule is difficult, – absence of Reticulin and diffuse lesion positivity for CD34. – New – glypican 3, glutamine synthetase, HSP70 – any 2 favour HCC

• If poorly differentiated, ? HCC – pCEA or CD10 canalicular staining. – Hep Par1 80- 90%, better differentiated. – AFP- around 10%, can be individual cells, poorly differentiated, serum AFP more reliable. – New - Glypican 3 – oncofetal, specific, glutamine synthetase, arginase 1

LP2 66 F Palliative resection of liver metastasis enlarging on chemotherapy with good response in others.

LP2 66 F Palliative resection of liver metastasis enlarging on chemotherapy with good response in others. met CRC with SIRT

LP2 • Central dirty necrosis surrounded by tumour, expansile. • Depressed capsule- indicates shrinkage from previous treatment. • SIRT microspheres in tumour and background liver. • Range of neoadjuvant treatments being used for metastatic colorectal cancer. • Commonly Oxaliplatin/ 5FU- association with sinusoidal obstruction syndrome in background liver.

LP3 22 F 3 month history of abdominal discomfort. Hepatomegaly.

Metastatic fibrolamellar carcinoma

LP3 • Distinctive histology. • Lamellar fibrosis, abundant eosinophillic cytoplasm in tumour cells, often also with cytoplasmic inclusions. • All tumour like this – sometimes see smaller areas in conventional HCC – this is not FLC • This is metastases in lymph node- conventional HCC metastasises via blood stream, but FLC via lymph node and through peritoneal cavity - can present as ?primary gynae malignancy in young women. • Not associated with chronic liver disease – therefore better prognosis than conventional HCC

LP4 76M Liver resection for metastatic colorectal cancer.

Metastatic CRC in bile duct

LP4 • Polypoid tumour, sharp cut off with normal bile duct epithelium. • With histological pattern of primary CRC, • Immunos CK7 & 20 • Background liver- portal inflammation of peritumoral effect, also portal features of large duct obstruction and parenchymal atrophy in the section of liver upstream from biliary obstruction

LP5 32 F Liver lesion for 4 years, detected on scan. Originally thought to be FNH but ? adenoma so resected. Macro: 4cm diameter lesion, ill defined,

Hepatocellular adenoma – inflammatory type

LP5

• Demarcated lesion without any capsule • No portal tracts - unaccompanied arteries with mononuclear cells. • Sinusoidal telangiectasis. • Age, sex and background liver important in differential.

• Check no Reticulin deficiency (may be absent in steatotic ones). CD34 can be positive throughout adenomas. • Differential from well-differentiated HCC and focal nodular hyperplasia- can be difficult on biopsy. • New classification of adenomas – molecular/immunos

– Inflammatory (I-HCA)– SAA, CRP +ve, telangiectasia, FNH-like • Some of these also beta catenin activated

– HNF1 inactivated (H-HCA) – steatotic, female, LFA binding protein –ve (background +ve) – B catenin activated (B-HCA) – atypia, glutamine synthetase +ve has higher risk of HCC development

New molecular classification of liver cell adenomas – ‘the French Revolution’ HNF1 inactivated

Beta catenin activated

Inflammatory (telangiectatic)

Gender

women

men

Women > men

Frequency

35-40%

10-15%

45-60%

10%

Histology

Fatty change

Atypia

Thick vessels, inflammation, ductular reaction

Nothing in particular

clinical

May be multiple

Risk of malignancy

CRP and ESR

Immunohisto Chemistry

LFABP –ve

Glutamine synthetase +ve, Nuclear b-catenin

Serum amyloid A +ve CRP +ve Some GS+ve

Male hormones, glycogenosis

Obesity, fatty liver,

(liver fatty acid binding protein)

diabetes

unclassified

All un-informative

LP6 52 M Liver transplant for PSC.

Hilar cholangioCa

LP 6 • Sleeve- like expansion of bile duct wall without intraluminal exophytic component. • Perineural infiltration. • Early lymph node micrometastases. • Early lymphatic invasion and often reaches serosaextent of tumour is not apparent at surgery or cut up. • Cholangiocarcinoma - TNM7 new 2010 classification distinguishes intrahepatic from hilar. • Intrahepatic usually expansile, mass forming. • Hilar usually periductal infiltrating.

LP7 • 40 F • Symptomatic mass in right liver

LP7 • 40 F • Symptomatic mass in right liver • Focal Nodular Hyperplasia

LP7 • With focal liver lesions, look for uninvolved background liver- rim of lesion can be quite subtle. • Distinction from adenoma- arteries often thick walled and associated with fibrous septa • Often areas of marginal ductular reaction +/- inflammation. • Maybe focal fatty change, steatohepatitis, sinusoidal dilatation. • If sinusoidal dilatation prominent - consider diagnosis of inflammatory adenoma • If in doubt about diagnosis – glutamine synthetase has map-like positivity in FNH, (diffuse in B-HCA). SAA or CRP positive in I-HCA • Typical FNH with central scar diagnosed on imaging, not usually resected. Indications for surgery – symptomatic or diagnosis uncertain.

LP8 • 52 F • Liver mets on ultrasound

LP8 • 52 F • Liver mets on ultrasound • Metastatic adenocarcinoma, Breast

LP8 • Note how portal tracts are still present with tumour replacing the parenchyma (different from met. CRC pattern). • Commonest primary sites with unknown primary are upper GI (stomach, pancreas, biliary tree) lung, breast. • Nice guidelines for metastases with unknown primary - CK7, CK20, TTF1, ER (women), PSA (men) PLAP (met germ cell tumour). • New RCPath dataset – cancer of unknown primary – lots of useful IHC tables based on morphological pattern. • Further markers depend on clinical circumstances.

LP9 34 F excision of liver cyst - previously deroofed.

mucinous cystic neoplasm (previously hepatobiliary cystadenoma)

LP9 • Uni or multiloculated cyst with columnar/ cuboidal lining and underlying cellular mesenchymal stroma, ovarian like • This one complicated by oedema/ epithelial loss - due to previous surgery/ partial excision. • Women only - multiple blocks for papillary tumour/ carcinoma - same spectrum as cystadenoma in ovary. • Differential diagnosis of liver cyst with epithelial lining.

– Simple bile duct/ biliary cyst – Multiple = Part of fibropolycystic spectrum (also von Meyenberg complexes). – Choledochal cyst. – Ciliated foregut cyst Neoplastic (= as for pancreas) : – Mucinous cystic neoplasm (hepatobiliary cyst adenoma with mesenchymal stroma). – Intraductal papillary neoplasia (cyst secondary to neoplasia). In situ or invasive adenocarcinoma: - Adenocarcinoma arising in mucinous cystic neoplasm or IPNB - Or in a choledochal cyst

LP10 • 50 F • Hepatitis C plus cirrhosis secondary to alcohol. • 1cm hypoechoic lesion segment IV, core biopsy.

LP10 • 50 F • Hepatitis C plus cirrhosis secondary to alcohol. 1cm hypoechoic lesion segment IV, core biopsy. • HCC and ? haemochromatosis

LP10 • Tumour plus background liver• Background liver- although little tissue here, fibrosis and nodularity suggests underlying cirrhosis (also given in history). • Plentiful iron in hepatocytes- check with Perl’s stain. This patient had haemochromatosis. • Tumour of well differentiated hepatocytes. Comparison with background cirrhotic nodules is helpful. • Thick cell plates, pseudo-glandular formations, unaccompanied arteries, sharp margin without ductules. • Differential diagnosis of nodular lesion in cirrhotic liver – macroregenerative nodule – dysplastic nodule – hepatocellular carcinoma.

• Reticulin, CD34,

– Glutamine synthetase, glypican 3, HSP70 – interpretation can be difficult.

Case 10 retic

LP11 • 30 M • Liver cyst

LP11 • 30 M • Liver cyst • hydatid cyst

LP11 • Laminated membrane characteristic, don’t always see scolices. • Dense fibrous wall with inflammation at outer edge characteristic. • No epithelial lining to cyst. • Generally come with diagnosis already madeother resected cysts quite often come as ?hydatid.

LP12 • 58 M • Jaundice with lesion in liver ?pancreatic primary. Recent treatment for head and neck SCC

LP12 • 58 M • Jaundice with lesion in liver ?pancreatic primary. Recent treatment for head and neck SCC • metastatic undifferentiated carcinoma

LP12 • Undifferentiated malignancy in liver• This one looks like angiosarcoma, but markers showed it to be metastatic undifferentiated carcinoma. • Always remember metastatic melanoma. • Comment on background liver- canalicular cholestasis- consider lesion obstructing bile duct, although with severe liver replacement could just reflect liver failure.

Case 12 AE1/3

Case 12 CD31

LP13 • 37 F • Multiple liver lesions said to be mainly FNH but large adenoma thought to contain HCC on MRI. (2 slides)

LP13 • 37 F • Multiple liver lesions said to be mainly FNH but large adenoma thought to contain HCC on MRI. (2 slides) • FNH and angiomyolipoma

LP13 • Two separate lesions in one of the slides with quite different features. • FNH, quite often multiple, patients with multiple lesions may have mixture of FNH and adenoma. • The other lesion has a superficial resemblance to hepatocytes, but cell morphology is quite different. • Needs multiple blocks to find the fatty bit. Patch work of different morphologies. Extramedullary haematopoiesis. • Angiomyolipoma- rare in liver, main thing is to think of it. Imagine getting this on a biopsy! • As ?HCC is not biopsied if surgical resection is feasiblesee a range of large tumours diagnosed first on resection specimen.

Case 13 MelanA

Liver special stains

Usual panel Architecture: Retic van Gieson Shikata Hepatocytes: PAS, PASD, Shikata

Pigment: Perl’s

Usual panel Architecture: Retic – liver cell plates, stage of chronic liver disease van Gieson – mature collagen, acute v. chronic liver disease, hepatic veins Shikata – elastic, in vessels and long standing fibrosis

Hepatocytes: PAS, PASD, Shikata

Pigment: Perl’s

60 M Treated haemochromatosis, Transplant for HCC

Van Gieson

Shikata

64M hepatitis B cirrhosis

Chronic liver disease stage scores and quantitative liver fibrosis measurements.

Standish RA et al, Gut 2006;55;569-578

http://www.virtualpathology.leeds.ac.uk/eqa/specialist/liver/live rdocs/2017/Fibrosis%20stage%20reference%20images.v%20Ju ne.pdf

reticulin

Van Gieson

Usual panel Architecture: Retic van Gieson Shikata Hepatocytes: PAS, PASD, Shikata

Pigment: Perl’s

Usual panel Architecture: Retic van Gieson Shikata Hepatocytes: PAS – well fixed biopsies, demonstrates hepatocytes, limiting plate PASD – active Kupffer cells, A1ATD, bile ducts, basement membrane Shikata – copper-associated protein, HBsAg Pigment: Perl’s

PAS

Interface hepatitis

PAS x20

PAS diastase

Shikata Orcein stain Elastic Hepatitis B sAg Copper-associated protein

Shikata

Rhodanine

Shikata

Usual panel Architecture: Retic van Gieson Shikata Hepatocytes: PAS, PASD, Shikata

Pigment: Perl’s – iron – hepatocytes, other cells

Perls

Immunohistochemistry? • Mallory bodies in steatohepatitis – Ubiquitin – CK8/18 – Cam 5.2

• Bile ducts and ductular reaction – CK7

• Others – alpha 1 antitrypsin,

viruses – hepatitis B, CMV, HSV

Tumours – another talk……..

CK8/18

ubiquitin

Medical liver biopsies

LP14 40 F previously fit and well. 1 week history of lethargy and nausea. No other symptoms. Negative liver screen. Autoantibodies negative ?seronegative AIH.

LP14 40 F previously fit and well. 1 week history of lethargy and nausea. No other symptoms. Negative liver screen. Autoantibodies negative ?seronegative AIH. Acute hepatitis

LP14 • Acute hepatitis• Key thing is to recognise lobular disarray- variation in liver cell size, staining, apoptotic (acidophil) cells, sinusoidal inflammation, Kupffer cells. • ?Any confluent necrosis- spotty, zonal, bridging, pan-acinar. • ?Amount of portal inflammation- if prominent with plasma cells- likely autoimmune. • If eosinophils- possibly drug related but unreliable sign. • Causes of acute hepatitis– – – –

Autoimmune, drugs, viral (ABE). Seronegative- about 70% in adults.

Case 14 PASD

Case 14 retic

Case 14 vG

LP15 • 40 F • Tired for 3 months, no itching. Increased bruising 2 weeks. Jaundice 2 days. PT 34, bilirubin 178, ALT 1438, ALP 390. Ultrasound scan- no biliary dilatation ?AIH.

LP15 • 40 F • Tired for 3 months, no itching. Increased bruising 2 weeks. Jaundice 2 days. PT 34, bilirubin 178, ALT 1438, ALP 390. Ultrasound scan- no biliary dilatation ?AIH. • acute hepatitis with confluent necrosis

LP15 • Areas of confluent pan acinar/ multi acinar necrosis• All hepatocytes have disappeared. Usually marked ductular reaction around portal tracts. • Elsewhere- acute lobular hepatitis with lesser degrees of necrosis and some regeneration- quickly forms nodules and mimics cirrhosis. • Important to recognise this entity - fall in ALT may be false impression that liver is improving - raised prothrombin is important mark of liver cell failure. • Important to recognise - needs referral to tertiary liver centre.

LP16 • 40F • Liver transplant for subacute liver failure. Liver explant

LP16 • 40F • Liver transplant for subacute liver failure. Liver explant • acute hepatitis with confluent necrosis (explant of case 15, 4 days after biopsy)

LP16 • Note geographic areas of confluent necrosis with wrinkled capsule, elsewhere bridging hepatic necrosis and emerging nodularity. • Histology did not indicate the underlying aetiology- clinically raised IgG and smooth muscle antibody. • 40% of autoimmune hepatitis present acutelyusually non-specific histology.

LP17 • 52 F • Rapid onset jaundice and ascites over 2 weeks. Previously well. Denies alcohol excess but may have been drinking 8 units/ day. • Initial suspicion of Budd- Chiari syndrome, but hepatic veins seen on CT to be patent.

LP17 • 52 F • Rapid onset jaundice and ascites over 2 weeks. Previously well. Denies alcohol excess but may have been drinking 8 units/ day. Initial suspicion of BuddChiari syndrome, but hepatic veins seen on CT to be patent. • alcoholic steatohepatitis with cirrhosis

LP17 •

Necessary features for steatohepatitis-

•

Helpful, more reproducible features not essential for diagnosis-

•

No features of Budd Chiari- sinusoidal fibrosis in ASH causes portal hypertension at relatively early stage in evolution.

•

Alcoholic SteatoHepatitis v Non-Alcoholic Steato Hepatitis

•

ASH vs. NASH - can only be made with clinical history but some features that would favour ASH:

– Fatty change, inflammation, ballooning. – Mallory bodies, pericellular fibrosis.

– Lots of fibrosis and Mallory bodies- tend to favour alcohol over NASH. • Extreme example = central sclerosing hyaline necrosis.

– Canalicular cholestasis- in severe alcoholic steatohepatitis, not NASH. – No nuclear glycogenation.

•

Reporting alcoholic biopsies-

– If high alcohol in clinical information- report as alcoholic steatohepatitis. – If no alcohol history given - report steatohepatitis, histology suggests alcohol related.

Case 17 PAS

Case 17 retic

Case 17 vG

LP 18 • 61 F • Obesity, hypertension, diabetes, ovarian cancer and low alpha- 1- antitrypsin level.

LP 18 • 61 F • Obesity, hypertension, diabetes, ovarian cancer and low alpha- 1- antitrypsin level. • NASH, minimal fibrosis

LP 18 • Fatty liver – macrovesicular steatosis • Additional features of steatohepatitis are mild and patchy. Nevertheless appreciable fibrosis. • Fibrosis is perivenular, occasionally with bridges to portal tracts. • Some portal tract inflammation is common assess whether this is component of NASH, or sufficient to consider a dual diagnosis with another chronic hepatitis. • History of low alpha- 1- antitrypsin – no globules visible, but need PASD to exclude.

LP 19 • 54 M • Has ulcerative colitis. Itching. Raised alk phos.

• Primary sclerosing cholangitis

LP19 • • • • •

Early stage chronic liver disease - Not much fibrosis. Patchy mild portal inflammation. Obvious ductopenia - match hepatic arteries and bile ducts, should be 90%. In this example- fibro-obliterative scars. Very little ductular reaction normally seen in chronic biliary disease. Parenchyma - cholestatic rosettes although bilirubin bile plugs difficult to find.

• • • •

Special stains will help. VG and Reticulin for fibrosis stage. Shikata for copper- associated protein. CK7 for bile ducts and ductular reaction . and periportal intermediate hepatobiliary cells

• •

Role of pathologist- recognise biliary disease. Needs imaging to evaluate. About 10% PSC is small duct only - changes like this with normal imaging of biliary tract.

LP 20 • 78 Male. • Recent onset jaundice, deranged LFTs

• Large bile duct obstruction

LP20 • Portal tracts all show oedema, enlargement, ductular reaction, inflammatory cells include neutrophils. • “Biliary gestalt”- with oedema, recent large duct obstruction. • Without oedema, with copper- associated protein – chronic duct obstruction.

• Variable among portal tracts- consider intrahepatic obstruction i.e. PSC. • Distinguish pigment in zone 3 hepatocytes- ceroid vs. bilirubin. • Comment on bile duct present/ ductopenia and ?neutrophils within main bile ducts – ascending cholangitis.

LP 21 • 12 M • recent onset abdominal swelling ascites and large liver.

• venous outflow obstruction

LP 21 • Red blood cell extravasation in to space of Disse, replacing hepatocytes• Sinusoids appear empty. • Not lobular hepatitis. • This is venous outflow obstructiondifferential diagnosis

– Budd Chiari syndrome, – veno-occlusive disease / sinusoidal obstruction syndrome.

• Do collagen stain to look for occluded hepatic veins.

LP 22 • 12 M • Liver explant. Previously failed hepatic vein stent. Factor V Leiden heterozygote. (2 slides)

• Budd Chiari in explant – • 6 weeks after biopsy LP21

LP 22 • Stenting failed. Factor 5 Leiden heterozygous. Enormous congested liver (2kg in 12 year old boy). • Variable chronicity, some areas with fibrosis. • Small intrahepatic terminal hepatic veins are patent- request van Gieson to make sure whenever see congested liver. • Large hepatic veins contain thrombus, variable organisation.

• Acute Budd Chiari syndrome - acute presentation, but usually the last straw with underlying chronic changes. Patient with ascites and hepatomegaly. • Most cases have underlying pro-coagulant abnormality. Initial management is stenting plus anticoagulants. • Important diagnosis not to miss.

Case 22 vG

LP 23 • 60 M • HIV on HAART.Non-cirrhotic portal hypertension.

• Obliterative portal venopathy

LP23 • Obliterative portal venopathy • Encompasses previous diagnoses:

– non-cirrhotic portal hypertension/ nodular regenerative hyperplasia/ hepatoportal sclerosis

• Subtle and easy to miss.

• Result of irregular perfusion due to obstructed portal vein branches, with increased arterial supply resulting in hyperplastic nodular parenchyma areas. • Portal hypertension/ varices but good synthetic function. • Associated with systemic inflammatory disorders, e.g. rheumatoid, also drugs- e.g. chemotherapy, recently reported in HIV. • Mild degrees are common and of no clinical significance- analogy with benign atherosclerotic nephrosclerosis in kidneys.

LP 24 • 27 M • HBV. Fluctuating LFT's/ viral levels.

LP 24 • 27 M • HBV. Fluctuating LFT's/ viral levels. • Mild HBV and a granuloma

LP 24 • Biopsy for staging HBV• Chronic hepatitis B, e-antigen negative, high viral load, raised ALT= usual indication for biopsy. • Stage and grade disease - descriptive or use Ishak. • This one portal fibrosis less than half portal tracts no bridging- stage 1. • Mild portal inflammation, minimal interface hepatitis, mild lobular necroinflammation- grade 2- interobserver variation. • Also a granuloma - may be explanation for raised ALT. • Differential diagnosis of granulomas in liver- in UK, – usually PBC, sarcoid, drugs, TB.

• Often no cause found.

Case 24 retic

Case 24 Shikata

LP 25 • 36 M • hepatitis C, genotype 1

LP 25 • 36 M • hepatitis C, genotype 1 • hepatitis C, stage 5, grade 5

LP 25 • Young man, clinically early stage, but pathologically stage 5, grade 5• Features of chronic hepatitis C - steatosis, bile duct lesions, lymphoid follicles, • Range of clinical progression- rapid progression commoner in – Older age of acquisition, male, co- infection with other viruses, alcohol. steatosis

• Fatty change- genotype 3, as direct viral effect. • Genotype 1 - cofactor with metabolic syndrome. • Unusual to see steatohepatitis as well - lobular necroinflammation and swollen hepatocytes should not be reported as steatohepatitis. • Indications for biopsy?

Previously this was the commonest indication for liver biopsy Now – very rarely biopsied – treatment successful for all genotypes and all stages do fibroscan to determine stage, Biopsy if clinical liver screen has evidence of an additional diagnosis

Thank you

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