GYNAECOLOGICAL PATHOLOGY by IHC001

Gynaecology Pathology Jan 15th 2020 Pedro Oliveira/Christie Hospital

The “Challenges”…

Review of the cases Overall approach Some modern concepts Practicalities

CASE 1 - 61 yr. Vulvar leukoplasia. Vulvar biopsy

Why

Case GY1

Dx: Lichen Sclerosus • Band of homogenised stroma in superficial dermis • Band of inflammatory cells below • Epithelial basal degeneration • 1-5% may develop SCC • Association with well-differentiated VIN

VIN Classic VIN

Well-differentiated VIN

• • • • •

• • • •

HPV Peak in younger women Loss of maturation Crowding Dyskeratosis

Post menopausal women Lichen sclerosus Elongation of rete ridges Prominent intercellular bridges • Keratin pearls • Abundant eosinophilic cytoplasm • Enlarged nuclei with nucleoli

Histopathology 2020, 76, 128–138. DOI: 10.1111/his.13989

REVIEW

Vulval squamous cell carcinoma and its precursors Why

Naveena Singh1 1

& C Blake Gilks2

Queen Mary University of London, London, UK, and 2Vancouver General Hospital, Vancouver, BC, Canada

Singh N & Gilks C B (2020) Histopathology 76, 128–138. https://doi.org/10.1111/his.13989

Vulval squamous cell carcinoma and its precursors Vulval squamous cell carcinoma (VSCC) can arise through two distinct pathways [human papillomavirus (HPV)-associated and HPV-independent], and these VSCC variants are recognised as different disease entities on the basis of different aetiologies, morphological features, molecular events during oncogenesis, precursor lesions, prognosis, and response to treatment. The precursor of HPV-associated VSCC, variously referred to as high-grade squamous intraepithelial lesion (HSIL) [vulvar intraepithelial neoplasia (VIN) 2/3] or usual-type VIN, is morphologically identical to the

more common HSIL (cervical intraepithelial neoplasia 2/3) of the cervix. The precursor lesions of HPVindependent VSCC include differentiated VIN, differentiated exophytic vulvar intraepithelial lesion, and vulvar acanthosis with altered differentiation; these have been under-recognised by pathologists in the past, leading to delays in treatment. This review will discuss the recent advances in diagnostic surgical pathology of VSCC and its precursors, and how these diagnoses can impact on patient management.

Keywords: DEVIL, dVIN, HSIL, squamous cell carcinoma, VAAD, VIN, vulva

136

N Singh & C Blake Gilks

HPV-Independent VIN

p53 wild-type

p53 Indeterminate

VAAD

DEVIL

Verrucous Carcinoma

VSCC “low-grade”

p53 abnormal

dVIN

VSCC “high-grade”

Figure 11. Precursors of human papillomavirus (HPV)independent vulval squamous cell carcinoma (VSCC) (HPVindependent vulvar intraepithelial neoplasia). A schematic is shown depicting the relationship between abnormal p53 immunostaining/TP53 mutation (second row), precursor lesions (third row), and the invasive carcinomas that they can give rise to (fourth row). ‘Low-grade’ and ‘high-grade’ refer to degree of nuclear atypia in the invasive VSCC.

recognise the very subtle histological findings in HPVhypothesis, given that the same differential sensitivity independent VSCC precursors and putative precursors, to radiation has been shown for head and neck squaespecially those that lack TP53 mutations. Close intermous cell carcinomas.51,52 Given that the HPV-indeaction with cliniciansacanthosis is required, with with excisional biopsy differentiation) pendent carcinomas are associated with a worse (vulvar altered of any clinically suspicious lesion, given that a superfiprognosis and are therefore more likely to receive cial biopsy may be non-diagnostic. A discrete hyperplasradiotherapy, it is particularly important to address tic lesion, in which there is no clinical factor identifiable this issue. Another aspect of treatment that might be vulvar intraepithelial that could(differentiated have incited such aexophytic hyperplastic reaction based on HPV statuslesion) is the extent of surgery. In data (that is, there is overgrowth of the squamous epithelium from our centre, a more favourable prognosis associas a result of autonomous growth, independently of ated with HPV-associated VSCC was seen only in normal signals, in a discrete geographical distribution cases from after 1995, when there was a shift from suggestive of clonality), cannot be ignored, even if an more extensive surgery to less disfiguring, more con-

• VAAD • DEVIL

L.A.S.T. terminology

Why

LSIL vs HSIL

Interpretation of p16 Immunohistochemistry In Lower Anogenital Tract Neoplasia

Why

Authors: Naveena Singh1, C Blake Gilks2, Richard Wing-Cheuk Wong3, W Glenn McCluggage4, C Simon Herrington5 1

Barts Health NHS Trust, London, UK; 2Vancouver General Hospital 3Pamela Youde Nethersole Eastern Hospital, Hong Kong, Belfast Health and Social Care Trust, Belfast, UK; 5University of Edinburgh

Background https://www. thebagp.org/resources/?wpdmc=bagp-guidance-documents p16INK4A •

p16INK4A (henceforth referred to as p16) immunohistochemistry (IHC) is a good

surrogate test for the presence of a potentially transforming human papillomavirus (HPV) infection in anogenital carcinomas and premalignant lesions1.

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Dx: Paget’s Disease • • • • •

Single cells/clusters in epidermis Pale often vacuolated cytoplasm Exclude invasion 30% ? Related to malignancy in pelvis 5% ? Synchronous/metachronous malignancy 30%

CK7, EMA, CEA, HER-2

VULVA - review

NON-TUMOUR • Lichen sclerosus • Dermatosis • Cysts • Inflammation

TUMOURS • VIN (LSIL/HSIL) • Paget’s • Melanoma • Soft tissue neoplasms • Skin adnexal tumours

CASE 2 - 51 yr. Hysterectomy 2 yrs ago. Vaginal bleeding? Granulation tissue at the vaginal vault - biopsied

Why

Case GY2

Dx: Falopian Tube Prolapse

• Clinical history – previous hysterectomy • Think laterally • Benign nature of epithelium – no atypia/ mitoses

VAGINA - review NON-TUMOUR • Infections • Cysts • Endometriosis • Fallopian tube prolapse

TUMOURS • VAIN + SCC • Adenocarcinomas – DES exposure • Melanoma • Soft tissue lesions – as vulva

CASE 3 - 37 yr. Hysterectomy for endometrial hyperplasia. Section of the cervix

Why

Case GY3

Dx: Mesonephric Remains

• Cluster of tubules • Hyaline secretion • Cuboidal cells with distinct basal membrane • CD10 +ve

Q&A How do you know that a LG Endoc ADC is

INVASIVE?

The Christie NHS Foundation Trust

164

REVIEW

Endocervical glandular lesions: controversial aspects and ancillary techniques W G McCluggage

J Clin Pathol

.............................................................................................................................

J Clin Pathol 2003;56:164–173

The incidence of malignant and premalignant endocervical glandular lesions is increasing. This review covers controversial and difficult aspects regarding the categorisation and diagnosis of these lesions. The terminology of premalignant endocervical glandular lesions is discussed because of the differences between the UK terminology and the widely used World Health Organisation classification. The morphology and histological subtypes of premalignant endocervical glandular lesions are described. Early invasive adenocarcinoma and difficulties in the diagnosis and recognition of this entity are covered, as is the measurement of early invasion within cervical adenocarcinoma. Several benign endocervical glandular lesions can mimic malignant and premalignant endocervical glandular lesions, and the distinction of these benign mimics from premalignant and malignant lesions using ancillary immunohistochemical studies is also covered. Antibodies used to distinguish between endometrial and endocervical adenocarcinoma, in the diagnosis of cervical minimal deviation adenocarcinoma of mucinous type (adenoma malignum), and in the diagnosis of cervical mesonephric lesions are also reviewed. ..........................................................................

M ....................... Correspondence to: Dr W G McCluggage, Department of Pathology, Royal Group of Hospitals Trust, Grosvenor Road, Belfast BT12 6BL, UK; glenn.mccluggage@bll.n-i. nhs.uk Accepted for publication 17 October 2002

.......................

www.jclinpath.com

alignant and premalignant endocervical glandular lesions are relatively rare but their incidence appears to be increasing.1 2 Most of this increase is more apparent than real because of the better recognition of premalignant endocervical glandular lesions by histopathologists and the realisation that some poorly differentiated cervical carcinomas are glandular in type. In addition, in many countries there has been a reduction in the incidence of invasive squamous cell carcinoma because of the success of organised cervical screening programmes. However, there is some evidence that there is also a real increase in the incidence of malignant and premalignant endocervical glandular lesions,3 which are thus assuming increasing importance in diagnostic surgical pathology. For example, a study from Sweden found that the incidence of cervical adenocarcinoma increased from 1.59/100 000 person years in the 1950s and 1960s to 2.36 in the early 1990s.3 The corresponding figures for cervical adenocarcinoma in situ

(AIS) were 0.04 and 1.37, reflecting an even greater increase. “There is some evidence that there is also a real increase in the incidence of malignant and premalignant endocervical glandular lesions, which are thus assuming increasing importance in diagnostic surgical pathology” Previous reviews have mainly concentrated on morphological subtypes of cervical adenocarcinoma and on the histopathological features of the many benign mimics of malignant and premalignant endocervical glandular lesions.4–6 I will not cover these topics in detail in this review. Rather, I will concentrate on controversial aspects of endocervical glandular lesions. These include terminological aspects of premalignant endocervical glandular lesions because different terminologies are in use. In addition, the morphological features of premalignant glandular lesions will be described, including some recently reported variants. The difficult area of early invasive cervical adenocarcinoma will be reviewed and some guidance given on how to measure early invasive foci. Ancillary immunohistochemical studies of value in the distinction of benign mimics from malignant and premalignant endocervical glandular lesions will be reviewed. Ancillary techniques useful in the distinction of endocervical and endometrial carcinoma, in the diagnosis of the mucinous variant of cervical minimal deviation adenocarcinoma (MDA) (adenoma malignum), and in the diagnosis of cervical mesonephric lesions will also be discussed.

TERMINOLOGY OF PREMALIGNANT CERVICAL GLANDULAR LESIONS The World Health Organisation (WHO), under the auspices of the International Society of Gynecological Pathologists, categorises premalignant endocervical glandular lesions as endocervical ................................................. Abbreviations: AIS, adenocarcinoma in situ; AISM, atypical immature squamous metaplasia; CEA, carcinoembryonic antigen; CGIN, cervical glandular intraepithelial neoplasia; CIN, cervical intraepithelial neoplasia; EGD, endocervical glandular dysplasia; ER, oestrogen receptor; HCGIN, high grade cervical glandular intraepithelial neoplasia; HPV, human papillomavirus; LCGIN, low grade cervical glandular intraepithelial neoplasia; MDA, minimal deviation adenocarcinoma; MGH, microglandular hyperplasia; PAS, periodic acid Schiff; TEM, tubo-endometrial metaplasia; WHO, World Health Organisation

56:164–173, 2003

“When cribriform and/or solid areas are extremely prominent and confluent then a diagnosis of invasion should be strongly considered, especially if there is an associated stromal reaction”

CASE 4 - 27 yr. Severe dyskaryosis on smear. Cervical biopsy

Why

Case GY4

Dx: CIN & CGIN • Look for both • Exclude invasion: CGIN - gland complexity, deep glands. • Exclude invasion: CIN – crypts with debris, inflamed vascular stroma • Correlate with smear • L.A.S.T. classification: HSIL/LSIL • p16 IHC

Q&A How do you ≠ an Endoc

vs Endom ADC? The Christie NHS Foundation Trust

Endocervical:

p16 and CEA (+); vimentin, ER, and PR (-)

Endometrial:

p16 and CEA (-); vimentin, ER, and PR (+)

CERVIX - review NON-TUMOUR

TUMOURS

• Infections • Microglandular hyperplasia • Mesonephric remnants • T.E.Metaplasia

• CIN, CGIN • Squamous cell carcinoma • Adenocarcinoma • Small cell carcinoma

CASE 5 - 35 yr. Heavy periods. Polycystic ovaries. Endometrial biopsy

Why

Case GY5

Dx: Disordered Proliferation

• Prolonged oestrogenic stimulation • Some normal glands cf. simple hyperplasia • Ciliated and syncytial metaplasia • Dilated irregular glands • Stromal aggregation and breakdown

CASE 6 - 42 yr. Menorrhagia. Day 7. Endometrial biopsy

Why

Case GY6

Dx: Menstrual Endometrium

• Glandular and stromal breakdown • Necrosis and haemorrhage • Predecidual stroma and glandular exhaustion • Nuclear dust at base of glandular epithelium • Condensed stroma with overlying papillarysyncytial change • Intravascular fibrin thrombi • Stromal Granulocytes

Exogenous Progesterone Effect

Dx: Progesterone effect

• Polypoidal appearance – may look worrying at hysteroscopy • Pseudodecidua • Thin ectatic vessels • Inactive/weakly secretory glands • Attention to Progesterone Receptor Modulator (PRM)-Associated endometrial changes

The spectrum of endometrial pathology induced by progesterone receptor modulators George L Mutter1, Christine Bergeron2, Liane Deligdisch3, Alex Ferenczy4, Mick Glant5, Maria Merino6, Alistair RW Williams7 and Diana L Blithe8 1

Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA; 2Department of Pathology, Laboratoire Pasteur-Cerba, Cergy Pontoise, France; 3Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA; 4Department of Pathology, Jewish General Hospital, Montreal, QC, Canada; 5 Department of Pathology, DCL Medical Laboratories Inc., Indianapolis, IN, USA; 6Department of Pathology, National Institutes of Health, Bethesda, MD, USA; 7Department of Pathology, University of Edinburgh, Edinburgh, UK and 8The Contraception and Reproductive Health Branch, Center for Population Research, National Institute of Child Health and Human Development, Bethesda, MD, USA

Progesterone receptor modulators (PRM) are hormonally active drugs effective in the management of endometriosis and uterine leiomyomata. The endometrial effects of progestin blockade by PRMs in premenopausal women are currently being evaluated in several clinical trials, but few pathologists have had access to these materials and published information of the histological changes is scanty. Eighty-four endometrial specimens from women receiving one of four different PRMs were reviewed by a panel of seven experienced gynecologic pathologists to develop consensus observations and interpretive recommendations as part of an NIH-sponsored workshop. Although the pathologists were blinded to agent, dose, and exposure interval, the review was intended to provide an overview of the breadth of possible findings, and a venue to describe unique features. Endometrial histology included inactive and normal-appearing cycling endometrium. Overtly premalignant lesions (atypical hyperplasia or EIN) were not seen. In a subset of cases, asymmetry of stromal and epithelial growth resulted in prominent cystically dilated glands with admixed estrogen (mitotic) and progestin (secretory) epithelial effects of a type not encountered in contemporary clinical practice. The variety of endometrial appearances suggested that findings might differ by agent and dose over time according to relationships that must be specified for each agent. The constellation of changes seen in those endometria with cystically dilated glands is so novel that new terminology and diagnostic criteria are required for pathologists to recognize them. The panel has designated these changes as PRM-associated endometrial changes (PAEC). Additional follow-up studies will be needed to fully define their natural history and relationship to specific agents and administration regimens. Modern Pathology (2008) 21, 591–598; doi:10.1038/modpathol.2008.19; published online 1 February 2008 Keywords: progesterone receptor modulators; endometrium; histology; pathology

Benign ENDOMETRIUM - review

• Metaplasia – look for mitoses, atypia • Hyperplasia – simple/complex +/cytological atypia • Polyps • APA (atypical polypoid adenomyoma) • Menstrual • Disordered proliferation • Arias-Stella

CASE 7 - 65 yr. PMB. Thickened endometrium on USS. Hysterectomy sampled

Why

Case GY7

Dx: Atypical Endometrial Hyperplasia (WHO 2014 Classification)

Non-atypical • Exagerated proliferation of glands • Glands with size and shape irregular • No cytological atypic

Atypical/EIN • Enlargement, pleomorphism, rounding, loss of polarity and nucleoli

CASE 8 - 80 yr. PMB. Thickened endometrium. Hysterectomy sampled

Why

Case GY8

Dx: Endometrioid ADC

• • • • • • •

Back to back glands Cribriform architecture Papillary or micropapillary architecture Labyrinthine (“maze-like”) architecture Necrotic debris within glands Desmoplastic stroma Myometrial invasion

Q&A What is MELF?

The Christie NHS Foundation Trust

Microcystic, ELongated, Fragmented … glands The Christie NHS Foundation Trust

360

R. J. ZAINO

Unusual Epithelial and Stromal Changes in Myoinvasive Endometrioid Adenocarcinoma: A Study of Their Frequency, Associated Diagnostic Problems, and Prognostic Significance 360

Shawn K. Murray, 360 M.D., Robert H. Young, M.D., and Robert E. Scully, M.D.

Summary: The authors have noted that when the myoinvasive glands of endometrioid carcinomas evoke a prominent fibromyxoid stromal reaction, they sometimes undergo distinctive changes. These are characterized by outpouchings from typical neoplastic glands that become detached and often lined by flattened epithelium, sometimes appearing as microcysts. The glands may less often become elongated or undergo fragmentation into small solid clusters or single cells. For this constellation of changes, which in aggregate are distinctive, the authors have coined the acronym MELF (microcystic, elongated, fragmented). The authors evaluated the prognostic significance of these stromal and glandular features and their association with each other and with other histopathologic and clinical prognostic factors by studying 115 unselected myoinvasive endometrial endometrioid carcinomas. The histologic slides and clinical records were reviewed to collect data on age, recurrences or metastases, survival, stromal reaction pattern (fibromyxoid, lymphocytic, or absent), presence of MELF, FIGO grade, depth of myometrial invasion, vascular invasion, squamous differentiation, and presence or absence of necrosis. Factors associated with an unfavorable outcome (recurrence or death) included a fibromyxoid stromal reaction, age older than 70 years, advanced stage, vascular invasion, FIGO grade, depth of myoinvasion, and the presence of tumor necrosis. The presence of a host lymphocytic reaction was associated with a favorable outcome. A multivariate logistic regression model identified stage and age older than 70 years as independent prognostic factors. The MELF changes were associated with the presence of a host stromal reaction (most strongly with a fibromyxoid reaction) and vascular invasion. Within the group associated with a fibromyxoid reaction, patients exhibiting MELF had a better survival. In conclusion, a fibromyxoid reaction in cases of endometrioid carcinoma is associated with a higher frequency of death or recurrence and it is frequently accompanied by distinctive morphologic changes (MELF) in myoinvasive glands as well as lymphatic or blood vessel invasion. MELF is associated with a fibromyxoid reaction but is not independently associated with an adverse effect on prognosis. A lymphocytic stromal reaction is associated with a favorable effect on prognosis and is less often accompanied by the distinctive morphologic changes (MELF) highlighted herein. Key Words: Endometrium—Carcinoma—Endometrioid carcinoma—Fibromyxoid stroma—Lymphocytic reaction—Prognosis.

R. J. ZAINO R. J. ZAINO

FIG. 1. Endometrioid carcinoma with microcystic, elongated, fragmented (MELF) pattern of invasio with attenuated malignant glands surrounded by a fibromyxoid stroma contrast with foci of conven circumscribed nests of neoplastic cells form the stromal interface (A). At higher magnification, neoplastic cells is present on the left, whereas an irregularly shaped gland with attenuated epitheliu elongated narrow glands (C) and cystically dilated glands lined by attenuated neoplastic cells (D).

From the QEII Health Sciences Center, Department of Pathology, Halifax, Nova Scotia, Canada, and the Department of Pathology, Dalhousie University (S.K.M.) and the James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and the Department of Pathology, Harvard Medical School (R.H.Y., R.E.S.), Boston, Massachusetts. Address correspondence and reprint requests to Shawn K. Murray, M.D., QEII Health Sciences Center, Department of Pathology, Room 736, 7th Floor, Mackenzie Building, 5788 University Avenue, Halifax, Nova Scotia, Canada B3H 1V8. E-mail: shawn.murray@cdha.nshealth.ca.

324

DOI: 10.1097/01.pgp.0000092161.33490.a9

FIG. 1. Endometrioid carcinoma with microcystic, elongated, fragmented (MELF) pattern of invasion. At low magnification, areas of MELF with attenuated malignant glands surrounded by a fibromyxoid stroma contrast with foci of conventional invasion in which lobulated, wellcircumscribed nests of neoplastic cells form the stromal interface (A). At higher magnification, an intraglandular papilla composed of FIG. 1. Endometrioid carcinoma withwhereas microcystic, elongated,shaped fragmented pattern of invasion. is Atpresent low magnification, of MELF neoplastic cells is present on the left, an irregularly gland(MELF) with attenuated epithelium on the right areas (B). Markedly with attenuated glands surrounded by a glands fibromyxoid stroma contrast with focicells of conventional invasion in which lobulated, wellelongated narrowmalignant glands (C) and cystically dilated lined by attenuated neoplastic (D). circumscribed nests of neoplastic cells form the stromal interface (A). At higher magnification, an intraglandular papilla composed of

CASE 9 - 63 yr. Endometrial cancer. Hysterectomy - sampled

Why

Case GY9

Dx: Serous ADC Endometrioid

Serous

• Rounded glands • Squamous differentiation • ER positive • Background hyperplasia

• • • • • •

Slit-like spaces Irregular papillae High-grade nuclear atypia Budding of cells p53 positive Background – atrophic, endometrial intraepithelial carcinoma

Talhouk and McAlpine Gynecologic Oncology Research and Practice (2016) 3:14 DOI 10.1186/s40661-016-0035-4

REVIEW

Open Access

New classification of endometrial cancers: the development and potential applications of genomic-based classification in research and clinical care A. Talhouk1 and J. N. McAlpine2* Abstract Endometrial carcinoma (EC) is the fourth most common cancer in women in the developed world. Classification of ECs by histomorphologic criteria has limited reproducibility and better tools are needed to distinguish these tumors and enable a subtype-specific approach to research and clinical care. Based on the Cancer Genome Atlas, two research teams have developed pragmatic molecular classifiers that identify four prognostically distinct molecular subgroups. These methods can be applied to diagnostic specimens (e.g., endometrial biopsy) with the potential to completely change the current risk stratification systems and enable earlier informed decision making. The evolution of genomic classification in ECs is shared herein, as well as potential applications and discussion of the essential research still needed in order to optimally integrate molecular classification in to current standard of care. Keywords: Endometrial carcinoma, Histotype, The Cancer Genome Atlas (TCGA), Risk stratification, Prognosis, POLE mutations, Mismatch repair deficiencies, p53, Molecular classification

Background Cancer care in the last decade has featured a concerted move towards the personalization of patient care, often called precision medicine. In the field of cancer, this has meant a progression from broad categorization of tumors

[4–6]. However, for those women who recur or for those who present with more advanced disease, response rates to conventional chemotherapy are low and clinical outcomes are extremely poor [7–10]. Renewed research focus on this disease site has

CASE 10 - 78 yr. Polypoid endometrial tumour. Hysterectomy sampled

Why

Case GY10

Dx: Carcinosarcoma • Malignant glands – high grade, mixture of epithelial types • Admixed sarcomatous areas • Heterologous/homologous sarcoma component • Fleshy, haemorrhagic polyp • Don’t use ‘MMMT’ • Different from Sarcomatoid Carcinoma

CASE 11 - 34 yr. Previous uterine tumour. Now abdominal wall mass resected and sampled

Why

Case GY11

Dx: Endometrial Stromal Sarcoma

• Proliferative-like stroma • Small arterioles • DDx: Endometrial stromal nodule – wellcircumscribed • Endometrial stromal sarcoma – infiltration, lymphovascular space invasion (Low Grade/High Grade/ Undifferentiated Uterine Sarcoma) • CD10 +ve

CASE 12 - 40 yr. Failed pregnancy. Raised 𝝱HCG. Section of uterine contents

Why

Case GY12

Dx: Complete Mole • • • • • • •

Hydropic, bulbous villi Central cisterns Trophoblast proliferation – circumferential Atypia Karyorrhectic debris No foetal tissue p57 (CDKN1C) -ve

CASE 13 - 18 yr. Miscarriage. Products of conception

Why

Case GY13

Dx: Partial Mole

• • • • • •

Mixed, enlarged and small villi Scalloped borders Trophoblast inclusions Focal lacy trophoblast proliferation Foetal rbc/tissue p57 (CDKN1C) +ve

Dx: Hydatidiform Mole

gure 13. Algorithmic approach to diagnoof hydatidiform moles. Per one approach, tentially molar specimens are universally bjected to immunohistochemical analysis of 7 expression, with triage to genotyping sed on this result. The p57" cases are agnosed as complete hydatidiform mole, d p57þ cases are genotyped to distinguish rtial hydatidiform moles from nonmolar ecimens. In another approach, potentially olar specimens are universally subjected to notyping. In yet another approach, some age to p57 immunohistochemistry versus notyping is performed based on morphogic assessment as favoring complete hydadiform mole versus partial hydatidiform ole, respectively.

ome morphologic abnormality of chorionic villi. Use of the 57 triage method represents a compromise between aditional morphologic assessment alone, which has mitations, and genotyping of all cases, which is clearly ostlier. The p57 component of the algorithm should capture sentially all CHMs, the most important group to readily entify for clinical management purposes. Because PHMs ave a low but real risk of persistent GTD and are managed

even for experienced gynecologic pathologists, the most ideal method of correctly classifying all hydatidiform moles and nonmolar specimens is a combined approach including (Arch Pathol Lab Med. 2018;142:1485–1502) correlation of morphologic features, p57 immunohistochemistry, and DNA genotyping. In investigational pursuits, all molar specimens should be evaluated with ancillary techniques to ensure the rigorous classification of cases, particularly when designed to ascertain risk of persistent

CASE 14 - 53 yr. Fibroid uterus. Hysterectomy - sampled

Why

Case GY14

Dx: Symplastic Leiomyoma

• Macroscopically looks like a “usual” uterine fibroid • Contains bizarre multinucleated tumor cells (moderate / severe atypia) • Less than 10 mitotic figures/10 HPF • NO tumor cell necrosis

CASE 15 - 50 yr. Menorrhagia. Hysterectomy. Multiple fibroids sampled

Why

Case GY15

Coagulative tumour necrosis

Hyaline necrosis

Dx: Leiomyosarcoma • • • • •

Coagulative tumour necrosis Cytological atypia prominent Mitotic activity (> 10MF/10 HPF) Infiltration Smooth muscle tumors of uncertain malignant potential (STUMP): tumor cell necrosis in a typical leiomyoma; necrosis of uncertain type with ≥ 10 MF/10 HPFs or marked diffuse atypia; marked diffuse or focal atypia with borderline mitotic counts and necrosis difficult to classify • Smooth muscle lesions cannot be adequately assessed on frozen section or small biopsy – sampling error

CASE 16 - 56 yr. Prolapse. Fibroid uterus. Hysterectomy - sampled

Why

Case GY16

Dx: Adenomatoid Tumour

• • • •

May mimic fibroid macroscopically Slit-like/gland spaces Cuboidal/attenuated cells +/-Muscle proliferation

• Calretinin, WT-1 positive

Practical issues related to uterine pathology: staging, frozen section, artifacts, and Lynch syndrome Robert A Soslow Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA This review covers three areas in endometrial tumor pathology: International Federation of Gynecology and Obstetrics (FIGO) staging, the use of frozen section, and Lynch syndrome. The section on FIGO staging will emphasize problems that practicing pathologists often confront, such as measuring the depth of myometrial invasion, assessing for the presence of cervical stromal invasion, detecting low-volume lymph node metastases, and recognizing synchronous endometrial and ovarian tumors and artifacts. The frozen section portion of this review will focus on the performance characteristics of intraoperative examination of the uterus to determine tumor grade and depth of myometrial invasion, including suggestions for alternative methods. The last portion of this review will provide an overview of Lynch syndrome and a discussion of the rationale and methods of screening for Lynch syndrome. Modern Pathology (2016) 29, S59 –S77; doi:10.1038/modpathol.2015.127

FIGO staging Table 1 provides the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging formulation for endometrial carcinoma and carcinosarcoma,1 which is simplified from the 1988 classification. Pathologists no longer need to distinguish less than 50% myometrial invasion from no myometrial invasion; use peritoneal washing status to inform stage; or differentiate between endocervical mucosal and endometrial involvement by tumor. Despite these simplifications, many complexities and unanswered questions remain. FIGO staging ignores significant clinical heterogeneity within each substage. For example, a 70-year-old patient with serous carcinoma who has undergone a hysterectomy, without peritoneal or lymph node staging and with 40% myometrial invasion (FIGO stage I), has an estimated 5-year survival rate of 66%; the same patient with FIGO grade 1 endometrioid carcinoma, 30 negative lymph nodes, and no myometrial invasion (FIGO stage I) has an estimated 5-year survival rate of 97% (http://nomo grams.mskcc.org/Uterine/EndometrialSurvival.aspx).

Given this example, it becomes apparent that the current FIGO staging system does not take into account the distinctiveness of each type of endometrial carcinoma or staging adequacy. We recently reported a proposal for substaging uterus-confined endometrial carcinoma that recognizes disease type and grade, as well as staging adequacy.2 This yields significantly more predictive information than does either the FIGO 1988 or FIGO 2009 systems, with uterus-confined unstaged serous or FIGO grade 3 carcinomas having the worst prognosis and patients with well-staged FIGO grade 1 endometrioid carcinomas having the best outcome. This system also fails to recognize the importance of different modes of dissemination, suggesting that lymphovascular and peritoneal spread, direct extension, and implantation without invasion are clinically equivalent. Furthermore, FIGO 2009 does not indicate whether lymphovascular tumor emboli in ovarian hilar vessels should be considered stage III disease, nor does it define cervical stromal invasion. Several other challenges pathologists face when trying to implement the FIGO 2009 staging system have been discussed.3–5 Myometrial Invasion

Correspondence: Dr RA Soslow, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. E-mail: soslowr@mskcc.org Received 16 July 2015; revised 18 September 2015; accepted 26 September 2015 www.modernpathology.org

Assessment for the presence and depth of myometrial invasion can be difficult. Several studies have reported interpathologist discrepancy rates of ~ 30%, with gynecological pathologists tending to report smaller measurements than non-specialized

S59

Mod Pathol 29:S59–S77, 2016

CASE 17 - 38 yr. Abdominal distension. Ovarian mass - sampled

Why

Case GY17

Dx: Serous Borderline Tumour

• Broad papillae • Moderately atypical, stratified epithelium with mitoses • Psammoma bodies • Micropapillary variant • Microinvasion - <5mm in diameter • Stage - implants

CASE 18 - 61 yr. Stage 4 ovarian cancer. Biopsy from peritoneal deposit

Why

Case GY18

Dx: Low-Grade Serous Carcinoma

Low-grade

High-grade

• Small papillae and nests • Uniform • Slight nuclear atypia • <12 mitoses per 10hpf • Psammoma bodies

• Complex papillae and glands • Slit-like spaces • Sheets of cells • Severe nuclear atypia • Bizarre nuclei • >12 mitoses per 10hpf • Necrosis

Serous Carcinoma • Two distinct tumour types (low and High grade OSC) • NOT TWO GRADES OF THE SAME NEOPLASM! • Different neoplasms with different underlying pathogenesis, molecular events, behaviour, prognosis. • High grade much more common than low-grade (18-19:1)

In LG-OSC no p53 mutations/ abnormalities. Mutations on BRAF or KRAS. In HG-OSC p53 mutations/ abnormalities in almost 100%. No BRAF and occasional KRAS mutations. BRAC 1/2 abnormalities.

The Christie NHS Foundation Trust

Q&A What means the pattern:

Wild-type p53? The Christie NHS Foundation Trust

In High-grade Serous Carcinoma p53 is either strong positive (>75% cells), completely negative or uncommonly cytoplasmic. Cases with focal p53 positivity mean “Wild-type” staining and are not considered High-grade serous tumours.

The Christie NHS Foundation Trust

Q&A How to report?

Wild-type or Mutation-type The Christie NHS Foundation Trust

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International Journal of Gynecological Pathology 38:S123–S131, Lippincott Williams & Wilkins, Baltimore Copyright © 2018 International Society of Gynecological Pathologists. Published by Wolters Kluwer Health, Inc. on behalf of the International Society of Gynecological Pathologists.

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Interpretation of P53 Immunohistochemistry in Endometrial Carcinomas: Toward Increased Reproducibility

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RCPath datasets and tissue pathways

M.D.,

Brigitte M. Ronnett, M.D., Naveena Singh, M.D., Robert A. Soslow, C. Blake Gilks, M.D., and W. Glenn McCluggage, M.D.

M.D.,

Summary: P53 immunohistochemistry has evolved into an accurate surrogate reﬂecting the underlying TP53 mutation status of a tumor, and has utility in the diagnostic workup of endometrial carcinomas. Recent work predominantly carried out in tubo-ovarian high-grade serous carcinoma has revealed 4 main patterns of p53 staining (normal/wild-type, complete absence, overexpression, and cytoplasmic); the latter 3 patterns are variably termed abnormal/ aberrant/mutation-type and are strongly predictive of an underlying TP53 mutation. The aim of this review is to provide practical advice to pathologists regarding various aspects of p53 immunohistochemical staining. These include laboratory methods to optimize staining, a description of the different patterns of staining, advice regarding the interpretation, and reporting of p53 staining and practical uses of p53 staining in endometrial carcinoma diagnosis. Illustrations are provided to aid in the interpretational problems. Key Words: Endometrial carcinoma—p53—TP53—Immunohistochemistry—Interpretation.

The mutational status of TP53 is the single most important molecular factor, which predicts prognosis in

serous and endometrioid histotype (3,4), predicting outcome within a given histotype (1,5) or predicting

Q&A Origin of HGSC? The Christie NHS Foundation Trust

Advances in the Recognition of Tubal Intraepithelial Carcinoma Applications to Cancer Screening and the Pathogenesis of Ovarian Cancer Yonghee Lee, MD, Fabiola Medeiros, MD, David Kindelberger, MD, Michael J. Callahan, MD, Michael G. Muto, MD, and Christopher P. Crum, MD

Prophylactic salpingo-oophorectomies from women with BRCA mutations (BRCA+) have identified the tube as a frequent site of early pelvic serous carcinoma (tubal intraepithelial carcinoma [TIC]). These observations have implications for both the early recognition of pelvic serous carcinoma in susceptible women and determining the ultimate site of origin for pelvic serous carcinomas. Moreover, the unique pathology of TIC has shifted attention from the more exuberant proliferations mentioned in prior studies to a spectrum of neoplastic atypias that can be morphologically subtle. This review addresses a multitude of epithelial changes; benign, malignant, and an intriguing third group, which we term ‘‘p53 signatures,’’ is found in benign, nonciliated epithelium and stain intensely positive for p53. Understanding all 3 is important for the proper management of women undergoing prophylactic salpingo-oophorectomy and possibly formulating an integrated model for the pathogenesis of serous carcinoma in the reproductive tract. A protocol for sectioning and extensively examining the fimbriated end (SEE-FIM), and its rationale, is described. Key Words: fallopian tube neoplasms, intraepithelial carcinoma, BRCA, ovarian neoplasms, p53 (Adv Anat Pathol 2006;13:1–7)

he pathogenesis of pelvic mullerian carcinomas in women has been the subject of extensive research and controversy. Its conceptual evolution has been limited in part by uncertainty over the precise origin of some of these tumors. The traditional view holds that ovarian cancer arises from müllerian epithelium on the ovarian surface or intracortical inclusion cysts. The origin of this epithelium remains unclear.1,2 Although few

From the Division of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital, Boston. Supported by P50 CA10500 (SPORE) (D. Cramer, PI), the Francis Ward Paine, and TSA Pemberton Funds of the Division of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital; and a grant from the Columbia Hospital for Women Research Foundation, Washington, DC. Reprints: Christopher P. Crum, MD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (e-mail: ccrum@ partners.org). Copyright ! 2006 by Lippincott Williams & Wilkins

cancers have been shown to arise directly from such cysts, they remain the leading candidate for the genesis of ovarian tumors, specifically those that develop within the ovarian cortex. This group of tumors includes most mucinous and endometrioid adenocarcinomas, which likely arise through direct transformation of the cyst epithelium to mucinous or—in endometrioid tumors and some mucinous tumors—acquisition of a benign endometrioid phenotype, from which malignancy may arise.3 Although a portion of serous carcinomas develop within the parenchyma of the ovary, consistent with an origin from either cortical inclusion or endometriotic cysts, an important subset of serous carcinomas present not as a cystic mass, but on the ovarian surface. This latter group is frequently associated with tumor in the mesosalpinx and the pelvic peritoneum. Although this group of tumors is responsible for much of the mortality associated with ovarian cancer, its origin has been a mystery. Studies addressing the origin of ovarian surface carcinomas have naturally focused on the ovarian surface epithelium.4 However, beginning in the late 1990’s, a shift in emphasis began to take place with the discovery of serous carcinomas in the fallopian tubes of women with a hereditary predisposition for breast and ovarian cancer.5–7 Consequently, protocols designed to remove the ovaries and fallopian tubes before the onset of cancer in susceptible individuals have entailed more detailed evaluation of both organs. This review addresses recent advances in this field, including evidence supporting the tube as a source of some serous carcinomas, protocols for optimizing histologic evaluation of the tubes, the histopathologic spectrum of tubal carcinoma, and the use and potential misuse of biomarkers to verify the diagnosis of tubal neoplasia.

THE FALLOPIAN TUBE AND PELVIC SEROUS CARCINOMA A significant proportion of pelvic serous carcinomas appear to arise in an extraovarian site, supported by the fact that ovarian involvement in such cases is often confined to the surface of the organ and is associated with extensive omental or pelvic peritoneal involvement.8 The 2 prime candidate sites are the pelvic surface and the fallopian tube. An origin from

Adv Anat Pathol ! Volume 13, Number 1, January 2006

Designating site of origin of HGSC International Journal of Gynecological Pathology 35:230–237, Lippincott Williams & Wilkins, Baltimore r 2016 International Society of Gynecological Pathologists

Opinion Piece

Adopting a Uniform Approach to Site Assignment in Tubo-Ovarian High-Grade Serous Carcinoma: The Time has Come Naveena Singh, F.R.C.Path., C. Blake Gilks, M.D., Lynn Hirshowitz, F.R.C.Path., Nafisa Wilkinson, F.R.C.Path., and W. Glenn McCluggage, F.R.C.Path.

Summary: There is currently suﬃcient evidence that nonuterine high-grade serous carcinoma (HGSC) originates in the fallopian tube in the majority of cases, but this is not uniformly reflected in our diagnostic terminology. This is because there remains wide variation in awareness and acceptance of this evidence, which conflicts with traditional views on origin. Accurate disease classification is fundamental to routine clinical practice and research, particularly at a time when exciting new approaches to therapy, early detection, and prevention are appearing on the horizon. We feel the time has come to minimize individual and institutional variations in practice, and agree on an evidencebased approach to uniform terminology and primary site assignment. In this paper we put forward a proposal for a unified approach based on published research evidence and discuss the reasons why it is vital to agree on a uniform protocol. We propose the term ‘‘Tubo-ovarian HGSC’’ in preference to ‘‘pelvic’’ or ‘‘Müllerian,’’ as it accurately reflects the origin of this disease in the vast majority of cases, and is unambiguous, distinguishing it clearly from uterine serous carcinoma and ovarian low-grade serous carcinomas. A detailed protocol for primary site assignment is presented for diﬀerent scenarios, which is easy to follow and has been developed with a view to promoting a uniform approach worldwide. Key Words: Ovary—High-grade serous carcinoma—Fallopian tube—STIC— Primary peritoneal carcinoma—Pathology—Staging—Origin.

There has been a dramatic evolution in our understanding of the origins of nonuterine highgrade serous carcinoma (HGSC) over the last few decades. Since 2001, evidence has steadily accumu-

lated favoring a tubal origin in most cases (1–3). Variation in awareness and acceptance of this evidence, which conflicts with traditional views on origin, results in significant variability in assignment of the primary site of nonuterine HGSC. Accurate disease classification is fundamental to routine clinical practice and research, particularly at a time when exciting new approaches to therapy and prevention are appearing on the horizon. The time has come to minimize individual and institutional variations in practice, and agree on an evidence-based approach to uniform site assignment. We have previously proposed criteria for primary site assignment (4,5) that have been incorporated in the International Collaboration on Cancer Reporting dataset for reporting of ovary, fallopian tube, and

From the Department of Cellular Pathology (N.S.), Barts Health NHS Trust, London; Department of Cellular Pathology (L.H.), Birmingham Women’s NHS Trust, Birmingham; Department of Pathology (N.W.), St James’s Hospital, Leeds; Department of Pathology (W.G.M), Belfast Health and Social Care Trust, Belfast, UK; and Department of Anatomic Pathology (C.B.G.), Vancouver General Hospital, and University of British Columbia, Vancouver, BC, Canada. The authors declare no conflict of interest. Address correspondence and reprint requests to Naveena Singh, FRCPath, Department of Cellular Pathology, Barts Health NHS Trust, 2nd Floor, 80 Newark Street, London E1 2ES, UK. E-mail: n.singh@bartshealth.nhs.uk.

DOI: 10.1097/PGP.0000000000000270

230

SEE-FIM protocol (sectioning and extensively examining the fimbriated end (SEE-FIM)

Q&A How about TRG (Tumour Regression Grading) in

HGSC? The Christie NHS Foundation Trust

VOLUME

NUMBER

AUGUST

2015

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Chemotherapy Response Score: Development and Validation of a System to Quantify Histopathologic Response to Neoadjuvant Chemotherapy in Tubo-Ovarian High-Grade Serous Carcinoma Steffen Böhm, Asma Faruqi, Ian Said, Michelle Lockley, Elly Brockbank, Arjun Jeyarajah, Amanda Fitzpatrick, Darren Ennis, Thomas Dowe, Jennifer L. Santos, Linda S. Cook, Anna V. Tinker, Nhu D. Le, C. Blake Gilks, and Naveena Singh Steffen Böhm, Asma Faruqi, Ian Said, Michelle Lockley, Elly Brockbank, Arjun Jeyarajah, Amanda Fitzpatrick, and Naveena Singh, Barts Health National Health Service Trust; Steffen Böhm, Michelle Lockley, Darren Ennis, and Thomas Dowe, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; Jennifer L. Santos, Anna V. Tinker, and Nhu D. Le, British Columbia Cancer Agency; C. Blake Gilks, University of British Columbia, Vancouver, BC, Canada; and Linda S. Cook, University of New Mexico, Albuquerque, NM. Published online ahead of print at www.jco.org on June 29, 2015. Supported by Grants No. BIL KLS-288302-2012 from Krebsliga Schweiz and Krebsliga Ostschweiz (S.B.). The Barts Gynae Tissue Bank received support from Barts and the London Charity and Cancer Research UK. C.B.G. and N.S. contributed equally to this work. Presented at the Annual Meeting of the United States and Canadian Academy of Pathology, San Diego, CA, March 1-8, 2014; and at the 26th European Congress of Pathology, London, United Kingdom, August 30-September 3, 2014. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Steffen Böhm, MD, Barts Health National Health Service Trust, St Bartholomew’s Hospital, West Smithfield, London, EC1A 7BE, United Kingdom; e-mail: steffen. boehm@bartshealth.nhs.uk. © 2015 by American Society of Clinical Oncology 0732-183X/15/3322w-2457w/$20.00 DOI: 10.1200/JCO.2014.60.5212

Purpose To develop and validate a histopathologic scoring system for measuring response to neoadjuvant chemotherapy in interval debulking surgery specimens of stage IIIC to IV tubo-ovarian high-grade serous carcinoma. Patients and Methods A six-tier histopathologic scoring system was proposed and applied to a test cohort (TC) of 62 patients treated with neoadjuvant chemotherapy and interval debulking surgery. Adnexal and omental sections were independently scored by three pathologists. On the basis of TC results, a three-tier chemotherapy response score (CRS) system was developed and applied to an independent validation cohort of 71 patients. Results The initial system showed moderate interobserver reproducibility and prognostic stratification of TC patients when applied to the omentum but not to the adnexa. Condensed to a three-tier score, the system was highly reproducible (kappa, 0.75). When adjusted for age, stage, and debulking status, the score predicted progression-free survival (PFS; score 2 v 3; median PFS, 11.3 v 32.1 months; adjusted hazard ratio, 6.13; 95% CI, 2.13 to 17.68; P ! .001). The three-tier CRS system applied to omental samples from the validation cohort showed high reproducibility (kappa, 0.67) and predicted PFS (CRS 1 and 2 v 3: median, 12 v 18 months; adjusted hazard ratio, 3.60; 95% CI, 1.69 to 7.66; P ! .001). CRS 3 also predicted sensitivity to first-line platinum therapy (94.3% negative predictive value for progression ! 6 months). A Web site was established to train pathologists to use the CRS system. Conclusion The CRS system is reproducible and shows prognostic significance for high-grade serous carcinoma. Implementation in international pathology reporting has been proposed by the International Collaboration on Cancer Reporting, and the system could potentially have an impact on patient care and research. J Clin Oncol 33:2457-2463. © 2015 by American Society of Clinical Oncology INTRODUCTION

Worldwide approximately 150,000 women die annually from ovarian cancer.1 Ovarian cancer is a heterogeneous group of diseases, and this term should be avoided in research studies in favor of more specific histotype definitions.2,3 Advancedstage tubo-ovarian high-grade serous carcinoma (HGSC) accounts for most cases of ovarian cancer in Europe and North America, and the majority of fatal cases. Surgery remains the cornerstone of treatment

for HGSC preceded or followed by chemotherapy. In patients who undergo surgery before they receive chemotherapy, the strongest prognostic factor is complete macroscopic disease resection.4,5 Optimal or complete primary debulking is often not technically feasible, but interval debulking surgery (IDS) after three to four cycles of neoadjuvant chemotherapy (NACT) is an accepted alternative approach. In two randomized controlled phase III trials, IDS has been shown to be equivalent in terms of progression-free survival (PFS) and overall © 2015 by American Society of Clinical Oncology

Information downloaded from jco.ascopubs.org and provided by at CAMBRIDGE UNIV MEDICAL LIBRARY on August 11, Copyright © 2015 American of Clinical Oncology. All rights reserved. 2015Society from 131.111.164.128

2457

CASE 19 - 36 yr. Large multicystic ovarian mass - sampled

Why

Case GY19

Dx: Borderline Mucinous Tumour

•

Usually large, unilateral, and cystic with a smooth ovarian surface, composed of multiple cystic spaces with variable diameter. The cysts are lined by columnar mucinous epithelium of gastric or intestinal differentiation, with papillary or pseudopapillary infoldings, and admixed goblet cells and neuroendocrine cells

•

The nuclei are basally located, isomorphic, and with evenly distributed chromatin

•

Mucinous cystadenomas are characterized by a similar mucinous epithelium but lack papillary infoldings. At least 10% of the epithelial volume must demonstrate increased proliferation with papillary infoldings or pseudostratification and mild to moderate nuclear atypia to qualify as mucinous borderline tumor

Malignant Mucinous Tumour

• Intestinal/endocervical-like Carcinoma Severe nuclear atypia • Expansile invasion – Confluent back-toback glands, cribriform complex areas • Infiltrative invasion – Single cells and glands infiltrate stroma

Metastatic Mucinous Tumours

• Think metastasis – colorectal, LAMN, upper GIT, pancreas, cervical. • Immuno, history, clinical findings. • Colorectal metastasis – cribriform pattern, garlanding, dirty necrosis. CK20 and CDX2 diffuse positivity.

CASE 20 - 54 yr. Abdominal distension. Section from left ovary cyst

Why

Case GY20

Dx: Clear Cell Carcinoma

• • • • • • • • •

Tubulocystic, papillary, solid Hyalinised papillary cores Hobnail cells Clear/eosinophilic cytoplasm Eosinophilic droplets Hyperchromatic nuclei Frequent association with endometriosis Worse prognosis than HG-SC HNF1 +ve; WT1 -ve

CASE 21 - 51 yr. Abdominal pain and 15 cm ovarian cyst. Section from ovary

Why

Case GY21

Dx: Brenner tumour with cystadenoma

• Nests of transitional cells (solid or cystic) with fibrous or cellular spindle cell stroma. • Frequent microcysts within epithelial nests. • Nuclei are round to oval, some with nucleoli and longitudinal nuclear grooves. • Associated with other epithelial tumours in up to 25 % of cases. • Borderline: with papillary pattern and low grade nuclear atypia resembling low grade urothelial carcinoma of bladder

CASE 22 - 72 yr. Pelvic mass. Section from mass

Why

Case GY22

Dx: Malignant Brenner Tumour (Transitional Cell Carcinoma)

• Resembles urothelial, squamous or undifferentiated carcinoma, but associated with benign or borderline Brenner component; stromal invasion is present. • The previously named ‘‘transitional cell tumors’’ is now entitled ‘‘Brenner Tumours’’ - WHO classification 2014 • WT1 +ve; CK20 -ve;

CASE 23 - 62 yr. Endometrial cancer. Hysterectomy with bilateral salpingo-oophorectomy. Section of ovary

Why

Case GY23

Dx: Fibroma • Collagen – hyaline plaques • Theca cells – round nuclei, cytoplasmic vacuolation • Luteinised cells – abundant eosinophilic cytoplasm, round nuclei • Cellular • Mitotically active - 4-29mitoses per 10hpf • CD10 -ve; Desmin -ve;

CASE 24 - 72 yr. Ovarian cyst? Endometrioma. Section of cyst wall

Why

Case GY24

Dx: Adult Granulosa Cell Tumour with CallExner bodies and “coffee-bean” nuclei

Dx: Adult Granulosa Cell Tumour

• Fibrothecomatous background • Call-Exner bodies (small follicle-like structures filled with acidophilic material) • Nuclear grooves • Diffuse, microfollicular, trabecular, gyriform, insular, watered-silk • Low mitotic rate • Oestrogenic manifestations • Late recurrence

CASE 25 - 23 yr. Abdominal pain. Ovarian mass on imaging. Section of ovarian mass

Why

Case GY25

Dx: Juvenile Granulosa Cell Tumour

• Diffuse • Macrofollicles • Granulosa cells – eosinophilic cytoplasm, round nuclei, no grooves • Variable mitotic activity and atypia • Young patients mainly (97% < 30 yrs) • Stage most important prognostic factor • DD clear cell carcinoma • Inhibin +ve; calretinin +ve

CASE 26 - 54 yr. Fibroid uterus. Hysterectomy and bilateral salpingooophorectomy. Section of the ovary

Why

Case GY 26

Dx: Sclerosing Stromal Tumour

• Pseudolobular • Cellular nodules + hypocellular collagenised/oedematous zones • Haemangiopericytoma-like vessels • Spindle/round cells • Low mitotic rate • Minimal atypia • Desmin +ve; SMA +ve

CASE 27 - 55 yr. Right ovarian tumour. Malignant on imaging. Section of ovary

Why

Case GY27

Dx: Struma Ovarii • Rare monodermal teratoma composed predominantly of mature thyroid tissue. • May show pathologic changes of thyroid gland including hyperfunctioning; malignancies are usually papillary thyroid carcinoma. • Associated with mucinous cystadenoma, Brenner tumour, carcinoid tumour and dermoid cyst. • PAX8 +ve; TTF1 +ve; Thyroglobulin +ve

CASE 28 - 67 yr. Incidental finding of a left ovarian cyst on USS. Section of ovarian cyst

Why

Case GY28

Dx: Mature Cystic Teratoma with Squamous cell Carcinoma in situ

• Very uncommon: < 2% in teratomas • Squamous cell carcinoma of ovary can be pure arising de novo or may represent extreme expression of squamous metaplasia in endometriosis, endometrioid carcinomas, transformation of ovarian teratomas and HPV related transformation • Often associated with dermoid cyst (50%) and endometriosis (20%) • SCC arising in dermoid are included in germ cell tumour by WHO; those arising in endometriosis are included in surface epithelial tumours

CASE 29 - 21 yr. Left complex pelvic mass. Section from mass

Why

Case GY29

Dx: Immature Teratoma

• Important: Presence and amount of neuro-epithelium. • Sample throughly to exclude immature elements, secondary malignancy – SCC, other germ cell component – yolk sac, carcinoid • Minimal immature tissue does not warrant a diagnosis of IT

Dx: Imature Teratoma

Immature Teratoma Histologic Grading Grade

Immature Tissue

+++

Neuroepithelium Rare; Not > 1 LPF/slide Common; not > 3 LPF/slide Prominent ≥ 4 LPF on any slide

Dx: Imature Teratoma

Immature Teratoma • Prognosis depends on: – – – –

Patient age Grade of primary tumor (range: 1-3) Stage Grade of metastases (range 0-3)

• Treatment and survival: – Stage I, G1 • Surgery only ~ 100% survival

– Stage I, G2, G3 or stage II-IV • NCCN guidelines suggest 3 to 4 cycles of BEP • > 90% survival if optimally debulked

CASE 30 - 6 yr. Ovarian mass - biopsed

Why

Case GY30

Dx: Yolk Sac Tumour • • • • • •

Reticular lacy pattern Schiller-Duval bodies Hyaline droplets Primitive cells, clear/pale cytoplasm Mitoses common Third most common malignant germ cell tumour after teratoma and dysgerminoma • AFP +ve; Glypican3 +ve

Ovarian Metastases

• • • • • •

History and clinico-radiological features Bilateral Surface nodules Desmoplasia Lymphovascular space invasion Infiltration of stroma by single cells

Endometriosis

• • • •

Look for glands and stroma Blood and pigment-laden histiocytes Exclude hyperplasia and carcinoma Decidualisation of stroma

@ IHC 2ask4

Immunohistochemistry in Gynecologic Pathology An Example-Based Practical Update Natalia Buza, MD; Pei Hui, MD, PhD

! Context.—Immunohistochemical stains are routinely applied in the pathology diagnostic workup of gynecologic lesions. The rapidly expanding repertoire of available markers helps in refining the diagnostic criteria for each disease entity; however, limitations and pitfalls exist. Objective.—To provide a practical, relevant update on the use of immunohistochemistry for commonly encountered differential diagnoses in gynecologic pathology.

Data Sources.—Literature review and authors’ diagnostic experience. Conclusions.—Immunohistochemistry is a helpful adjunct tool in gynecologic pathology. Although the primary application is in the diagnostic workup, novel prognostic and predictive markers, and immunostains to screen for genetic cancer syndromes, have also been recently introduced in the field. (Arch Pathol Lab Med. 2017;141:1052–1071; doi: 10.5858/arpa.2016-0541-RA)

cally consistent with low-grade squamous intraepithelial lesion (LSIL) with mitotic activity extending up to the second third of the epithelium (Figure 1, A and B). The background cervical tissue had marked chronic inflammation. Should p16 immunostaining be performed to rule out high-grade dysplasia? Both when to order and how to interpret a p16 immunohistochemical study for squamous lesions of the cervix remain a common diagnostic challenge and are discussed in detail below. Human Papillomavirus–Associated Squamous Lesions of the Cervix, Vagina, and Vulva.—The pathology diagnosis and classification of squamous intraepithelial lesions of the lower anogenital tract continue to be problematic, despite availability of p16 immunostain for at least a decade in the routine practice.1,2 The Lower Anogenital Squamous Terminology Project and the 2014 World Health Organization classification of female genital tract tumors recommend a new 2-tier system—low-grade intraepithelial lesion (LSIL; intraepithelial neoplasia 1 [-IN1], condyloma, koilocytosis) and high-grade intraepithelial lesion (high-grade squamous intraepithelial lesion [HSIL]; -IN2 and -IN3)—for reporting precursor lesions of the cervix, vagina, and vulva to reflect the biology and clinical relevance of lesions, which also generated a renewed interest in improving the diagnostic accuracy for these entities.3,4 While the typical histologic features of squamous intraepithelial lesions are well characterized and illustrated in the literature, several important morphologic mimics and diagnostic pitfalls exist. In addition, the interobserver and intraobserver agreement on histologic grading of cervical and vulvar intraepithelial neoplasia, especially -IN2, based on hematoxylin-eosin stain (H&E) slides alone, has been reported as moderate at best.5–10 Abortive/transforming infections with high-risk HPV types in high-grade intraepithelial lesions produce increased levels of E7 viral oncoprotein, which binds to and inactivates

he available immunohistochemical stains and their routine application in diagnostic surgical pathology continue to expand with our better understanding of pathogenesis, characterization of new disease entities, and increasing clinical demand for better tumor prognostication and prediction of response to targeted therapies. This article provides a focused review of the most recent developments on the use of immunohistochemistry in selected diagnostic gynecologic pathology topics in an organ-based fashion. While most immunomarkers discussed here fall under the diagnostic category, certain prognostic and predictive markers and markers of screening for inherited cancer syndromes are also included. LOWER GENITAL TRACT—UTERINE CERVIX, VAGINA, AND VULVA Illustrative Example 1 A 38-year-old patient with a history of atypical squamous cells of undetermined significance and positive high-risk human papillomavirus (HPV) test result on Papanicolaou smear underwent a colposcopy examination, which revealed a cervical acetowhite lesion at the 6-o’clock position. A biopsy was performed that showed changes morphologiAccepted for publication December 27, 2016. From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. The authors have no relevant financial interest in the products or companies described in this article. This manuscript was presented at the First Chinese American Pathologists Association (CAPA) Diagnostic Pathology Course: Best Practices in Immunohistochemistry in Surgical Pathology and Cytopathology; August 22–24, 2015; Flushing, New York. Reprints: Pei Hui, MD, PhD, Yale University School of Medicine, 310 Cedar St, LH108, PO Box 208023, New Haven, CT 06520-8023 (email: pei.hui@yale.edu). 1052 Arch Pathol Lab Med—Vol 141, August 2017

Immunohistochemistry in Gynecologic Pathology—Buza & Hui

Arch Pathol Lab Med 141:1052-1071, 2017

Endometrial Cancer Histopathology Reporting Guide Family/Last name

Date of birth

DD – MM – YYYY

Given name(s) Patient identifiers

Date of request

Accession/Laboratory number

DD – MM – YYYY Elements in black text are CORE. Elements in grey text are NON-CORE. OPERATIVE PROCEDURE

HISTOLOGICAL GRADE (Note 5)

Simple hysterectomy

Grade 1

Radical hysterectomy

Not gradeable Not applicable

Grade 2

Other, specify

Grade 3 MYOMETRIAL INVASION (Note 6) None

< 50%

≥ 50%

ATTACHED ANATOMICAL STRUCTURES Left fallopian tube Right fallopian tube Parametria

Vaginal cuff Left ovary Right ovary

PERCENTAGE OF MYOMETRIUM INFILTRATED BY CARCINOMA (Note 7)

DISTANCE OF MYOINVASIVE TUMOUR TO SEROSA (Note 8)

ACCOMPANYING SPECIMENS None submitted Peritoneal biopsies Other, specify

Omentum Lymph nodes

LYMPHOVASCULAR INVASION (Note 9) Present

Not identified

Indeterminate

Specify site TUMOUR SITE (Note 1) Fundus

Body

Isthmus/lower uterine segment

MAXIMUM TUMOUR DIMENSION (Note 2)

CERVICAL SURFACE OR CRYPT INVOLVEMENT (Note 10) Present

HISTOLOGICAL TUMOUR TYPE (Note 3)

Not identified

Indeterminate

CERVICAL STROMAL INVASION (Note 11)

Endometrioid carcinoma

Present

Not identified

Indeterminate

Mucinous carcinoma Serous endometrial intraepithelial carcinoma (SEIC)

DISTANCE OF TUMOUR TO CERVICAL RESECTION MARGINS (Note 12) mm

Serous carcinoma Clear cell carcinoma Mixed cell adenocarcinoma Undifferentiated carcinoma

VAGINA

Dedifferentiated carcinoma

Involved

Not involved

Not applicable

Not involved

Not applicable

Neuroendocrine tumour OMENTUM

Specify subtype

Carcinosarcoma (Note 4)

Involved

% & Epithelial

Involved

Not involved

Not applicable

Sarcomatous Homologous Heterologous

Version 3.0 Published July 2017

PERITONEAL BIOPSY/BIOPSIES

UTERINE SEROSA (Note 13) Involved

ISBN: 978-1-925687-02-6

Not involved

Indeterminate Page 1 of 2

Carcinoma of the Cervix Histopathology Reporting Guide Family/Last name

Date of birth

DD – MM – YYYY

Given name(s) Date of request

Patient identifiers

Accession/Laboratory number

DD – MM – YYYY Elements in black text are REQUIRED. Elements in grey text are RECOMMENDED. SPECIMEN DIMENSIONS (Note 3)

PRIOR TREATMENT (Note 1) Previous procedure performed Loop Information not provided Cone No prior procedure Trachelectomy (simple or radical) Other, specify

Number of tissue pieces* Tissue piece dimensions* (Note: Record for each piece) mm

Previous therapy Chemotherapy Radiation Chemoradiation

Information not provided No prior therapy Other, specify Cervix**

DIAMETER OF ECTOCERVIX SPECIMENS SUBMITTED (select all that apply) (Note 2) Loop excision* Cone biopsy Trachelectomy Simple Type not specified Hysterectomy Simple Part of exenteration

Not specified

Left tube Left ovary Left parametrium Vaginal cuff Pelvic exenteration Urinary bladder Vagina Other, specify

Right tube Right ovary Right parametrium

DEPTH OF SPECIMEN

Vaginal cuff*** Radical

Radical Type not specified

Not applicable MINIMUM LENGTH

MAXIMUM LENGTH

Left parametrium Not applicable LATERAL EXTENT

Rectum Sigmoid colon

Not applicable LATERAL EXTENT

Lymphadenectomy specimen/s Sentinel node/s Left Right Regional nodes: pelvic Left Right Non-regional nodes: inguinal Left Right Non-regional: para-aortic Other node group, specify

Right parametrium

*Applicable to loop/cone biopsies only **Applicable to loop/cone biopsies and trachelectomy specimens only ***Applicable to trachelectomy and hysterectomy specimens

MACROSCOPIC APPEARANCE OF TUMOUR(S) (Note 4) No macroscopically visible tumour Exophytic/polypoid Flat Ulcerated Circumferential/barrel shaped cervix Other, specify

Other, specify

*Loop excision includes – loop electrosurgical excision procedure (LEEP) and large loop excision of the transformation zone (LLETZ)

Version 1.0 Carcinoma of the Cervix - published March 2017

Page 1 of 4

Ovary, Fallopian Tube and Primary Peritoneal Carcinoma Histopathology Reporting Guide Family/Last name

Date of birth

DD – MM – YYYY

Given name(s) Patient identifiers

Date of request

Accession/Laboratory number

DD – MM – YYYY Elements in black text are REQUIRED. Elements in grey text are RECOMMENDED. GENETIC STATUS (Note 1)

MACROSCOPIC TUMOUR SITE (select all that apply) (Note 5)

BRCA1

Not known

BRCA2 Lynch syndrome Other

PRIOR CHEMOTHERAPY (Note 2) No chemotherapy administered Prior chemotherapy administered

Not known

Left ovary Right ovary Left fallopian tube Fimbrial Non fimbrial Right fallopian tube Fimbrial Non fimbrial Peritoneum Other (specify)

Indeterminate

SPECIMEN TYPE (select all that apply) (Note 3) Right ovary Left ovary Right ovarian cystectomy Left ovarian cystectomy Right fallopian tube Left fallopian tube Uterus Cervix Omentum Peritoneal biopsies Peritoneal washings/ascitic fluid Lymph nodes (specify site/s)

Not specified TUMOUR DIMENSIONS mm

(Note 6) mm

(Note: If separate tumours specify dimensions for each site)

MACROSCOPIC DESCRIPTION OF OMENTUM (Note 7) Required only if omentum submitted Omentum dimensions

Other eg bowel, bladder, appendix (specify)

Omental involvement Involved

SPECIMEN INTEGRITY (Note 4) Required only if ovary(ies)/fallopian tube(s) are submitted Right ovary Ovarian capsule intact Ovarian capsule ruptured Tumour on surface Fragmented specimen Other

Left ovary Ovarian capsule intact Ovarian capsule ruptured Tumour on surface Fragmented specimen Other

Not involved Maximum dimension of largest deposit mm

BLOCK IDENTIFICATION KEY (Note 8) (List overleaf or separately with an indication of the nature and origin of all tissue blocks)

Right fallopian tube Left fallopian tube Serosa intact Serosa intact Serosa ruptured Serosa ruptured Tumour on serosal surface Tumour on serosal surface Fragmented specimen Fragmented specimen Other Other

Version 1.0 Ovary, Fallopian Tube, Primary Peritoneal Carcinoma - INTERNATIONAL COLLABORATION ON CANCER REPORTING

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GY1 Lichen Sclerosus GY2 Fallopian Tube Prolapse GY3 Mesonephric Remnants GY4 CIN & high-grade CGIN GY5 Disordered Proliferation GY6 Menstrual GY7 Complex and Atypical Hyperplasia GY8 Endometrioid Carcinoma GY9 Serous Carcinoma GY10 Carcinosarcoma

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GY11 Endometrial Stromal Sarcoma GY12 Complete Mole GY13 Partial Mole GY14 Symplastic (Bizarre) Leiomyoma GY15 Leiomyosarcoma GY16 Adenomatoid Tumour GY17 Serous Borderline Tumour GY18 Low-grade Serous Carcinoma GY19 Borderline Mucinous Tumour GY20 Clear Cell Carcinoma

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GY21 Brenner with Mucinous Cystadenoma GY22 Malignant Brenner Tumour GY23 Fibroma GY24 Adult GCT GY25 Juvenile GCT GY26 Sclerosing Stromal Tumour GY27 Struma Ovarii GY28 MCT with SCC in-situ GY29 Immature Teratoma GY30 Yolk Sac Tumour