Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma

Appendix A: Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma

Introduction correct determination of tumor subtype is therefore of as much signifi cance as disease stage, if Cancer staging is vital for correct patient man- not of greater signifi cance, a factor even more agement, is based on the biology of the individual relevant in the evolving era of personalized medi- tumor type, and is determined by internationally cine and targeted treatment. The histotype of agreed protocols which enable comparison and ovarian cancer is therefore included in the 2013 sharing of experience. The major staging body staging system as it is recognized to be funda- for gynecological cancers is FIGO, and the UICC mental to successful treatment. The fi ve major has broadly developed parallel and concordant histotypes of ovarian carcinoma are listed below: systems of TNM staging. The FIGO staging for • High-grade serous carcinoma (HGSC) ovarian cancer has been revised in 2013 • Clear cell carcinoma (CCC) (Table A1 ). The previous staging system was • Endometrioid carcinoma (EC) developed in 1988, and two major changes led to • Low-grade serous carcinoma (LGSC) recognition of the need to change the existing • Mucinous carcinoma (MC) system: fi rstly, the knowledge that ovarian cancers are not a single disease with varying morphology but fall into fi ve separate discrete major Pathogenesis of High-Grade disease categories and, secondly, insight into the Serous Carcinoma origins of the most common of the subtypes, high-grade serous carcinoma (HGSC). These The second signifi cant discovery infl uencing the factors are considered below. current approach to staging was the recognition in 2001 that a high percentage of HGSC arise in the fi mbrial end of the fallopian tube. This dis- Histological Types covery was made in risk reducing salpingo- of Ovarian Carcinoma oophorectomy specimens (RRSO) in BRCA1 mutation carriers which were found to harbor The majority (90 %) of ovarian malignancy is of serous tubal intraepithelial carcinoma (STIC). epithelial origin, i.e., carcinoma, with the remain- Since then STIC has been found in signifi cant ing 10 % being predominantly of sex cord- numbers of sporadic “ovarian” and “primary stromal or germ cell origin. It is now clear that peritoneal” carcinomas. Although there is com- there are fi ve major subtypes of ovarian carcinoma pelling evidence that the majority of HGSC arise that differ in their origins, morphology, immuno- from the fallopian tube through studies on RRSO histochemical staining characteristics, and specimens, it is also possible that in some cases molecular genetics. These tumor subtypes differ STIC represents secondary involvement or evi- in their behavior and response to treatment. The dence of multicentric tumor origin. These

N. Wilkinson (ed.), Pathology of the Ovary, Fallopian Tube and Peritoneum, 497 Essentials of Diagnostic Gynecological Pathology, DOI 10.1007/978-1-4471-2942-4, © Springer-Verlag London 2014 498 Appendix A: Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma

Table A1 FIGO staging to be used from January 2014: for ovary, fallopian tube, and peritoneum [4 ] Existing FIGO stage group 2013 description Stage 1 Stage 1 : Tumor confi ned to ovaries or fallopian tube (s ) IA IA: Tumor limited to 1 ovary (capsule intact) or fallopian tube; no tumor on ovarian or fallopian tube surface; no malignant cells in the ascites or peritoneal washings IB IB: Tumor limited to both ovaries (capsules intact) or fallopian tubes; no tumor on ovarian or fallopian tube surface; no malignant cells in the ascites or peritoneal washings IC ( Stage 1C ) Tumor limited to 1 or both ovaries or fallopian tubes , with any of the following : IC1: Surgical spill IC2: Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface IC3: Malignant cells in the ascites or peritoneal washings Stage 2 ( Stage 2 ) Tumor involves 1 or both ovaries or fallopian tubes with pelvic extension (below pelvic brim ) or primary peritoneal cancer IIA IIA: Extension and/or implants on uterus and/or fallopian tubes and/or ovaries IIB IIB: Extension to other pelvic intraperitoneal tissues Stage 3 Stage 3 : Tumor involves 1 or both ovaries or fallopian tubes , or primary peritoneal cancer , with cytologically or histologically confi rmed spread to the peritoneum outside the pelvis and / or metastasis to the retroperitoneal lymph nodes IIIA IIIA1: Positive retroperitoneal lymph nodes only (cytologically or histologically proven) IIIA1(i): Metastasis up to 10 mm in greatest dimension IIIA1(ii) Metastasis more than 10 mm in greatest dimension IIIA2: Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes IIIB IIIB: Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes IIIC IIIC: Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ) Stage 4 Stage 4 : Distant metastasis excluding peritoneal metastases IV IVA: Pleural effusion with positive cytology IVB: Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity) The stage values shown in bold on the left hand column correspond to the 2013 stage values shown in the right hand column and should be used until the options have been updated and aligned to the 2013 classifi cation

alternative possibilities cannot be ruled out at tube, even if this is not demonstrable pathologi- present. It is also relevant that some cases of cally at the time of presentation. Furthermore ovarian and primary peritoneal carcinoma do not HGSC, which accounts for the majority of “ovar- show STIC lesions despite complete examination ian” carcinomas and also the majority of fatal of the fallopian tube using a standard protocol. cases, shows identical clinical behavior, includ- While the putative precursor of HGSC is eas- ing progression patterns and responses to chemo- ily identifi ed in RRSO specimens, HGSCs gener- therapy, irrespective of apparent site of origin. ally present at high stage, at which point any For these reasons the FIGO 2013 staging system precursor lesions are largely obscured. It is how- has been unifi ed for primaries of each of these ever clear that HGSC, whether presenting as three sites. Proposals to unify HGSC of ovarian, “tubal,” “ovarian,” or “primary peritoneal” carci- tubal, and peritoneal origins as “pelvic serous noma based on criteria formerly used to assign carcinoma” were rejected to avoid confusion by primary site, represents a single disease with the introducing new and ambiguous terminology. As majority of cases probably arising in the fallopian part of staging, however, the primary site for each Appendix A: Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma 499 case needs to be designated as ovarian, tubal, or origin is uncertain, the convention of designating primary peritoneal. It is recognized that this may all serous carcinoma as originating in the ovary not be possible in some cases and these should be should not be used” [2 ] and “the term HGSC of categorized as undesignated. ovary should be kept until the different origins The remaining minority of ovarian carcinoma are better understood” [1 ]. subtypes, namely, clear cell, endometrioid, low- In this scenario there is high potential for grade serous, and mucinous carcinomas, have categorizing identical cases differently. For distinct precursors and origins. The 2013 FIGO example, high-grade serous carcinoma with staging system is applicable to these subtypes. low-volume ovarian involvement, widespread peritoneal spread, and STIC in the fallopian tube could potentially be categorized as being of Determining the Site of Origin fallopian tube, ovary, primary peritoneal, or of High-Grade Serous Carcinoma undesignated origin by different pathologists. Similarly it is also possible for an ovarian mass Complete Sampling with complete obscurement of the fallopian tube of the Fallopian Tube where demonstration of a precursor lesion is not possible and an identical case of advanced ovar- A fundamental step in pathological evaluation of ian carcinoma in the presence of demonstrable cases of ovarian, tubal, and primary peritoneal STIC to be categorized differently as ovarian/ carcinoma has emerged from the aforementioned undetermined and fallopian tubal, respectively, developments, which is detailed examination of if STIC is taken to be proof of origin whenever the fi mbrial end of the fallopian tube. The recom- it is found. Another diffi cult scenario is assign- mended protocol, designated SEE-FIM, enables ing origin to a large ovarian mass which obscures examination of the fi mbrial end for the presence the ipsilateral fallopian tube in the presence of of STIC, as detailed in Chap. 20 , Specimen STIC on the contralateral fallopian tube. One Cutup. This step is essential for correct staging as further confounding factor is the aggressive the changes are not visible to the naked eye and nature of STIC; it is accepted that this lesion, there is a potential to under-stage disease if these although intraepithelial, is capable of wide- are missed. In addition, although currently there spread metastasis and presentation as ovarian or is no universal agreement on how the presence of primary peritoneal carcinoma; it therefore should STIC should infl uence assignment of site of ori- be included in cancer staging as an involved gin, recording this fi nding systematically will site, irrespective of the absence of invasive provide evidence to inform future guidance. disease in the tube. While the new staging system ensures that the patient will be staged and therefore treated and prognosticated identically, Problems in Assigning Site of Origin there is potential for confusion with regard to assignment of primary site. STIC lesions are found in 60 % of BRCA1- positive high-grade serous carcinomas and an undetermined percentage of sporadic ovarian Suggestions for Assigning carcinomas. In the remainder the relative propor- Site of Origin tions of true tubal and ovarian origin are not known. There is also the possibility that rather In the absence of internationally agreed guide- than representing a precursor, the presence of lines, it is not possible to give a recommendation STIC and similar lesions represents secondary for every possible scenario. Overall assignment involvement or even multicentric origin. There is of site of origin should be based on common no accepted consensus regarding terminology in sense, experience, and professional judgment but these cases with polar views being “ when the a few broad suggestions are listed below. This is 500 Appendix A: Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma not an exhaustive list nor intended to be binding, 8. Cases should be categorized as primary and assignment of origin in an individual case is peritoneal carcinoma by the conventional left to the discretion of the pathologist and the criteria below and only after complete local multidisciplinary team: examination of the fallopian tubes (includ- 1. The fallopian tubes, or at least their fi mbrial ing the non-fi mbrial portions) have ends, should be totally sampled in all cases of excluded the presence of STIC or a small HGSC by a SEE-FIM-like protocol to avoid HGSC: missing this important site of disease, which • Both ovaries must be normal in size or probably represents the precursor lesion and enlarged by a benign process. tumor origin in the majority of cases. • The involvement in the extraovarian sites 2. The presence of STIC, in the absence of must be greater than the involvement on invasive disease in the fallopian tube, should the surface of either ovary. be considered as tubal involvement for stag- • The ovarian tumor involvement must be ing purposes; by the same token, the pres- nonexistent, be confi ned to the ovarian ence of STIC without invasion or extratubal surface without stromal invasion, or spread should be staged as FIGO stage IA involve the cortical stroma with tumor tubal carcinoma (although these have favor- size less than 5 × 5 mm. able prognosis, based on limited experience 9. All cases classifi ed as “undesignated” for to date) but with an annotation that there is FIGO staging purposes should be further no invasive carcinoma. described as “tubo-ovarian” or “tubal/ovar- 3. Cases with only STIC, ovarian surface ian” to distinguish them from serous carci- involvement or parenchymal involvement not noma originating in the uterus. Using our exceeding 5 mm, and widespread peritoneal suggestions, these should represent a small involvement, which would traditionally be proportion of HGSC. categorized as primary peritoneal carcinoma, 10. Cases with unilateral or bilateral HGSC in should be classifi ed as tubal primaries. the ovary and/or STIC or HGSC in the tube 4. Cases with invasive HGSC located within but with an endometrial serous intraepithe- the mucosa of the fallopian tube, including lial or invasive carcinoma should be care- its fi mbrial end, with or without STIC in any fully evaluated for an endometrial versus a portion of the fallopian tube and with no, tubo-ovarian primary (WT1 may be of minimal, or even substantial ovarian involve- value); a majority of such cases will repre- ment should be categorized as tubal sent adnexal metastases from an endometrial primaries. serous carcinoma. 5. Cases in which the fallopian tube is not identifi able, having presumably been overgrown by the ipsilateral adnexal mass, or the distal The 2013 FIGO (and TNM) Staging end of the fallopian tube is incorporated into of Ovarian, Fallopian Tube, a large tubo-ovarian mass should also, based and Primary Peritoneal Carcinoma on current understanding, be diagnosed as Including Summary of Changes tubal primaries. It is emphasized that a care- Since the 1988 FIGO Staging ful effort must be made to identify the tube in all cases. The 2013 FIGO Staging of Ovarian, 6. Cases with dominant ovarian mass(es) and Fallopian Tube, and Primary identifi able fallopian tubes with STIC should Peritoneal Carcinoma be classifi ed as tubal primaries. 7. Cases with dominant ovarian mass(es) and The staging system is given below. This has been identifi able fallopian tubes without STIC approved by the American Joint Commission should be classifi ed as ovarian primaries. on Cancer and the International Union Against Appendix A: Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma 501

Cancer, and the equivalent TNM stages are given Stage II: Tumor Involves 1 or Both alongside. Ovaries or Fallopian Tubes with Pelvic The following are implicit in the 2013 Extension (Below Pelvic Brim) or staging system as indicated in the notes at the Primary Peritoneal Cancer end: T2-N0-M0 • The tumor type should be designated as IIA: Extension and/or implants on uterus and/or HGSC, EC, CCC, MC, and LGSC; other or fallopian tubes and/or ovaries cannot be classifi ed; and malignant germ cell T2a-N0-M0 tumors and potentially malignant sex cord- IIB: Extension to other pelvic intraperitoneal tissues T2b-N0-M0 stromal tumors. Comment • The primary site (i.e., ovary, fallopian tube, Stage II ovarian cancer is still diffi cult to defi ne. It or peritoneum) should be designated where comprises a small and heterogeneous group making up possible (see “ Suggestions for assigning site less than 10 % of ovarian cancers. It is defi ned as of origin ”). In some cases, it might not be extension or metastasis to extraovarian/extratubal possible to delineate the primary site clearly; pelvic organs and may include curable tumors that have directly extended to adjacent organs but have not such cases should be listed as yet metastasized, as well as tumors that have seeded “undesignated.” the pelvic peritoneum by metastasis and, therefore, have a poor prognosis. Of note, the sigmoid colon is within the pelvis, and therefore sigmoid involvement only is considered stage II. The Committee felt that subdividing this small category further into IIB1 and Stage I: Tumor Confi ned to Ovaries IIB2 (i.e., microscopic and macroscopic pelvic or Fallopian Tube(s) peritoneal metastases) was not based on evidence/ T1-N0-M0 biology. All stage II disease is treated with adjuvant chemotherapy, so subclassifi cation is not essential. IA: Tumor limited to 1 ovary (capsule intact) or Also, the old substage IIC (i.e., IIA or IIB but with fallopian tube; no tumor on ovarian or fallopian tube tumor on surface, capsule ruptured, or ascites or surface; no malignant cells in the ascites or positive peritoneal washing) was considered redundant peritoneal washings and eliminated. T1a-N0-M0 IB: Tumor limited to both ovaries (capsules intact) or fallopian tubes; no tumor on ovarian or fallopian tube surface; no malignant cells in the ascites or Stage III: Tumor Involves 1 or Both peritoneal washings Ovaries or Fallopian Tubes, or Primary T1b-N0-M0 Peritoneal Cancer, with Cytologically IC: Tumor limited to 1 or both ovaries or fallopian tubes, with any of the following: or Histologically Confi rmed Spread to IC1: Surgical spill the Peritoneum Outside the Pelvis and/ T1c1-N0-M0 or Metastasis to the Retroperitoneal IC2: Capsule ruptured before surgery or tumor on Lymph Nodes ovarian or fallopian tube surface T1/T2-N1-M0 T1c2-N0-M0 IIIA1: Positive retroperitoneal lymph nodes only IC3: Malignant cells in the ascites or peritoneal (cytologically or histologically proven): washings IIIA1(i) Metastasis up to 10 mm in greatest T1c3-N0-M0 dimension Comment IIIA1(ii) Metastasis more than 10 mm in greatest Stage I ovarian or fallopian tube cancer is confi ned to dimension the ovaries or the fallopian tubes and peritoneal fl uid/ IIIA2: Microscopic extrapelvic (above the pelvic washings. Tumor rupture or surface involvement by brim) peritoneal involvement with or without tumor cells warrants a stage of IC. It is not possible to positive retroperitoneal lymph nodes have stage I peritoneal cancer. T3a2-N0/N1-M0 502 Appendix A: Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma

IIIB: Macroscopic peritoneal metastasis beyond the Comment pelvis up to 2 cm in greatest dimension, with or Stage IV is defi ned as distant metastasis and includes without metastasis to the retroperitoneal lymph nodes patients with parenchymal liver/splenic metastases and T3b-N0/N1-M0 extra-abdominal metastases; 12–21 % of patients present IIIC: Macroscopic peritoneal metastasis beyond the with stage IV disease. Extension of tumor from omentum pelvis more than 2 cm in greatest dimension, with or to spleen or liver (stage IIIC) should be differentiated without metastasis to the retroperitoneal lymph from isolated parenchymal metastases (stage IVB). nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ) Notes T3c-N0/N1-M0 • The primary site (i.e., ovary, fallopian tube, Comment Most ovarian cancers are HGSCs that usually present in or peritoneum) should be designated where stage III, with the vast majority (84 %) stage IIIC. These possible. In some cases, it might not be pos- tumors characteristically spread along peritoneal sible to delineate the primary site clearly; surfaces involving both pelvic and abdominal such cases should be listed as peritoneum including the omentum, surfaces of the small and large bowel, mesentery, paracolic gutters, “undesignated.” diaphragm, and peritoneal surfaces of the liver and • The histologic type should be recorded. spleen. A fi nding of ascites occurs in two-thirds of cases. • The staging includes a revision of stage III Lymph node metastases are found in the majority of patients; assignment to stage IIIA1 is based patients who undergo node sampling or dissection and in up to 78 % of advanced stage patients. Approximately on spread to the retroperitoneal lymph 9 % of patients with tumors that otherwise appear to be nodes without intraperitoneal dissemination stage I have lymph node metastases; the corresponding because an analysis of these patients indi- fi gures for stages II, III, and IV are 36, 55, and 88 %, cates that their survival is signifi cantly bet- respectively. Rarely, inguinal or supraclavicular (stage IV) node metastases will be the presenting manifestation ter than that of patients with intraperitoneal of ovarian carcinoma. dissemination. Less than 10 % of ovarian carcinomas extend beyond • Involvement of retroperitoneal lymph the pelvis with exclusively retroperitoneal lymph node nodes must be proven cytologically or involvement. Evidence in the literature indicates that histologically. these cases have a better prognosis than that of tumors with abdominal peritoneal involvement. The new • Extension of tumor from omentum to spleen staging includes a revision of stage III patients and or liver (stage IIIC) should be differentiated assignment to stage IIIA1 based on spread to the from isolated parenchymal metastases (stage retroperitoneal lymph nodes without intraperitoneal IVB). dissemination. Stage IIIA1 is further subdivided into IIIA1(i) (metastasis ≤10 mm in greatest dimension) and IIIA1(ii) (metastasis >10 mm in greatest dimension), even if there are no retrospective data Summary of Changes supporting quantifi cation of the size of metastasis in from the 1988 FIGO Staging IIIA1. Involvement of retroperitoneal lymph nodes must be proven cytologically or histologically. The two staging systems and changes are sum- marized in Table A2 . There is no longer a separate staging system for tubal and primary Stage IV: Distant Metastasis Excluding peritoneal carcinoma. Tumor type is to be Peritoneal Metastases included in the stage. The primary site should be Stage IVA: Pleural effusion with positive cytology designated as ovary, fallopian tube, or primary Stage IVB: Parenchymal metastases and metastases to peritoneal wherever possible or as “undesig- extra-abdominal organs (including inguinal lymph nated” if not (see “Suggestions for assigning site nodes and lymph nodes outside of the abdominal cavity) of origin”). Any T, any N, M1 Appendix A: Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma 503

Table A2 Comparison of 1988 and 2013 FIGO staging systems for ovarian cancer 1988 FIGO stage 2013 FIGO stage Difference I: Tumor limited to the ovaries I: Tumor confi ned to ovaries or No change; same staging for ovary and fallopian tube(s) fallopian tube IA: Tumor limited to 1 ovary; IA: Tumor limited to 1 ovary (capsule No change; same staging for ovary and capsule intact, no tumor on intact) or fallopian tube; no tumor on fallopian tube ovarian surface, no malignant ovarian or fallopian tube surface; no cells in ascites or peritoneal malignant cells in the ascites or washings peritoneal washings IB: Tumor limited to both IB: Tumor limited to both ovaries No change; same staging for ovary and ovaries; capsule intact, no tumor (capsules intact) or fallopian tubes; fallopian tube on ovarian surface, no malignant no tumor on ovarian or fallopian tube cells in ascites or peritoneal surface; no malignant cells in the washings ascites or peritoneal washings IC: Tumor limited to 1 or both IC: Tumor limited to 1 or both Change: Separation into substages ovaries with any of the following: ovaries or fallopian tubes, with any depending on presence of surgical spill capsule ruptured, tumor on of the following: or capsule rupture prior to surgery or ovarian surface, malignant cells IC1: Surgical spill surface involvement or malignant cells in ascites or peritoneal washings IC2: Capsule ruptured before surgery in ascites/peritoneal washings or tumor on ovarian or fallopian tube surface IC3: Malignant cells in the ascites or peritoneal washings II: Tumor involves 1 or both II: Tumor involves 1 or both ovaries or No change; same staging for ovary, ovaries with pelvic extension fallopian tubes with pelvic extension fallopian tube, and primary peritoneal (below pelvic brim) or primary cancer peritoneal cancer IIa: Extension and/or implants IIA: Extension and/or implants on No change; same staging for ovary, on uterus and/or tube(s); no uterus and/or fallopian tubes and/or fallopian tube, and primary peritoneal malignant cells in ascites or ovaries cancer peritoneal washings IIB: Extension to other pelvic IIB: Extension to other pelvic No change; same staging for ovary, tissues; no malignant cells in intraperitoneal tissues fallopian tube, and primary peritoneal ascites or peritoneal washings cancer IIC: Pelvic extension IIA or IIB Change: There is no stage IIC in the with malignant cells in ascites 2013 staging system or peritoneal washings III: Tumor involves 1 or both III: Tumor involves 1 or both ovaries No change; same staging for ovary, ovaries with microscopically or fallopian tubes, or primary fallopian tube, and primary peritoneal confi rmed peritoneal metastasis peritoneal cancer, with cytologically cancer outside the pelvis and/or regional or histologically confi rmed spread to lymph node metastasis the peritoneum outside the pelvis and/ or metastasis to the retroperitoneal lymph nodes IIIA: Microscopic peritoneal IIIA1: Positive retroperitoneal lymph Change (1): Regional nodal metastasis metastasis beyond pelvis nodes only (cytologically or was classifi ed as stage IIIC in the 1988 histologically proven): staging system IIIA1(i) Metastasis up to 10 mm in Change (2): Stage IIIA is subdivided greatest dimension into: IIIA1(ii) Metastasis more than IIIA1: Retroperitoneal lymph node 10 mm in greatest dimension involvement, substaged by dimension of metastatic deposits IIIA2: Microscopic extrapelvic (above IIIA2: Microscopic extrapelvic the pelvic brim) peritoneal peritoneal involvement +/− nodal involvement with or without positive spread retroperitoneal lymph nodes (continued) 504 Appendix A: Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma

Table A2 (continued) 1988 FIGO stage 2013 FIGO stage Difference IIIB: Macroscopic peritoneal IIIB: Macroscopic peritoneal No change in dimensions of peritoneal metastasis beyond pelvis 2 cm or metastasis beyond the pelvis up to deposits but irrespective of nodal less in greatest diameter 2 cm in greatest dimension, with or involvement without metastasis to the retroperitoneal lymph nodes IIIC: Peritoneal metastasis IIIC: Macroscopic peritoneal Change: This stage is now deﬁ ned beyond pelvis more than 2 cm metastasis beyond the pelvis more solely by dimensions of peritoneal in greatest diameter and/or than 2 cm in greatest dimension, tumor deposits, irrespective of regional lymph node metastasis with or without metastasis to the retroperitoneal nodal spread. Nodal retroperitoneal lymph nodes (includes involvement alone, without peritoneal extension of tumor to capsule of liver spread, is now classiﬁ ed as stage IIIA and spleen without parenchymal involvement of either organ) IV: Distant metastasis (excludes IV: Distant metastasis excluding Change: Separation into substages IVA peritoneal metastasis) peritoneal metastases and IVB Note: Liver capsule metastasis is Stage IVA: Pleural effusion with stage III, liver parenchymal positive cytology metastasis is stage IV. Pleural Stage IVB: Parenchymal metastases effusion must have positive and metastases to extra-abdominal cytology for stage IV organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)

• Involvement of fi mbrial end of the tube by STIC Controversies, Problematic Areas alone does not constitute surface involvement; in the New Staging System such lesions should be staged as IA as they have with Recommendations been demonstrated to have a good prognosis. • Invasive carcinoma at the fi mbrial end of the Many continuing controversies are discussed tube should be taken as constituting surface alongside the new staging system, and it is involvement as this portion of the tube is acknowledged that these cannot be resolved until exposed to the peritoneal surface. further data emerge. Recommendations on the • Distinction between rupture prior to surgery use of this staging system and for future research and during surgery may not be possible without have been made. These are listed and briefl y dis- access to the surgical notes or after discussion cussed below. at the multidisciplinary team meeting. • It is acknowledged that bilateral involvement • Dense adhesions often cause rupture during (stage IB) could represent independent contralat- surgery and could represent involvement of eral primary tumor or implants/metastases with pelvic tissues by tumor. At present tumors are potentially different prognostic implications. not upstaged based on dense adhesions as the • Assessment of surface involvement requires available data are inconclusive. Staging in the careful gross examination. Surface involvement presence of adhesions depends on tumor rup- of the ovary or fallopian tube should be consid- ture or microscopic evidence of involvement ered present only when tumor cells are exposed of extraovarian pelvic tissues. to the peritoneal cavity, characterized by exo- • Histologic grade has been shown in several phytic papillary tumor on the surface of the studies to infl uence prognosis of stage I ovary or fallopian tube or on the outer surface of tumors. The tumor grade is now implicit in the a cystic neoplasm replacing these organs; rarely, tumor type for HGSC, CCC, and LGSC and a smooth ovarian tumor surface will be shown currently most grade 3 ECs are considered to to have an exposed layer of neoplastic epithe- be HGSC. EC and MC should continue to be lium on microscopic examination. graded and distinguished from metastases Appendix A: Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma 505

from the gastrointestinal tract or female geni- given. Further, distinction should be made tal tract. between single small lesions within the • It is not established whether rupture during omentum (<2 cm) and diffuse peritoneal surgery worsen prognosis in the absence of disease including the upper abdomen and excrescences, ascites, or positive washings. diaphragm. • Data from several studies suggest that stage I • Transmural bowel infi ltration with mucosal CCC is more frequently stage IC compared involvement and umbilical deposits (both cur- with other cell types, possibly because of an rently IVB) are specifi cally mentioned. Some increased risk of rupture and/or surface consider that involvement of the umbilicus involvement due to coexisting endometriosis. should be IIIC rather than IV as it represents • It is unclear whether positive washings are worse peritoneal extension into the urachal remnant. than capsule rupture as a prognostic factor. Similarly, isolated parenchymal liver metasta- Separation into separate categories of stage IC sis and splenic parenchymal metastasis are should help to resolve such issues in the future. susceptible to cytoreductive surgery and, • It may not be biologically justifi ed to separate according to some investigators, should be the pelvic from the extrapelvic peritoneum. IIIC. None of these were adopted by the FIGO Some investigators have the view that the peri- Committee, i.e., transmural bowel infi ltration, toneum is an anatomic unit and that pelvic and umbilical deposits, and parenchymal metasta- extrapelvic involvement are prognostically ses in the liver and spleen are all considered similar and therefore that all peritoneal stage IVB. involvement should be regarded as stage • The results for splenectomy for isolated III. This view was not supported unanimously metastases are superior to those of partial hep- and stages IIA and IIB remain. atectomy. In the future, isolated splenic metas- • It is possible that some carcinomas that have tasis may be considered stage IIIC rather than extended beyond the pelvis with exclusively stage IV, whereas parenchymal liver metasta- retroperitoneal lymph node involvement (stage sis would remain stage IVB. IIIA1) represent independent LGSCs arising in • It is unclear whether positive lymph nodes retroperitoneal lymph nodes from endosalpin- above the renal vessels should be considered giosis. Serous borderline tumors and LGSCs stage III or IV. may develop in retroperitoneal and cervical Recommendations for Stage I lymph nodes from endosalpingiosis, often in • Histologic type, which in most cases includes association with serous borderline tumors of grade, should be recorded. the ovary and with favorable prognosis. • All individual subsets of stage IC disease • The new stage IIIA1 is limited to involvement should be recorded. of the retroperitoneal lymph nodes below the • Dense adhesions with histologically proven diaphragm. It was suggested that upward nodal tumor cells justify upgrading to stage II. involvement (e.g., mediastinal nodes) should • If rupture is noted, peritoneal washing and be included, but, for now, the Committee felt cytology study are indicated. that the stated limitation was appropriate. Recommendations for Stage II • Cytological confi rmation of involved nodes or • To separate direct extension from metastases peritoneal disease would be insuffi cient for • To compare outcome of stage II and early substaging into IIIA1 and IIIA2. stage III cases • Regarding the amount of peritoneal involve- Recommendations for Stage III ment, it was maintained that stage III tumors • To classify IIIA1 cases histologically should be divided into microscopic and • To compare outcome of stage IIIA1(i) and macroscopic peritoneal spread, and for the lat- IIIA1(ii) cases ter the measurement (in centimeters) of the • To compare outcome of stage IIIA1 and IIIA2 largest dimension of a single nodule should be cases 506 Appendix 1: Staging of Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma

References 4. Wilkinson N, McCluggage WM. Standards and datasets for reporting cancers: datasets for the histopathological reporting of neoplasms of the ovaries and 1. Prat J. Staging classiﬁ cation for cancer of the ovary, fallopian tubes and primary carcinomas of the perito- fallopian tube, and peritoneum. Int J Gynaecol Obstet. neum. 3rd ed. The Royal College of Pathologists 2014 Jan;124(1):1–5. (UK); 2010. http://www.rcpath.org/publications- 2. Bereka JS, Crum C, Friedlander M. FIGO CANCER media/publications/datasets/datasets-TP.htm . REPORT 2012: cancer of the ovary, fallopian tube, 5. WHO Classiﬁ cation of Tumours. Chapter 2. Tumours and peritoneum. Int J Gynecol Obstet. 2012; of the breast and female genital organs. In: Tumours 119S2(2012):S118–29. of the ovary and peritoneum. Lyons: IARC Press; 3. Singh N, Gilks CB, Wilkinson N, McCluggage 2003. WG. Assignment of primary site in high-grade serous 6. National Cancer Intelligence Network: cancer out- tubal, ovarian and peritoneal carcinoma: a proposal. comes and services dataset: http://www.ncin.org.uk/ Histopathology. 2014 Mar 25. doi: 10.1111/his.12419 . collecting_and_using_data/data_collection/cosd [Epub ahead of print]. Appendix B: Datasets and Information About Gynecological Cancer Web Sites

We have not provided a dataset for completion as ICCR dataset link: http://www.rcpa.edu.au/ these are presently being updated by the Royal Library/Practising-Pathology/ICCR/Cancer-Datasets College of Pathologists and are being written by the This is a link to the United Kingdom Cancer International Collaboration on Cancer Reporting Proﬁ les: http://www.ncin.org.uk/cancer_type_and_ (ICCR). topic_specific_work/cancer_type_specific_work/ We recommend that these Web sites are con- gynaecological_cancer/gynaecological_cancer_ sulted for the most recent dataset, and for further hub/proﬁ les helpful information further links have been This is a link to the cancer services and out- provided. comes datasets: http://www.ncin.org.uk/collect- Royal College of Pathologists link to cancer ing_and_using_data/data_collection/cosd dataset publications: http://www.rcpath.org/ publications- media/publications/datasets/datasets- TP.htm

507 Index

A Brenner tumors , 142, 146 Actinomycosis , 399 benign tumors , 279 Adnexal torsion , 55 borderline tumors , 279 Adult granulosa cell tumors (AGCT) , 164, 165 macroscopic features , 278 differential diagnosis malignant tumors , 279–280 endometrial stromal sarcoma , 332 mucinous metaplasia , 278 ovarian small cell carcinoma , 332–333 osseous metaplasia , 278 transitional/undifferentiated carcinoma , 331 squamous metaplasia , 278 macroscopy , 328 TCCs , 280–281 microscopy tubal-mesothelial junction , 277–278 brisk mitotic activity , 329, 330 cystic change , 330, 332 cytoplasm , 329, 331 C longitudinal nuclear grooves , 328, 329 Carcinoid tumors , 380–381 microfollicular pattern , 328, 329 Carcinosarcomas , 284–285 pseudopapillary pattern , 329, 331 Cartilage tumor Alpha-fetoprotein (AFP) , 309 chondroma , 468 Angiosarcoma , 471 chondrosarcoma , 468–469 Appendix , 493–494 Cediranib , 94 Arias-Stella reaction , 409, 410 Cervical carcinoma Autoimmune oophoritis , 48–50 clinical features , 377 Avastin Use in Platinum-Resistant Epithelial Ovarian differential diagnosis , 378–379 Cancer (AURELIA) , 90, 92, 93 pathology , 377–378 Chondroma , 468 Chondrosarcoma , 468–469 B CHORUS trial , 82, 120 Bevacizumab Classifi cation of Ovarian Cancer (CLOVAR) , 80 cost-effectiveness and availability , 91 Clear cell carcinoma , 97–98 dose-dense chemotherapy , 92 clinical presentation , 260 fi rst-line treatment , 88–89 confi rmatory endometrioid features , 252–253 GOG-218 and ICON7 , 90, 91 differential diagnoses IDS , 93 endometrioid carcinomas , 269 IP chemotherapy , 92 renal cell carcinomas , 269 NACT , 93 serous carcinomas , 268–269 PFS advantage , 92–93 endometrioid ovarian carcinomas relapsed treatment confi rmatory endometrioid features , 252–253 AURELIA trial , 90, 92 FATWO , 253 OCEANS trial , 89–90, 92 metastatic and synchronous adenocarcinomas , 253 single-agent activity , 88 prognosis and staging , 254–255 Bilateral salpingo-oophorectomy , 33, 50, 54, 64, 485 tumor genetics , 253–254 Borderline serous tumors , 447 frozen section , 142, 145 Breast carcinoma grading system , 264–265 clinical features , 374 histological appearances differential diagnosis , 374–375 adenofi broma , 261–262 pathology , 374 cytological atypia , 262

N. Wilkinson (ed.), Pathology of the Ovary, Fallopian Tube and Peritoneum, 509 Essentials of Diagnostic Gynecological Pathology, DOI 10.1007/978-1-4471-2942-4, © Springer-Verlag London 2014 510 Index

Clear cell carcinoma (cont .) D endometriosis , 261 Desmoplastic small round cell tumor gene expression , 263 (DSRCT), 449–450 HNF-1 beta , 263, 269 Diagnostic tests treatment , 264 cervical metastasis , 129–130 yolk sac tumor , 263 CT incidence , 259–260 assessment , 122 macroscopic appearances , 260–261 CHORUS study , 120 metastatic and synchronous adenocarcinomas , 253 CMN , 118 oxyphilic tumors , 268–269 epithelial ovarian cancer , 118–119 papillary pattern , 266, 267 guided biopsy , 121–122 peritoneal washing cytology , 154, 157 metastatic disease , 117 prognosis and staging , 254–255 peritoneal carcinomatosis , 120 prognosis and treatment , 269–270 pleural effusion , 118 solid pattern PPC , 120, 121 abundant oxyphilic cytoplasm , 269 RDOG , 119 adenocarcinoma , 263, 265 staging assessment , 113, 117 AFP negative globules , 267 IGCB , 110 atypical cytology and complex , 268 inoperable disease , 110, 111 tubulocystic pattern , 265–267 malignancy metastatic , 110, 112 tumor genetics , 253–254 MR imaging Colorectal carcinoma adnexal incidentaloma , 116 clinical features , 365 complex cystic/cystic-solid masses , 115–116 differential diagnosis , 368–369 DCEMR , 116 pathology DWI , 116 colloid carcinoma pattern , 367 follow-up , 116 “garland pattern,” 366 , 367 T1-and T2-weighted sequences , 114 immunohistochemistry , 368 T1 bright masses , 115 malignant epithelium and glands , 367 T2 solid masses , 115 primary endometrioid carcinoma , 365 ultrasound (see Ultrasound) Complete androgen insensitivity syndrome Diffusion-weighted imaging (DWI) , 116 (CAIS) , 321, 322 Disorders of sex development (DSD) Computed tomography (CT) classiﬁ cation of , 316 assessment , 122 diagnosis of , 322 CHORUS study , 120 gonadal dysgenesis , 316–318, 321 CMN , 118 gonadoblastoma , 320 epithelial ovarian cancer , 118–119 hypervirilization , 321 guided biopsy , 121–122 hypovirilization , 321 IGCB , 120 risk factors , 319 metastatic disease , 117 WT1 mutations , 321 peritoneal carcinomatosis , 120 Dynamic contrast-enhanced MR imaging pleural effusion , 118 (DCEMR), 116 PPC , 120, 121 Dysgerminoma , 163 RDOG , 119 clinical features , 304 staging assessment , 113, 117 differential diagnosis , 304–305 Contrast medium nephrotoxicity (CMN) , 118 immunocytochemistry , 314 Corpus albicans cysts , 35 macroscopic features , 304 Cortical granulomas , 48 microscopic features , 304–306 Crohn’s disease , 48 prognosis , 306 CT. See Computed tomography (CT) somatic differentiation , 305–306 Cytology FNA ( see Fine-needle aspiration (FNA)) peritoneal washing ( see Peritoneal washing Cytology) E serous ﬂ uids Echinococcus , 48 diagnosis , 160 Ectopic decidua , 43–44 features of , 160 Embryological origins lymphoreticular tumors , 165, 168 granulosa cells , 4 mesothelioma , 161, 165 gubernacular remnants , 5 metastatic adenocarcinoma , 160–163 oocytes development , 4 mucinous tumors , 161, 164 PGCs , 3, 4 non-epithelial ovarian tumors , 161, 165–167 sexual differentiation , 4 Index 511

Endocervical-like mucinous borderline tumors (EMBT) Endometriosis , 20–21 clinical features , 223 atypical endometriosis , 439 clinical outcome and prognosis , 225 clear cell carcinoma , 261 club-shaped papillae , 223–224 clinical features , 50 differential diagnoses , 225 defi nition , 50 gross features , 223 differential diagnosis , 52 intraepithelial carcinoma , 224, 225 etiology and pathogenesis , 435–437 microinvasion , 224–225 fallopian tube synonyms , 222–223 blood and macrophages , 400, 401 Endometrial polyp , 410 CD10 immunostain , 403, 404 Endometrial stromal sarcoma , 382–383 diagnosis , 403, 404 Endometrioid ovarian carcinomas endometrial-type stroma , 403 adenocarcinoma , 142 hemosiderin-laden macrophages , 400, 401 carcinosarcoma , 252 mucosa/serosa , 400 ciliated cell and oxyphilic variants , 249 myosalpinx , 402 clear cell variant , 249 pregnancy , 403, 404 clinical association and features , 243 signet-ring cell decidual change , 403, 404 confi rmatory endometrioid features , 246 tubal endometriosis , 401 cribriform, villoglandular/papillary , 243, 244 incidence and distribution , 435 differential diagnoses , 250, 251 liesegang rings , 439–440 endometriosis , 245 macroscopic fi ndings , 50–51 expansile/confl uent growth , 245, 246 malignant change development , 52–53 glandular architecture , 243, 244 metaplasia , 437–439 grading system , 246–247 microscopic fi ndings , 51–52 high-grade serous carcinoma , 252 morphology , 437 immunoprofi le , 249–250 necrotic pseudoxanthomatous macroscopic features , 243, 244 nodules , 439 metaplastic changes , 244 peritoneal washing cytology , 152, 154, 155 sex cord-like/sertoliform variant , 247–248 serous tumors , 200 sex cord-stromal tumors , 250, 252 stromal endometriosis , 437, 438 spindle-cell variant , 248–249 Endosalpingiosis , 440 squamous morules , 245 Enterobiasis , 47 benign tumors Epithelial ovarian carcinoma (EOC) clinical associations and features , 240 BRCA1/BRCA2 germ line mutation , 178 differential diagnosis , 241 clear cell carcinoma , 189 macroscopic features , 240 clinical and pathological study , 178 microscopic features , 240–241 distal fallopian tube-peritoneal junction , 191 treatment and behavior , 241 early stage vs. late stage carcinoma , 179–180 borderline tumors endometrioid adenocarcinoma , 188–189 clinical associations and features , 241 FIGO grading system , 181 differential diagnosis , 242 germ cell/sex cord-stromal lineage , 192 macroscopic features , 241, 242 growth patterns , 190 microscopic features , 240–242 morphological alterations , 180–181 treatment and behavior , 242–243 mucinous carcinoma clear cell carcinoma expansile invasion , 186 confi rmatory endometrioid features , 252–253 intestinal type , 186–187 FATWO , 253 Mullerian type , 187 metastatic and synchronous adenocarcinomas , 253 pathogenesis , 187–188 prognosis and staging , 254–255 pathological features , 186 tumor genetics , 253–254 prognosis , 188 endometrial carcinoma prevalence , 178 clinical features , 375 relative frequency of , 179 pathology , 375–377 Royal College of Pathologists Ovarian Cancer fallopian tube Dataset, 181 female adnexal tumor , 423 serous carcinoma (see Serous carcinoma) spindle cell differentiation , 417 Shimizu-Silverberg system , 181 stage Ia-0 , 415 transitional carcinoma , 189 female adnexal tumor , 423 type I and type II , 191 incidence , 239–240 undifferentiated carcinoma , 189–190 spindle cell differentiation , 417 wild-type staining , 191 stage Ia-0 , 415 WT1 staining , 190 512 Index

F primary tubal choriocarcinomas , 407–408 Fallopian tube prolapse , 405–406 acute salpingitis pseudocarcinomatous hyperplasia , 406 actinomycosis , 399 salpingitis isthmica nodosa , 399–400 causes , 396 sarcomas , 421–422 neutrophils and fi brin , 396 specimen cut-up , 490–492 physiological conditions , 395 torsion , 404 adenomatoid tumor , 419 trophoblastic lesions , 407 Arias-Stella reaction , 409, 410 tuberculous salpingitis , 398–399 benign tumors , 410 Female adnexal tumor of probable Wolffi an Origin borderline tumors , 411 (FATWO) , 253, 422–424 calcifi cation , 405 Fertility-sparing surgery , 65–67 carcinomas Fibroma BRCA-related tubal carcinomas , 417–419 differential diagnosis , 336 clinical features , 411 epidemiology and clinical correlation , 334 differential diagnosis , 417 macroscopy , 334–335 endometrioid carcinomas (see Endometrioid microscopy , 335–336 ovarian carcinomas, fallopian tube) Fine-needle aspiration (FNA) general features , 411 diagnosis , 166 gross features , 411 diagnostic accuracy , 168–169 microscopic features , 412 harmless procedure , 166 mucinous carcinomas , 415 intraoperative cytology , 172 primary transitional cell carcinomas , 415 MGG , 167 prognosis , 416–417 nonneoplastic and neoplastic categories , 166 serous carcinomas , 412–413 ovarian cysts serous tubal intraepithelial carcinoma , 412–415 dermoid cysts , 171 chronic salpingitis , 397–398 endometriotic cysts , 169, 171 ectopic decidua , 410 epithelial-lined cysts , 170, 171 ectopic pregnancy functional cysts , 169, 170 implantation site trophoblasts , 406, 408 paraovarian and paratubal sponge like tissue , 406 cysts , 170, 171 endometriosis solid ovarian tumors , 171–172 blood and macrophages , 400, 401 Papanicolaou method , 167 CD10 immunostain , 403, 404 utility , 167–168 diagnosis , 403, 404 Folliculogenesis endometrial-type stroma , 403 antral follicle , 12–13 hemosiderin-laden macrophages , 400, 401 caloric intake , 17 mucosa/serosa , 400 corpus albicans , 15–16 myosalpinx , 402 corpus luteum , 14–15 pregnancy , 403, 404 follicle selection and atresia , 13–14 signet-ring cell decidual change , 403, 404 lactation , 16–17 tubal endometriosis , 401 menopause , 18 epithelial tumors , 424 nutritional sensing and reproductive function , 18 hydatidiform moles , 408 ovulation , 14 hyperplasia , 410–411 pituitary gonadotrophins , 7, 8 intermediate trophoblast lesions , 408–409 pre-antral/gonadotrophin-independent phase , 7 leiomyoma , 421 pregnancy and lactation , 16 malignant Müllerian mixed tumor primary follicle , 7–11 carcinomatous and sarcomatous primordial follicle , 7, 9 components , 420, 421 secondary follicle , 9–11 gross examination , 419 Frozen section (FS) microscopic features , 420 appearance/artifacts , 137–138 mesenchymal tumors , 424 block selection , 137 metaplasias borderline diagnosis , 134–135 mucinous , 402–403 broadline diagnosis , 139 squamous , 404 communication , 135–136 transitional cell , 403, 405 germ cell lesions , 146 metastatic tumors , 422 health and safety aspects , 136 paratubal lesions intact simple serous cyst , 136 FATWO , 422–424 MDT preoperatively , 135 paratubal cysts , 422 mucinous cyst , 136, 137 Index 513

nonneoplastic diagnoses , 139–141 epidemiology and clinical correlates , 328 parafﬁ n section , 139 JGCTs (see Juvenile granulosa cell tumor (JGCT)) pediatric ovarian , 146–147 macroscopy , 328 primary ovarian epithelial lesions microscopy , 328–331 adult granulosa cell tumor , 145, 146 Growing teratoma syndrome (GTS) , 298 borderline mucinous cyst , 141, 144 Gynaecologic Oncology Group (GOG) borderline serous lesion , 141, 143 Brenner tumor , 142, 146 clear cell carcinoma , 142, 145 H metastatic colonic adenocarcinoma , HAIR-AN syndrome , 38 142, 145 Hemangioma , 470–471 necrotic/solid ovarian tumor , 141, 143 Hepatoid carcinomas , 283–284 serous cysts , 141, 142 Hereditary non-polyposis colorectal cancer simple mucinous cyst , 141, 144 (HNPCC), 388–389 reliable cryostat , 135 Hilus/Leydig cell hyperplasia , 39–40 sample , 134 Hydatidiform moles (HM) , 408 secondary tumors , 147–148 Hydrosalpinx , 397, 398 sensitivity and speciﬁ city , 138 Hyperplasia , 410–411 sex cord-stromal lesions , 144–145 Hyperplasia/hyperthecosis. See Stromal hyperplasia/ stage 1/2 disease , 134 hyperthecosis statistical approaches , 138, 139 surgical timing , 135

I G Image-guided core biopsy (IGCB) , 120 Ganglioneuroma , 470 colorectal metastasis , 129 Gastrointestinal stromal tumor , 383, 452 high-grade serous carcinoma , 125–127 Germ cell tumors (GCT) low-grade serous carcinoma , 127 autoimmune disorders , 322–323 mucinous lesions , 127–129 carcinoid tumors , 315 transabdominal/transvaginal route , 125 choriocarcinoma , 312, 313, 315 IMBT. See Intestinal-type mucinous borderline DSD (see Disorders of sex development (DSD)) tumors (IMBT) dysgerminoma (see Dysgerminoma) Immature teratoma embryonal carcinoma clinical features , 295 immunocytochemistry , 314, 315 gliomatosis peritonei , 298, 299 microscopic features , 310–312 grading , 296–297 estrogen receptors , 315–316 GTS , 298 gonadal development macroscopic features , 295 dioecy , 289 microscopic appearance , 295, 296 DSD , 290 prognosis , 297–298 embryonic stem cells , 290 International Federation of Gynecologists and gonocytes , 290 Obstetricians (FIGO), 149 primordial germ cells , 290 Interval debulking surgery (IDS) , 93, 495 SCF-KIT pathway , 290 Intestinal-type mucinous borderline Sertoli cells , 291 tumors (IMBT) sex-speciﬁ c pathway , 290 clinical outcome and prognosis , 222 SOX17 , 290 differential diagnosis , 221–222 gonadoblastoma , 320 glands and cysts , 219–220 heterogeneity , 291–292 gross features , 218–219 PLAP , 314 intraepithelial carcinoma , 220, 221 seminoma , 303 microinvasion , 220–221 surgery , 67–68 mucin granulomas , 220 teratomas (see Teratomas) Intrafollicular cytokines , 7 YST (see Yolksac tumor (YST)) Intrauterine contraceptive device (IUCD) , 45, 46 Giant cell arteritis , 48 Gonadotrophin-releasing hormone (GnRH) , 5, 6 Graaﬁ an follicle , 12 J Granulosa cell tumors (GCT) Japanese JCOG 0602 study , 83 adult AGCT (see Adult granulosa cell Juvenile granulosa cell tumor (JGCT) , 165 tumors (AGCT)) differential diagnosis , 333–335 differential diagnosis , 331–334 macroscopy , 328 514 Index

K paclitaxel scheduling , 84–85 Kidney and urinary tract , 381 PARP inhibitors , 85–87 Klinefelter syndrome , 291, 316, 319 pathogenesis Krukenberg tumors clinicopathological , 78 clinical features , 359–360 molecular phenotype , 78 deﬁ nition , 359 origin , 80 differential diagnosis , 364–365 type 1 tumors , 79 pathology type 2 tumors , 79–80 immunohistochemical markers , 363 platinum agents signet ring cells , 360–361 carboplatin , 80 stromal proliferation , 361–362 cisplatin chemotherapy , 80 paclitaxel , 81 small-molecule-targeted therapies L cediranib , 94 Lipoma , 472 nintedanib , 95 Liposarcoma , 472 pazopanib (votrient) , 93–94 Lobular carcinoma , 147 trebananib , 94–95 Low-grade ovarian carcinoma , 95–97 surgical specialization issues , 81–82 Lymphangioma , 471 taxanes , 81 timing of surgery , 82–83 Mesenchymal tumors , 424 M adipose tissue , 472 Magnetic resonance (MR) imaging cartilage tumor , 468–469 adnexal incidentaloma , 116 endometrioid stromal sarcoma , 472 complex cystic/cystic-solid masses , 115–116 ganglioneuroma , 470 DCEMR , 116 malignant peripheral nerve sheath tumor , 470 DWI , 116 myxoma , 472–473 follow-up , 116 neuroﬁ broma , 469 T1-and T2-weighted sequences , 114 osteoma , 469 T1 bright masses , 115 osteosarcomas , 469 T2 solid masses , 115 paraganglioma , 470 Malignant melanoma , 379–380 PEComa , 474 clinical features , 379 rhabdomyoma , 468 differential diagnosis , 379–380 rhabdomyosarcoma , 468 pathology , 379 Schwannomas , 469 Malignant Müllerian mixed tumor smooth muscle tumors carcinomatous and sarcomatous leiomyoma , 466 components , 420, 421 leiomyosarcoma , 466–467 gross examination , 419 vascular and lymphatic tissue microscopic features , 420 angiosarcoma , 471 Malignant peripheral nerve sheath tumor , 470 hemangioma , 470–471 Mature cystic teratoma (MCT) lymphangioma , 471 clinical features , 292 Mesothelial tumors , 383–384 cytogenetics , 294 Metaplastic papillary tumor , 410 epidermoid cyst , 293 Metastatic ovarian tumors macroscopic appearance , 292–293 breast carcinoma mature solid teratoma , 294–295 clinical features , 374 microscopic appearance , 293, 294 differential diagnosis , 374–375 prognosis , 293–294 pathology , 374 May-Grünwald Giemsa (MGG), 167 carcinoid tumors , 380–381 Medical management cervical carcinoma angiogenesis , 87–88 clinical features , 377 bevacizumab (see Bevacizumab) differential diagnosis , 378–379 conventional chemotherapy drugs , 85 pathology , 377–378 cytotoxic drugs , 83 clinical features , 355 high-dose chemotherapy , 83 colorectal carcinoma (see Colorectal carcinoma) intraperitoneal therapy , 83–84 endometrial carcinoma morphological and molecular differences clinical features , 375 clear cell ovarian carcinoma , 97–98 pathology , 375–377 low-grade ovarian carcinoma , 95–97 endometrial stromal sarcoma , 382–383 mucinous ovarian carcinoma , 98–99 gastrointestinal stromal tumors , 383 Index 515

gross features clinical outcome and prognosis , 225 laterality , 355, 356 club-shaped papillae , 223–224 surface involvement , 358 differential diagnoses , 225 tumor size , 355–356 gross features , 223 histological features , 358–359 intraepithelial carcinoma , 224, 225 kidney and urinary tract , 381 microinvasion , 224–225 Krukenberg tumors endocervical-like carcinoma clinical features , 359–360 clinical features , 229 defi nition , 359 gross features , 229 differential diagnosis , 364–365 immunohistochemistry , 230–231 pathology , 360–364 microscopic features , 229, 230 liver , 381–382 prognostic factors , 229, 230 malignant melanoma , 379–380 IMBT mesothelial tumors , 383–384 clinical outcome and prognosis , 222 mucinous ovarian tumors, PMP differential diagnosis , 221–222 clinical features , 369 glands and cysts , 219–220 defi nition , 369 gross features , 218–219 differential diagnosis , 370–371 intraepithelial carcinoma , 220, 221 pathology , 369–372 microinvasion , 220–221 pancreatic and biliary tract mucin granulomas , 220 clinical features , 371–372 intestinal-type carcinoma differential diagnosis , 373–374 clinical features , 225 pathology , 372–373 differential diagnosis , 227–228 respiratory tract , 381 expansile invasion , 226–227 synchronous endometrial tumors FIGO stage , 228–229 clinical features , 384 gross features , 226 differential diagnosis , 385, 386 infi ltrative invasion , 227 and HNPCC , 388–389 molecular pathology , 216 molecular changes , 386–387 NAC , 233–234 pathology , 384–385 pseudomyxoma peritonei , 231–233 prognostic factors , 387–388 SLMN , 233–234 in young women , 388 Myxoma , 472–473 Microsatellite instability (MSI) , 254 Mixed epithelial tumors borderline seromucinous tumor , 282 N carcinosarcomas , 284–285 Necrotic pseudoxanthomatous nodules collision tumor pattern , 281–282 (NPN), 439 Monodermal teratoma , 146, 147 Neurofi broma , 469 Mucinous carcinomas , 415 NICE guidelines , 64 Mucinous cystadenoma Nintedanib , 95 clinical features , 217 Nonneoplastic disorders clinical outcome and prognosis , 217 adnexal torsion , 55 condensed ovarian stroma , 217 autoimmune oophoritis , 48–50 epithelial cells , 217–218 corpus albicans cysts , 35 fi brous stroma , 217 corpus luteum cyst , 35, 36 gross features , 216 cystic follicles , 34 mucin granuloma , 217 endometriosis (see Endometriosis) Mucinous metaplasia , 402–403 fi bromatosis , 56–57 Mucinous ovarian carcinoma , 98–99 follicle cysts Mucinous tumors clinical features , 34 classifi cation , 216 differential diagnosis , 34–35 cystadenoma etiology and pathogenesis , 34 clinical features , 217 histopathological appearances , 34, 35 clinical outcome and prognosis , 217 hemorrhage , 55 condensed ovarian stroma , 217 hilus/Leydig cell hyperplasia , 39–40 epithelial cells , 217–218 histopathological , 33–34 fi brous stroma , 217 hyperplasia (see Stromal hyperplasia/hyperthecosis) gross features , 216 infl ammatory conditions mucin granuloma , 217 actinomycosis , 46 EMBT cytomegalovirus , 47 clinical features , 223 fungal infection , 48 516 Index

Nonneoplastic disorders (cont .) P mumps , 47 Paclitaxel , 81 oophoritis , 45–46 Papanicolaou method , 167 parasitic infection , 47–48 Parasitic infection tuberculosis , 46–47 echinococcus , 48 massive ovarian edema , 56 enterobiasis , 47 mesothelial proliferations , 54 schistosomiasis , 47 noninfectious infl ammatory conditions , 48 Partial androgen insensitivity syndrome (PAIS) , 321, 322 ovarian remnant syndrome , 54–55 Pazopanib (votrient) , 93–94 PCOS ( see Polycystic ovary syndrome (PCOS), PCOS. See Polycystic ovary syndrome (PCOS) nonneoplastic disorders) Peritoneal strumosis , 299 pregnancy Peritoneal washing cytology corpus luteum , 40 collagen balls , 154, 155 cytoplasmic vacuoles , 40, 41 diagnostic accuracy , 158–160 ectopic decidua , 43–44 endometriosis , 152, 154, 155 hyperreactio luteinalis , 42–43 endosalpingiosis , 151–152 ovarian ectopic , 44–45 FIGO staging classifi cation , 149 solitary luteinized follicular cyst , 43 high-grade serous carcinoma , 154, 156 theca-lutein hyperplasia , 40–41 immunohistochemistry , 154, 156–158 rete cysts , 54 mesothelial hyperplasia , 150, 152 simple/indeterminate cysts , 54 mimic tumor cells , 150, 151 stromal hyperthecosis non-serous primary ovarian carcinomas clinical features , 39 clear cell carcinoma , 154, 157 defi nition , 38 endometrioid adenocarcinoma , 154, 158 differential diagnosis , 39 mucinous carcinoma , 154, 159 histopathological fi ndings , 39 prevalence , 150 surface epithelial inclusion cyst , 53 psammoma bodies , 150, 153 surface stromal proliferations , 54 risk-reducing surgery , 160 SBT , 150, 152, 153 SurePath™ , 150 surgical staging procedure , 150 O ThinPrep® , 150 Omentum , 492–493 Peritoneum Oocyte-bearing follicles , 1 adenosarcoma , 448 Oophoritis , 45 anatomy , 431–432 Osteoma , 469 benign lymph node inclusions , 454–455 Osteosarcomas , 469 carcinosarcoma , 448 Ovarian anatomy , 2–3 deciduosis , 441 Ovarian Cancer Study Comparing Effi cacy and Safety of diffuse peritoneal leiomyomatosis , 450 Chemotherapy and Antiangiogenic Therapy in endocervicosis and mucinous lesions , 440 Platinum-Sensitive Recurrent Disease endometriosis (see Endometriosis) (OCEANS), 89–90, 92 endosalpingiosis , 440 Ovarian cancer surgery extraovarian mucinous neoplasms , 448 abdominal cytoreduction , 71 histology , 432 borderline ovarian tumors , 69–70 infl ammatory myofi broblastic tumor , 452 debulking surgery , 71, 72 intra-abdominal DSRCT , 449–450 diagnosis , 64–65 mesothelial lesions epithelial , 65–67 multicystic mesothelial proliferation , 441–442 FIGO stages III and IV , 71 unilocular mesothelial cyst , 441 germ cell tumors , 67–68 metastatic disease , 453–454 lymphadenectomy , 71 mucinous ascites and pseudomyxoma peritonei , 448 NICE guidelines , 64 neoplastic lesions prevealance , 65 adenomatoid tumor , 442 risk-reducing surgery , 72–73 differential diagnosis , 445–446 serous borderline tumors , 69–70 epithelioid malignant mesothelioma , 443 sex cord-stromal tumors , 68–69 malignant mesothelioma , 443 transverse colectomy , 71 sarcomatoid mesotheliomas , 443–445 Ovarian remnant syndrome , 54–55 WDPM , 442–443 Index 517

nonneoplastic lesions pathogenesis , 36–37 actinomyces , 433 pathophysiology , 36 granulomatous infl ammation , 432 pathogenesis , 19 infections , 432 Premature ovarian failure (POF) , 48–49 noninfectious granulomatous causes of , 19 infl ammation , 434 ovarian steroid and peptide hormones , 19 tuberculous peritonitis , 433 X chromosome abnormalities , 19 primary peritoneal carcinoma Primary peritoneal carcinoma (PPC) , 120, 121 borderline serous tumors , 446–447 borderline serous tumors , 446–447 high-grade serous carcinoma , 447 high-grade serous carcinoma , 447 low-grade papillary serous carcinoma , 447 low-grade papillary serous carcinoma , 447 peritoneal implants , 447 peritoneal implants , 447 psammocarcinoma , 447 psammocarcinoma , 447 secondary Mullerian system/Mullerianosis , 434 Primordial germ cells (PGCs) , 3, 4 solitary fi brous tumor , 450–452 Psammocarcinoma , 447 synovial sarcoma , 452–453 Pseudocarcinomatous hyperplasia , 406 transitional epithelium , 441 Pseudomyxoma peritonei (PMP) , 231–233 Perivascular epithelioid cell tumors (PEComas) , 474 clinical features , 369 PETROC/OV21 trial , 84 defi nition , 369 Physiological function differential diagnosis , 370–371 endocrine function pathology follicular phase , 6 appendiceal tumor , 369, 370 hypothalamic-pituitary-ovarian control , 5–6 capsular surface , 370, 371 luteal phase , 7 low-grade mucinous neoplasm , 369, 370 folliculogenesis and histology mucin extravasation , 370, 371 antral follicle , 12–13 mucin-fi lled cysts , 370, 371 caloric intake , 17 corpus albicans , 15–16 corpus luteum , 14–15 R follicle selection and atresia , 13 Radiology Diagnostic Oncology Group lactation , 16 (RDOG), 119 menopause , 18 Respiratory tract , 381 nutritional sensing and reproductive Rete ovarii , 285–286 function, 17–18 Rhabdomyoma , 468 ovulation , 13–14 Rhabdomyosarcoma , 468 pre-antral/gonadotrophin-independent phase , 7 pregnancy and lactation , 16 primary follicle , 7–9 primary pre-antral follicle , 7 S primordial follicle , 7, 9 Salpingitis isthmica nodosa , 399–400 secondary follicle , 9–11 Sarcoidosis , 48 functional disorders Sarcoma-like mural nodules (SLMN), 232–233 endometriosis , 20–21 Schistosomiasis , 47 PCOS , 19–20 SCST. See Sex cord-stromal tumors (SCST) POF , 18–19 Secondary follicle , 9–11 Placental alkaline phosphatase (PLAP) , 172, 314 Serous borderline tumors (SBT) , 69–70, 150, PMP. See Pseudomyxoma peritonei (PMP) 152, 153 Polycystic ovary syndrome (PCOS) Serous carcinoma abnormal steroidal milieu , 19 high-grade carcinoma GnRH pulsatility , 20 behavior , 183–184 hypothalamicpituitary-ovarian axis , 20 molecular events , 182–183 multiple follicular cysts , 19 origin , 184–185 nonneoplastic disorders postulated developmental pathways , 182, 183 clinical features , 37 low-grade carcinoma differential diagnosis , 37 behavior , 183–184 endocrine disorder , 36 molecular events , 182–183 ESHRE/ASRM workshop , 36 origin , 185 histopathological fi ndings , 37 postulated developmental pathways , 182, 183 518 Index

Serous carcinomas Sertoli–stromal tumors brisk mitotic activity , 412, 413 Leydig cells (see Sertoli-Leydig cell tumors) grade 3 nuclear features , 412, 413 sertoli cell tumors , 346 muscularis invasion , 412, 413 Sex cord-stromal tumors (SCST) stage Ia-0 , 412 fi broma stage Ia-2 , 412 differential diagnosis , 336 Serous tubal intraepithelial carcinoma epidemiology and clinical correlation , 334 nonneoplastic epithelium , 413, 414 macroscopy , 334–335 normal epithelium , 413, 414 microscopy , 335–336 P53 immunostain , 413, 415 frozen section , 144 Serous tubal intraepithelial carcinoma GCT (see Granulosa cell tumors (GCT)) (STIC), 73, 184 genetics , 346–347 Serous tumors gynandroblastoma , 347 benign tumors Leydig cell tumors , 348 cystically dilated follicles , 200 sertoli–stromal tumors (see Sertoli–stromal tumors) endometriosis , 200 sex cord tumors with annular tubules , 346 fi brotic, cystic, and papillar growth , 198, 199 steroid cell tumors NOS , 347–349 high-grade , 199 stromal luteomas , 347–348 hydrosalpinx , 200 surgery , 68–69 polycystic ovarian disease , 200 thecoma borderline tumors cellular and mitotically active thecomas , 337 cystadenoma , 205 luteinized thecomas , 337 epithelial cells , 201, 202 malignant thecomas , 338 hierarchical papillary growth , 200, 201 microcystic stromal tumor , 339–341 high-grade carcinoma , 205, 209 sclerosing stromal tumor , 338 ink and microscopic examination , 201 signet-ring stromal tumor , 338–339 low-grade carcinoma , 205, 208 Sex cord tumors with annular tubules (SCTAT) , 346 lymph node involvement , 205, 207 Signet ring carcinomas mesothelial lesions , 207 cystic areas , 362, 363 microinvasion , 203 eosinophilic cytoplasm , 360, 361 micropapillary architecture , 202–203 SLMN. See Sarcoma-like mural nodules (SLMN) peritoneal implants , 204–206 Small cell carcinomas, hypercalcemia type retiform sertoli-Leydig cell tumor , 207 (SmCCHT) routine hematoxylin and eosin eosinophilic , 274, 275 staining , 201, 202 follicle-like cystic areas , 274, 275 struma ovarii , 207 immunohistochemical profi le , 275 terminology , 200 juvenile granulosa cell tumor , 275 high-grade carcinomas mucinous element , 274–275 cystic, solid and papillary areas , 209, 210 prognosis , 276 endometrioid carcinoma , 211 TTF1 positive , 275–276 immunohistochemistry , 211–212 Small cell carcinomas, pulmonary type low-grade/borderline tumor , 211 (SmCCPT), 276–277 malignant mesothelioma , 211 Solitary fi brous tumor , 450–452 metastatic carcinoma , 211 Specimen cut-up primary site assignment , 210, 211 appendix , 493–494 transitional cell carcinoma , 210 bilateral salpingo-oophorectomies , 485 low-grade carcinomas , 208–209 clinical information and patient consent , 482 molecular pathology , 197–198 fallopian tubes , 490–492 Sertoli–Leydig cell tumors (SLCTs) , 145, 228 hysterectomy specimens , 488–489 differential diagnosis , 345–346 interval debulking surgery , 495 epidemiology and clinical correlates , 341 lymph nodes , 493 immunohistochemistry , 344–345 macroscopic dissection , 483–484 macroscopy , 341–342 omentum , 492–493 microscopy ovarian cysts, fragments , 485 intermediately and poorly differentiated ovarian masses tumor , 343, 344 borderline serous tumors , 487 retiform tumor , 344 contralateral ovary , 488 well-differentiated tumor , 342 hemorrhage/necrosis , 487 Index 519

macroscopic examination , 485 sebaceous tumor , 303 sampling , 487 squamous cell carcinoma , 301–302 ovary biopsies , 484–485 thyroid tumor group , 299–300 peritoneal biopsies , 493 Theca-lutein hyperplasia , 40–41 small intestine and large intestine , 494–495 Thecoma spleen , 495 cellular and mitotically active thecomas , 337 tissue preparation preparation , 482–483 luteinized thecomas , 337 Squamous cell tumors , 282–283 malignant thecomas , 338 Squamous metaplasia , 404 microcystic stromal tumor , 339–341 Stromal hyperplasia/hyperthecosis sclerosing stromal tumor , 338 clinical features , 38, 39 signet-ring stromal tumor , 338–339 cortex and medulla , 37 Transitional cell carcinomas (TCCs) defi nition , 38 benign tumors , 279 differential diagnosis , 38, 39 borderline tumors , 279 histopathological fi ndings , 38, 39 differential diagnoses , 281 luteinized cells , 38 immunohistochemical profi le , 281 postmenopasual endometrial macroscopic features , 278 adenocarcinoma, 37 malignant tumors , 279–280 “Swiss roll” approach , 137 mucinous metaplasia , 278 Synchronous endometrial tumors osseous metaplasia , 278 clinical features , 384 papilloma-like features , 280 differential diagnosis , 385, 386 squamous metaplasia , 278 and HNPCC , 388–389 tubal-mesothelial junction , 277–278 molecular changes , 386–387 Transitional cell metaplasia , 403, 405 pathology , 384–385 Trebananib , 94–95 prognostic factors , 387–388 Turner syndrome , 19 young women , 388 Synovial sarcoma , 452–453 U Ultrasound T adnexal mass , 114 TCC. See Transitional cell carcinomas (TCCs) challenge , 110 Teratomas , 282–283 guided core biopsy immature teratoma advantages , 122 clinical features , 295 omental biopsy , 122–123 gliomatosis peritonei , 298, 299 transvaginal biopsy , 123, 124 grading , 296–297 imaging pathway , 110, 113 GTS , 298 malignancy metastatic , 110, 111 macroscopic features , 295 malignant cysts microscopic appearance , 295, 296 ascites , 113 prognosis , 297–298 blood fl ow , 113 MCT calcifi cation , 113 clinical features , 292 confounding features , 113–114 cytogenetics , 294 microbubble agents , 113 epidermoid cyst , 293 mixed cystic and solid masses , 113 immature neural tissue , 294–296 papillarities , 113 macroscopic appearance , 292–293 size , 111 mature solid teratoma , 294–295 wall thickness , 113 microscopic appearance , 293, 294 Meig’s syndrome , 112 prognosis , 293–294 transabdominal route , 111 monodermal teratomas transvaginal route , 111 biphasic and triphasic teratoma , 298 Undifferentiated carcinomas carcinoids , 300–301 frozen section , 277 central nervous system tumor , 301 immunohistochemistry , 274 malignant melanomas , 303 low-grade endometrioid carcinoma , 276 pituitary-type tumor , 303 neuroendocrine type , 277 retinal anlage tumor , 303 non-small cell carcinoma , 277 sarcomas , 302–303 NOS , 277 520 Index

Undifferentiated carcinomas (cont .) X SmCCHT Xanthogranulomatous oophoritis , 46 eosinophilic , 274, 275 follicle-like cystic areas , 274, 275 immunohistochemical proﬁ le , 275 juvenile granulosa cell tumor , 275 Y mucinous element , 274–275 Yolksac tumor (YST) , 163 prognosis , 276 AFP production , 307, 309 TTF1 positive , 275–276 characteristic feature , 306 SmCCPT , 276–277 clinical features , 308 US National Comprehensive Cancer Network (NCCCN) differential diagnosis , 309–310 Guidelines, 81 immunocytochemistry , 314, 315 macroscopic appearance , 309 prognosis and treatment , 310 W Schiller-Duval sinus , 306–307 Well-differentiated papillary mesothelioma (WDPM), 442–443