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Background
These are uncommon ovarian tumors accounting for less than 5% of all ovarian neoplasms and 15% of ovarian carcinomas. Its name is derived from the histologic similarity to endometrial carcinomas of the uterus. About 5-10% of cases are associated with endometriosis. In addtion, 10% of patients have evidence of ovarian or ovarian-breast cancer syndrome. These patients have mutations in the BRCA1 genes.
One potentially confusing association is 20% of these tumors may be associated with an endometrial adenocarcinoma of the uterus. In the majority of these cases, both tumors usually represent synchronous or metachronous events. However, findings that may favor a primary endometrial adenocarcinoma of the uterus metastasizing to the ovary include deep myometrial invasion of the primary uterine tumor and bilateral involvement of the ovaries with capsular involvement. In addition, the presence of endometriosis in the ovary or atypical endometrial hyperplasia in the uterus is also helpful in favoring one organ over another as the primary site.
OUTLINE
TUMOR TYPE GROSS FEATURES MICROSCOPIC FEATURES Endometrioid adenofibromas/cystadenofibromas Usually solid with small cysts Tubular glands histologically similar to endometrium, in different phases Endometrioid adenofibromas of borderline malignancy Usually solid with small cysts Atypical glandular epithelium with appearance of low-grade adenocarcinoma but does not invade the stroma Endometrioid adenocarcinoma Solid or cystic Similar to endometrial adenocarcinoma of the uterus with invasion
Squamous metaplasia in 1/3 of cases
May have mucin secretion, usually in surface of the cells
SYNCHRONOUS TUMORS
- Synchronous endometrioid carcinomas of the uterine corpus and ovary: Alterations in the beta-catenin (CTNNB1) pathway are associated with independent primary tumors and favorable prognosis.
Irving JA, Catasus L, Gallardo A, Bussaglia E, Romero M, Matias-Guiu X, Prat J.
Hum Pathol. 2005 Jun;36(6):605-19 Abstract quote.
Summary Diagnosis of synchronous endometrioid carcinomas of the uterine corpus and ovary as either separate independent primary or as metastatic tumors requires careful consideration of a number of gross and histological features. Although such assessment is often sufficient, recent evidence has suggested that molecular analysis may facilitate the diagnosis in problematic cases. Furthermore, as independent synchronous tumors limited to the uterus and ovary are generally associated with favorable outcome, determination of genetic alterations associated with this group of neoplasms may indicate molecular markers of less aggressive behavior.
We examined 12 cases of synchronous carcinomas of the uterus and ovary, correlating conventional gross and histological parameters with molecular genetic alterations common to single endometrioid carcinomas occurring in these sites.
We identified a frequency of molecular alterations in both independent and metastatic tumors, including microsatellite instability (uterine tumors, 50% and 67%, respectively; ovarian tumors, 33% and 67%) and PTEN mutations (uterine tumors, 38% and 100%; ovarian tumors, 33% and 83%) that is higher than that observed in single sporadic tumors. Loss of heterozygosity for chromosome 17p and 10q was also frequently observed. Nuclear immunoreactivities for beta -catenin and CTNNB1 mutations were restricted to independent uterine and ovarian tumors and were absent in all of the metastatic tumors, providing direct evidence for a divergence of molecular oncogenetic mechanisms in the subset of synchronous endometrioid carcinomas.
Furthermore, our data show that molecular genetic classification of synchronous independent versus metastatic tumors based on beta -catenin expression/mutation correlates with clinical outcome.Genetics of synchronous uterine and ovarian endometrioid carcinoma: combined analyses of loss of heterozygosity, PTEN mutation, and microsatellite instability.
Fujii H, Matsumoto T, Yoshida M, Furugen Y, Takagaki T, Iwabuchi K, Nakata Y, Takagi Y, Moriya T, Ohtsuji N, Ohtsuji M, Hirose S, Shirai T.
Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Hum Pathol 2002 Apr;33(4):421-8 Abstract quote Synchronous development of carcinomas in the endometrium and ovaries is a fairly common phenomenon, but distinction of a single clonal tumor with metastasis from 2 independent primary tumors may present diagnostic problems.
To determine clonality and the occurrence of progression, we microdissected multiple foci from 17 cases of synchronous endometrioid carcinomas and studied loss of heterozygosity (LOH), microsatellite instability (MI), and PTEN mutations. In 14 of the 17 cases, genetic alterations were either homogeneous or found in only some of the foci. LOH was detected for 10q (4 cases), 17p (2 cases), and 2p, 5q, 6q, 9p, 11q, 13q, and 16q (1 case each). Four cases had the MI phenotype with discordant MI patterns between both tumor sites, thus indicating a biclonal or triple clonal process. In 3 of 6 cases with PTEN mutations, identical mutations in both tumor sites indicated a single clonal neoplasm. Altogether, 14 synchronous tumors were genetically diagnosed as follows: single clonal tumor, characterized by concordant genetic alterations in both tumor sites, including identical LOH, identical PTEN mutations, and/or identical sporadic allelic instability patterns (4 cases); single clonal tumor with genetic progression, homogeneous LOH or identical PTEN mutations in both tumor sites and progressive LOH in ovarian metastatic foci (2 cases); and double (7 cases) or triple clonal tumors (1 case), determined by discordant PTEN mutations, heterogeneous LOH, and/or discordant MI patterns. Thus, 35% of synchronous tumors were monoclonal, 47% were polyclonal, and 18% were undetermined.
The favorable prognosis of synchronous endometrioid carcinomas may be due to the occurrence of PTEN mutations in both independent and metastatic tumors, the MI-positive independent primary tumors, and the low frequency of LOH.
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HISTOPATHOLOGIC
VARIANTSDESCRIPTION
Ovarian endometrioid tumors of low malignant potential: a clinicopathologic study of 30 cases with comparison to well-differentiated endometrioid adenocarcinoma.
Roth LM, Emerson RE, Ulbright TM.
Department of Pathology, Indiana University School of Medicine and Hospital, Indianapolis, 46202-5280, USA.
Am J Surg Pathol. 2003 Sep;27(9):1253-9. Abstract quote
Thirty cases of ovarian endometrioid tumor of low malignant potential (ETLMP) were studied and compared with 32 cases of well-differentiated endometrioid adenocarcinoma. ETLMP was distinguished from well-differentiated endometrioid adenocarcinoma by the absence of destructive stromal invasion, glandular confluence, or stromal disappearance. Intraepithelial carcinoma in a low malignant potential tumor was defined as areas showing grade 3 nuclei, sometimes associated with an intracystic villoglandular or cribriform pattern.Microinvasion in an ETLMP was defined as one or more areas of invasion with an area of < or =10 mm2. Because a cribriform pattern may be seen in purely intraglandular proliferations, the latter was not taken as evidence of invasion. The patients with ETLMP ranged from 28 to 86 years of age (mean 54.9 years), and only one patient (3%) had other than stage I disease at presentation. The patients with well-differentiated endometrioid carcinoma ranged from 26 to 87 years of age (mean 51.1 years), and three patients (9%) had stage II disease at presentation. An adenofibromatous pattern was present in 47% of cases of ETLMP and squamous differentiation in 47%; intraepithelial carcinoma occurred in 7% of cases and stromal microinvasion in 7%. None of these findings appeared to influence the prognosis because all patients with ETLMP were free of recurrent disease or metastasis on follow-up, whereas 20% of patients with well-differentiated endometrioid adenocarcinoma followed for >6 months developed recurrent disease.
Thus, the prognosis of ETLMP, when defined by the above criteria, is favorable and is superior to that of well-differentiated endometrioid adenocarcinoma.A Clinicopathologic Analysis of Atypical Proliferative (Borderline) Tumors and Well-Differentiated Endometrioid Adenocarcinomas of the Ovary
Karen A. Bell, M.D.; Robert J. Kurman, M.D.
From the Division of Gynecologic Pathology, Department of Pathology (K.A.B., R.J.K.) and the Department of Gynecology and Obstetrics (R.J.K.), The Johns Hopkins Hospital, Baltimore, Maryland, U.S.A.
Am J Surg Pathol 2000;24:1465-1479 Abstract quote
Atypical proliferative (borderline) endometrioid tumors (APTs) and well-differentiated endometrioid carcinomas of the ovary constitute a spectrum of morphologically diverse proliferative tumors. There is currently no agreement on the criteria for distinguishing them.
We report the clinicopathologic features of 56 proliferative endometrioid tumors focusing on the criteria for invasion, the clinical significance of microinvasion and cytologic atypia, and prognosis.
Endometriomas, adenofibromas, adenosarcomas and moderately to poorly differentiated carcinomas were excluded, as were patients with concurrent endometrioid carcinoma of the endometrium. The tumors were classified as atypical proliferative tumor (APT) (33 tumors), APT with intraepithelial carcinoma (high-grade cytology in a tumor lacking stromal invasion) (three tumors), APT with microinvasion (invasion <5 mm) (five tumors), and invasive carcinoma (invasion 5 mm) (15 tumors).
All tumors were confined to the ovary (stage I). In 50 patients, the tumor involved one ovary, and in three patients, the tumors were bilateral. The predominant growth pattern was adenofibromatous in 29 tumors and glandular or papillary in 27 tumors. In 8 (24%) of 41 APTs, areas of benign adenofibroma were identified, and in 13 (87%) of 15 carcinomas, areas of associated APT were identified. Stromal invasion was manifested by confluent glandular growth in all 15 invasive carcinomas and all tumors with microinvasion. Destructive infiltrative growth was also present in 2 (13%) of 15 carcinomas.
Confluent glandular growth was the most common manifestation of stromal invasion and therefore served as the best criterion for the diagnosis of carcinoma. Squamous differentiation was observed in 24 tumors, and mucinous differentiation was seen in 20 tumors and was most often seen in APTs. Endometriosis was present in 14 patients with APTs and one patient with carcinoma. Four patients had hyperplasia or atypical hyperplasia of the endometrium. One patient with an APT had a concurrent peritoneal serous neoplasm. Twenty-one patients had available clinical follow-up. Twenty (95%) of 21 patients, including six with invasive carcinoma, two with microinvasion, one with intraepithelial carcinoma, and 11 with APT were alive with no evidence of disease with a mean follow-up of 47 months. One patient with carcinoma had recurrent tumor after 46 months and was alive 40 months after resection of the recurrent tumor. In this large series of proliferative endometrioid tumors, all were stage I and only one patient had a recurrence. Most carcinomas contained evidence of a precursor APT, and in some APTs, an associated benign adenofibroma was identified. Microinvasion or intraepithelial carcinoma occurred in 19% of APTs. This finding likely reflects the various stages of endometrioid carcinogenesis in the ovary.
For clinical management, we suggest that these tumors be divided into two categories—APTs and well-differentiated carcinoma—because based on the available data, cytologic atypia and microinvasion appear not to affect the prognosis.
CLEAR CELL
*Departments of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX †The James Holer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
The presence of clear cells in genital tract neoplasms often reflexly prompts the diagnosis of a clear cell tumor but clear cells may be seen in many other neoplasms. In one such, those of endometrioid type, they are well known and generally readily characterized when they have the secretory pattern that recapitulates the well-known morphology of early secretory endometrium.
In this report, we describe various clear cell morphologies, some possibly related to the secretory variant, but others not, and all potentially the source of significant diagnostic difficulty.
We reviewed 21 endometrioid tumors that occurred in patients from 27 to 88 (median 64) years. Most had an adnexal mass (13) or abdominal swelling (4), but 4 presented with vaginal bleeding. One tumor formed a cystic mass in the pelvis, 1 tumor involved the right fallopian tube, 1 the endometrium, and 18 the ovary. One tumor was a cystadenofibroma, 1 a borderline tumor, and 19 were adenocarcinomas. Twelve patients had stage I, 4 stage III, 1 stage IV, and 4 were unstaged. One patient who had a previous hysterectomy and salpingo-oophorectomy underwent resection of a cystic pelvic mass; others all were treated with abdominal hysterectomy and salpingo-oophorectomy. All the neoplasms had the typical architecture of endometrioid tumors but differed markedly in their cytoplasmic features. In 18 of the tumors at least one-third of the cells had clear cytoplasm and 3 had only clear cells. The clear cytoplasm varied from foamy to empty and the nuclei had a variable location, basilar, central, and apical. The clear cells were associated with squamous differentiation in only 1 case in which the change appeared hydropic.
By immunohistocytochemistry, the clear cells were focally positive for epithelial markers in most cases but in some cases one or more of these immunostains were negative. Tubulocystic, solid, and papillary patterns of clear cell carcinoma were absent. Periodic acid-Schiff was focally positive for glycogen in the cytoplasm in 5 cases. Although a few cases had a focal slight resemblance to secretory endometrioid carcinoma most did not and the orderly morphology of classic secretory carcinoma was noteworthy for its absence. The nature of the cytoplasmic clarity is usually uncertain but is likely variably owing to lipid, mucin or glycogen accumulation, or is a hydropic change. The distinction from clear cell carcinoma depends on awareness of this unusual variant of endometrioid neoplasia and a lack of the distinctive patterns of clear cell carcinoma; at this time, special studies, including immunohistochemistry, do not aid significantly although certainly negative reactions, such as for thyroglobulin protein (arguing against clear cell struma ovarii) may play a role in some differential diagnostic considerations.
There are prognostic and therapeutic implications in the distinction with clear cell carcinoma.SEX CORD STROMAL TUMOR-LIKE
Small glands and solid tubular structures resembling Sertoli cells
Adenofibromatous component, squamous differentiation, or mucin favors endometrioid carcinomaGRANULOSA CELL TUMOR-LIKE Epithelial islands and trabeculae with microfollicles and acini
- Granulosa cell tumor-like variant of endometrioid carcinoma of the ovary exhibiting nuclear clearing with biotin activity: a subtype showing close macroscopic, cytologic, and histologic similarity to adult granulosa cell tumor.
Fujibayashi M, Aiba M, Iizuka E, Igarashi A, Okamura M, Takagi K.
Department of Surgical Pathology, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
Arch Pathol Lab Med. 2005 Oct;129(10):1288-94. Abstract quote
CONTEXT: The sex cord-like variant of endometrioid carcinoma of the ovary shows many similarities to Sertoli-Leydig cell tumor and granulosa cell tumor. However, few cases of the granulosa cell tumor-like variant have been reported, suggesting this tumor might often be hidden under the diagnosis of granulosa cell tumor.
OBJECTIVE: To investigate the similarities and differences between the granulosa cell tumor-like variant of endometrioid carcinoma and granulosa cell tumor of the ovary and to evaluate a newly observed feature, namely, nuclear clearing (or optically clear nuclei), in this variant tumor.
DESIGN: A comparative macroscopic, cytologic, histopathologic, and immunohistochemical study in specimens obtained from the following patients: 1 patient with granulosa cell tumor-like variant of endometrioid carcinoma diagnosed by frozen section examination, 3 patients with granulosa cell tumor, and 6 patients with classic endometrioid carcinoma.
RESULTS: The granulosa cell tumor-like variant showed close macroscopic, cytologic, and microscopic similarities to granulosa cell tumor. However, the 2 tumors could be differentiated immunohistochemically. The former also showed intense staining for progesterone receptors and contained nonmorular nests that exhibited the so-called nuclear clearing with biotin activity.
CONCLUSION: Because the granulosa cell tumor-like variant is pathologically similar to granulosa cell tumor, showing only some dissimilarities to the latter, it can easily be misdiagnosed if the possibility of this variant is not kept in mind. Identification of the typical endometrioid histologic features or related lesions or immunohistochemistry may lead to a proper diagnosis. The observation of nuclear clearing with biotin activity in nonmorular nests suggests that this tumor has endometrioid epithelial characteristics.SERTOLI-LEYDIG CELL TUMOR-LIKE With luteinized stromal cells MALIGNANT MIXED MULLERIAN TUMOR-LIKE Spindle cells merging with epithelial cells YOLK SAC TUMOR-LIKE Areas of AFP positive yolk sac epithelial components. ADENOCARCINOMA, METASTATIC-LIKE Most difficult area, especially with metastatic colon adenocarcinomas
May need immunohistochemical stains
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES SERTOLI CELL TUMOR
*Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, Washington, DC daggerDivision of Gynecologic Pathology, Johns Hopkins Hospital, Baltimore, MD.
The main neoplasms in the differential diagnosis for primary ovarian tumors with a tubule-rich pattern are pure Sertoli cell tumor, endometrioid tumors (including borderline tumor, well-differentiated carcinoma, and the sertoliform variant of endometrioid carcinoma), and carcinoid tumor. Because traditional immunohistochemical markers [pan-cytokeratin (pan-CK), low molecular weight cytokeratin (CK8/18), epithelial membrane antigen (EMA), inhibin, calretinin, CD99, chromogranin, and synaptophysin] can occasionally have diagnostic limitations, the goal of this study was to determine whether or not any alternative markers [cytokeratin 7 (CK7), estrogen receptor (ER), progesterone receptor (PR), CD10, and CD56] have better diagnostic utility when compared with traditional markers for this differential diagnosis.
Immunohistochemical stains for alternative, as well as traditional, markers were performed on the following primary ovarian tumors: pure Sertoli cell tumor (n=40), endometrioid borderline tumor (n=38), sertoliform endometrioid carcinoma (n=13), well-differentiated endometrioid carcinoma (n=27), and carcinoid tumor (n=42). Extent and intensity of immunostaining were semiquantitatively scored. In addition, immunohistochemical composite scores (ICSs) in positive cases were calculated on the basis of the combination of extent and intensity scores. Cytokeratin 7 (CK7) was positive in 97% of endometrioid tumors, 13% of Sertoli cell tumors, and 24% of carcinoid tumors. The differences in the mean ICSs for endometrioid tumors versus Sertoli cell tumor or carcinoid tumor were statistically significant (P values ranging from <0.001 to 0.018). ER and PR were positive in 87% and 86% of endometrioid tumors, 8% and 13% of Sertoli cell tumors, and 2% each of carcinoid tumors, respectively. The differences in the mean ICSs for endometrioid tumors versus Sertoli cell tumor were statistically significant (P values ranging from <0.001 to 0.012). Among the epithelial markers, EMA seemed to be the most discriminatory but only slightly better than CK7, ER, or PR. Pan-CK and CK8/18 were not helpful. CD10 showed overlapping patterns of expression in all categories of tumors. Among the sex cord markers, CD10 was markedly less useful than inhibin or calretinin; CD99 was not discriminatory. CD56 showed overlapping patterns of expression in all categories of tumors. Among the neuroendocrine markers, CD56 was less useful than chromogranin or synaptophysin.
When traditional immunohistochemical markers are problematic for the differential diagnosis of ovarian Sertoli cell tumor versus endometrioid tumors versus carcinoid tumor, adding CK7, ER, and/or PR to a panel of markers can be helpful. Endometrioid tumors more frequently express CK7, ER, and PR and show a greater extent of immunostaining in contrast to Sertoli cell tumor and carcinoid tumor. Compared with traditional epithelial markers, CK7, ER, and PR are nearly as advantageous as EMA. Inhibin is the most discriminatory sex cord marker, and CD10 is not helpful in the differential diagnosis. Chromogranin and synaptophysin are excellent discriminatory markers for carcinoid tumor, and CD56 is neither sufficiently sensitive nor specific enough for this differential diagnosis to warrant its use in routine practice.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS HISTOPATHOLOGY
- Invasion patterns in stage I endometrioid and mucinous ovarian carcinomas: a clinicopathologic analysis emphasizing favorable outcomes in carcinomas without destructive stromal invasion and the occasional malignant course of carcinomas with limited destructive stromal invasion.
Chen S, Leitao MM, Tornos C, Soslow RA.
1Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Mod Pathol. 2005 Jul;18(7):903-11. Abstract quote
Stage I, low-grade endometrioid and mucinous ovarian carcinomas have an excellent prognosis. Published data have suggested that destructive stromal invasion, a relatively uncommon finding in these tumors, is a poor prognostic factor.
We investigated this by studying all FIGO stage I, grades 1 and 2 (of 3) endometrioid and mucinous ovarian carcinomas that were surgically staged at the Memorial Sloan-Kettering Cancer Center from 1980 to 2000. We undertook a careful review of all available slides using current diagnostic criteria and correlated histopathologic indices with clinical outcome data. Cases studied included 13 endometrioid ovarian carcinomas (stage IA, eight; stage IC, five) and six intestinal mucinous ovarian carcinomas (stage IA, three; stage IC, three).
All of the tumors contained areas of expansile invasion, greater than that acceptable for microinvasion, and were thus diagnosed as carcinomas instead of borderline tumors. Nevertheless, nearly all demonstrated borderline tumor (noninvasive) components. Six tumors contained at least one focus of destructive stromal invasion (two endometrioid and four mucinous ovarian carcinomas). Four additional cases showed a focus suspicious for but not diagnostic of destructive invasion ('indeterminate for destructive invasion') (two endometrioid and two mucinous ovarian carcinomas). Follow-up data were available for 17 patients. The median follow-up was 81 months (range, 9-161 months). In all, 14 patients were alive with no evidence of disease (expansile invasion alone, eight; destructive stromal invasion, four; and indeterminate for destructive invasion, two). Three patients died of their disease (destructive stromal invasion, two; and indeterminate for destructive invasion, one). The size, number, and nuclear grade of destructive stromal invasion foci did not appear to have an impact on survival in this relatively limited number of patients.
Outcome data in patients with stage I, low-grade endometrioid and mucinous ovarian carcinomas without destructive stromal invasion indicate that these tumors have a very limited malignant potential. The literature has not documented recurrences in this setting when the staging has been complete, the sampling adequate, and the cytologic features no more than grade 2, and metastasis to the ovary has been excluded. In contrast, carcinomas harboring even limited foci of destructive stromal invasion, although frequently cured surgically, can pursue a malignant clinical course.Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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