JOINT MEETING OF THE

BRITISH DIVISION OF THE

INTERNATIONAL ACADEMY OF PATHOLOGY

AND THE

A SYMPOSIUM ON

GYNAECOLOGICAL PATHOLOGY

Friday 18^th April 2008

and

Saturday 19^th April 2008

Postgraduate Medical Centre

Manchester Royal Infirmary

Department of Histopathology

1^st Floor Clinical Sciences Building

Manchester Royal Infirmary

Oxford Road

Manchester

M13 9WL

Tel: 0161 276 8725

P R O G R A M M E

FRIDAY 18^TH APRIL 2008

A SYMPOSIUM ON

GYNAECOLOGICAL PATHOLOGY

Postgraduate Medical Centre, Manchester Royal Infirmary

8:30 – 9:15 Coffee and registration

9:15 – 9:30 Presidential welcome

Morning session chaired by Dr Sanjiv Manek(Oxford)

9:30 – 10:00 Advantages and Pitfalls of Liquid Based Cervical Screening

Dr John Smith, Sheffield

10:00 – 10:30 What’s New in Vulvovaginal Pathology

Professor Glenn McCluggage, Belfast

10:30 – 11:00 Recent Advances in Molecular Gynaecological Pathology

Professor Simon Herrington, St Andrews

11:00 – 11:30 Coffee break

11:30 – 12:00 Variants of Cervical Adenocarcinoma

Dr Laurence Brown, Leicester

12:00 – 13:00 Guest Lecture: Mucinous Tumours of the Ovary

Dr Brigitte Ronnett, USA

13:00 – 14:00 Lunch break

Afternoon session chaired by Dr Sezgin Ismail (Manchester)

14:00 – 14:30 Clinical management of VIN and Vulval Cancer

Professor Henry Kitchener, Manchester

14:30 – 15:00 Review of the new Minimum Data Sets

Dr Lynn Hirschowitz, Bristol

15:00 – 15:30 What’s New in Ovarian Sex Cord-Stromal Tumours

Dr Nafisa Wilkinson, Leeds

15:30 – 16:00 Tea break

16:00 – 16:30 Synchronous Tumours in the Female Genital Tract

Dr Naveena Singh, London

16:30 – 17:00 Common Problems in Consultation Practice in Gynaecological Pathology

Professor Michael Wells, Sheffield

P R O G R A M M E

SATURDAY 19^TH APRIL 2008

A SYMPOSIUM ON

GYNAECOLOGICAL PATHOLOGY

Postgraduate Medical Centre, Manchester Royal Infirmary

09:30 – 13:00 SLIDE SEMINAR

session chaired by Dr Godfrey Wilson (Manchester)

Contributors: - Dr Adam Boyde Cardiff

Dr Raji Ganesan Birmingham

Dr David Millan Glasgow

Dr Brigitte Ronnett USA

Dr Michael Scott Manchester

Dr Neil Sebire London

JOINT MEETING OF THE

BRITISH DIVISION OF THE

INTERNATIONAL ACADEMY OF PATHOLOGY

AND THE

Lecture Abstracts

and

References

ADVANTAGES AND PITFALLS OF LIQUID-BASED CERVICAL CYTOLOGY

Dr J H F Smith

Royal Hallamshire Hospital, Sheffield

As full implementation of liquid based cervical cytology (LBC) approaches, the predicted beneficial impact has already being seen. LBC, combined with the change in the screening age range and frequency, has resulted in a decrease in the total number of tests examined despite an increased number of women aged 25 – 64 being screened, reflecting a more efficient screening programme with fewer unnecessary tests outside the recommended screening age range ¹. Laboratories in England and Scotland have reported a decreased workload plus increased productivity and efficiency, with no adverse effect on quality ^2-5. There is a growing mismatch between screening workload and capacity, with the potential to achieve improved efficiency by laboratory reconfiguration within a managed network, as recommended in the Carter Report ⁶. However the potential for conflict between the Carter Report recommendations and the autonomy of NHS Foundation Trusts will need to be addressed if laboratory reconfiguration and the Cancer Reform Strategy targets achieved ⁷. Furthermore, assessment of specimen adequacy; the increased prevalence and interpretation of the significance of endometrial cells; and the interpretation of hyperchromatic crowded cell groups, new types of dyskaryosis and solitary cells remain to be defined for LBC samples.

LBC will also provide the platform for automation of the screening process and HPV and other evolving molecular testing. The MAVARIC trial due to report in 2010 will inform the decision about the adoption or otherwise of automation in the NHSCSP. In previous studies the systems currently under evaluation (Focal Point™ GS and ThinPrep^® Imager) have been shown to increase productivity with no loss of sensitivity or specificity ^{8, 9}. The adoption of automation in cervical screening will be a further driver for laboratory reconfiguration. It may also call into question the role of the cytology screener as currently utilised in the UK cervical screening programmes.

Whilst the results of the ARTISTIC and TOMBOLA trials are awaited, sentinel sites have been established to evaluate the practical implications of introducing HPV testing for triage of low grade cytological abnormalities and follow up after treatment of CIN ¹⁰. A recent study from the USA suggests that the adoption of primary HPV testing in conjunction with cytology screening in women aged 30 years and older would result in a 30% reduction in the number of cervical screening tests performed ¹¹, and this will be another driver for laboratory reconfiguration.

However, whether the developments described above are affordable measured against manual test evaluation estimated to prevent up to 3500 deaths per annum in England at a cost of £157 million remains to be determined ¹².

References

NHSCSP Annual Review 2006. Patnick J, editor. 2007. Sheffield, NHSCSP.

NHSCSP Annual Review 2007. Patnick J, editor. 2008. Sheffield, NHSCSP.

Dowie R, Stoykova B, Crawford D, Desai M, Mather J, Morgan K et al. Liquid-based cytology can improve efficiency of cervical smear readers: evidence from timing surveys in two NHS cytology laboratories. Cytopathology 2006; 17(2):65-72.

Williams AR. Liquid-based cytology and conventional smears compared over two 12-month periods. Cytopathology 2006; 17(2):82-85.

Gregory LS, Dudding N, Smith JHF. The impact of introducing liquid based cytology into a routine screening laboratory. Cytopathology 2006; 17(s1):24.

Lord Carter of Coles. Report of the Review of NHS Pathology Services in England. 2006. Department of Health.

Department of Health. Cancer Reform Strategy. 3 December 2007.

Kardos TF. The FocalPoint System: FocalPoint slide profiler and FocalPoint GS. Cancer 2004; 102(6):334-339.

Biscotti CV, Dawson AE, Dziura B, Galup L, Darragh T, Rahemtulla A et al. Assisted primary screening using the automated ThinPrep Imaging System. Am J Clin Pathol 2005; 123(2):281-287.

Eltoum IA, Roberson J. Impact of HPV testing, HPV vaccine development, and changing screening frequency on national Pap test volume: projections from the National Health Interview Survey (NHIS). Cancer 2007; 111(1):34-40.

NHSCSP. HPV Sentinel Sites Implementation Project. http://www.cancerscreening.nhs.uk/cervical/hpv.html#sentinel-sites (accessed 31 March 2008).

Peto J, Gilham C, Fletcher O, Matthews FE. The cervical cancer epidemic that screening has prevented in the UK. Lancet 2004; 364(9430):249-256.

WHAT’S NEW IN VULVOVAGINAL PATHOLOGY?

W Glenn McCluggage

Royal Group of Hospitals Trust, Belfast

Biopsies from the vulvovaginal region are relatively uncommon and constitute a minor proportion of the workload of most surgical pathology laboratories. Due in part to the uncommon or even rare nature of many of the lesions arising at this site, problems in diagnosis are proportionally more common than at other sites in the female genital tract. In this talk, I discuss recent advances in vulvovaginal pathology. A variety of morphologically bland mesenchymal lesions arise at this site, the best known of which is aggressive angiomyxoma, an infiltrative lesion with a marked propensity for local recurrence. Recent developments with regard to aggressive angiomyxoma include the description of occasional metastasising cases ¹, the potential value of gonadotropin releasing hormone agonists in management ² and the description of HMGA2 as a valuable diagnostic marker ³. Aggressive angiomyxoma exhibits HMGA2 immunoreactivity in approximately 50% of cases and this nuclear architectural factor is emerging as a relatively specific marker for this neoplasm, although occasional vulvovaginal smooth muscle neoplasms are positive. HMGA2 is useful in the diagnosis of aggressive angiomyxoma and its distinction from mimics, in the evaluation of resection margins and in the assessment of the presence or absence of residual disease in re-excisions. The morphological spectrum of two recently described mesenchymal lesions, cellular angiofibroma and superficial myofibroblastoma of the lower female genital tract, has been expanded with the publication of recent series ^4-7. Many mesenchymal lesions in the vulvovaginal region exhibit immunoreactivity with both CD34 and desmin, an unusual immunophenotype in mesenchymal lesions at other sites. Relatively newly described mesenchymal lesions in the vulvovaginal region include massive vulval oedema ⁸ and prepubertal vulval fibroma ^9,10. Gastrointestinal stromal tumours have been described in the rectovaginal septum (termed extra gastrointestinal stromal tumours) (eGISTs) ¹¹. It is now recognised that there are two broad types of vulval intraepithelial neoplasia (VIN) and vulval squamous carcinoma with HPV associated and non-HPV associated pathways. HPV associated VIN is referred to as classic VIN and non-HPV associated as differentiated VIN ¹². The latter often arises in a vulval dystrophy, is rarely diagnosed in pure form and is associated in some cases with p53 mutation. HPV associated vulval squamous carcinomas are of basaloid or warty type and the more common non-HPV associated of keratinising type. There is clinical and pathological overlap between HPV associated and non-HPV associated squamous carcinomas and p16 may be more useful than morphology alone in predicting the presence of HPV ¹³. Recent studies on vulval Paget’s disease have largely focused on markers of value in diagnosis. The cells of primary Paget’s disease are characteristically positive with CK7, CEA, CAM 5.2, androgen receptor, gross cystic disease fluid protein 15 and HER 2 ^14-16. A recent study has described a morphologically distinct benign polyp, usually located in the upper vagina and termed tubulo-squamous polyp to reflect the admixture of squamous and tubular elements ¹⁷. The tubular elements are characteristically positive with prostatic markers, raising the possibility that this polyp is derived from paraurethral Skene’s glands, the female equivalent of prostatic glands in the male.

References

Blandamura S, Cruz J, Faure Vergara L, et al Aggressive angiomyxoma: a second case of metastasis with patient’s death. Hum Pathol 2003;34:1072-1074.

McCluggage WG, Jamieson TJ, Dobbs SP, et al. Aggressive angiomyxoma of the vulva: Dramatic response to gonadotropin releasing hormone agonist therapy. Gynecol Oncol 2006; 100; 623-625.

Medeiros F, Oliveira AM, Lloyd RV, et al. HMGA2 expression as a biomarker for aggressive angiomyxoma. Mod Pathol 2008;21;214A (abstract).

McCluggage WG, Ganesan R, Hirschowitz L, et al. Cellular angiofibroma and related fibromatous lesions of the vulva: report of a series with a morphological spectrum wider than previously described. Histopathology 2004;45;360-368.

Iwasa Y, Fletcher CD. Cellular angiofibroma: clinicopathologic and immunohistochemical analysis of 51 cases. Am J S urg Pathol 2004;28;1426-1435.

Ganesan R, McCluggage WG, Hirschowitz L, Rollason TP. Superficial myofibroblastoma of the lower female genital tract : report of a series including tumours with a vulval location. Histopathology 2005;46;137-143.

Stewart CJ, Amanuel B, Brennan BA, et al. Superficial cervicovaginal myofibroblastoma: a report of five cases. Pathology 2005;37;144-148.

McCluggage WG, Young RH. Massive vulval edema secondary to obesity and immobilization: a potential mimic of aggressive angiomyxoma. Int J Gynecol Pathol (in press).

Iwasa Y, Fletcher CDM. Distinctive prepubertal vulval fibroma. A hitherto unrecognized mesenchymal tumor of prepubertal girls: analysis of 11 cases. Am J Surg Pathol 2004;28;1601-1608.

Vargas SA, Kozakewich HP, Boyd TK, et al. Childhood asymmetric labium majus enlargement mimicking a neoplasm. Am J Surg Pathol 2005;29;1007-1016.

Lam MM, Corless CL, Goldblum JR, et al. Extragastrointestinal stromal tumors presenting as vulvovaginal/rectovaginal septal masses: a diagnostic pitfall. Int J Gynecol Pathol 2006;25;288-292.

Hart WR. Vulvar intraepithelial neoplasia: historical aspects and current status. Int J Gynecol Pathol 2001;20;16-30.

Santos M, Landolfi S, Olivella A, et al.. p16 overexpression identifies HPV-positive vulvar squamous cell carcinomas. Am J Surg Pathol 2006;30;1347-1356.

Mazoujian G, Pinkus GS, Haagensen DE Jr. Extramammary Paget’s disease-evidence for an apocrine origin: an immunoperoxidase study of gross cystic disease fluid protein-15, carcinoembryonic antigen, and keratin proteins. Am J Surg Pathol 1984;8;43-50.

Liegl B, Horn LC, Moinfar F. Androgen receptors are frequently expressed in mammary and extramammary Paget’s disease. Mod Pathol 2005;18;1283-1288.

Tanskanen M, Jahkola T, Asko-Seljavaara S, et al. HER2 oncogene amplification in extramammary Paget’s disease. Histopathology 2003;42;575-579.

McCluggage WG, Young RH. Tubulo-squamous polyp: a report of ten cases of a distinctive hitherto uncharacterized vaginal polyp. Am J Surg Pathol 2007; 31;1013-1019.

RECENT ADVANCES IN MOLECULAR GYNAECOLOGICAL PATHOLOGY

Prof C Simon Herrington

University of St Andrews and Ninewells Hospital, Dundee.

Cervix

It is now accepted that almost all cervical neoplasia is causally associated with high-risk human papillomavirus (HPV) infection. However, HPV infection alone is not sufficient for the development of neoplasia and other factors must therefore be involved. HPV integration has emerged as an important factor in the progression of HPV-associated neoplasia¹ and the effects of integration, notably loss of HPV E2 expression and up-regulation of HPV E6 and E7 expression, can lead to many of the molecular features associated with the development of high-grade intraepithelial and invasive squamous and glandular lesions, for example telomerase activation and chromosome abnormalities. Sites of frequent chromosome abnormality include 3q², 5p³ and 20q⁴, all of which have been associated with gain and/or elevated expression of specific genes. Methylation of several tumour suppressor gene promoters during the development of HPV-associated neoplasia has also been reported⁵. Thus, both genetic and epigenetic changes are driven by the effects of HPV infection and integration. Diagnostically, our understanding of the cell cycle effects of HPV infection has led to the use of p16 immunohistochemistry for the identification of high-risk HPV-driven lesions. The addition of other markers, for example MCM2 and TopIIA, may improve diagnostic accuracy, particularly for low-grade intraepithelial lesions⁶.

Vulva

There is strong evidence that vulval neoplasia develops through two distinct pathways. The first, which is associated with undifferentiated (warty/basaloid) VIN, is related to HPV infection and occurs in younger women, who have a greater risk of HPV-associated neoplasia elsewhere in the anogenital region. HPV-associated disease is thought to develop through similar pathways to neoplasia of the cervix, and is associated with similar HPV types. The second, which is associated with differentiated (simplex) type VIN, is unrelated to HPV infection and shows clinicopathological association with lichen sclerosus and keratinising squamous cell carcinoma in elderly women. There has been recent debate about the independence of these two pathways, with some evidence that VIN associated with lichen sclerosus, particularly in the absence of invasive disease, is more likely to be undifferentiated⁷. Diagnostically, there are no good markers of differentiated type VIN, reflecting our lack of understanding of this entity: previous reports that p53 expression may be helpful have not been confirmed⁸.

Endometrium

Two molecular pathways to the development of endometrial carcinoma are now recognised: type I (endometrioid and mucinous tumours) and type II (serous and clear cell tumours)⁹. Endometrioid carcinomas are associated with abnormalities of the PTEN, b-catenin, KRAS and PIK3CA genes. Loss of PTEN expression can be identified in normal proliferative endometrium, suggesting that this may be an early event in tumour development ¹⁰. Endometrioid tumours are also associated with microsatellite instability, which can occur in association with germline mutation of mismatch repair genes as part of the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, or by promoter methylation, particularly of MLH1. Immunohistochemistry for mismatch repair proteins may be of value for the identification of these abnormalities¹¹. Non-endometrioid carcinomas, particularly uterine papillary serous carcinoma, are associated with p53 mutations and diffuse overexpression of p53 protein, which can be useful diagnostically⁹, as well as inactivation of p16 and E-cadherin. Mixed serous and endometrioid tumours are being increasingly recognised: there is some evidence to suggest that the serous components of these tumours may be related to the ‘de-differentiation’ of endometrioid tumours. This concept would explain the presence in some tumours of overlapping type I and type II features, both morphological and molecular.

Ovary and Fallopian Tube

Recent clinico-pathological studies and molecular pathological data suggest that the traditional classification of primary epithelial tumours of the ovary requires some modification, with delineation of distinct categories, some of which cross-traditional morphological boundaries^12,13. High-grade serous and endometrioid tumours, and undifferentiated carcinomas, have a common association with p53 mutation and loss of BRCA1/2 function. Low-grade serous carcinomas are associated with serous borderline tumours and mutations in the BRAF/KRAS genes. Similarly, mucinous carcinomas are associated with borderline mucinous tumours and KRAS mutation. Low-grade endometrioid tumours are associated with ovarian endometriosis and mutation of the b-catenin and PTEN genes. The situation for clear cell and transitional cell carcinomas is less clear, although there is some evidence that different sub-types of these tumours may also exist.

There is evidence that high-grade serous carcinomas of the ovary can develop directly from ovarian surface epithelium or Mullerian inclusions¹⁴. Recent data, based on careful morphological assessment of Fallopian tube specimens, has led to an additional hypothesis, namely that these tumours, and other pelvic serous carcinomas, may also arise from the epithelium of the distal end of the Fallopian tube. Focal abnormalities of p53 expression have been identified in morphologically benign tubal epithelium (p53 signatures), and these abnormalities form a spectrum with tubal intraepithelial carcinomas (TICs)^15-17. As many ovarian carcinomas present late, such small precursor lesions could be destroyed by tumour progression, or overlooked during histopathological assessment.

References

Pett M, Coleman N. Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 2007;212:356-67.

Hopman AH, Theelen W, Hommelberg PP, Kamps MA, Herrington CS, Morrison LE, Speel EJ, Smedts F, Ramaekers FC. Genomic integration of oncogenic HPV and gain of the human telomerase gene TERC at 3q26 are strongly associated events in the progression of uterine cervical dysplasia to invasive cancer. J Pathol 2006;210:412-9.

Muralidhar B, Goldstein LD, Ng G, Winder DM, Palmer RD, Gooding EL, Barbosa-Morais NL, Mukherjee G, Thorne NP, Roberts I, Pett MR, Coleman N. Global microRNA profiles in cervical squamous cell carcinoma depend on Drosha expression levels. J Pathol 2007;212:368-77.

Wilting SM, Snijders PJ, Meijer GA, Ylstra B, van den Ijssel PR, Snijders AM, Albertson DG, Coffa J, Schouten JP, van de Wiel MA, Meijer CJ, Steenbergen RD. Increased gene copy numbers at chromosome 20q are frequent in both squamous cell carcinomas and adenocarcinomas of the cervix. J Pathol 2006;209:220-30.

Henken FE, Wilting SM, Overmeer RM, van Rietschoten JG, Nygren AO, Errami A, Schouten JP, Meijer CJ, Snijders PJ, Steenbergen RD. Sequential gene promoter methylation during HPV-induced cervical carcinogenesis. Br J Cancer 2007;97:1457-64.

Shi J, Liu H, Wilkerson M, Huang Y, Meschter S, Dupree W, Schuerch C, Lin F. Evaluation of p16INK4a, minichromosome maintenance protein 2, DNA topoisomerase IIalpha, ProEX C, and p16INK4a/ProEX C in cervical squamous intraepithelial lesions. Hum Pathol 2007;38:1335-44.

van Seters M, ten Kate FJ, van Beurden M, Verheijen RH, Meijer CJ, Burger MP, Helmerhorst TJ. In the absence of (early) invasive carcinoma, vulvar intraepithelial neoplasia associated with lichen sclerosus is mainly of undifferentiated type: new insights in histology and aetiology. J Clin Pathol 2007;60:504-9.

Liegl B, Regauer S. p53 immunostaining in lichen sclerosus is related to ischaemic stress and is not a marker of differentiated vulvar intraepithelial neoplasia (d-VIN). Histopathology 2006;48:268-74.

Lax SF. Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular-based classification. Virchows Arch 2004;444:213-23.

Mutter GL, Ince TA, Baak JP, Kust GA, Zhou XP, Eng C. Molecular identification of latent precancers in histologically normal endometrium. Cancer Res 2001;61:4311-4.

Modica I, Soslow RA, Black D, Tornos C, Kauff N, Shia J. Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma. Am J Surg Pathol 2007;31:744-51.

Gilks CB. Subclassification of ovarian surface epithelial tumors based on correlation of histologic and molecular pathologic data. Int J Gynecol Pathol 2004;23:200-5.

Soslow RA. Histologic subtypes of ovarian carcinoma: an overview. Int J Gynecol Pathol 2008;27:161-74.

Russell SE, McCluggage WG. A multistep model for ovarian tumorigenesis: the value of mutation analysis in the KRAS and BRAF genes. J Pathol 2004;203:617-9.

Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, Cramer DW, McKeon FD, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol 2007;211:26-35.

Jarboe E, Folkins A, Nucci MR, Kindelberger D, Drapkin R, Miron A, Lee Y, Crum CP. Serous carcinogenesis in the fallopian tube: a descriptive classification. Int J Gynecol Pathol 2008;27:1-9.

Jarboe EA, Folkins AK, Drapkin R, Ince TA, Agoston ES, Crum CP. Tubal and ovarian pathways to pelvic epithelial cancer: a pathological perspective. Histopathology 2008 Feb 22 [Epub ahead of print]; doi: 10.1111/j.1365-2559.2007.02938.x

VARIANTS OF ADENOCARCINOMA OF THE CERVIX

Laurence Brown

University Hospitals Leicester

This short presentation will cover the major variants of cervical adenocarcinoma and expand on the WHO classification^{1 2}

The incidence of adenocarcinoma of the cervix, especially in women under 35, is increasing worldwide^{1 3 4}, reflecting a screening-related reduction in the number of squamous carcinomas and a real increase in adenocarcinoma.

The main diagnostic problems are

· Distinguishing

o cervical adenocarcinoma: P16 +ve⁵, ER –ve, Vim –ve, CEA +ve

o from endometrial adenocarcinoma: Er +ve, Vim +ve and CEA -ve⁶

· Separating superficially invasive disease from CGIN

o Buds of invasive adenocarcinoma (often squamoid)

o obliteration of the normal endocervical crypts

o extension beyond the normal glandular field

o a desmoplastic stromal response⁷

o proximity to deep medium sized arterioles

· Acknowledging that

o SMILE⁸ Stratified mucin-producing intraepithelial lesion of the cervix is an indicator of a high risk of adenocarcinoma.

o Intestinal differentiation is rarely, if ever, seen in non-neoplastic epithelium. “Intestinal metaplasia” may not exist¹.

o Villoglandular carcinoma can be an in situ surface growth with no underlying invasion

o Minimum deviation carcinoma (adenoma malignum) is difficult to diagnose on biopsy and has several benign mimics

o Endometrioid and serous variants may have spread to the cervix from the endometrium

o Mesonephric (Gartner’s duct) hyperplasia is common, but may very rarely be the source of mesonephric carcinoma

· Recognising rare variants²

o Adenoid cystic carcinoma, resembling salivary gland tumours⁹

o Adenoid basal carcinoma, a basaloid tumour with some gland formation⁹

o Adenoid cystic and adenoid basal carcinomas may form part a continuum⁹

o Glassy cell carcinoma, abundant cytoplasm with prominent eosinophils in the stroma¹⁰

o A large mucinous cell component in poorly differentiated large cell carcinoma indicates an adenocarcinoma.

References

Brown LJR WM. Malignant and premalignant glandular lesions of the cervix. In: Fox H WM, editor. Obstetrical and Gynaecological Pathology. 5 ed: Churchill Livingstone, 2003:339-367.

Wells M OA, Crum CP et al. Epithelial tumours. In: Tavassoli FA DP, editor. WHO Classification of tumours. Pathology and genetics of tumours of the breast and female genital organs. . Lyon: IARC Press 2003:272-279.

Smith HO, Tiffany MF, Qualls CR, Key CR. The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States--a 24-year population-based study. Gynecol Oncol 2000;78(2):97-105.

Bray F, Carstensen B, Moller H, Zappa M, Zakelj MP, Lawrence G, et al. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev 2005;14(9):2191-9.

Negri G, Egarter-Vigl E, Kasal A, Romano F, Haitel A, Mian C. p16INK4a is a useful marker for the diagnosis of adenocarcinoma of the cervix uteri and its precursors: an immunohistochemical study with immunocytochemical correlations. Am J Surg Pathol 2003;27(2):187-93.

McCluggage WG, Sumathi VP, McBride HA, Patterson A. A panel of immunohistochemical stains, including carcinoembryonic antigen, vimentin, and estrogen receptor, aids the distinction between primary endometrial and endocervical adenocarcinomas. Int J Gynecol Pathol 2002;21(1):11-5.

Ostor AG. Early invasive adenocarcinoma of the uterine cervix. Int J Gynecol Pathol 2000;19(1):29-38.

Park JJ, Sun D, Quade BJ, Flynn C, Sheets EE, Yang A, et al. Stratified mucin-producing intraepithelial lesions of the cervix: adenosquamous or columnar cell neoplasia? Am J Surg Pathol 2000;24(10):1414-9.

Grayson W, Taylor LF, Cooper K. Adenoid cystic and adenoid basal carcinoma of the uterine cervix: comparative morphologic, mucin, and immunohistochemical profile of two rare neoplasms of putative 'reserve cell' origin. Am J Surg Pathol 1999;23(4):448-58.

Kato N, Katayama Y, Kaimori M, Motoyama T. Glassy cell carcinoma of the uterine cervix: histochemical, immunohistochemical, and molecular genetic observations. Int J Gynecol Pathol 2002;21(2):134-40.

OVARIAN MUCINOUS TUMORS: CURRENT CONCEPTS

Brigitte M. Ronnett, M.D.

Department of Pathology The Johns Hopkins University School of Medicine, Baltimore MD

Topics:

• Primary ovarian mucinous tumors

• Terminology

• Clinicopathologic features

• Ovarian mucinous tumors associated with pseudomyxoma peritonei (PMP)

• Evidence clarifying site of origin and relationship to primary ovarian mucinous tumors

• Metastatic mucinous carcinomas

• Distinction of primary ovarian mucinous tumors from metastases

• Diagnostic evaluation

• Intraoperative consultation

• Immunohistochemical analysis

PRIMARY OVARIAN MUCINOUS TUMORS

Primary Ovarian Mucinous Tumor Terminology:

• Mucinous borderline tumor

• Mucinous tumor of low malignant potential

• Atypical proliferative mucinous tumor (APMT)

• Intraepithelial carcinoma (non-invasive carcinoma)

• Microinvasion / microinvasive carcinoma

• Primary ovarian mucinous carcinoma

Synonymous terminology*:

• Mucinous borderline tumor

• Mucinous tumor of low malignant potential

• Atypical proliferative mucinous tumor

(* 2003/2004 NCI/NIH Consensus Conference)

Borderline / Low Malignant Potential / Atypical Proliferative Mucinous Tumor, Gastrointestinal Type

• Multiloculated cystic tumor, smooth surface

• Large (often >15 cm; mean/median size = 22 cm)

• >95% unilateral

• Non-invasive tumor with glands/cysts having intraglandular epithelial proliferation

• Variable degrees of stratification and nuclear atypia (usually mild to moderate)

• Absent stromal invasion

• Stage I (recent studies with rigorously classified tumors)

• Survival for stage I is virtually 100%

• “Advanced stage disease” has worse prognosis (~ 50% survival) and is associated with pseudomyxoma peritonei (PMP) in ~90%

• PMP is caused by ruptured appendiceal low-grade adenomatous mucinous neoplasms (adenomas); ovarian mucinous tumors are secondary (see below)

• Advanced stage tumors with PMP are not primary ovarian "borderline" mucinous tumors with "implants"

Borderline / Low Malignant Potential / Atypical Proliferative Mucinous Tumor, Endocervical-like / Müllerian / Seromucinous Type

• Gross and architectural features of serous tumor: papillary, intracystic or exophytic, often bilateral, often associated with endometriosis

• Mixed serous (ciliated and eosinophilic cells) and endocervical-type mucinous differentiation (+/- minor endometrioid component)

• Immunohistochemical features of serous tumor (CK7+/CK20-, ER+/PR+, CA125+)

• Survival is 100% (including stage >I and intraepithelial and microinvasive carcinomas)

Distinction of Borderline / Atypical Proliferative / Low Malignant Potential Tumors from Primary Ovarian Mucinous Carcinomas: Four Forms of Carcinoma Recognized

• Tumors exhibiting destructive stromal invasion

• Frankly invasive

• Microinvasive

• Tumors lacking destructive stromal invasion

• Intraepithelial (non-invasive) carcinoma

• Invasive mucinous carcinoma with a confluent glandular/cribriform (expansile) pattern

Borderline / Low Malignant Potential / Atypical Proliferative Mucinous Tumor with Intraepithelial (Non-invasive) Carcinoma

• Diagnosis reserved for tumors with marked/severe (grade 3) cytologic atypia

• Stratification or complex intraglandular growth (regardless of degree) in the absence of severe atypia does not qualify

• ~95% survival reported for stage I tumors overall in literature; most with adverse behavior not well sampled and reported in older studies; recent studies report essentially 100% survival

• A small number of so-called “advanced stage borderline tumors with intraepithelial carcinomas”, with some reported deaths due to disease, are suspect as either metastases simulating primary ovarian mucinous tumors or primary ovarian mucinous carcinomas in which destructive invasion was not identified (present in unsampled tissue)

Borderline / Low Malignant Potential / Atypical Proliferative Mucinous Tumor with Microinvasion

• Foci of stromal invasion £3-5 mm (greatest dimension per focus) or <10 mm²

• Small glands, clusters of cells, or individual tumor cells in stroma

• Confluent glandular/cribriform pattern in stroma between cysts (cribriform growth confined to intraglandular spaces = intraepithelial CA when marked atypia is present)

• No criteria set for number of foci allowed within a given tumor

• Borderline mucinous tumor with "microinvasion” is used by some pathologists to designate a tumor in which the small invasive foci appear similar to the borderline tumor (that is, cytologically low-grade)

• The term “microinvasive carcinoma” is used by some pathologists to designate a tumor in which the small invasive foci have a higher-grade cytologic appearance (moderate-marked nuclear atypia) and/or the small invasive foci are arising in a tumor with intraepithelial carcinoma

• No recurrences or deaths due to disease have been reported, with the exception of one inadequately sampled tumor

Primary Ovarian Mucinous Carcinoma

• Infiltrative type

• Foci of destructive stromal invasion >3-5 mm (greatest dimension per focus) or >10 mm²

• Less common pattern, which should raise concern for metastatic carcinoma especially when accompanied by any of the following features:

– Bilateral ovarian tumor

– Nodular pattern

– Surface/superficial cortical tumor

– Extra-ovarian disease

• Confluent glandular/cribriform (expansile) type

• Complex interconnected labyrinthine glandular and/or papillary epithelial growth lacking typical destructive stromal invasion

• Common pattern of primary ovarian mucinous carcinoma, often arising in association with borderline/atypical proliferative mucinous tumor

• Most primary ovarian mucinous carcinomas are unilateral stage I tumors

• Most have a gastrointestinal-type or generic appearance; rare subtype with seromucinous features exists

• Adverse prognosis is associated with advanced stage and infiltrative type

• Uncommon once metastases are rigorously excluded (especially those with deceptive patterns of invasion simulating primary ovarian tumors)

OVARIAN MUCINOUS TUMORS ASSOCIATED WITH PSEUDOMYXOMA PERITONEI (PMP)

Obstacles to Understanding the Relationship between Primary Ovarian Mucinous Tumors and PMP

• “Synchronous” appendiceal and ovarian mucinous tumors are common

• Appendix can appear “normal” or be obscured by peritoneal disease; it is not always removed or completely examined microscopically

• Ovarian tumors can be large and responsible for the clinical presentation (to gynecologist/gynecologic oncologist)

• Default is to interpret ovarian mucinous tumor as primary and at least “borderline” due to the presence of extra-ovarian disease ("implants")

Keys to Understanding the Relationship between Ovarian Mucinous Tumors and PMP

• Behavior of true primary ovarian atypical proliferative (borderline) mucinous tumors

• Consequences of rupture of true primary ovarian atypical proliferative (borderline) mucinous tumors

• Features of ovarian mucinous tumors in PMP compared with true primary ovarian atypical proliferative (borderline) mucinous tumors without PMP

• Morphology

• Immunophenotype

• Molecular genetic profile

Borderline / Low Malignant Potential / Atypical Proliferative Mucinous Tumors and PMP: The Facts

• Stage I tumors (recent studies with rigorously classified tumors)

• Survival for stage I is virtually 100%

• “Advanced stage disease” (reported virtually exclusively in older literature) has worse prognosis (~ 50% survival) and is associated with pseudomyxoma peritonei (PMP) in ~90%

• Rupture of primary ovarian mucinous tumors has not been demonstrated to lead to subsequent development of PMP

• Morphologic, immunohistochemical, and molecular genetic data provide evidence that the ovarian mucinous tumors in PMP are secondarily derived from appendiceal low-grade adenomatous mucinous tumors (ruptured adenomas)

• PMP is of appendiceal, not ovarian, origin and does not reflect an advanced stage ovarian mucinous tumor (rare exception: teratomatous ovarian mucinous tumors)

Morphologic Evidence Supporting the Appendiceal Origin of PMP in Women

Mucinous tumors associated with PMP:

• Variably enlarged (often <15 cm)

• Bilateral (~80%)

• Surface and superficial cortical involvement (+/- stroma)

• Prominent pseudomyxoma ovarii

• Scant low-grade adenomatous mucinous epithelium

• Associated appendiceal low-grade adenomatous mucinous tumor

Atypical proliferative (borderline) mucinous tumors:

• Large (>15 cm)

• Unilateral (>95%)

• Stromal involvement (rarely surface)

• Absent/minimal pseudomyxoma ovarii

• Abundant proliferative mucinous epithelium

• No association with independent primary appendiceal mucinous tumors

Immunohistochemical Evidence Supporting the Appendiceal Origin of PMP and the Associated Ovarian Mucinous Tumors in Women

	Appendiceal mucinous tumors	Ovarian mucinous tumors in PMP	Primary ovarian APMT
CK7	Negative (few positive, often focal)	Negative (few positive, often focal)	Positive (usually diffuse)
CK20	Positive (diffuse)	Positive (diffuse)	Often positive (variable extent)

METASTATIC MUCINOUS CARCINOMAS

Metastatic Mucinous Carcinoma in the Ovary

• Metastatic mucinous carcinomas are more common than primary ovarian mucinous carcinomas

• Carcinomas of colorectum, appendix, pancreas, biliary tract, stomach, and endocervix can simulate primary ovarian mucinous tumors

Distinction of Primary and Metastatic Mucinous Tumors in the Ovary:

• Primary ovarian mucinous tumors (atypical proliferative and carcinoma)

• Unilateral (>95%)

• Large (mean/median sizes ~22 cm)

• Absent surface or superficial cortical tumor

• Multicystic and/or solid without parenchymal nodules

• Typically stage I

• Metastatic mucinous carcinomas

• Often bilateral

• Typically smaller (usually <15 cm, many <10 cm) but can be large

• Involvement of ovarian surface and/or superficial cortex

• Nodular pattern with preserved or compressed intervening stroma, but can be multicystic

• Often accompanied by extra-ovarian tumor (peritoneum, omentum)

Problematic Features of Some Metastatic Mucinous Carcinomas in the Ovary

• Initial clinical presentation in the ovary (occult primary tumor)

• Unilateral large tumor with cyst formation

• Deceptive patterns of invasion, simulating primary ovarian “borderline” mucinous tumor with intraepithelial carcinoma or confluent glandular pattern of invasive mucinous carcinoma

• Greater differentiation than the primary tumor

• Highly differentiated areas simulating a benign ovarian precursor mucinous tumors (cystadenoma and "borderline" tumor), suggesting origin in the ovary

• Hormonal symptoms (virilization) suggesting a primary ovarian sex cord-stromal tumor

Intraoperative Assessment of Ovarian Mucinous Tumors

• Clinicopathologic correlation (communication with surgeon, clinical database)

• History of any tumors

• Operative and gross findings

• Unilateral versus bilateral ovarian tumor

• Size of ovarian tumor(s)

• Presence of extra-ovarian disease

• Frozen section diagnosis sampling limitations

• Practical to examine only 1-2 sections

• Mucinous tumors can be heterogeneous

• Metastases can simulate primary ovarian tumors (even on permanent sections)

• Staging decisions (differs for primary versus metastatic tumor)

Distinction of Primary and Secondary/Metastatic Mucinous Tumors in the Ovary: Guidelines

• Requires synthesis of clinical and pathologic features

• Clinical history; sometimes subsequent clinical evaluation is required to search for a non-ovarian source

• Gross and microscopic features

• Size and laterality can distinguish many tumors: bilateral tumors of any size or unilateral tumor <10-12 cm = metastatic (some exceptions occur)

• Signet ring cell patterns = metastatic

• Selected panel of immunohistochemical markers

• Distinguish primary from metastatic tumors

• Predict primary site for metastases of unknown origin

Immunohistochemical Profiles of Mucinous Tumors

	CK7	CK20	Dpc4	p16	ER/PR
Ovary*	+ (CK7>CK20)	+/- (~75%)	+	-/F+	-
Colorectum	- (~90%)	+ (CK20>CK7)	+ (~90%)	-/F+	-
Appendix	- (70-90%)	+ (CK20>CK7)	+	-/F+	-
Pancreaticobiliary tract	+ (CK7>CK20)	+/- (~80%)	- (~50%)	-/F+	-
Stomach	+/-	+/-	+	-/+	-
Endocervix	+ (CK7>CK20)	-/+	+	D+	-

D = diffuse; F = focal/patchy

* A subset of mucinous tumors of probable teratomatous origin is CK7-/CK20+

New Understanding of Ovarian Mucinous Tumors: Implications for Nomenclature

• Diagnosis of ovarian mucinous tumors has been refined and their behavior has been clarified by:

• Recognition of ovarian mucinous tumors in PMP as secondary tumors of appendiceal origin

• Recognition of certain metastatic mucinous carcinomas having deceptive patterns of invasion as non-ovarian tumors

• Excluding these tumors from the true primary ovarian mucinous tumor category eliminates the need for ambiguous terminology (“borderline”) to account for uncertain behavior of the subsets now known to be non-ovarian tumors

• True primary ovarian mucinous tumors with “borderline-type” morphology are non-invasive, proliferative, variably atypical tumors with an overwhelmingly benign behavior

• Nomenclature should reflect these attributes

• “Atypical proliferative” is a morphologically and clinically more meaningful term

New Understanding of Ovarian Mucinous Tumors: Implications for Investigation

• Primary ovarian mucinous tumors and metastatic mucinous carcinomas from various sites are biologically unique tumors with distinct genetic profiles (some known, some yet to be elucidated)

• Clinicopathologic studies and molecular genetic analyses require rigorous classification, with careful exclusion of ovarian mucinous tumors associated with PMP and metastatic mucinous carcinomas having deceptive patterns of invasion, so that pathogenetic mechanisms, behavior, and assessment of therapeutic responses are not obscured by misclassification

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CLINICAL MANAGEMENT OF VIN AND VULVAL CANCER

Professor Henry Kitchener

University of Manchester, St Mary’s Hospital

Abstract

Vulval Cancer is a relatively rare disease affecting about 1,000 women each year in England. It is usually preceded by either vulval intraepithelial neoplasia or lichen sclerosus but these often do not present prior to cancer. Most, but not all, cases of vulval neoplasia are due to oncogenic HPV infection with rising rates of vulval intraepithelial neoplasia at a younger age. VIN may be associated with distressing symptoms of itch and pain.

The treatment of VIN is challenging because of multifocal disease, high rates of recurrence and disfiguration of the vulva. The traditional and most widely used measurement is surgical excision but this is associated with recurrence rates of up to 40%, particularly in multifocal disease and often necessitating repeat excision. In order to reduce skin loss, laser is used but this also has high failure rates. The prognosis is better with unifocal disease than multifocal disease. Many women prefer surveillance. Vulval cancer is treated principally by radical local excision and groin node dissection. Adjuvant therapy is reserved for those with more than one positive node. The most important recent development has been the use of sentinel site surgery to restrict the number of women undergoing full groin dissection with its risk of lymphoedema.

Novel non-surgical therapy for VIN has been studied in Manchester for a decade aimed at reducing morbidity. Recent phase II trials of photodynamic therapy and vaccine, incorporated imiquimod to optimise outcomes. The recent development of prophylactic HPV 16/18 vaccines should lead to a significant reduction in vulval neoplasia.

References

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REVIEW OF THE NEW GYNAECOLOGICAL PATHOLOGY CANCER DATASETS

Dr Lynn Hirschowitz

Southmead Hospital, Bristol

All cancer datasets must conform to a standardised format, content and 'College style' to ensure a consistent approach across all specialties. The title of the series has been changed to 'Standards and Datasets for reporting Cancers'. To date the vulval, cervical and ovarian cancer datasets have been submitted to the Working Group on Cancer Services (WGCS) and the vulval and cervical datasets have been available as consultation documents on the RCPath website and submitted to stakeholders for comment. The ovarian cancer dataset will be subject to the same scrutiny process shortly, and it is hoped that the endometrial dataset will be submitted to the WGCS within the next few months.

All datasets now include a succinct section on frozen sections (where relevant), the application of relevant immunohistochemical markers, handling of small biopsy specimens and comprehensive lists of SNOMED, TNM codes and FIGO staging for each tumour type. As a result of editorial style requirements that all text (including the text in proformas) should be in Times New Roman font size 11, some of the proformas can no longer be accommodated on one side of A4.

The main changes in the vulva dataset are the requirement for more precise specification of the nature of resection specimens, clarification of the resection margin perameters, inclusion of Paget's disease, acknowledgement of lichen planus as a risk factor for vulval squamous carcinoma and inclusion of more details on lymph node involvement and the status of the sentinel node. The text also provides more detailed guidance on measuring depth of invasion, and a schematic illustration has been provided as an Appendix to assist with specimen orientation and description of tumour location.

The cervix dataset includes the recommendation of the BAGP working group that the term 'microinvasive carcinoma' be avoided and the specific FIGO stage be used instead, because of the lack of clarity of the former term and the wide variation in the criteria that are applied in its use. Measurement of multifocal carcinoma is discussed, details about tumour margins have been clarified and expanded in the proforma that covers the reporting of large resection specimens, and the small/excisional resection specimen proforma has been re-ordered so that the emphasis is placed on the details of the invasive component, rather than preinvasive lesions (which now include SMILE/stratified mucin-producing intraepithelial lesion). Because of the prognostic and therapeutic importance of identifying neuroendocrine carcinomas, these are now listed separately as a subtype of cervical carcinoma in the reporting proformas.

The ovarian carcinoma dataset includes proformas for primary fallopian tube and primary peritoneal carcinomas but the proforma for reporting of non-epithelial tumours has been removed. An important change is the recommendation that serous carcinomas of the ovary, fallopian tube and peritoneum are graded using a two-tier system and more specific guidance is provided regarding the grading of other tumour subtypes. The effect of pre-operative chemotherapy on ovarian tumours is highlighted – often it is not possible to type or grade such tumours reliably. The importance of documenting the different morphological subtypes, especially in early-stage ovarian neoplasms, is stressed (even if these comprise <10% of the neoplasm) because of the prognostic importance of even a minor component of a more aggressive subtype. Details of microinvasion, omental sampling and the necessity for meticulous examination and recording of the status of the ovarian capsule are also included.

The endometrial cancer proforma now includes the status of the parametria and the dataset stresses the importance of subtyping of endometrial carcinomas.

The importance of having robust local mechanisms to ensure that supplementary or revised histology reports are issued is stressed. This ensures that decisions which affect patient treatment are documented and that data collected by Cancer Registries are accurate. The BAGP Working Group has recommended that the pathological FIGO stage of all gynaecological cancers be regarded as provisional, and that the stage is finalised only after all information has been taken into account at MDT meetings. The WGCS envisages that the dataset series will continue to evolve and that authors will be invited to review the content every two years following publication to ensure that new information is incorporated as it becomes available.

WHAT’S NEW IN OVARIAN SEX CORD-STROMAL TUMOURS?

Nafisa Wilkinson

Leeds

A sex cord-stromal tumour is one that is composed of granulosa cells, theca cells, Sertoli cells, Leydig cells and fibroblasts of stromal origin, singly or in various combinations. As a result a wide range of patterns are encountered and include a long list of differential diagnoses. In the great majority of cases the patterns are distinctive in routinely stained sections and as in ovarian tumour pathology in general, the importance of thorough sampling cannot be over-emphasized.

Granulosa Cell tumours are divided into adult the predominant type and the rarer juvenile type based on their morphological characteristics.The designation “juvenile” was coined by Dr Robert Scully because of the recognised features that differed from the adult type, greater irregularity of follicular size and shape, more abundant cytoplasm, more immature nuclei lacking groves and greater mitotic activity. These features were characteristic of the tumours seen in the young compared to the typical neoplasm encountered in the adult group. A small “hybrid” group exists where both morphological patterns are seen in the same tumour. There is insufficient information on such uncommon neoplasms tumours to comment on prognosis.

A pseudopapillary pattern has been described recently in granulosa cell tumours. This was seen in both juvenile and adult types. Pseudopapillae develop as a secondary or degenerative phenomenon lacking true stromal cores. The tumours tended to be cystic, unilocular or multilocular, with multiple papillary-like formations projecting into cystic spaces. In all tumours thorough sampling revealed areas with architectural and cytological features of typical granulosa cell tumour.

The distinction of a Granulosa cell tumour from a surface epithelial carcinoma can be aided by the use of EMA (positive in carcinomas) and inhibin and Calretinin (positive in granulosa cell tumours.) A negative inhibin on immunohistochemistry does not exclude a diagnosis of granulosa cell tumour.

The classification of fibromas has recently been addressed prompted by the significant numbers of fibrosarcomas that pursued a good clinical outcome. Many pathologists had been making a diagnosis of fibrosarcoma based exclusively on the mitotic count, > 4 MF /10 HPF. The study by Irving et al emphasizes the distinction of a group of “mitotically active”, cytologically bland, cellular fibromatous tumours from fibrosarcomas. These tumours showed a mean of 6.7 MF/10HPF and a range of 4 to 19 MFs/10HPF. This group of patients have a favourable outcome in contrast to fibrosarcoma which show moderate to severe atypia and elevated mitotic rates. Those cellular or mitotically active cellular neoplasms associated with rupture or adherence occasionally recurred and therefore long term follow up would be appropriate. Cellular fibromas is reserved for those cytologically bland, cellular neoplasms that have a mitotic count of up to 3 MF/10HPF.

Luteinized thecomas occur in younger women than typical thecomas, mean age 46 years. They are histologically composed of clusters of large eosinophilic lipid laden or vacuolated lutein cells scattered in the stroma. Luteinization is particularly common in tumours from pregnant women. These tumours may be functional, 10% (androgenic), 50 % (oestrogenic).

A distinct variant of luteinized thecoma is that associated with sclerosing peritonitis. This was described by Clement et al. They are frequently bilateral, typically exhibit a brisk mitotic rate and histologically show a cellular neoplasm that range from fusiform to spindled cells associated with weakly luteinized cells often showing a microcystic appearance. It is uncertain if these lesions are neoplastic or non-neoplastic. Staats et al recommend that thecomatosis be used in parenthesis after the preferred terminology of luteinized thecoma to designate this entity until further information becomes available.

Microcystic stromal tumour is a newly recognised entity. 12 examples of this non-functioning, neoplasm have been described all occurring in adults. On microscopy the tumour is composed of lobulated cellular masses separated by hyaline bands and fibrous plaques. Focally in areas or sometimes more strikingly there is a microcystic pattern characterized by small cysts that anastomose with each other. Mitoses are rare. These neoplasms are inhibin negative and CD 10 positive.

Sertoli cell tumours are rare in their pure form. They often present with oestrogenic manifestations in young women. Occasional cases are seen in the Peutz-Jeghers syndrome. They usually have an excellent prognosis. In a recent study of 54 Sertoli cell tumours studied, 6 had foamy cytoplasm and one clear. The so-called “lipid-rich” variant. In addition to the tubular morphology other patterns encountered are cords or trabeculae, diffuse, pseudopapillary, retiform, alveolar and spindled. Moderate to severe cytological atypia, brisk mitotic activity >5MF/10HPF and sometimes necrosis are features associated with malignancy. Endometrioid adenocarcinoma and carcinoid tumour enter into the differential and EMA, inhibin and chromogranin are useful immunohistochemical markers in their distinction.

Sertoli-Leydig cell tumours are virilizing in about half the cases. Occasionally tumours may be oestrogenic. Poorly differentiated tumours are composed of immature, cellular mesenchymal tissue with a high mitotic count resembling a sarcoma. Tubular, sex cord-like and other more distinctive patterns are required to establish the diagnosis. Like thecomas and granulosa cell tumours Sertoli-Leydig cell tumours can also contain cells with bizarre nuclei. 16% have a retiform component. Heterologous elements are encountered in approximately 20%. The commonest element is mucinous epithelium of gastro-intestinal type. Mesenchymal heterologous elements are encountered in approximately 5% and they include cartilage and areas of embryonal rhabdomyosarcoma arising on a sarcomatous background. Caution should be exercised before a diagnosis of a pure ovarian sarcoma is made in a young woman and the diagnosis of a poorly differentiated Sertoli-Leydig cell tumour should be considered.

Gynandroblastoma is a term that does not convey any concrete diagnostic information to the clinician. It is therefore preferable to make a primary diagnosis of a mixed sex cord-stromal tumour and then give the components present with a rough indication of the percentage of each component identified.

References

McCluggage W G, Young R H. Immunohistochemistry as a diagnostic aid in the evaluation of ovarian tumours. Semin Diagn Pathol 2005; 22: 3-32.

Zaloudek C, Norris H J. Granulosa tumors of the ovary in children. A clinical and pathological study of 32 cases. Am J Surg Pathol 1982; 6: 503-12.

Irving J, Young R H. Granulosa cell tumors of the ovary with a pseudopapillary pattern: A study of 14 cases of an unusual morphologic variant emphasizing their distinction from transitional cell neoplasms and other papillary ovarian tumors. Am J Surg Pathol 2008; 32:581-586

Irving J A, Abdulmohsen A, Young R H, Clement P B. Cellular fibromas of the Ovary: A study of 75 cases including 40 mitotically active tumors emphasizing their distinction from fibrosarcoma. Am J Surg Pathol 2006; 30: 929-938.

Staats P N, McCluggage W G, Clement P B, Young R H. Luteinized thecomas (thecomatosis) of the type typically associated with sclerosing peritonitis: A clinical, histopathological and immunohistochemical analysis of 27 cases. Am J Surg Pathol In press.

Irving J A, Young R H. Microcystic stromal tumor of the ovary; report of 12 cases of a hitherto uncharacterized distinctive ovarian neoplasm. Mod Pathol 2008; 21: suppl: 207

Young R H, Scully R E. Ovarian Sertoli-Leydig cell tumors: A clinicopathological analysis of 207 cases. Am J Surg Pathol 1985; 9: 543-569.

McCluggage W G, Young R H. Ovarian Sertoli-Leydig cell tumors with pseudoendometrioid tubules (pseudoendometrioid Sertoli-Leydig cell tumors). Am J Surg pathol 2007; 31: 592-596.

Roth L.M. Recent advances in the pathology and classification of ovarian sex cord-stromal tumors. Int J Gynecol Pathol 2006; 25: 199-215.

Wilkinson N, Osborn S, Young R.H. Sex Cord-Stromal Tumours of the Ovary: A review highlighting recent advances. Current Diagnostic Pathology (in press)

SYNCHRONOUS TUMOURS IN THE FEMALE GENITAL TRACT

Dr Naveena Singh, MD, FRCPath

Division of Cellular Pathology, Barts and the London NHS Trust, London

It is reported that 1-2% of all women with gynaecological cancers will be found to have two or more simultaneous independent primary malignancies involving the female genital tract. A fair proportion of these represent coincidental tumours of completely different histological types, each deserving treatment on its own merit; these need not be discussed further. Far more problematic is the occurrence of synchronous tumours of similar or identical histology, most frequently involving the endometrium and ovary. This phenomenon is relatively unique to the female genital tract and poses a not infrequent conundrum for the gynaecological pathologist faced with distinguishing between low stage multiple primaries and a tumour that has metastasised from one to other site, with completely different prognostic and management implications.

Synchronous tumours in the ovary or endometrium are reported to occur respectively in 5% of women with endometrial cancer and 10% of women with ovarian cancer. The distinction of synchronous endometrial and ovarian primaries from stage 3 endometrial cancer is crucial for correct patient management. The diagnosis of synchronous primaries should be made with extreme caution, if at all, in grade 3 endometrioid and type 2 endometrial cancers. For endometrioid cancers, most cases can be accurately categorised on the basis of standard histological features: within the endometrial tumour superficial or no myoinvasion and lack of vascular invasion favour an independent primary while deep myoinvasion and vascular invasion would correlate with metastasis; within the ovarian tumour presence of an intraparenchymal solitary mass and endometriosis favour an independent primary while multinodularity, surface or hilar involvement and vascular invasion favour metastasis.

Molecular testing can provide valuable adjunctive information in ambiguous cases but must be interpreted with clinicopathological correlation and not in isolation. The most common techniques that have been advocated are loss of heterozygosity profiling and testing for mutations in pTEN or beta-catenin genes, or for microsatellite instability. Gene expression profiling also has potential for enabling accurate staging of synchronous tumours in the future. Nuclear, as opposed to membranous, expression of beta-catenin on immunohistochemistry is reported to favour synchronous independent primaries but requires wider testing for confirmation of this observation.

Poor prognostic features are tumour grade, vascular invasion and stage-related factors: deep myoinvasion, positive peritoneal washings and metastasis outside the uterus and ovaries.

A very low percentage of women with synchronous primaries in the uterus and ovary are HNPCC patients and genetic or immunohistochemical testing for mismatch repair gene mutations are unnecessary in all cases, even if young; the diagnosis of HNPCC should be based on clinical including family history and fulfilment of Amsterdam criteria.

Women with endometrial cancer under 50 are much more likely than older patients to have a synchronous ovarian tumour and this should be taken into account if ovarian conservation is being considered.

Rarer combinations of synchronous tumours are less well studied but may also represent a mixture of unusual patterns of metastasis and multifocal origin.

References

Zaino, R., Whitney, C., Brady, M.F., DeGeest, K., Burger, R.A., Buller, R.E. Simultaneously detected endometrial and ovarian carcinomas--a prospective clinicopathologic study of 74 cases: a gynecologic oncology group study. Gynecol Oncol, 2001. 83(2): p. 355-62.

Soliman, P.T., Slomovitz, B.M., Broaddus, R.K., Sun, C.C., Oh, J.C., Eifel, P.J., Gershenson, D.M., Lu, K. Synchronous primary cancers of the endometrium and ovary: a single institution review of 84 cases. Gynecol Oncol, 2004. 94(2): p. 456-62.

Walsh, C., Holschneider, C., Hoang, Y., Tieu, K. Karlan, B., Cass, I. Coexisting ovarian malignancy in young women with endometrial cancer. Obstet Gynecol, 2005. 106(4): p. 693-9.

Ulbright, T.M. and L.M. Roth, Metastatic and independent cancers of the endometrium and ovary: a clinicopathologic study of 34 cases. Hum Pathol, 1985. 16(1): p. 28-34.

Scully, R.E., Young, R. H., Clement, P. B., Tumors of the Ovary, maldeveloped gonads, fallopian tube and broad ligament. Atlas of Tumor Pathology. Bethesda, MD: Armed Forces Institute of Pathology., 1998.

Ayhan, A., Guvenal, T., Coskun, F., Basaran, M., Salman, M.C. Survival and prognostic factors in patients with synchronous ovarian and endometrial cancers and endometrial cancers metastatic to the ovaries. Eur J Gynaecol Oncol, 2003. 24(2): p. 171-4.

Moreno-Bueno, G., Gamallo, C., Perez-Gallego, L., de Mora, J.C., Suarez, A., Palacios, J. beta-Catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas. Diagn Mol Pathol, 2001. 10(2): p. 116-22.

Irving, J.A., Catasus, L., Gallardo, A., Bussaglia, E., Romero, M., Matias-Guiu, X., Prat, J. Synchronous endometrioid carcinomas of the uterine corpus and ovary: alterations in the beta-catenin (CTNNB1) pathway are associated with independent primary tumors and favorable prognosis. Hum Pathol, 2005. 36(6): p. 605-19.

Prat, J. Clonality analysis in synchronous tumors of the female genital tract. Hum Pathol, 2002. 33(4): p. 383-5.

Soliman, P.T., Broaddus, R.K., Schmeler, K.M., Daniels, M.S., Gonzalez, D., Slomovitz, B.M., Gershenson, D.M., Lu, K. Women with synchronous primary cancers of the endometrium and ovary: do they have Lynch syndrome? J Clin Oncol, 2005. 23(36): p. 9344-50.

Drake, A.C., Campbell, H., Porteous, M.E.M., Dunlop, M.G. The contribution of DNA mismatch repair gene defects to the burden of gynecological cancer. Int J Gynecol Cancer, 2003. 13(3): p. 262-77.

Ramus, S.J., Elmasry, K., Zhiyuan, L., Gammerman, A., Lu, K., Ayhan, A., Singh, N., McCluggage, W. G., Jacobs, I. J., Whitaker, J., Gayther, S. A. Predicting Clinical Outcome in Patients Diagnosed with Synchronous Ovarian and Endometrial Cancer. Submitted for publication, 2008.

JOINT MEETING OF THE

BRITISH DIVISION OF THE

INTERNATIONAL ACADEMY OF PATHOLOGY

AND THE

Case Presentation Abstracts

and

References

Case Histories for Slide Seminar Session

CASE 1 74 year old female. Irregular PV bleeding. Cervical tumour, ? Malignant. Macro – Pale nodular tissue, 35 x 30 x 15mm, with separate fragments, up to 15 x 15 x 10mm

Dr A Boyde (Cardiff).

CASE 2 43 year old female. Presented with menorrhagia. Had a hysterectomy following failed endometrial ablation. Macro – Uterus and cervix, 150 x 120 x 60mm, distorted by multiple fibroids.

Dr A Boyde (Cardiff).

CASE 3 35 year old female - paratubal mass. Markers normal.

Macro – Fallopian tube 80mm was stretched over a nodular mass 80 x 50 x 50mm, cut surface was solid, uniform with focal calcification.

Dr R Ganesan (Birmingham).

CASE 4 18 year old female presented with a mass in the vulva with a history of it having been present there for a ‘few’ years.

Dr R Ganesan (Birmingham).

CASE 5 43 year old female. History of vulval pruritis.

Examination of the patient showed that there was a striking cobblestone pattern of thickening affecting vulval tissues (5a).

This was followed two years later by a further biopsy (5b).

Dr D Millan (Glasgow).

CASE 6 47 year old female. History of menorrhagia, followed by an attempt at microwave endometrial ablation. This procedure was unsuccessful and the patient was operated on with a view to removing her uterus. At operation there was an unexpected finding of fleshy tissue on the surface of the uterus, adnexae and peritoneal structures. The omentum also appeared abnormal and felt thickened. In view of this a total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy was carried out by the operating general Gynaecologist. The current sample is a representative piece of omental tissue.

Dr D Millan (Glasgow).

CASE 7 33 year old female. Presented with pelvic mass. Ovarian tumour discovered at surgery which was 12.5cm greatest dimension and multicystic with mucoid material within the cyst locules. Capsule smooth. No extra-ovarian disease and no known primary tumour elsewhere.

Dr B Ronnett (USA).

CASE 8 43 year old female. Presented with venous thrombosis progressive despite anticoagulation. Elevated CA125 (1906 u/ml) and CEA (525 ng/ml). Adenopathy on imaging studies. GI tract endoscopy negative but rectal biopsy positive for adenocarcinoma with signet ring cell features in lymphatic spaces. Complex ovarian lesion on imaging study. Diagnostic laparoscopy: ovaries grossly normal, cervix abnormal to palpation but no gross lesions, multiple peritoneal nodules. Oophorectomy and multiple biopsies performed.

Dr B Ronnett (USA).

CASE 9 Mid 50’s female. Presented with abdominal distension and pain. Raised CA125. Massive unilateral cystic ovarian tumour, 14kg, 500 x 250 x 160mm. Dissection demonstrated a multiloculated mucinous tumour with smooth-walled septae. A few solid nodules (largest 20mm diameter) were noted in the walls of some locules. Smooth external capsular surface. Uterus, contralateral adnexa and omentum unremarkable.

Dr M Scott (Manchester).

CASE 10 Mid 60’s female. Presented with intermenstrual bleeding. CT scan showed unilateral ovarian tumour, 170 x 130 x 100mm. Dissection demonstrated a predominantly solid but focally cystic mucinous tumour with smooth capsular surface. Uterus, contralateral adnexa and omentum unremarkable.

Dr M Scott (Manchester).

CASE 11 45 year old female with vaginal bleeding, section from hysterectomy specimen.

Dr N Sebire (London).

CASE 12 2 separate cases but to be looked at in comparison to each other.

(12a & 12b) 30 year old females, miscarriage, POC.

Dr N Sebire (London).

Dr Adam Boyde

Cardiff

Case 1

Preferred diagnosis: Carcinosarcoma of the uterine cervix

Diagnostic features

The tumour has a biphasic appearance, comprising malignant epithelial and mesenchymal elements. The epithelial component comprises squamous cell carcinoma of basaloid and keratinizing types. The mesenchymal component shows no heterologous differentiation. The subsequent radical hysterectomy specimen shows residual, invasive, squamous cell carcinoma of basaloid and keratinizing types, together with adenoid basal carcinoma.

Comments

Carcinosarcoma is a rare tumour of the uterine cervix, which typically presents in elderly post-menopausal women with vaginal bleeding and a polypoid cervical mass. The epithelial components are frequently non-glandular. There have been five reported cases of carcinosarcoma with associated adenoid basal carcinoma of the uterine cervix. The sarcomatous components do not differ significantly from those seen in carcinosarcomas of the uterine corpus and may be divided into homologous and heterologous types.

Differential diagnosis

The differential diagnosis includes cervical involvement by a primary carcinosarcoma of the uterine corpus, adenosarcoma, or a pure sarcoma, such as leiomyosarcoma, with epithelioid features. If one component of a carcinosarcoma predominates, the tumour may be misdiagnosed as a pure carcinoma or sarcoma in a biopsy specimen.

References

Clement PB, Zubovits JT, Young RH, Scully RE. Malignant Mullerian mixed tumours of the uterine cervix: A report of nine cases of a neoplasm with morphology often different from its counterpart in the corpus. Int J Gynecol Pathol 1998; 17: 211-222

Grayson W, Taylor L, Cooper K. Carcinosarcoma of the uterine cervix: A report of eight cases with immunohistochemical analysis and evaluation of human papillomavirus status. Am J Surg Pathol 2001; 25(3): 338-347.

Takeshima Y, Amatya V, Nakayori F, Nakano T, Iwaoki Y, Daitoku K, Inai K. Co-existent carcinosarcoma and adenoid basal carcinoma of the uterine cervix and correlation with human papillomavirus infection. Int J Gynecol Pathol 2002; 21: 186-190.

Dr Adam Boyde

Cardiff

Case 2

Preferred diagnosis: Uterine tumour resembling an ovarian sex-cord tumour (UTROSCT)

Diagnostic features

The section shows uterus with a relatively well-circumscribed cellular lesion (8mm) in the superficial myometrium, which infiltrates the myometrium at the periphery. There is atrophy of the overlying endometrium. The lesion comprises epithelioid cells, forming solid areas, nests, glands and tubular structures. There is little nuclear atypia or mitotic activity. Occasional cells have eosinophilic cytoplasm and some have a foamy appearance. Immunocytochemistry shows strong and diffuse staining of the lesional cells for AE1/AE3 and Desmin, with focal reactivity for Inhibin within the tubules. H-Caldesmon and HMB-45 are both negative.

Comments

The appearances are those of a uterine tumour resembling an ovarian sex-cord tumour. These tumours generally arise in the myometrium, tend to be relatively circumscribed and resemble leiomyomata, although they lack the whorled pattern, are more lobulated and are usually yellow/tan in colour. These tumours are composed of epithelioid cells and architecturally resemble ovarian sex-cord stromal tumours, with solid areas, trabeculae, glands and tubules. The co-expression of epithelial, myoid and sex-cord markers is characteristic, although not all of the markers are expressed in every case. Pure UTROSCTs appear to behave in a benign fashion, although there are some reports of recurrence and metastasis. The number of cases is small and follow-up data is limited. Some may represent endometrial stromal sarcomas with sex-cord differentiation.

Differential diagnosis

The differential diagnosis includes endometrial stromal sarcoma, epithelioid smooth muscle tumours, adenocarcinoma and metastatic ovarian sex-cord stromal tumours.

References

Hauptmann S, Nadjari B, Kraus J, Turnwald W, Dietel M. Uterine tumor resembling ovarian sex-cord tumor – A case report and review of the literature.

Virchows Arch 2001; 439: 97-101.

Kabbani W, Deavers M, Malpica A, Burke T, Liu J, Ordonez N, Jhingran A, Silva E. Uterine tumour resembling ovarian sex-cord tumour: A report of a case mimicking cervical adenocarcinoma. Int J Gynecol Pathol 2003; 22: 297-302.

Krishnamurthy S, Jungbluth A, Busam K, Rosai J. Uterine tumours resembling ovarian sex-cord tumours have an immunophenotype consistent with true sex-cord differentiation. Am J Surg Pathol 1998; 22(9): 1078-1082

McCluggage WG. Uterine tumours resembling ovarian sex cord tumours:

Immunohistochemical evidence for true sex-cord differentiation. Histopathology 1999; 34: 373-380.

Dr Raji Ganesan

Birmingham

Case 3

Preferred diagnosis: FATWO – Female Adnexal Tumour of Wolffian Origin

35 year old female - paratubal mass. Markers normal.

Macro – Fallopian tube 80mm was stretched over a nodular mass 80 x 50 x 50mm, cut surface was solid, uniform with focal calcification.

The mass is well circumscribed and shows a variety of patterns. There are areas showing a solid architecture composed of closely packed tubules with an inconspicuous stroma, a sieve-like appearance created by scattered microscopic cysts, coalescing spaces lied by attenuated epithelium resembling an adenomatoid tumour and elongated spaces with jagged branching patterns. Individual tubules possess prominent basement membranes. The cuboidal cells have small vesicular nuclei and moderate amounts of cytoplasm. On IHC, the cells express calretinin, inhibin, WT1, CAM 5.2, Vimentin and c-kit. EMA is generally negative.

Differential diagnosis includes

1. Surface epithelial tumours of Mullerian origin, in particular endometrioid carcinoma of ovary or Fallopian tube: Endometrioid ovarian carcinomas can display a wide range of histological patterns, including glands containing colloid-like secretion, tubular glands and spindle cell areas, but the cytological atypia and mitotic activity, lack of circumscription, location in ovary or within the lumen or wall of tube rather than paraovarian or paratubal tissues, presence of squamous metaplasia and generally positivity for EMA are all characteristic of carcinomas. Wolffian tumours co express cytokeratin and vimentin and generally lack EMA reactivity.
2. Granulosa cell tumours: GCTs may mimic diffuse and tubular patterns of female adnexal tumours of probable Wolffian origin but there are cytological differences particularly grooved nuclei. Endocrine manifestations can be seen in GCTs but not in FATWO.
3. Sertoli-Leydig cell tumour: The closely packed tubules and cords of well differentiated Sertoli-Leydig cell tumours and retiform areas of less well differentiated Sertoli – Leydig cell tumours are architecturally similar to the tubular patterns of Wolffian tumours but the presence of Leydig cells or heterologous elements is against the diagnosis of FATWO.

Immunohistochemical stains do not allow absolute distinction - both typically show coexpression of vimention and cytokeratin, immunoreactivity with inhibin and are nonreactive with EMA.

4. Adenomatoid tumours: Some FATWOss may show foci of coalescing vacuoles resembling a pattern seen in adenomatoid tumors, which rarely may involve the ovary and juxtaovarian region.

In 1973, Kariminejad and Scully described nine examples of a distinctive tumour that arose in the broad ligament or from the serosa of the Fallopian tube. The belief that they are of mesonephric origin is based on: (a) the finding that they are found in the same sites as mesonephric remnants; (b) their morphological dissimilarity to other ovarian tumours of either epithelial-stromal or sex cord-stromal types; and (c) some ultrastructural and immunohistochemical homology with the mesonephric duct. FATWOs generally exhibit a benign clinical behaviour but malignant FATWOs have been reported. The key features are the size of tumour generally the cut off being 100 mm, apparent hypercellularity, capsular invasion, and rupture of the capsule with demonstrable tumour implants and metastases.

References

Kariminejad MH, Scully RE. Female adnexal tumor of probable Wolffian origin. Cancer 1973; 31; 671-677.

Young RH, Scdly RE. Ovarian tumors of probable Wolffian origin. A report of 11 cases. Am. J. Surg. Pathol. 1983; 7: 125-135.

Daya D, Young RH, Scully RE. Endometrioid carcinoma of the Fallopian tube resembling an adnexal tumour of, probable Wolffian origin: A report of six cases. Int. J. Gynecol. Pathol. 1992; 11; 122-130

Rahilly MA, Williams AR, Krausz T, Nafussi AA. Female adnexal tumour of probable Wolffian origin: a clinicopathological and immunohistochemical study of three cases. Histopathology 1995; 26; 69 -74.

Devouassoux-Shisheboran M, Silver SA, Tavassoli FA. Wolffian adnexal tumor, so-called female adnexal tumor of probable Wolffian origin (FATWO): Immunohistochemical evidence in support of a Wolffian origin. Human Pathol. 1999; 30; 856-863.

Tiltman AJ, Allard U.Female adnexal tumours of probable Wolffian origin: an immunohistochemical study comparing tumours, mesonephric remnants and paramesonephric derivatives. Histopathology. 2001 Mar;38(3):237-42.

Dr Raji Ganesan

Birmingham

Case 4

Preferred diagnosis: Prepubertal vulval fibroma

18 year old female presented with a mass in the vulva with a history of it having been present there for a ‘few’ years.

The lesion is located in the submucosa. It has an ill defined outline and is hypocellular. It is composed of bland spindle-shaped cells in a variably collagenous to edematous or myxoid stroma, diffusely infiltrating between preexisting normal vascular, adipose, and neural tissues. There is no cytologic atypia or mitotic activity. The tumor cells were immunoreactive for CD34, but not for smooth muscle actin, desmin, and S-100 protein.

Differential diagnosis includes

1. Aggressive angiomyxoma: Infiltrative margins of the tumor, hypocellularity with minimal atypia and rare mitotic figures, and stroma often showing edematous or myxoid change are features shared with aggressive angiomyxoma. The stroma of aggressive angiomyxoma is diffusely myxoid and collagenisation is not prominent. Prepubertal vulval fibroma shows prominent collagenisation in the form of short bundles of thick, wavy collagen with a less impressive myxoid change. The cells of aggressive angiomyxoma are typically immunoreactive for desmin whilst prepubertal vulval fibroma is negative.

2. Fibroepithelial stromal polyp is commoner in vagina of women of reproductive age but also occurs in the vulva. The lesion is poorly outlined, with component cells extending up to the submucosal/mucosal junction. The cells are spindle or stellate-shaped cells with presence of mononuclear /multinucleate bizarre cells in an edematous to collagenous stroma with prominent thick-walled vessels. Fibroepithelial stromal polyp does not generally show significant entrapment of nerves or vessels, and the cells are usually immunoreactive for desmin.

3. Neurofibroma: The neoplastic cells of neurofibroma are diffusely spread without any particular pattern and somewhat resemble a prepubertal vulval fibroma. The nuclei are wavy or buckled. Intralesional nerve bundles in neurofibroma are small, round and more diffusely distributed. Neurofibromas are consistently positive for S100 whilst prepubertal vulval fibromas are negative.

References

Iwasa Y, Fletcher CDM Distinctive Prepubertal Vulval Fibroma A Hitherto Unrecognized Mesenchymal Tumor of Prepubertal Girls: Analysis of 11 Cases Am J Surg Pathol _ Volume 28, Number 12, December 2004, 1601 - 1608

David Millan

Glasgow

Case 5

Preferred diagnosis: Hailey-Hailey Disease

This lady presented with the very common presentation of itch and a careful clinical history would have given vital clues to the diagnosis. The vulval lesions were also typically affecting skin folds.

The initial biopsy revealed an acantholytic process within the epidermis of the vulval biopsy. There is a variable pattern of discohesion between keratinocytes. In areas there is suprabasal cleft formation whilst in other areas there is a pan-epithelial intercellular oedema, reflective of loss of adhesion between adjacent cells throughout the thickness of the epidermis. There is no significant death of individual cells in the epidermis and therefore no civette body formation.

This is important as the main differential diagnosis is Darier’s Disease which typically has a more prominent suprabasal split with death of individual cells and corps rond formation.

Another commonly quoted differential diagnosis is pemphigus vulgaris. However, this has a very different clinical presentation and is a much more serious, generalised condition which is usually easily elicited with minor trauma. Immunofluoresence studies are also very typically positive in this and the other variants of pemhigus and pemphigoid but are negative in Hailey-Hailey and Darier’s disease. There is usually no associated scarring unlike other mucosal conditions such as pemphigoid (e.g. cicatricial pemphigoid). Vulval intraepithelial neoplasia is also quoted as a potential differential diagnosis but this is rarely a difficult histological diagnosis and is more of a clinical problem because of the post inflammatory pigmentation changes which occur in relation to old healed lesions mimicking those changes seen some cases of VIN.

Hailey-Hailey disease is an autosomal dominant heritable condition; hence it’s other misleading name of Benign Familial Pemphigus. The fundamental cause is a disorder in the intercellular adhesion process between keratinocytes. There are different defective variants of a junctional/membrane secretory pathway Calcium/Manganese ATPases in both Darier’s disease and Hailey-Hailey disease and these have been characterised in recent years.

The cobblestone appearance with a central area of keratosis is a typical clinical appearance and because it is often initiated by and possibly colonised by local infection the lesions may be foul smelling and they may be associated with a wet weeping discharge. In view of the site of these intercrural lesions, exacerbation in hot sweaty weather, symptoms and secondary colonisation they may be diagnosed as primary local fungal or bacterial infections. In such circumstances a biopsy of a vulval itch which is not responding to therapy together with a detailed combined dermatological and gynaecological clinical history may be diagnostic of this rare and difficult condition.

References

Dhitavat J. et al.

Calcium pumps and keratinocytes: lessons from Darier’s disease and Hailey-Hailey disease.

Brit.J.Dermatol. 2004 may; 150(5):821-828.

Szigeti R, Kellermayer R

Autosomal-Dominant Calcium ATP-ase Disorders

J. Invest Dermatol. 2006 Nov; 26(11):2370-6.

David Millan

Glasgow

Case 6

Preferred diagnosis: Ectopic Omental Decidua (Deciduosis)

This patient was given Norethisterone to help manage her menorrhagia after the failure of the attempt at microwave endometrial ablation. At the time of operation the surgeon was alarmed by the appearance of the pelvic organs.

On the surface of the uterus and in the adnexal structures there was soft fleshy pale tissue. The clinical impression was of a uterine sarcoma arising from the uterus.

This is an example of decidua developing within peritoneal tissues. It is a common, virtually physiological, condition usually seen at the time of caesarean section. However, it is unusual for the clinician to see any significant amount of tumour–like mass of tissue. The more common situation is for the pathologist to see small microscopic islands of decidua within serosal tissues as an incidental finding. Traditionally this has been seen in samples taken from pregnant patients where it may rarely, as in this case, form significant masses seen on imaging and prompting further investigations. There are several reports in the literature of complications arising from Deciduosis. These include bleeding, obstruction of labour and appendicitis. There are also rare reports of fibrosing Deciduosis and a mixture of decidua and smooth muscle, as in peritoneal leiomyomatosis.

It is likely that with the common use of progestational agents to manage menstrual problems that clinicians and pathologists will see this more commonly.

Histologically there are typical collections of eosinophilic polygonal cells with mildly pleomorphic nuclei as seen in decidualised or pseudodecidualised endometrial stromal tissues. It is typically present in subserosal tissues.

The precise origin is not known but it has been suggested that these foci may have developed from pre-existing islands of endometriosis or from cells within the subserosal tissues which have been induced by progestational hormones to differentiate into decidua. This condition represents one of several, usually benign, conditions which present diffuse lesions within the peritoneal cavity.

It is a benign condition which regresses after delivery or on withdrawal of the hormonal therapy. It presumably can recur with each pregnancy or repeated hormonal treatment.

The main differential diagnosis is of a mesothelioma which may also have a rare decidua–like appearance .The presence of more marked nuclear pleomorphism, mitotic activity, more typical mesothelial areas and cytokeratin positivity in mesothelioma should make this distinction straightforward. In small biopsy specimens decidua can also be mistaken for metastatic squamous carcinoma, although the clinical history should give a sufficient clue as to the nature of the lesion.

References

Zaystev P, Taxy J B

Pregnancy-associated Ectopic decidua. Am J Surg Pathol. 1987 Jul; 11(7):526-30

Kondi-Pafiti A et al.

Ectopic decidua mimicking metastatic lesions-report of three cases and a review of the literature.

Eur J Gynaecol Oncol. 2005;26(4):459-61.

Dr Brigitte Ronnett, USA

Case 7

Preferred Diagnosis: Metastatic endocervical carcinoma

• 33 year old woman with pelvic mass

• Ovarian tumor discovered at exploration

– Multicystic, mucoid

– Smooth capsule

– 12.5 cm

• No extra-ovarian disease

• No known primary tumors elsewhere

Consultation case question:
Is this an atypical proliferative (borderline) mucinous tumor with intraepithelial carcinoma?

Immunohistochemical Markers for Evaluation of Mucinous Tumors to Elucidate Primary Site

CK7/CK20: general use

CDX2: gastrointestinal differentiation marker

Dpc4: pancreaticobiliary tract

GCDFP: breast

TTF-1: lung

ER/PR: gynecologic/breast

p16: cervix (HPV-related type)

CK7/CK20 Coordinate Expression Profiles to Elucidate Primary Site
Immunoprofile	Site(s)
CK7+/CK20-	Ovary, endometrium, cervix, pancreaticobiliary tract, stomach, breast, lung
CK7-/CK20+	Colorectum, appendix; stomach
CK7+/CK20+ CK7>CK20 CK20>CK7	Non-specific profile Upper GI tract, ovary, cervix Lower GI tract (rare upper GI tract)
CK7-/CK20-	Uncommon profile (not helpful)

Mucinous Tumors: Immunohistochemistry
	CK7	CK20	Dpc4	p16	ER/PR
Ovary*	+ (CK7>CK20)	+/- (~75%)	+	-/F+	-
Colorectum	- (~90%)	+ (CK20>CK7)	+ (~90%)	-/F+	-
Appendix	- (70-90%)	+ (CK20>CK7)	+	-/F+	-
Pancreas/ biliary tract	+ (CK7>CK20)	+/- (~80%)	- (~50%)	-/F+	-
Stomach	+/-	+/-	+	-/+	-
Endocervix	+ (CK7>CK20)	-/+	+	D+	-
(* A subset of mucinous tumors of probable teratomatous origin is CK7-/CK20+)

Primary Ovarian Mucinous Tumors*:
Immunohistochemistry
(*Gastrointestinal type/NOS)

CK7: positive (usually diffuse)**

CK20: variably positive (patchy: CK20<CK7)*

CDX2: positive or negative

Dpc4: positive (retained expression)

p16: negative to focally positive (rarely diffuse)

ER/PR: negative

(** A subset of mucinous tumors of probable teratomatous origin is CK7-/CK20+)

Immunohistochemical Evaluation to Elucidate Primary Site
Stain	Result
CK7	Positive (diffuse/strong)
CK20	Negative (few positive cells)
CDX2	ND
Dpc4	Positive
p16	Positive (diffuse/strong)
ER	Negative (very focal/weak)
PR	Negative
GCDFP	ND
TTF-1	ND

Potential Primary Sites
Site	Morphology?	Immunoprofile?
Stomach	NO	YES
Pancreaticobiliary tract	YES	NO
Small intestine	?	?
Appendix	YES	NO
Colorectum	POSSIBLE	NO
Cervix	YES	YES
Endometrium	RARE	YES
Ovary	YES	YES
Breast	NO	YES
Lung	UNLIKELY	YES

Preferred Diagnosis:

• Metastatic endocervical carcinoma

• Simulates atypical proliferative (borderline) mucinous tumor with intraepithelial carcinoma and areas of carcinoma (confluent glandular pattern)

• Endocervical carcinoma fragments (HPV16+) found in follow-up endocervical/endometrial curettings

• Invasive adenocarcinoma found in cone biopsy and radical hysterectomy

References

Vang R, Ronnett BM. Distinction of primary ovarian mucinous tumors and mucinous tumors metastatic to the ovary: a practical approach with guidelines for prediction of primary site for metastases of uncertain origin. Pathol Case Rev 2006;11:18-30.