Pathology and Classification of Ovarian Tumors - Cursuri Medicina

2638 CANCER Supplement May 15, 2003 / Volume 97 / Number 10tive years. In most cases, surgical excision is curative.Rupture of the tumor may result in peritoneal implants.In rare cases, mature cystic teratomas may undergomalignant transformation, most often in postmenopausalpatients, that most commonly results insquamous cell carcinoma. Other malignant tumortypes, including carcinoid, thyroid carcinoma, basalcell carcinoma, intestinal adenocarcinoma, melanoma,leiomyosarcoma, and chondrosarcoma, may arise.Prognosis is generally unfavorable; reported 5-yearsurvival rate are only 15–31%. Better prognosis is observedif the malignant component is squamous cellcarcinoma and if the tumor is confined to the ovary.Immature teratomas contain primitive, immature,or embryonal structures in addition to well-developedor mature tissues. These tumors usually are unilateral,large, and predominantly solid. Immature cystic teratomasare rare and most frequently occur in the firsttwo decades of life. Immature teratomas exhibit malignantbehavior, grow rapidly, spread by implantationthroughout the peritoneal cavity, and metastasize primarilythrough the lymphatic system. Excision usuallyis followed by local recurrence, but combination chemotherapyoften leads to permanent remission.CLASSIFICATION OF OVARIAN TUMORSThe primary purpose of a tumor classification systemis to provide a standardized, reproducible communicationtool that reflects the variations in the naturalhistory of the disease and can be readily used byeveryone involved in the management of cancer. Developmentof such a system for ovarian tumors is awork in progress. In the past, a number of approacheswere advanced, but all fell short of the stated goal.Some systems were purely clinical, based on the hormonaleffects of ovarian tumors; however, differentovarian tumors may give rise to similar hormonal effects,similar tumors may have different hormonaleffects, and hormonal products may be derived insome cases from nonneoplastic (e.g., stromal) sourcesrather than from the tumor itself. Systems based onthe gross appearance of the tumors (solid or cystic)also were inadequate. A classification system based ontumor histogenesis would be a logical alternative, althoughthe histogenesis of some ovarian tumors iscontroversial.A significant stride in the direction of a histogenesis-basedclassification system was made in 1973with the publication of the World Health Organization(WHO) Classification of Ovarian Tumors. 14 This classificationsystem was updated in 1999 10 and was approvedby the International Society of GynecologicalPathologists (Table 1). A summarized version of theTABLE 1WHO Histologic Classification of Ovarian Tumors a1 Surface epithelial-stromal tumors1.1 Serous tumors: benign, borderline, malignant1.2 Mucinous tumors, endocervical-like and intestinal-type: benign, borderline,malignant1.3 Endometrioid tumors: benign, borderline, malignant, epithelial-stromal andstromal1.4 Clear cell tumors: benign, borderline, malignant1.5 Transitional cell tumors: Brenner tumor, Brenner tumor of borderlinemalignancy, malignant Brenner tumor, transitional cell carcinoma (non-Brenner type)1.6 Squamous cell tumors1.7 Mixed epithelial tumors (specify components): benign, borderline, malignant1.8 Undifferentiated carcinoma2 Sex cord-stromal tumors2.1 Granulosa-stromal cell tumors: granulosa cell tumors, thecoma-fibromagroup2.2 Sertoli-stromal cell tumors, androblastomas: well-differentiated, Sertoli-Leydigcell tumor of intermediate differentiation, Sertoli-Leydig cell tumor poorlydifferentiated (sarcomatoid), retiform2.3 Sex cord tumor with annular tubules2.4 Gynandroblastoma2.5 Unclassified2.6 Steroid (lipid) cell tumors: stromal luteoma, Leydig cell tumor, unclassified3 Germ cell tumors3.1 Dysgerminoma: variant-with syncytiotrophoblast cells3.2 Yolk sac tumors (endodermal sinus tumors): polyvesicular vitelline tumor,hepatoid, glandular3.3 Embryonal carcinoma3.4 Polyembryoma3.5 Choriocarcinoma3.6 Teratomas: immature, mature, monodermal, mixed germ cell4 Gonadoblastoma5 Germ cell sex cord-stromal tumor of nongonadoblastoma type6 Tumors of rete ovarii7 Mesothelial tumors8 Tumors of uncertain origin and miscellaneous tumors9 Gestational trophoblastic diseases10 Soft tissue tumors not specific to ovary11 Malignant lymphomas, leukemias, and plasmacytomas12 Unclassified tumors13 Secondary (metastatic) tumors14 Tumorlike lesionsWHO: World Health Organization.a Source: Scully R, Sobin L. Histological typing of ovarian tumours, volume 9. New York: Springer Berlin,1999. 10WHO classification system was proposed in 1998 bythe International Agency for Research on Cancer 15 foruse in comparative studies; this system was used toclassify histologic types of ovarian cancer in the currentmonograph (Table 2). Two coding systems, theWHO International Classification of Diseases for Oncology16 and the College of American Pathologists SystematizedNomenclature of Medicine, 17 are commonlyused to code the histology/morphology oftumors.

Ovarian Tumor Pathology and Classification/Chen et al. 2639TABLE 2IARC Histologic Groups of Ovarian Tumors aHistologic typeWHO ICD-O morphology code1. Carcinoma 8010–8570, b 9014–9015, 91101.1 Serous carcinoma c 8441–8462, 90141.2 Mucinous carcinoma c 8470–8490, 90151.3 Endometrioid carcinoma 8380–8381, 8560, 85701.4 Clear cell carcinoma 8310–8313, 91101.5 Adenocarcinoma NOS 8140–8190, 8211–8231, 8260, 84401.6 Other specified carcinomas1.7 Unspecified carcinoma 8010–80342. Sex cord-stromal tumors 8590–86713. Germ cell tumors 8240–8245, 9060–91024. Other specified cancers (includingmalignant Brenner tumor,müllerian mixed tumor, andcarcinosarcoma)5. Unspecified cancer 8000–8004IARC: International Agency for Research on Cancer; WHO: World Health Organization; ICD-O: InternationalClassification of Diseases for Oncology; NOS: not otherwise specified.a Source: Parkin DM, Shanmugaratnam K, Sobin L, Ferlay J, Whelan SL. Histological groups forcomparative studies, volume 31. IARC technical report. Lyon: International Agency for Research onCancer, 1998. 15b Excludes 8240 – 8245.c Includes tumors of borderline malignancy (low malignant potential). Unlike borderline tumors ofother types, borderline tumors of serous and mucinous types are included with carcinomas by ICD-O.This approach remains to be validated fully.STAGING OF OVARIAN CANCERThe extent of tumoral spread, also known as stage ofdisease, at diagnosis is typically established by radiologicevaluation and surgical excision. Surgical managementmay include debulking of the tumor resectionof one or both ovaries, fallopian tubes, anduterus, as well as sampling of lymph nodes, liver, andsuspicious sites within the abdomen. Staging of ovariansurface epithelial-stromal tumors is performed accordingto the TNM system, 18 the set of guidelinesestablished by the American Joint Committee on Cancer,which is comparable to an alternative stagingsystem approved by the International Federation ofGynecology and Obstetrics (FIGO) (Table 3). 19HISTOLOGIC GRADING AND PROGNOSTIC FACTORSMicroscopic examination is critical for predicting tumorbehavior and deciding the best therapeutic approach.Such examination includes the assessment ofspecific histologic type and extent of disease and thegrading of tumor differentiation (i.e., the extent towhich the tumor resembles the normal tissue). Tumorsare graded as well-differentiated (G1), moderatelydifferentiated (G2), poorly differentiated (G3), orundifferentiated (G4). As discussed above, surface epithelial-stromaltumors also can be classified as borderlinemalignancy (GB). Attempts to identify prognosticallyrelevant pathologic features in ovariancancers are hindered by the diversity of tumors thatare encountered. Most reported prognostic informationaddresses surface epithelial-stromal tumors.The two most important prognostic factors forsurface epithelial-stromal tumors are tumor stage andthe presence or absence of residual disease after treatmentintervention. 18 Specific histologic typing andgrading may have prognostic significance as well;however, the independent contribution of each ofthese factors after adjusting for tumor stage has notbeen well established. Assessment of their contributionis hampered by interobserver variability amongpathologists, lack of standardization of gradingschemes, and differences in treatment among publishedseries. Most grading schemes analyze architecturaland cellular characteristics of tumors and delineatethree or four groups with increasing risks ofaggressive behavior. Unfortunately, it is difficult toapply a single grading system consistently to all histologictypes of ovarian cancer. Recently, modifiedgrading systems that can be applied to all epithelialovarian cancers have been proposed. 20,21 Early confirmatorystudies are encouraging, as they indicate thathistologic grading may finally establish itself as animportant prognostic factor for patients with ovariancarcinoma. 22The grading of sex cord-stromal tumors has beenfrustrating. This is not unexpected, given that the histogenesisof several subtypes still is unclear. For somesubtypes, definitive histologic criteria for making thedistinction between benign and malignant tumors arelacking. Histologic features that relate to the potentialfor aggressive behavior appear to be subtype-specific;for example, all granulosa cell tumors are consideredto have malignant potential. Attempts to grade thesetumors using nuclear characteristics or mitotic activitycounts have produced inconsistent results, whereastumor size and stage appear to be more reproducibleprognostic factors. Most stromal tumors are benign.The uncommon malignant variant, fibrosarcoma, isassociated with an aggressive clinical course, but itlacks an established grading system. The steroid celltumors (luteoma and Leydig cell tumor) also are difficultto classify as benign or malignant based onmicroscopic features alone. Pathologic features thatare reported to be correlated with malignant behaviorinclude large size, high mitotic rate, necrosis, hemorrhage,and prominent nuclear atypia. Other sex cordtumors (Sertoli cell tumor, Sertoli-Leydig cell tumor,sex cord tumor with annular tubules, and gynandroblastoma)have varied clinical behaviors that showsome correlation with specific differentiation criteria

2640 CANCER Supplement May 15, 2003 / Volume 97 / Number 10TABLE 3Ovarian Surface Epithelial-Stromal Tumor Staging Protocols: AJCC TNM System a and FIGO Staging System bAJCC FIGO DescriptionTXPrimary tumor cannot be assessed.T0No evidence of primary tumor.T1 I Tumor limited to ovaries (one or both).T1a IA Tumor limited to one ovary; capsule intact, no tumor on ovarian surface. Nomalignant cells in ascites c or peritoneal washings.T1b IB Tumor limited to both ovaries; capsules intact, no tumor on ovarian surface. Nomalignant cells in ascites or peritoneal washings.T1c IC Tumor limited to one or both ovaries, with any of the following: capsule ruptured,tumor on ovarian surface, malignant cells in ascites or peritoneal washings.T2 II Tumor involves one or both ovaries with pelvic extension.T2a IIA Extension and/or implants on uterus and/or tube(s). No malignant cells in ascites orperitoneal washings.T2b IIB Extension to other pelvic tissues. No malignant cells in ascites or peritonealwashings.T2c IIC Pelvic extension (2a/IIA or 2b/IIB) with malignant cells in ascites or peritonealwashings.T3 and/or N1 III Tumor involves one or both ovaries, with microscopically confirmed peritonealmetastasis outside the pelvis and/or regional lymph node metastasis. dT3a IIIA Microscopic peritoneal metastasis beyond pelvis.T3b IIIB Macroscopic peritoneal metastasis (2 cm or less in greatest dimension) beyondpelvis.T3c and/or N1 IIIC Peritoneal metastasis (more than 2 cm in greatest dimension) beyond pelvis and/orregional lymph node metastasis.M1 IV Distant metastasis (excludes peritoneal metastasis). eAJCC: American Joint Committee on Cancer, FIGO: International federation of Gynecology and Obstetrics.a Source: Fleming ID, Cooper JS, Henson DE, Hutter RVP, Kennedy BJ. American Joint Committee on Cancer (AJCC) cancer staging manual. Philadelphia:Lippincott-Raven, 1997. 18b Source: Heintz AP, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. J Epidemiol Biostat. 2001;6:107–138. 19c Ascites is the accumulation of excessive fluid within the abdominal (peritoneal) cavity. The presence of nonmalignant ascites is not classified. The presence ofascites does not affect staging unless malignant cells are present.d Lymph nodes located in the pelvis or in the back of the abdomen on either side of the aorta (para-aortic). Liver metastases confined to the capsule are T3/StageIII. Liver parenchymal metastases are M1/Stage IV.e Pleural effusion must have positive cytology for M1/Stage IV malignancy.that are well defined in the gynecologic pathologyliterature. 8Stage of disease at diagnosis is the most importantprognostic factor for germ cell tumors. Determinationof the specific histologic subtype has prognostic relevance,but grading within or across these categoriesgenerally is not performed. One exception is the immatureteratoma, for which histologic grading is basedon the amount of immature tissue (usually neuroectodermal)that is present. 11EXTRAOVARIAN PERITONEAL CARCINOMABeginning in the 1940s, several reports described theoccurrence of an apparent ovarian cancer in womenlong after removal of their ovaries. The cause washotly debated, but the microscopic resemblance of themalignancy to surface epithelial ovarian tumors (serous,mucinous, and endometrioid subtypes) wasstriking. Women with the disease experienced a clinicalcourse similar to that of women with primaryovarian cancer. Some investigators believed that thiswas a latent manifestation of metastatic ovarian cancerthat preceded removal of the ovaries. Otherspointed to malignant transformation of ectopic endometrialtissue (e.g., endometriosis) as the source ofthese cancers, while another hypothesis was that thecoelomic epithelium was shed throughout the peritoneumas it traveled along its migratory course throughthe embryonic female.Whatever the cause, it is clear that a small proportion( 5%) of cancers that microscopically appearto be ovarian actually do not originate in the ovary andinstead arise from the peritoneum. The morphologicsubtypes of extraovarian peritoneal carcinomas(EOPC), now commonly referred to as primary peritonealcarcinomas (PPC), are limited to the more commonsubtypes of surface epithelial malignancies (serous,mucinous, and endometrioid), and the