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Received Date : 10-Feb-2014 Revised Date : 19-Mar-2014 Accepted Date : 22-Mar-2014 Article type

: Review

ASSIGNMENT OF PRIMARY SITE IN HIGH-GRADE SEROUS TUBAL, OVARIAN AND PERITONEAL CARCINOMA: A PROPOSAL

Naveena Singh1, C. Blake Gilks2, Nafisa Wilkinson3, W. Glenn McCluggage4 1

Department of Cellular Pathology, Barts Health NHS Trust, London, United Kingdom; Department of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver, Canada; 3Department of Histopathology, St James’s Hospital, Leeds, United Kingdom; 4Department of Pathology, Belfast Health and Social Care Trust, Belfast, United Kingdom. 2

Address for Correspondence: Dr Naveena Singh Consultant Pathologist Department of Cellular Pathology Barts Health NHS Trust 2nd Floor 80 Newark Street London E1 2ES United Kingdom Telephone: (44) 203 2460217/0198 Fax: (44) 203 2460202 Email: [email protected]

Running head: Site assignment in HGSC

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/his.12419 This article is protected by copyright. All rights reserved.

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Key words: high grade serous carcinoma, ovary, staging, diagnosis, primary site

ABSTRACT/SUMMARY The revised FIGO 2013 staging for carcinomas of the ovary, fallopian tube and peritoneum has introduced a single system for tumours originating at these sites. The system requires pathologists to assign a primary site (ovary, tube or peritoneum) but does not provide guidance to aid this assignment. This is particularly problematic in cases of advanced stage (stage II or greater) high-grade serous carcinoma (HGSC) where there is commonly involvement of two or more sites by tumour and practice amongst pathologists in determining where a tumour has arisen varies widely. This has significant implications for recording of tumour incidence and mortality, data collection by cancer registries and entry into clinical trials. We propose guidelines for assigning primary site of HGSC based on careful macroscopic and histological assessment. The use of these guidelines, in conjunction with the new FIGO staging system, is intended to act as an impetus to promote debate and a uniform and consistent approach in assigning primary tumour site which will facilitate comparison of data between centres.

INTRODUCTION Cancer staging is vital for correct patient management, is based on the biology of the individual tumour type and determined by internationally agreed protocols which enable comparison and sharing of experience. The major staging body for gynaecological cancers is FIGO and the UICC has developed broadly parallel and concordant systems of TNM staging. The FIGO staging for ovarian cancer was revised in 2013 (1). The previous staging system was published in 1988 (2) and two major changes in how we think about “ovarian cancer” led to recognition of the need to revise the existing system. The first was the realisation that ovarian epithelial cancer (or ovarian carcinoma) is not a single disease with varying morphology but can be subdivided into 5 major disease categories that differ in their epidemiological risk factors, histogenesis, molecular genetics, morphology, immunophenotype, behaviour and response to treatment (3-5). The correct determination of tumour subtype is of great significance, particularly in the evolving era of personalised medicine and targeted treatment. Although not part of staging, it is now recommended that

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the histotype of ovarian cancer should be designated at staging (1). The 5 major histotypes of epithelial ovarian carcinoma are: •

High-grade serous carcinoma (HGSC)



Clear cell carcinoma (CCC)



Endometrioid carcinoma (EC)



Low-grade serous carcinoma (LGSC)



Mucinous carcinoma (MC)

The second significant discovery influencing the current approach to staging was the recognition in 2001 (6,7) that a high percentage of so-called ovarian HGSC probably arise in the fimbrial end of the fallopian tube. This was first noticed in risk reducing salpingooophorectomy specimens (RRSO) in BRCA mutation carriers, which were found to harbour serous tubal intraepithelial carcinoma (STIC) (6-8). Since then STIC has been identified in significant numbers of sporadic “ovarian” and “primary peritoneal” HGSCs (9-13). These STICs harbour identical p53 mutations to the extratubal tumour, establishing that they are clonal (9). Comparison of telomere length and centrosome amplification in matched STIC and ovarian HGSC suggests that the STICs develop before the ovarian tumours (14,15). Finally, although numbers are small, early, incidental non-BRCA1/2 associated (sporadic) HGSCs are predominantly detected in the fallopian tube mucosa, especially the fimbria, rather than the ovary (16). Thus, there is compelling evidence that many, if not most, HGSCs arise from the fallopian tube. This is now accepted by most authorities in gynaecological pathology, although some scepticism still exists. However, it is also possible that in some cases STIC represents secondary involvement / mucosal colonisation from either an ovarian or uterine serous carcinoma or is a manifestation of multicentric tumour origin, though there is little evidence to support the latter possibility. Metastases to the adnexa from sites outside the female genital tract can rarely produce lesions closely resembling STIC (17). It is also relevant that some cases of ovarian and primary peritoneal HGSCs do not show STIC lesions despite complete examination of the fallopian tube. For example, in a consecutive series of non-uterine HGSCs in which the fallopian tubes were examined in their entirety, STICs were identified in 59% of cases (18), indicating that in the others the carcinoma arises in the ovary.

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A confounding factor is that HGSCs generally present at high stage, at which point any precursor lesions are largely obscured. It is, however, clear that HGSC, whether presenting as “tubal”, “ovarian” or “primary peritoneal” carcinoma based on criteria currently used to assign primary site, represents a single disease with the majority of cases probably arising in the fallopian tube. HGSC, which accounts for the majority of “ovarian” carcinomas (approximately 70% (19, 20) and also a great majority of tumour related deaths (greater than 90%), shows identical clinical behaviour, including progression patterns and responses to chemotherapy, irrespective of apparent site of origin.

For these reasons, the FIGO 2013 staging system has been unified for primaries of each of these 3 sites (1). Proposals to unify diagnostic terminology to be inclusive of all HGSCs of ovarian, tubal and peritoneal origin, designating them as “pelvic serous carcinoma” (9), were rejected to avoid confusion by introducing new and ambiguous terminology. In particular, such terminology may obscure the clinically important distinction between tubal/ovarian/peritoneal HGSC and endometrial serous carcinoma; while the former are associated with a high-likelihood of BRCA1 and BRCA2 abnormalities, including germ-line and somatic mutations, endometrial serous carcinoma is not (21,22). Moreover, some molecular events, for example mutation in PPP2R1A, are much more common in endometrial serous carcinomas than in non-uterine HGSCs (23).

For FIGO 2013 staging purposes, however, the primary site of non-uterine HGSCs needs to be designated as ovarian, tubal or primary peritoneal. It is recognised that this may not be possible in some cases and these should be categorised as “undesignated” in the new staging system (1). The descriptor “tubo-ovarian HGSC” can also be used in practice for those cases of advanced stage HGSC where there is uncertainty about primary site. The problems in ascertaining the primary site and the variation amongst pathologists has significant implications for epidemiological studies, determination of tumour incidence and mortality, data collection by cancer registries and entry into clinical trials.

A unified approach to the diagnosis of non-uterine HGSC is essential at this juncture while its underlying genetic abnormalities are being unravelled and new therapies being developed. There are two potential ways to achieve a unified approach: one would be to designate all cases as ‘tubo-ovarian’ or ‘tubo-ovarian type’, to distinguish them from uterine serous carcinomas. While this has merits in terms of uniformity in diagnosis and acknowledgement This article is protected by copyright. All rights reserved.

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that distinction between sites of origin currently appears to have no prognostic or therapeutic relevance, it is significant that such an approach was considered and rejected by the FIGO committee. This approach also has a ‘lumping’ aspect and may blur subtle differences of clinical relevance which may emerge in the future. The other approach is to adopt the FIGO directive but encourage pathologists worldwide to use a standard and systematic approach based on current knowledge so that we are not giving different diagnostic labels to the same disease in different centres. Unfortunately in the absence of guidelines, it is likely that some pathologists will prefer not to devote any significant effort towards assigning a primary site to these tumours, classifying them as undetermined or tubo-ovarian, while others will assign primary sites but with highly variable results.

In the following sections, we propose guidelines for assigning primary site of HGSCs based on careful macroscopic and histological assessment and where required ancillary immunohistochemistry. Determining the primary site of the other types of ovarian carcinoma does not usually constitute a problem since these tumours are often confined to the ovary at diagnosis and tubal involvement is rare.

DETERMINING THE SITE OF ORIGIN OF HGSC Extensive Sampling of the Fallopian Tube A fundamental step in pathological evaluation of cases of ovarian, tubal and primary peritoneal HGSC is detailed examination of the fimbrial end of the fallopian tube. The recommended protocol, designated SEE-FIM (“Sectioning and Extensively Examining the Fimbriated” end of the fallopian tube), enables histological assessment of the largest possible surface area of the fimbriae to look for the presence of STIC or a small HGSC (9). This is important for correct staging and assignment of primary site as STIC is not visible to the naked eye, resulting in a potential to understage apparent Stage I ovarian HGSC. In addition, although currently there is no universal agreement as to how the presence of STIC should influence assignment of site of origin (our proposals are detailed below), recording this finding systematically and consistently by all pathologists will provide evidence to inform future practice. As well as examination of the entire fimbriae of both tubes, we also recommend that the non-fimbrial portion of the tubes should be examined

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since STICs occasionally occur here (9). Ideally, this would entail examination of transverse sections of the entire tubes but practically examination of several sections is acceptable. While there are no formal guidelines for this, 4-6 sections taken at intervals along the nonfimbrial portions of the tubes, in addition to the entire fimbriated ends, may be acceptable. It is important to point out also that the recognition of STIC can be difficult. The detailed examination of fimbrial tubal epithelium and the widespread use of immunohistochemistry for p53 and Ki67 have led to the recognition of a spectrum of lesions that can be challenging to interpret. It has been documented that the diagnosis of STIC based on H&E morphology alone has sub-optimal reproducibility (24). Since this diagnosis has major therapeutic implications, an algorithm has been recommended and validated which is useful in excluding mimics of STIC (25, 26).

Problems in Assigning Site of Origin STICs (or small HGSCs) are found in up to 60% of BRCA1 associated HGSCs and 40-60% of sporadic HGSCs of presumed ovarian origin when the fallopian tube is examined carefully, as detailed above (9-11, 18). In a further percentage of cases (approximately 20%), the fimbrial end of the fallopian tube and ovary are obliterated by a large adnexal mass such that the tube cannot be identified. As noted previously, there is also the possibility that rather than representing a precursor to the ovarian HGSC, the STIC represents a multicentric process (“field-effect”) or secondary involvement from the ovary. There is no consensus amongst pathologists regarding terminology in these cases with polar views including "when the origin is uncertain, the convention of designating all serous carcinomas as originating in the ovary should not be used" (27) versus "the term HGSC of the ovary should be kept until the different origins of ovarian tumours are better understood" (1).

STIC-like lesions involving the mucosa of the fallopian tube can also be seen in association with serous carcinoma of the endometrium (11,28). While there are insufficient data to conclusively determine the relationship between the endometrial serous carcinoma and STIClike lesions, we believe that most probably represent examples of tubal mucosal implantation by endometrial serous carcinoma, analogous to mucosal involvement of the endocervix by endometrial adenocarcinoma. Others may represent spread from the tube to the endometrium; multicentric origin is also a possibility but this is less likely. WT1 may assist in such cases in that negative staining of both the tubal and endometrial lesions suggests a primary in the This article is protected by copyright. All rights reserved.

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uterus while positive staining suggests a STIC with spread to the endometrium (29-31). However, there is sufficient overlap such that WT1 cannot be relied upon in all cases. The designation STIC should be reserved for lesions which do not represent a metastasis from non-ovarian/tubal/peritoneal primary sites.

Given all these factors, there is significant potential for pathologists to categorise identical or similar cases differently. For example, a HGSC with ovarian surface involvement, widespread peritoneal disease and STIC in a fallopian tube could potentially be categorised as being of fallopian tube, ovary, primary peritoneal or undesignated origin by different pathologists. Similarly an adnexal mass with obliteration of the ovary and tube and a similar adnexal mass in which the tube can be shown to harbour a STIC or small HGSC could be categorised as ovarian, tubal or undetermined, depending on whether STIC is taken to be proof of tubal origin. One further confounding factor is the potentially aggressive behaviour of STIC; it is accepted that STIC, although intraepithelial, is capable of exfoliation and widespread metastasis. Therefore, STIC should be included in cancer staging as an involved site, irrespective of the absence of invasive disease in the tube. It should be noted that the clinical outcome of STIC when encountered without disease elsewhere is good, although follow up in published cases is short, and it is debatable, based on currently available data, whether this merits categorisation as FIGO stage IA carcinoma of the tube, equivalent to other stage IA cancers (32).

Suggestions for Assigning Site of Origin As discussed, there is significant potential for confusion in assigning primary site when using the new FIGO staging system because no specific criteria are provided to guide this assignment. For this reason, we believe it is wise to encourage the gynaecological oncology community worldwide to adopt a uniform approach to site assignment in HGSC, as the new FIGO staging system is implemented. It would be wise also to use this opportunity to acknowledge and adopt into routine practice the concept that the majority of non-uterine HGSC are in fact tubal in origin, and recognise that although both secondary involvement and multicentric origin are theoretically possible, the first is a rare event and the second is not supported by research evidence. In the absence of internationally agreed guidelines, it is not possible to give a recommendation for every possible scenario. Overall assignment of site of origin should be based on common sense, experience and professional judgement but a few This article is protected by copyright. All rights reserved.

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broad suggestions are listed below, which should be applicable to both chemo-naïve and postchemotherapy cases. This is not an exhaustive list nor intended to be binding and assignment of origin in an individual case is left to the discretion of the pathologist and the clinical team, ideally in the setting of a multidisciplinary team meeting. Undoubtedly, there will be evolution over time in our ability to accurately assign primary site but the following are intended as practical guidelines for uniform handling cases at the present time. Further studies will demonstrate whether or not this is a valid approach.

1. The fallopian tubes, or at least their fimbrial ends, should be totally sampled in all cases of HGSC by a SEE-FIM-like protocol to avoid missing this important site of disease, which probably represents the precursor lesion and tumour origin in the majority of cases. 2. The presence of STIC, in the absence of invasive disease in the fallopian tube, should be considered as tubal involvement for staging purposes; by the same token, the presence of STIC without invasion or extratubal spread should be staged as FIGO stage IA tubal carcinoma (although, as discussed, these have favourable prognosis, based on limited experience to date (32) but with an annotation that there is no invasive carcinoma. 3. Cases with only STIC, ovarian surface involvement or parenchymal involvement not exceeding 5 mm and widespread peritoneal involvement, which would traditionally be categorised as primary peritoneal carcinoma (33), should be classified as tubal primaries. 4. Cases with invasive HGSC located within the mucosa of the fallopian tube, including its fimbrial end, with or without STIC in any portion of the fallopian tube and with no, minimal or even substantial ovarian involvement should be categorised as tubal primaries. 5. Cases in which the fallopian tube is not identifiable, having presumably been overgrown by the ipsilateral adnexal mass, or the distal end of the fallopian tube is incorporated into a large tubo-ovarian mass should also, based on current understanding, be diagnosed as tubal primaries. It is emphasised that a careful effort must be made to identify the tube in all cases. 6. Cases with dominant ovarian mass(es) and identifiable fallopian tubes with STIC should be classified as tubal primaries.

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7. Cases with dominant ovarian mass(es) and identifiable fallopian tubes without STIC should be classified as ovarian primaries. 8. Cases should be categorised as primary peritoneal carcinoma by the conventional criteria below (33) and only after complete examination of the fallopian tubes (including the non-fimbrial portions) has excluded the presence of STIC or a small HGSC o both ovaries must be normal in size or enlarged by a benign process o the involvement in the extraovarian sites must be greater than the involvement on the surface of either ovary o the ovarian tumour involvement must be non-existent, confined to the ovarian surface without stromal invasion or involve the cortical stroma with tumour size less than 5 mm x 5 mm. 9. All cases classified as “undesignated” for FIGO staging purposes should be further described as “tubo-ovarian” or “tubal/ovarian” to distinguish them from serous carcinoma originating in the uterus. Using our suggestions, these should represent a small proportion of HGSC. 10. Cases with unilateral or bilateral HGSC in the ovary and/or STIC or HGSC in the tube but with an endometrial serous intraepithelial or invasive carcinoma should be carefully evaluated for an endometrial versus a tubo-ovarian primary (as stated, WT1 may be of value); a majority of such cases will represent adnexal metastases from an endometrial serous carcinoma.

CONCLUSION The new FIGO staging system has commendably unified the staging of ovarian, tubal and primary peritoneal carcinoma based on the understanding that HGSC currently categorised as arising from these three sites represents the same disease. While some aspects regarding the origins and progression of this aggressive tumour type remain unknown, it is important to encourage a uniform approach to assignment of the site of origin; allowing the category of “undesignated” has the potential drawback that the majority of HGSCs may be placed within this category. There is also significant potential for identical or similar cases being categorised differently by different pathologists or multidisciplinary teams based on individual viewpoints. The future holds exciting prospects as new therapies are developed and HGSC becomes better understood. It would be beneficial to promote a uniform approach

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to site assignment in clinical practice at the outset, as the new staging system is implemented. Our proposals are intended to act as an impetus to promote debate and a uniform approach in assigning tumour site.

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29 McCluggage WG. WT1 is of value in ascertaining the site of origin of serous carcinomas within the female genital tract. Int J Gynecol Pathol 2004:23:97-99. 30 Shimizu M, Toki T, Takagi Y, Konishi I, Fujii S. Immunohistochemical detection of the Wilms’ tumor gene (WT1) in epithelial ovarian tumors. Int J Gynecol Pathol 2000 :19:158-163 31 Al-Hussaini M, Stockman A, Foster H, McCluggage WG. WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing between serous and endometrioid ovarian carcinoma. Histopathology 2004;44;109-115. 32 Wethington SL, Park KJ, Soslow RA, et al. Clinical outcome of isolated serous tubal intraepithelial carcinomas (STIC). Int J Gynecol Cancer 2013;23:1603-11. 33 Bloss JD, Liao S, Buller RE et al. Extraovarian peritoneal serous papillary carcinoma: a case-control retrospective comparison to papillary adenocarcinoma of the ovary. Gynecol Oncol 1993: 50: 347-351.

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Assignment of primary site in high-grade serous tubal, ovarian and peritoneal carcinoma: a proposal.

The revised FIGO 2013 staging for carcinomas of the ovary, fallopian tube and peritoneum has introduced a single system for tumours originating at the...
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