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Background
Ovarian cancer is a devastasting disease. In 2000, about 23,100 women in the United States will be diagnosed with this disease and about 14,000 women will die of the disease. Pathologists were responsible for identifying a borderline malignant form of ovarian cancer that has a much better prognosis than most ovarian cancers.
Recently, there has been excitement over the discovery of an ovarian cancer susceptibility gene. This gene, the BRCA1 gene, is also known as the breast/ovarian cancer susceptibility gene. About 5% of women with ovarian cancer carry germline mutations in this gene. In one study that examined tumors arising in women carrying germline mutations of this gene, the tumors were more likely to be high grade and nonmucinous. There was also an absence of borderline tumors suggesting that mutations in this gene do not play a role in the development of these tumors.
Adenofibromas, Borderline, and Cystadenosarcomas
BRCA1 and BRCA2 Genes (Hereditary Ovarian Cancer)
CA-125
Carcinoid Tumor
Clear Cell Carcinoma
Dysgerminoma
Endometrioid Tumors (Benign, Borderline, and Malignant)
Gonadoblastoma
Adult Granulosa Cell Tumor
Juvenile Granulosa Cell Tumor
Krukenberg Tumor-Gross Photo
Mucinous Tumors (Mucinous cystadenomas, Borderline Malignancy, Mucinous cystadenocarcinomas)
Polycystic Ovaries
Serous Tumors (Serous cystadenoma, Borderline Malignancy, Serous cystadenocarcinomas)
Sertoli-Leydig Cell Tumor
Steroid Cell Tumors, NOS
Teratoma (Includes Dermoid Cyst)
Transitional Cell Tumors (Brenner Tumors)
Yolk Sac TumorsOUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION ENDOMETRIOSIS Endometriosis-associated ovarian carcinoma (EAOC): an entity distinct from other ovarian carcinomas as suggested by a nested case-control study.
Erzen M, Rakar S, Klancar B, Syrjanen K.
Department of Obstetrics and Gynecology, University Medical Centre, 1105 Ljubljana, Slovenia.
Gynecol Oncol 2001 Oct;83(1):100-8 Abstract quote
OBJECTIVES: Endometriosis-associated ovarian carcinoma (EAOC) has recently received increasing attention due to its suggested biological behavior, distinctive from those of usual epithelial ovarian cancer. To elucidate some of the controversies on this intriguing entity, a series of patients with EAOC were compared to ovarian carcinoma cases without concomitant endometriosis.
METHODS: To control the confounding effect of age, a nested case-control study was designed, where all 58 EAOC patients (mean age 54.5 +/- 11.5 years) were nested with four perfectly age-matched non-EAOC patients (n = 232; mean age 54.7 +/- 11.7 years) selected among 425 women representing all FIGO stages of ovarian carcinomas without endometriosis. Pertinent clinical data and results of analysis of the tumors were subjected to statistical analyses using life-table, univariate (Kaplan-Meier), and multivariate (Cox) survival techniques to disclose dissimilarities in the key biological characteristics of these two groups as well as the independent prognostic predictors of disease outcome.
RESULTS: When compared in a case-control design with four perfectly age-matched non-EAOC patients nested to each EAOC case, the patients with EAOC proved to: (1) have a lower stage disease (both FIGO and TNM) (P = 0.000), (2) show a completely different distribution of histological subtypes (significant overpresentation of endometrioid and clear cell carcinomas) (P = 0.0001), (3) have predominantly lower grade lesions (P = 0.029), (4) be devoid of any primary residual tumor (P = 0.0001), and, most importantly (5) have demonstrated a significantly better overall survival (47/58 versus 126/232; OR 2.89, 95% CI 1.56-5.34, P = 0.0001). This better survival was evident (a) in all age groups and (b) for all histological subtypes, but (c) not explained by a better stage-specific survival in any FIGO stage. The two series also differed in their significant prognostic predictors in Kaplan-Meier and Cox analyses. In the EAOC group, the most significant (P = 0.0001) predictors of OS in univariate analysis were age, histological type, observation time for endometriosis, and distribution of endometriosis. In the non-EAOC group, such significant predictors were age, residual tumor, and type of therapy. In the multivariate (Cox) model, age and FIGO stage were the only two significant independent prognostic factors shared by these two series. In addition, histological type and type of therapy proved to be significant independent predictors in the non-EAOC series.
CONCLUSIONS: These data suggest that EAOC deviates from the non-EAOC in many of its key biological characteristics. The implications of these data in the diagnosis, treatment policy, and prognostication still require confirmation by further studies, however.
HORMONE REPLACEMENT THERAPY
PATHOGENESIS CHARACTERIZATION CHROMOSOMAL ABNORMALITIES Validation of tissue microarray technology in ovarian carcinoma.
Rosen DG, Huang X, Deavers MT, Malpica A, Silva EG, Liu J.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4095, USA.
Mod Pathol. 2004 Jul;17(7):790-7. Abstract quote
High-throughput tissue microarray allows many clinical specimens to be analyzed simultaneously on a single slide. One potential limitation of tissue microarray is the correct representation of each tumor with the small tissue core. Because tumors from different organs have different levels of heterogeneity, it requires a validation study for each one of them.
We compared immunostaining of Ki-67, estrogen receptors, and p53 in whole sections of 45 cases of high-grade serous ovarian carcinoma with six core samples from those sections with regard to the number of tissue cores needed to reliably represent a whole section. Staining for Ki-67 was graded high or low by automated image analysis of 10 high-power fields; staining for estrogen receptor and p53 was scored on a 0-to-3 scale. Correlation coefficients for whole-section vs core stains were 0.86 for Ki-67, 0.93 for estrogen receptors, and 0.82 for p53.
A total of 54 (6.6%) of the cores were inadequate for scoring. The probability that results from one core would correctly represent all three markers in the whole section was 91%; that for two cores was 96%; and that for three cores was 98%.
Our results show that analysis of a single readable core matched the staining pattern of a whole section more than 90% of the time, and analysis of two cores increased that value to more than 95%, demonstrating that ovarian carcinoma tissue microarray is a reliable technique to analyze the expression of markers.
Genetic alterations in epithelial ovarian tumors analyzed by comparative genomic hybridization.Hauptmann S, Denkert C, Koch I, Petersen S, Schluns K, Reles A, Dietel M, Petersen I.
Institute of Pathology and Department of Gynecology and Obstetrics, Charite Hospital Berlin, Berlin, Germany.
Hum Pathol 2002 Jun;33(6):632-41 Abstract quote The genetic changes involved in the pathogenesis of ovarian carcinoma are not completely understood.
To investigate this matter, we studied paraffin-embedded, microdissected tissue of 47 ovarian epithelial tumors (9 adenomas, 11 tumors of low malignant potential [LMP], 14 serous carcinomas, and 13 nonserous carcinomas) using comparative genomic hybridization (CGH). (The primary data used in this study are available at our CGH online tumor database at http://amba.charite.de/cgh.)
Chromosomal imbalances were found in 1 serous adenoma and in 7 LMP tumors. In the latter the alterations appeared randomly and showed no overlap with alterations found in invasive carcinomas. Although the mean aberration number of low-grade serous carcinomas was comparable to LMP tumors, the imbalances of the former occurred with high incidence (>50%) and were found at different localizations. High-grade serous carcinomas had more than twice as much chromosomal imbalances as low-grade serous carcinomas and also had pronounced alterations. In serous carcinomas, gains were found on 3q, 6p, 7, 8q, and 20, and losses were found on 4q, 6q, 12q, 13q, and 16q. Comparing serous and nonserous carcinomas, the mean aberration number was comparable, but the number of high incidence changes was lower, and the most frequent imbalances were losses on 13q and gains on 20p. Overlapping alterations occurring in serous and nonserous carcinomas were gains on 3q and 6p, as well as losses on 4q. Chromosomal imbalances associated with poor prognosis of ovarian carcinomas were gains on 6p, 7q, and 13q and losses on 15q, 17p, 18q, and 21q.
Our data indicate that serous LMP tumors and invasive carcinomas have different genetic aberrations, indicating that invasive carcinomas do not arise from preexisting serous LMP tumors. On the other hand, there are common genetic abnormalities in serous and nonserous carcinomas, suggesting that they have very early lesions in common but take different paths of further development.
CAS (CELLULAR APOPTOSIS SUSCEPTIBILITY) CAS (Cellular Apoptosis Susceptibility) Gene Expression in Ovarian Carcinoma
Correlation With 20q13.2 Copy Number and Cyclin D1, p53, and Rb Protein Expression
Gloria Peiró, MD, Joachim Diebold, MD, and Udo Löhrs, MD
Am J Clin Pathol 2002;118:922-929 Abstract quote
We immunohistochemically analyzed cellular apoptosis susceptibility (CAS) protein expression and compared it with 20q13.2 copy number and the expression of cell cycle–associated proteins retinoblastoma (Rb), cyclin D1, and p53 and prognosis on paraffin-embedded tissue from 69 ovarian carcinomas (OCs).
CAS protein reactivity was present in 100%, Rb in 54%, cyclin D1 in 47%, and p53 in 49%. Significant reciprocal correlation was observed between high levels of CAS and histologic type, FIGO (International Federation of Obstetrics and Gynecology) stage III and grade 3, residual tumor (>2 cm), 20q13.2 (ZNF217 gene) amplification (>4 copies in >20% cells), and high expression of cyclin D1 (all P < .05). No association was found between cyclin D1, p53, or Rb levels with clinicopathologic factors. In univariate analysis, residual tumor, FIGO stage and grade, ZNF217 amplification, and CAS levels predicted outcome (all P < .05). In multivariate analysis, stage, grade, amount of residual tumor, and ZNF217 amplification showed independent prognostic value (all P < .05).
In OC, alteration of CAS and ZNF217 genes, both located at 20q13, is frequent and relevant prognostically. Cyclin D1, Rb, and p53 seem to have a secondary role.c-erb-B
Yun Wang, MD, etal.
By using tissue microarrays and immunohisto-chemical analysis, we studied protein expression of genes in the erb-b signaling pathway (erb-b1; erb-b2; phosphoinositide-3-kinase, catalytic, a polypeptide [PIK3CA]; phosphatase and tensin homologue [PTEN]; phosphorylated AKT [p-AKT]; and phosphorylated extracellular signal–regulated kinase [p-ERK]) in 118 advanced ovarian carcinomas and related expression to clinicopathologic features and survival. High protein expression was seen in 15.3% of cases for erb-b2, 44.1% for erb-b1, 43.2% for PIK3CA, 51.6% for p-AKT, and 28.0% for p-ERK. Low protein levels of PTEN were seen in 41.5% of the cases and tended to be more common in well-differentiated tumors.
In multivariate analysis, only high expression of both erb-b1 and erb-b2 was an independent factor in progression-free and disease-specific survival (P = .009, hazard ratio = 2.46; P = .002, hazard ratio = 3.023, respectively). The PI3K/AKT and RAS/MEK/ERK pathways seem to be activated in some cases of advanced ovarian carcinomas, although PIK3CA, p-AKT, p-ERK, and PTEN do not seem to be independent prognostic markers in this group of patients.Fas RECEPTOR PROTEIN
- Significance of Fas receptor protein expression in epithelial ovarian cancer.
Reed J, Hakam A, Nicosia SV, Coppola D.
Department of Pathology, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.
Hum Pathol. 2005 Sep;36(9):971-6. Abstract quote
Fas receptor (FasR) is a cell surface receptor that, when activated, triggers apoptosis. It has been postulated that this receptor may be involved in the clearance of benign ovarian epithelial inclusion cysts (IC).
In this study, we test the hypothesis that the expression of FasR changes among IC, cystadenoma (AD), tumors of low malignant potential (LMP), and invasive cancer (cystadenocarcinoma, CA). Formalin-fixed paraffin-embedded sections from 53 oophorectomy specimens representing 26 IC, 17 AD, 17 LMP, and 24 CA were stained using the immunohistochemical avidin-biotin-peroxidase method.
We used a mouse antihuman monoclonal antibody Apo-1/Fas (Dako), at 1:5 dilution, after antigen retrieval. The stain was semiquantitatively scored by 3 observers evaluating the intensity of the stain and percentage of positive tumor cells. Statistical analysis was performed using the Wilcoxon rank sum test. Strong (score 6+/7+) and diffuse (>75%) luminal FasR stain was identified in 22 (85%) of 26 IC and 16 (94%) of 17 AD, but only in 6 (35%) of 17 LMP and 1 (4%) of 24 CA. Conversely, weak (score 2+/3+) and focal (<25%) FasR staining was observed in 7 (29%) of 24 CA, but in none of the IC, AD, or LMP. These differences were statistically significant (P < .05).
The decreased expression of FasR in malignant ovarian epithelial neoplasms as compared with benign ovarian epithelial lesions suggests that a decreased sensitivity to Fas-mediated apoptosis may be involved in ovarian epithelial carcinogenesis.KALLIKREIN GENE 14 Steroid Hormone Regulation and Prognostic Value of the Human Kallikrein Gene 14 in Ovarian Cancer
George M. Yousef, MD, PhD
Stefano Fracchioli, MD
Andreas Scorilas, PhD, etal.Am J Clin Pathol 2003;119:346-355 Abstract quote
To study KLK14 gene expression in endocrine-related cancers, we studied its hormonal regulation in breast and ovarian cancer cell lines. Our kinetic and blocking experiments suggest that this up-regulation is mediated through the androgen receptor.We then studied the expression of KLK14 by quantitative reverse transcriptase–polymerase chain reaction in 155 consecutive ovarian tumors and correlated these findings with clinicopathologic parameters, response to chemotherapy, and survival. A stepwise reduction was observed in the levels of KLK14 messenger RNA in normal, benign, and cancerous tissues (P < .001). Expression levels were significantly higher in patients with early stage disease and optimal debulking and in patients who responded to chemotherapy. Kaplan-Meier survival curves demonstrated longer progression-free and overall survival in patients with KLK14-positive tumors than in patients with KLK14-negative tumors (P < .001).
When all other prognostic variables were controlled in the multivariate analysis, KLK14 retained its prognostic significance (progression-free and overall survival, respectively, hazard ratios, 0.43 and 0.53; P = .027 and .014). A weak negative correlation was found between KLK14 expression and serum CA-125. KLK14 is a new, independent, and favorable prognostic marker for ovarian cancer.
p53 Combined analysis of p53 and RB pathways in epithelial ovarian cancer
Yasunori Hashiguchi, MD
Hiroshi Tsuda, MD, PhD
Kumio Yamamoto, MD, PhD
Takeshi Inoue, MD, PhD
Osamu Ishiko, MD, PhD
Sachio Ogita, MD, PhDHum Pathol 2001;32:988-996 Abstract quote
Disruptions of the p16-CDK4/cyclin D1-pRb pathway (RB pathway) and the p14ARF-MDM2-p53 pathway (p53 pathway) are important mechanisms in the development of human malignancies.
In this study, we investigated RB and p53 pathways in 46 epithelial ovarian cancers (EOCs). In the RB pathway, 16 (34.8%) of 46 cases had p16 gene alterations or loss of expression. The deletion of the p16 gene was a rare event. In 7 cases, we observed methylation in the 5`CpG island in the promoter region of the p16 gene. Abnormal expressions of pRb and CDK4/cyclin D1 were 10.9% and 30.4%, respectively. In the p53 pathway, 10 (21.7%) of 46 cases had p14ARF gene alterations or abnormal expression. In 4 cases, methylation in the 5`CpG island in the promoter region of the p14ARF gene was present. MDM2 overexpression was a rare event. Thirty-six (78.3%) of 46 patients had p53 gene alterations or expression.
In our studied cases, p14ARF abnormalities were independent of p16 abnormalities. Abnormal RB and p53 pathways were present in 60.9% and 80.4% of cases, respectively.
In conclusion, disruptions of p53 and RB pathways are frequent events and the inverse correlations were present between the abnormality of p16 and p14ARF in EOCs.
TYROSINASE KINASE RECEPTOR
- Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRalpha, and PDGFRbeta in ovarian cancers.
Wilczynski SP, Chen YY, Chen W, Howell SB, Shively JE, Alberts DS.
Hum Pathol. 2005 Mar;36(3):242-9. Abstract quote
Summary Most women with epithelial ovarian cancer are diagnosed with advanced disease. Despite surgery and initial tumor reduction by standard chemotherapy, the tumors frequently recur and the patients eventually die of their disease. New drugs that inhibit tyrosine kinase receptors (TKRs) are being investigated for treatment and this study was undertaken to determine the expression and mutational state for 3 TKRs (c-kit, platelet-derived growth factor receptor [PDGFR] alpha , and PDGFR beta ) in ovarian cancer. Tissue arrays containing 84 epithelial ovarian tumors were studied by immunohistochemistry with antibodies specific for c-kit, PDGFR alpha , and PDGFR beta .
Immunoreactivity was detected in 78% of the tumor to at least one TKR. PDGFR alpha was expressed in the largest percentage of ovarian tumors (58%) whereas 29% expressed PDGFR beta . Two commercial antibodies against c-kit were studied and 33% of the tumors stained with one but only 6% were interpreted as positive with the second antibody. Activation of TKRs may occur through mutations but, by sequence analysis, no mutations were detected in 6 ovarian tumors with elevated immunoreactivity for each of the TKRs (c-kit, PDGFR alpha , and PDGFR beta ). Tyrosine kinase receptors could also be activated through autocrine or paracrine stimulation of receptor by its ligand. Of 43 (35%) tumors tested for both c-kit receptor and its ligand (stem cell factor), 15 expressed both proteins indicating the possibility that this autocrine stimulation feedback loop is a factor in the growth of some ovarian cancers.
This study demonstrates that PDGFR alpha , PDGFR beta , and c-kit are expressed in a high percentage of epithelial ovarian cancers suggesting that tyrosine kinase inhibitors may be useful in the treatment of these tumors.
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOLOGIC LABORATORY MARKERS OSTEOPONTIN Osteopontin as a Potential Diagnostic Biomarker for Ovarian Cancer
Jae-Hoon Kim, MD; Steven J. Skates, PhD; Toshimitsu Uede, MD; Kwong-kwok Wong, PhD; John O. Schorge, MD; Colleen M. Feltmate, MD; Ross S. Berkowitz, MD; Daniel W. Cramer, MD, ScD; Samuel C. Mok, PhD
JAMA. 2002;287:1671-1679 Abstract quote
Context
Development of new biomarkers for ovarian cancer is needed for early detection and disease monitoring. Analyses involving complementary DNA (cDNA) microarray data can be used to identify up-regulated genes in cancer cells, whose products may then be further validated as potential biomarkers.Objective
To describe validation studies of an up-regulated gene known as osteopontin, previously identified using a cDNA microarray system.Design, Setting, and Participants
Experimental and cross-sectional studies were conducted involving ovarian cancer and healthy human ovarian surface epithelial cell lines and cultures, archival paraffin-embedded ovarian tissue collected between June 1992 and June 2001, and fresh tissue and preoperative plasma from 144 patients evaluated for a pelvic mass between June 1992 and June 2001 in gynecologic oncology services at 2 US academic institutions. Plasma samples from 107 women selected from an epidemiologic study of ovarian cancer initiated between May 1992 and March 1997 were used as healthy controls.Main Outcome Measures
Relative messenger RNA expression in cancer cells and fresh ovarian tissue, measured by real-time polymerase chain reaction as 2-CT(a quantitative value representing the amount of osteopontin expression); osteopontin production, localized and scored in ovarian healthy and tumor tissue with immunohistochemical studies; and amount of osteopontin in patient vs control plasma, measured using an enzyme-linked immunoassay.Results
The geometric mean for 2-CTfor osteopontin expression in 5 healthy ovarian epithelial cell cultures was 4.1 compared with 270.4 in 14 ovarian cancer cell lines (P = .03). The geometric mean 2-CTfor osteopontin expression in tissue from 2 healthy ovarian epithelial samples was 9.0 compared with 164.0 in 27 microdissected ovarian tumor tissue samples (P = .06). Immunolocalization of osteopontin showed that tissue samples from 61 patients with invasive ovarian cancer and 29 patients with borderline ovarian tumors expressed higher levels of osteopontin than tissue samples from 6 patients with benign tumors and samples of healthy ovarian epithelium from 3 patients (P = .03). Osteopontin levels in plasma were significantly higher (P<.001) in 51 patients with epithelial ovarian cancer (486.5 ng/mL) compared with those of 107 healthy controls (147.1 ng/mL), 46 patients with benign ovarian disease (254.4 ng/mL), and 47 patients with other gynecologic cancers (260.9 ng/mL).Conclusions
Our findings provide evidence for an association between levels of a biomarker, osteopontin, and ovarian cancer and suggest that future research assessing its clinical usefulness would be worthwhile.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION HEREDITARY
- Hereditary ovarian cancer.
Prat J, Ribe A, Gallardo A.
Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, 08025 Barcelona, Spain.
Hum Pathol. 2005 Aug;36(8):861-70. Abstract quote
Family history is the strongest risk factor for ovarian cancer. Three clinical manifestations of hereditary ovarian cancer have been recognized: (1) "site-specific" ovarian cancer, (2) the breast and ovarian cancer syndrome, and (3) the hereditary nonpolyposis colorectal cancer (HNPCC; Lynch II) syndrome.
The first 2 groups are associated with germ line mutations in the BRCA1 and BRCA2 tumor suppressor genes, whereas HNPCC is associated with germ line mutations in the DNA mismatch repair (MMR) genes, primarily hMLH1 and hMSH2. At least 10% of all epithelial ovarian cancers are hereditary, with mutations in the BRCA genes accounting for approximately 90% of cases and most of the remaining 10% attributable to HNPCC. Hereditary ovarian cancers exhibit distinct clinicopathologic features compared with sporadic cancers. The cumulative lifetime risk of ovarian cancer is 40% to 50% for BRCA1 mutation carriers and 20% to 30% for BRCA2 mutation carriers. Both BRCA proteins participate in transcriptional regulation of gene expression as well as the recognition or repair of certain forms of DNA damage, particularly double-strand breaks. Mutations of BRCA1 and BRCA2 are mainly of the frameshift or nonsense variety. Most ovarian cancers associated with germ line BRCA mutations are diagnosed at a younger age and are high-grade and advanced-stage serous carcinomas. BRCA mutations do not seem to play a significant role in the development of mucinous or borderline ovarian tumors. Hereditary ovarian cancers have a distinctly better clinical outcome with longer overall survival and recurrence-free interval after chemotherapy than sporadic cancers.
Women with a family history including 2 or more first- or second-degree relatives with either ovarian cancer alone or both breast and ovarian cancers should undertake prophylactic oophorectomy immediately after childbearing has been completed to reduce the risk of ovarian cancer.
The cumulative risk of ovarian cancer in HNPCC families is more than 12%. Ovarian cancer in HNPCC syndrome is diagnosed at younger age than in the general population. Most tumors are low-stage well-differentiated or moderately differentiated carcinomas. Annual follow-up is recommended for these patients.PEDIATRIC
Malignant ovarian tumors in children: 22 years of experience at a single institution.Akyuz C, Varan A, Buyukpamukcu N, Kutluk T, Buyukpamukcu M.
Department of Pediatric Oncology, Institute of Oncology, Hacettepe University, Ankara, Turkey.
J Pediatr Hematol Oncol 2000 Sep-Oct;22(5):422-7 Abstract quote PURPOSE: Malignant ovarian tumors of childhood are relatively rare and thus, management is still unclear. We reviewed our experience with these tumors to evaluate their histopathologic characteristics, treatment, and outcome.
PATIENTS AND METHODS: From January 1975 to December 1997, 56 patients had their malignant ovarian tumors diagnosed, treated, and followed-up in our institution. All tumors were completely excised when possible; otherwise, biopsy was performed. Staging was made according to Federation Internationale de Gynecologie Oncologique classification. Chemotherapy was recommended for all patients. Twelve cases were treated with vincristine, actinomycin, cyclophosphamide (VAC) before 1986; 12 with cisplatin, vinblastine, and bleomycin (PVB) from 1986 to 1989; and 23 with the bleomycin, etoposide, and cisplatin (BEP) regimen from 1989 to present. The Kaplan-Meier survival method was used to calculate the survival. The log-rank test was used to compare groups with respect to survival.
RESULTS: Age range was 0 to 16 years (median 11 yrs; average 9.8 yrs). Only two patients were younger than 1 year. The most common presenting symptom was abdominal pain, occurring in 27 patients (48.2%). Thirty-three patients (60%) had total one-sided salpingo-oophorectomy and three patients had bilateral salpingo-oophorectomy. Nineteen patients had stage I, 15 had stage II, 19 had stage III, and 3 had stage IV disease. Dysgerminoma was the most common type. Overall survival (OAS) and event-free survival were 68% (median follow-up time: 71 mos) and 57%, respectively, after 22 years. Histopathology was not correlated with survival. Two important predictors for survival are age (P < 0.0001) and treatment protocol (P = 0.013). The BEP protocol was superior to the other regimens. The OAS was 74.6% in BEP, 55% in PVB, and 63.6% in VAC regimens.
CONCLUSION: Although age at diagnosis and treatment with BEP regimen have major roles in determining prognosis of the ovarian tumors in childhood, for patients with advanced ovarian germ cell tumors, intensification of chemotherapy or the development of new approaches is necessary.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL GIANT CELLS, OSTEOCLAST-LIKE
A malignant ovarian tumor with osteoclast-like giant cells.Fadare O, Mariappan MR, Ocal IT, Parkash V.
Am J Surg Pathol. 2003 Jun;27(6):854-60. Abstract quote Neoplasms that are composed focally, predominantly, or exclusively of osteoclast-like giant cells admixed with variably pleomorphic mononuclear cells have been described in a wide variety of organs.
In this report, we describe the case of a 76-year-old woman with an 8-cm tumor that appeared to be localized to the ovary, that was composed predominantly of diffusely distributed, bland-appearing osteoclast-like giant cells admixed with pleomorphic mononuclear cells, and that was not associated with an ovarian cystic neoplasm. Hemorrhage, large zones of necrosis, and a high mitotic index were the other characteristics of the tumor.
Immunohistochemically, the mononuclear cells were strongly positive for vimentin and proliferating cell nuclear antigen and were negative for keratin AE 1/3, CAM 5.2, cytokeratin 7, epithelial membrane antigen, beta-human chorionic gonadotropin, desmin, smooth muscle actin, p53, leukocyte common antigen, S-100, inhibin, alpha-1-antichymotrypsin, and CD68. The osteoclast-like giant cells displayed immunoreactivity for CD68, vimentin, alpha-1-antichymotrypsin, and leukocyte common antigen only.
Ultrastructurally, rare intercellular junctions were present between mononuclear cells, suggestive of an epithelial histogenesis. Less than a dozen ovarian lesions with the "giant cell" designation have been described, and most of these cases are thought to be analogous to the "sarcoma-like" nodules or other such lesions that have a well-known association with ovarian cystic neoplasms.Our case, in contrast, did not have an easily identifiable epithelial component and demonstrated both an infiltrative border and vascular invasion. This is, to the authors' knowledge, the first detailed clinicopathologic description of such a case as an ovarian lesion.
TUBAL FIMBRIA
The Tubal Fimbria Is a Preferred Site for Early Adenocarcinoma in Women With Familial Ovarian Cancer Syndrome.
Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, Garber JE, Cramer DW, Crum CP.
From the *Division of Women's and Perinatal Pathology, Department of Pathology, and the daggerDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital; and the double daggerDana Farber Cancer Research Institute, Boston, MA.
Am J Surg Pathol. 2006 Feb;30(2):230-236. Abstract quote
A proportion of adenocarcinomas in prophylactic adnexectomies (bilateral salpingo-oophorectomies [BSOs]) from women with BRCA mutations (BRCA positive) occur in the fallopian tube.
We analyzed a consecutive series of BSOs from BRCA-positive women following an index case of fimbrial serous carcinoma. To determine if the fimbria is a preferred site of origin, we followed a protocol for Sectioning and Extensively Examining the FIMbria (SEE-FIM). Immunostaining for p53 and Ki-67 was also performed. Thirteen BRCA-positive women (cases) and 13 women undergoing BSOs for other disorders (controls) were studied. Tubal carcinoma was detected in 4 cases at the initial histologic evaluation and in no controls. A fifth carcinoma was discovered following further sectioning of the fimbriae. Three were BRCA2 positive and two BRCA1 positive. Three were in the fimbria, one in both the fimbria and proximal tube, and one involved the ampulla. Four were serous carcinomas, four were confined to the tube, and three were noninvasive (intraepithelial). No ovarian carcinomas were identified. All tumors were Ki-67 positive (>75% of cell nuclei), and excluding one endometrioid carcinoma, p53 positive (>75% cell nuclei); p53 positivity in the absence of elevated Ki-67 did not correlate with morphologic neoplasia.
The fimbria was the most common location for early serous carcinoma in this series of BRCA-positive women. Protocols that extensively examine the fimbria (SEE-FIM) will maximize the detection of early tubal epithelial carcinoma in patients at risk for ovarian cancer.
Investigative strategies targeting the fimbriated end of the fallopian tube should further define its role in the pathogenesis of familial and sporadic ovarian serous carcinomas.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE
- Expression of WT1, CA 125, and GCDFP-15 as Useful Markers in the Differential Diagnosis of Primary Ovarian Carcinomas Versus Metastatic Breast Cancer to the Ovary.
Tornos C, Soslow R, Chen S, Akram M, Hummer AJ, Abu-Rustum N, Norton L, Tan LK.
From the Departments of *Pathology, daggerGynecologic Oncology, double daggerEpidemiology & Biostatistics, and section signMedicine, Memorial Sloan-Kettering Cancer Center, New York, NY; and the parallelDepartment of Pathology, Magee Woman's Hospital, Pittsburgh, PA.
Am J Surg Pathol. 2005 Nov;29(11):1482-1489. Abstract quote
Metastatic breast carcinoma to the ovary is sometimes difficult to differentiate from primary ovarian carcinoma. This problem is often encountered in breast carcinoma patients who develop adnexal masses. ER and PR can be positive in a high percentage of breast and ovarian carcinomas, and therefore cannot be used in the differential diagnosis of these entities. WT1 and CA125 have been identified as possible markers for ovarian cancer. However, no studies have been done that specifically compare the immunophenotype of breast carcinoma metastatic to ovary with that of primary ovarian cancer.
Thirty-nine cases of metastatic breast carcinoma to the ovary, 36 primary breast carcinomas, and 42 primary ovarian carcinomas were examined immunohistochemically for the expression of WT1, CA125, carcinoembryonic antigen, MUC2, MUC1, and GCDFP. The percentage of cells stained and the intensity of staining were recorded. Thirty-two ovarian carcinomas (76%) were positive for WT1, including 31 of 33 (94%) serous carcinomas. Most of them had strong and diffuse staining. None of the breast cancers either primary or metastatic to the ovary expressed WT1. Thirty-eight (90%) ovarian carcinomas were positive for CA125, most of them with strong and diffuse staining. Most breast carcinomas were negative for CA125, with only 6 (16%) of the primary ones and 5 (12%) of the metastatic showing weak and focal positivity. All ovarian carcinomas were negative for GCDFP. Five primary breast cancers (14%) and 17 (43%) metastatic to the ovary were positive for GCDFP. Nine (21%) ovarian carcinomas, 8 (22%) primary breast carcinomas, and 13 (33%) metastatic to the ovary were positive for carcinoembryonic antigen. Almost all tumors examined were positive for MUC1 (100% ovarian carcinomas, 100% primary breast carcinomas, and 95% metastatic breast carcinomas to ovary). MUC2 was positive in 10 (24%) ovarian carcinomas, 3 (8%) primary breast cancers, and 12 (30%) metastases to the ovary. The presence of immunoreactivity for WT1 and CA125 in a carcinoma involving ovary strongly favors a primary lesion.
Most ovarian carcinomas are positive for both markers, whereas the majority of metastatic breast carcinomas to the ovary are negative. GCDFP can be complementary in this differential diagnosis.Association of E-cadherin and beta-catenin immunoexpression with clinicopathologic features in primary ovarian carcinomas.
Faleiro-Rodrigues C, Macedo-Pinto I, Pereira D, Ferreira VM, Lopes CS.
Hum Pathol. 2004 Jun;35(6):663-9. Abstract quote
Epithelial cadherin forms a complex with alpha-, beta-, and gamma-catenin proteins. Reduced expression of E-cadherin-catenins has been shown in human carcinomas and is associated with low histologic differentiation, increased risk of invasion, and metastatic disease.
The immunoexpression pattern of E-cadherin and beta-catenin (reduced versus preserved phenotype) was evaluated in 104 primary ovarian carcinomas and related to clinicopathologic features of the tumors. The immunoexpression pattern of E-cadherin was associated with International Federation of Gynaecology and Obstetrics (FIGO) staging (P = 0.043), histologic subtype (P = 0.001), peritoneal metastasis (P = 0.006), and residual tumor (P = 0.036). The reduced phenotype of E-cadherin that was observed in 64% of the carcinomas (67/104) was associated with advanced stage tumors, serous carcinomas, presence of peritoneal metastasis, and residual tumor larger than 2 cm. The immunoexpression pattern of beta-catenin was associated with histologic subtype (P = 0.005), tumor differentiation (P = 0.025), and peritoneal metastasis (P = 0.041). The reduced phenotype of beta-catenin that was observed in 74% of the carcinomas (77/104) was associated with advanced stage tumors, poorly differentiated serous and clear cell carcinomas, presence of peritoneal metastasis, and residual tumor. The immunoexpression pattern of E-cadherin was correlated with beta-catenin (P = 0.001). The reduced phenotype for both E-cadherin and beta-catenin was associated with histologic subtype (P < 0.001) and peritoneal metastasis (P = 0.001).
In conclusion, the immunohistochemical profile of E-cadherin and beta-catenin may be useful in identifying a particular subpopulation of ovarian cancer patients who are characterized by an adverse clinical outcome, because the reduced phenotype of these molecules was associated with poor tumor differentiation, peritoneal metastasis, and advanced FIGO stage tumors.
Expression of CEA, Tag-72, and Lewis-Y antigen in primary and metastatic lesions of ovarian carcinoma.
Chhieng DC, Rodriguez-Burford C, Talley LI, Sviglin H, Stockard CR, Kleinberg MJ, Barnes MN, Partridge EE, Khazaeli Mb M, Grizzle WE.
Hum Pathol. 2003 Oct;34(10):1016-21. Abstract quote Ovarian carcinoma has a high mortality rate, because most ovarian carcinomas are detected at a late stage. Traditional therapies, such as surgical debulking and chemotherapy, have not been successful in improving the long-term survival of these patients. Alternative therapies targeting various biomarkers, such as carcinoembryonic antigen (CEA), Tag-72, and Lewis-Y antigen, have been developed to treat patients with advanced ovarian cancers.
To ensure that therapies targeting these biomarkers are effective, it is imperative to determine whether there is any differential expression of these targeted biomarkers between primary and metastatic ovarian carcinomas. In the present study, primary and metastatic lesions from 68 and 58 patients, respectively, including primary and matched metastatic lesions from 31 patients, were evaluated for cytoplasmic and membranous expression of CEA (clone Col-1), Tag-72 (clone CC-49), and Lewis-Y antigen (clone BR-96) by immunohistochemistry. No significant differences were observed with cytoplasmic and membranous expression of Tag-72 (CC-49) and Lewis-Y antigen (BR-96) in the primary and metastatic, matched and unmatched lesions (Wilcoxon signed-rank test). Although there was no statistically significant difference in the scores of CEA (Col-1) between primary and metastatic lesions, 5 of 11 (45%) cases with positive staining with CEA (Col-1) demonstrated discordant results between primary and metastatic lesions. There was a moderate positive correlation of the cytoplasmic and membranous expression of Tag-72 (CC-49), as well as cytoplasmic expression of BR-96 between primary and metastatic ovarian carcinomas. There was a weak negative correlation between the membranous expression of CEA (Col-1) and that of Lewis-Y antigen (BR-96); however, the difference was not statistically significant. No correlation was observed with other combinations of biomarkers.
Our findings suggest that samples from either primary or metastatic ovarian carcinomas can be used for the evaluation of the expression of Tag-72 (CC-49) and Lewis-Y antigen (BR-96) to identify targets for novel therapies in patients with disseminated ovarian carcinomas. CEA (Col-1), due to its low expression and variation in phenotypic expression between primary and metastatic lesions, should be evaluated carefully in metastatic lesions before targeting the CEA antigen with CEA (Col-1)-like antibodies.
Decreased CD44 Standard Form Expression Correlates With Prognostic Variables in Ovarian Carcinomas
Jeffrey S. Ross, MD, Christine E. Sheehan, Susan S. Williams, MD, John H. Malfetano, MD, Wanda M. Szyfelbein, MD, and Bhaskar V.S. Kallakury, MD
Am J Clin Pathol 2001;116:122-128 Abstract quote
Expression of CD44 standard form (CD44s) was evaluated by automated immunohistochemical analysis using the anti-CD44 A3D8 clone in 101 ovarian epithelial neoplasms including 82 primary tumors (64 carcinomas and 18 tumors of low malignant potential [LMP]), 9 lymph node metastases, 8 malignant ascites, and 2 peritoneal implants. Immunostaining was scored semiquantitatively. Tumors were graded according to the FIGO (International Federation of Gynecology and Obstetrics) classification system. Tumor stage and patient survival were determined from the patient records. While 9 of 18 LMP tumors expressed CD44s, only 15 of 64 carcinomas expressed it. In the carcinomas, univariate analysis revealed that decreased CD44s expression correlated with high tumor grade, advanced stage, and shortened survival. Loss of CD44s expression also was noted in the tumor cells in 8 of 9 lymph node metastases, 7 of 8 malignant ascites, and 1 of 2 implants. Multivariate analysis revealed that only tumor stage independently correlated with patient survival.
Loss of CD44s expression determined by immunohistochemical analysis is more common in ovarian carcinomas than in LMP tumors; correlates with prognostic variables including tumor grade, stage, and survival; and may have an important role in the dissemination of ovarian cancer.
Immunohistochemical confirmation of pulmonary papillary adenocarcinoma metastatic to ovaries.Householder J, Han A, Edelson MI, Eager JM, Rosenblum NG.
Department of Obstetrics and Gynecology, The Reading Hospital and Medical Center, West Reading, PA 19612, USA.
Arch Pathol Lab Med 2002 Sep;126(9):1101-3 Abstract quote Metastatic papillary adenocarcinomas of the ovary are rare compared to primary ovarian papillary serous carcinomas.
We report a case of pulmonary papillary adenocarcinoma metastatic to the ovary and show how this tumor can be differentiated immunohistochemically from an ovarian primary.
Paraffin blocks of the ovarian tumor were analyzed for carcinoembryonic antigen, CA 125, surfactant, E-cadherin, N-cadherin, and vimentin. These markers are useful in differentiating epithelial tumors of lung versus ovarian origin. The papillary tumor showed expression of carcinoembryonic antigen, surfactant, and E-cadherin, but was negative for CA 125, N-cadherin, and vimentin. These findings support a lung carcinoma metastatic to the ovary.
CYTOKERATINS
Expression of cytokeratins 7 and 20 in ovarian neoplasia.Cathro HP, Stoler MH.
Robert E. Fechner Laboratory of Surgical Pathology, University of Virginia Health System, Charlottesville, USA.
Am J Clin Pathol 2002 Jun;117(6):944-51 Abstract quote To further delineate specific staining patterns and refine the differential usefulness of cytokeratin (CK) 7/20 staining, we studied multiple ovarian tumors and primary nongynecologic neoplasms likely to metastasize to the ovary.
Immunohistochemical analysis with semiquantitative grading to give quartile scores (0-4) was performed on 127 cases. Subsequent analysis indicated that a more informative diagnostic segregation could be achieved with a biphasic grading system (>50% staining, positive; 50% or less, negative).
Lower intestinal tumors were CK7- and usually CK20+, while upper gastrointestinal tumors, including those of pancreatobiliary origin, were mostly CK7+ and CK20-. Serous papillary ovarian tumors were all CK7+ and CK20-. Mucinous ovarian carcinomas were all CK7+ and slightly more often CK20-, whereas the small number of ovarian borderline mucinous tumors studied were the most problematic, with no clear pattern. Multiple different tumor types from all nonovarian gynecologic sites were fairly consistently CK7+ and almost always CK20-.
Differential CK staining of mucinous tumors of the female genital tract using CK7 and CK20 is useful for predicting the site of origin, provided samples are adequate in size. The most specific usefulness is the identification of lower gastrointestinal vs "other" neoplasms.
Expression of cytokeratins 7 and 20 in primary carcinomas of the stomach and colorectum and their value in the differential diagnosis of metastatic carcinomas to the ovary.Park SY, Kim HS, Hong EK, Kim WH.
Center for Colorectal Cancer, Center for Gastric Cancer, and Department of Pathology, National Cancer Center, Goyang, Gyeonggi, Korea and the Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
Hum Pathol 2002 Nov;33(11):1078-85 Abstract quote The expressions of cytokeratin (CK) 7 and 20 have been studied in various primary and metastatic carcinomas, and their determination may help distinguish the site of origin of metastatic carcinomas. However, little is known about the factors that determine variations in their expression patterns in primary gastric and colorectal carcinomas.
We investigated the expressions of CK7 and CK20 in 289 cases of gastric carcinoma and 225 cases of colorectal carcinoma using a tissue microarray. To evaluate CK7 and CK20 expression patterns of ovarian metastases from gastric or colorectal carcinomas, 54 cases of metastatic carcinomas to the ovary were examined. It was found that 71% (207 of 289) of the gastric carcinomas stained positively for CK7, whereas only 9% (21 of 225) of the colorectal carcinomas proved to be CK7 positive, and that 41% (117 of 289) of the gastric carcinomas and 73% (165 of 225) of the colorectal carcinomas were CK20 positive.
The proportion of CK7+/CK20- was highest in the gastric carcinomas at 46% (132 of 289), and was independent of the histologic classification of Lauren (46% of the intestinal type, 45% of the diffuse type). The CK7 and CK20 expression patterns were different in colorectal carcinomas according to histologic grade and location of the tumor. CK7-/CK20+ had the greatest proportion (68%) in colorectal carcinomas, and this was dependent on the tumor's histologic grade (75% of low-grade versus 52% of high-grade) and location (46% of right-sided versus 76% of left-sided). Moreover, 42% (18 of 43) of gastric carcinomas metastatic to the ovary were CK7+/CK20-, whereas 19% (8 of 43) were CK7-/CK20+. All colorectal cancers metastatic to the ovary were CK7-/CK20+, except 1 case that was CK7-/CK20-.
In conclusion, the CK7 and CK20 expression patterns in primary gastric carcinomas vary considerably, and those in colorectal carcinomas are associated with histologic grade and tumor location. The CK7-/CK20+ expression pattern is specific for metastatic colorectal carcinomas to the ovary, but has low predictability for colorectal origin in metastatic ovarian carcinoma.
EPIDERMAL GROWTH FACTOR RECEPTOR
- Epithelial growth factor receptor status in primary and recurrent ovarian cancer.
Stadlmann S, Gueth U, Reiser U, Diener PA, Zeimet AG, Wight E, Mirlacher M, Sauter G, Mihatsch MJ, Singer G.
1Institute for Pathology, University Hospital of Basel, Basel, Switzerland.
Mod Pathol. 2006 Apr;19(4):607-10. Abstract quote
Success of epidermal growth factor receptor (EGFR) targeting agents in different cancer types is related to EGFR gene mutations and/or copy number gains. We investigated the EGFR gene status and protein expression by DNA mutational analysis, fluorescence in situ hybridization (FISH), and immunohistochemistry in tumor tissues from 80 patients with primary and corresponding recurrent ovarian serous carcinomas.
The patients were classified into six groups with ascending EGFR gene copy numbers. EGFR amplification and high polysomy (FISH+) was present in a significant fraction of the primary (20%) and recurrent (22%) ovarian carcinomas. On mutational analysis, only one tumor with a silent EGFR mutation was observed, and this was the only carcinoma with high-level amplification. EGFR protein immunoexpression was seen in 28% of primary and 33% of recurrent carcinomas and correlated to amplification in the primary tumors (P=0.003). In recurrent carcinoma, moderate and strong EGFR expression was associated with amplification (P=0.034).
These molecular events potentially have impact on the responsiveness to EGFR targeting agents in ovarian cancer.
DIFFERENTIAL DIAGNOSIS OF OVARIAN TUMORS AND MASSES*
KEY DIFFERENTIATING FEATURES TUMORS WITH MODERATE TO LARGE GLANDS OR HOLLOW TUBULES Endometrioid carcinoma
Endometrioid-like yolk sac tumor
Mucinous carcinoma
Other surface epithelial tumors
Sertoli-Leydig cell tumor
Yolk sac tumor, intestinal glandular type
Ependymoma
Tumor of probable wolffian origin
Struma ovariiUterine endometrioid carcinoma
Gastrointestinal carcinoma
Biliary and pancreatic carcinomaSOLID TUBULAR OR PSEUDOTUBULAR PATTERN Sertoli and Sertoli-Leydig cell tumors
Sex cord tumors with annular tubules
Tumor of probable wolffian origin
Struma ovarii
Carcinoid tumor
Endometrioid carcinoma
DysgerminomaKrukenberg tumor
Carcinoid
OthersCORDS AND RIBBONS Sertoli-Leydig cell tumor
Trabecular and strumal carcinoid
Granulosa cell tumor, adult type
Endometrioid carcinoma
Endometrioid stromal sarcoma
OthersBreast carcinoma
Endometrial stromal sarcoma
Lymphoma and leukemia
Intra-abdominal desmoplastic small round cell tumorINSULAR TUMORS Carcinoid
Granulosa cell tumor, adult type
Transitional cell tumors, especially Brenner
Others (eg, endometrioid carcinoma, dysgerminoma, lymphoma)Carcinoid
Breast carcinoma
Intra-abdominal desmoplastic small round cell tumor
Endometrial stroma sarcoma
OthersSLIT-LIKE AND RETICULAR SLIT-LIKE Serous carcinoma
Endometrioid carcinoma
Transitional cell carcinoma
Sertoli-Leydig cell tumor, retiform type
Rete tumors
AngiosarcomaSerous carcinoma
MesotheliomaMesothelial hyperplasia RETICULAR Yolk sac tumor Clear cell carcinoma
Serous carcinoma
Malignant mesodermal mixed tumor
Sertoli-Leydig cell tumorMICROFOLLICLES, MICROGLANDS, AND OTHER SMALL SPACES Granulosa cell tumor, adult type
Carcinoid
Struma ovarii
Pituitary-type adenoma
Endometrioid carcinoma
OthersBreast carcinoma
Carcinoid
OthersLARGE FOLLICLES OR PSEUDOFOLLICLES Granulosa cell tumors and Sertoli-Leydig cell tumors
Small cell carcinoma, hypercalcemic type
Struma ovarii
Clear cell carcinoma
Endometrioid carcinoma
Tumor of probable wolffian origin
OthersCarcinoid
Malignant melanoma
Lymphoma
Alveolar rhabdomyosarcomaFollicle cyst
Large luteinized solitary follicle cyst of pregnancy and puerperium
Pregnancy luteomaPAPILLAE OR PSEUDOPAPILLAE Serous tumors
Endometrioid carcinoma
Mucinous tumors
Mixed epithelial borderline tumor
Clear cell carcinoma
Transitional cell tumors
Retiform Sertoli-Leydig cell tumor
Granulosa cell tumors
Yolk sac tumor
Embryonal carcinoma
Papillary carcinoma in struma
EpendymomaMesothelioma
Serous carcinoma
Clear cell carcinoma
OthersMesothelial hyperplasia FIBROMATOUS OR THECOMATOUS COMPONENT Stromal tumor with minor sex cord elements
Surface-epithelial adenofibromas
Transitional cell tumors, especially Brenner tumor
Carcinoid
Sclerosing stromal tumor
Endometrioid stromal sarcoma
Adenosarcoma
OthersKrukenberg tumor
Carcinoid
Endometrial stromal sarcoma
OthersMassive edema
FibromatosisBIPHASIC AND PSEUDOBIPHASIC TUMORS Mesodermal mixed tumors
Sertoli-Leydig cell tumors
Yolk sac tumors
Primitive neuroectodermal tumor
Teratoma, immature
Endometrioid carcinoma
OthersKrukenberg tumor SMALL ROUND CELL TUMORS Granulosa cell tumors
Sertoli-Leydig cell tumor of intermediate and poor differentiation
Luteinized thecoma with sclerosing peritonitis
Endometrioid stromal sarcoma
Tumor of probable wolffian origin
Carcinoid
Small cell carcinoma, hypercalcemic type
Small cell carcinoma, pulmonary type
Malignant melanoma
Undifferentiated carcinoma
Lymphoma-Leukemia
Primitive neuroectodermal tumors
RhabdomyosarcomaEndometrial stromal sarcoma
Breast carcinoma
Intra-abdominal desmoplastic small round cell tumor
Melanoma
Carcinoid
Small cell carcinoma
Primitive neuroectodermal tumor and neuroblastoma
RhabdomyosarcomaArtifactual displacement of granulosa cells SPINDLE CELL TUMORS Fibroma, cellular fibroma, fibrosarcoma
Luteinized thecoma
Smooth muscle tumors
Other soft tissue-type tumors
Sex cord-stromal tumors
Endometrioid stromal sarcoma
Sarcomatoid endometrioid carcinoma
Squamous cell carcinomaEndometrioid stromal sarcoma
Malignant melanoma
OthersStromal hyperplasia
Stromal hyperthecosis
Massive edema
FibromatosisMUCINOUS CELLS Mucinous tumors, pure and of mixed cell types
Brenner tumors
Sertoli-Leydig cell tumor, heterologous type
Small cell carcinoma, hypercalcemic type
Mucinous carcinoid
TeratomasAppendiceal tumors associated with pseudomyxoma peritonei
Mucinous carcinomas from diverse sites
Mucinous carcinoidSIGNET RING AND SIGNET RING LIKE TUMORS Krukenberg tumor
Mucinous carcinoidMucinous carcinoid
Clear cell carcinoma
Small cell carcinoma, hypercalcemic type
Signet-ring stromal tumor
Sclerosing stromal tumor
Sertoli-Leydig cell tumor
Steroid cell tumor
Adenomatoid tumor
Endometrioid carcinoma
OtherMucicarciminophilic histiocytosis
Oxidized regenerated cellulose deposition in histiocytes
Epithelial inclusion glands and cysts with hydropic change
Ectopic deciduaCLEAR CELLS AND THEIR MIMICS Clear cell carcinoma
Endometrioid carcinoma
Transitional cell tumors
Dysgerminoma
Yolk sac tumor
Struma ovarii
Steroid cell tumor
Sertoli cell tumorClear cell carcinoma from elsewhere in female genital tract
Renal cell carcinoma
Intestinal clear cell carcinoma
Clear cell melanoma
OtherArias-Stella reaction in endometriosis HOBNAIL CELLS Clear cell carcinoma
Other surface-epithelial tumors
Juvenile granulosa cell tumor
Sertoli-Leydig cell tumor
Yolk sac tumor
AngiosarcomaClear cell carcinoma of the genital tract Arias-Stella reaction in endometriosis OXYPHILIC TUMORS Luteinized granulosa cell tumor
Luteinized thecoma
Oxyphilic Sertoli cell tumorClear cell
Endometrioid
Anaplastic carcinoma in mucinous cystic tumors
Small cell carcinoma, hypercalcemic type, large cell variant
Squamous cell
HepatoidHepatoid yolk sac tumor
Struma ovarii
Pituitary adenoma in dermoid cyst
Malignant melanomaEpithelioid smooth muscle tumor
AngiosarcomaMalignant melanoma
Hepatocellular carcinoma
Breast carcinoma
Large cell carcinoma of the lung
Carcinoid
OtherPregnancy luteoma
MalakoplakiaADDITIONAL METASTATIC TUMORS COLON CANCERS
- Ovarian involvement by metastatic colorectal adenocarcinoma: still a diagnostic challenge.
Lewis MR, Deavers MT, Silva EG, Malpica A.
From the Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX.
Am J Surg Pathol. 2006 Feb;30(2):177-84. Abstract quote
Ovarian involvement by metastatic colorectal adenocarcinoma, although not an uncommon occurrence, remains a diagnostic challenge.
The gross and histologic features of such metastases overlap those of primary ovarian epithelial neoplasms such as endometrioid or mucinous adenocarcinoma. The clinical and pathologic features of 86 cases of metastatic colorectal adenocarcinoma involving the ovary were reviewed.
Patients ranged in age from 19 to 85 years (median, 51 years); 24% were younger than 40 years. Presenting symptoms included abdominal or pelvic pain (45 cases), rectal bleeding (13 cases), change in bowel habits (20 cases), and vaginal bleeding (5 cases). In 23 cases, an ovarian mass was the first manifestation of the disease.
Ovarian involvement was bilateral in 49 cases and unilateral in 33 (including 20 cases in which the only involved ovary measured at least 10 cm in greatest dimension). Involved ovaries ranged from 2 to 24 cm (mean, 10.1 cm), and most featured both solid and cystic areas. Many involved ovaries featured smooth capsules without gross evidence of surface involvement by tumor. In general, the tumors had typical histologic features of metastatic colorectal adenocarcinoma, including a garland pattern and dirty necrosis. In 23 cases, foci with a benign or low malignant potential appearance were seen.
Immunohistochemical studies showed that 29 of 29 tumors (100%) were positive for CK20; focal CK7 positivity was seen in 5 of 30 cases (17%). In 9 of the cases, an ovarian primary was diagnosed or favored initially, and 5 of these cases were initially treated as ovarian primaries.
Metastatic colorectal adenocarcinoma should be considered in the differential diagnosis of an ovarian mass, even if the mass is large and unilateral or in a young patient, to secure proper treatment of these patients.GASTROINTESTINAL STROMAL TUMORS
- Gastrointestinal stromal tumors metastatic to the ovary: a report of five cases.
Irving JA, Lerwill MF, Young RH.
James Homer Wright Pathology Laboratories of Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, MA, USA.
Am J Surg Pathol. 2005 Jul;29(7):920-6. Abstract quote
Five cases of gastrointestinal stromal tumor metastatic to the ovary are reported. The average patient age was 59 years (range, 44-81 years). The primary tumor was in the small bowel or its mesentery (4 cases) or stomach (1 case). The primary and metastatic tumors were discovered synchronously in 3 cases. In the other 2 cases, the ovarian tumors were discovered 18 months before a gastric tumor was identified and 27 years after a small bowel tumor had been resected. The ovarian tumors (three of which were bilateral) were usually solid, tan, and lobulated.
Microscopically, three tumors had a pure spindle cell morphology, and two both spindle and epithelioid cell components. The diagnosis in all 5 cases was confirmed with positive c-kit (CD117) and negative desmin immunostaining. Variably positive immunoreactivity for either or both h-caldesmon and smooth muscle actin was seen in all 5 cases, and 3 cases were CD34-positive. Four patients died between 1 and 6.5 years (mean, 2.8 years) from the time of ovarian tumor diagnosis. The main differential diagnostic consideration was leiomyosarcoma; the most important features to help exclude this diagnosis were an absence of tumor in the uterus, low histologic grade, and a desmin-negative, c-kit-positive immunophenotype. Other differential considerations, including endometrial stromal sarcoma and fibrosarcoma, are discussed.
Most of the ovarian tumors in this series were initially diagnosed as tumors of other types, a misdiagnosis with significant therapeutic and prognostic implications because of the specific therapy now available for gastrointestinal stromal tumors.KRUKENBERG TUMORS
- Krukenberg tumors of the ovary: a clinicopathologic analysis of 120 cases with emphasis on their variable pathologic manifestations.
Kiyokawa T, Young RH, Scully RE.
James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and the Department of Pathology, Harvard Medical School, Boston, MA.
Am J Surg Pathol. 2006 Mar;30(3):277-99. Abstract quote
120 Krukenberg tumors were analyzed with emphasis on their wide microscopic spectrum and resultant problems in differential diagnosis. The patients ranged from 13 to 84 years (average, 45 years) with 43% of them under 40 years. Abdominal swelling or pain usually accounted for the clinical presentation, but 17 had abnormal vaginal bleeding, 4 had virilization, and 4 had hirsutism without virilization. Ascites was present in 43% of the cases.
Sixty-three percent of the tumors were documented to be bilateral, but both ovaries were not always removed or rigorously examined microscopically. The mean diameter of the tumors was 10.4 cm, and they typically had intact, bosselated external surfaces without adhesions. The sectioned surfaces were typically solid and firm to edematous to gelatinous; one third of the tumors also had cysts.
Microscopic examination showed great variation from case to case and within individual neoplasms. Multiple nodules separated by normal stroma were seen in small neoplasms and focally in many larger ones. The tumors were often more cellular at their periphery and edematous to gelatinous centrally. An irregular distribution of cellular and less cellular areas often imparted a pseudolobular pattern. The cellularity of the stroma ranged from densely cellular to paucicellular; the latter regions ranged from edematous to mucoid. The overall morphology varied according to the prominence of signet-ring cells, extracellular mucin, edema, and various epithelial patterns. Signet-ring cells were numerous in most neoplasms (and by definition occupied at least 10% of the neoplasm) but were often absent or inconspicuous in significant areas of them. The signet-ring cells typically had modest but sometimes copious amounts of pale to basophilic cytoplasm; occasionally, it was eosinophilic. The signet-ring cells varied widely in their arrangement, growing singly, in clusters, forming confluent masses or pseudo-tubular arrays or lining part of all of a true tubule. Small glands and tubules were common, often resembling microcysts (when the lining cells were flattened) or Sertoli tubules; mucinous glands and cysts and medium-sized to large intestinal-type glands were also relatively common, particularly the latter. Extracellular mucin was often conspicuous and, when associated with scant acellular collagenous stroma, gave a distinctive appearance referred to by us as "feathery degeneration." Stromal luteinization was present in the tumors of the 8 pregnant patients and was seen in 14% of the nonpregnant patients.
Unusual features that complicated the microscopic picture included diffuse sheets or other arrangements of mucin-free indifferent cells, squamous cells, clear cells, transitional cells, and corded, trabecular, and insular patterns. Vascular space invasion was common. Two thirds of the primary carcinomas were detected synchronously with, or subsequent to, detection of the Krukenberg tumor compounding the diagnostic difficulty posed by the cases. Two thirds of the primary tumors were in the stomach; other primary sites in order of frequency were appendix, colon, breast, small intestine, rectum, gallbladder, and urinary bladder.
Our observations emphasize that the microscopic spectrum of the Krukenberg tumor is broader that often presented in the literature, in particular tubules, glands, and cysts often being present, and the wide pathologic differential diagnosis is discussed.LUNG
- Lung Carcinoma Metastatic to the Ovary: A Clinicopathologic Study of 32 Cases Emphasizing Their Morphologic Spectrum and Problems in Differential Diagnosis.
Irving JA, Young RH.
From the *Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada; and the daggerJames Homer Wright Pathology Laboratories of the Massachusetts General Hospital and the Department of Pathology, Harvard Medical School, Boston, MA.
Am J Surg Pathol. 2005 Aug;29(8):997-1006. Abstract quote
Thirty-two cases of lung carcinoma metastatic to the ovary in women 26 to 76 years of age (mean, 47 years) are reported. A history of prior lung carcinoma was documented in 53% of cases (17 of 32), with the ovarian tumor detected at a mean interval of 1 year.
In 10 cases (31%), the lung and ovarian tumors occurred synchronously, and in 5 (16%) the ovarian tumor was detected up to 26 months before the lung cancer. Small cell carcinoma was more likely to present with ovarian manifestations than other subtypes. A history of smoking was obtained in 9 cases (28%), but detailed histories were not always available and the figure may be spuriously low. Forty-four percent of the tumors were small cell carcinomas (14 of 32), 34% adenocarcinomas (11 of 32), and 16% large cell carcinomas (5 of 32); there was a single squamous cell carcinoma and one atypical carcinoid. Thirteen percent of cases (4 of 32) had a coexisting primary ovarian tumor. The mean ovarian tumor size was 9.7 cm, and one third of the ovarian metastases were bilateral. Tumor was limited to the lung and one or both ovaries in 13 cases (40%). Morphologic features common to many of the ovarian tumors were multinodular growth, widespread necrosis, and extensive lymphovascular invasion; involvement of the ovarian surface was rare. Attention to these features, to the usual absence of associated typical surface epithelial neoplasia, and to the clinical history enabled the correct diagnosis to be made in the majority of cases without need of special studies.
In a minority of cases, immunohistochemical staining for thyroid transcription factor-1 was a useful ancillary marker in the distinction from primary ovarian carcinoma. The differential diagnosis with the primary ovarian tumors most often meriting consideration, including unusual variants of surface epithelial tumors, is discussed.STOMACH
James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Department of Pathology, Harvard Medical School, Boston, MA.
Ovarian metastases of intestinal-type gastric adenocarcinomas are rare, and information on them is very limited compared with that on signet-ring cell carcinomas that result in the Krukenberg tumor. Four cases are reported herein. The patients averaged 55 years of age. In 3 patients, the ovarian metastases were identified several to 21 months after the diagnosis of the gastric primary, and the tumors were synchronous in the fourth. Two tumors were bilateral, 1 unilateral, and for 1, the laterality was unknown.
The ovarian tumors were characteristically solid and cystic, with multinodular growth in 2. In 2 cases, the ovarian tumors had a pseudoendometrioid morphology with tubulo-glandular, cribriform, and papillary patterns; they also had focal trabecular and insular patterns. Prominent necrosis was present, including segmental and intraluminal "dirty" necrosis. In the other 2 cases, the ovarian tumors had a mucinous appearance, 1 being dominantly cystic with occasional goblet cells and the other with prominent foveolar-type cells. Nuclei ranged from deceptively bland to highly atypical. Surface implants were identified in 2 cases. Two ovarian tumors examined expressed cytokeratin 7 and 20 but not estrogen receptor. Three patients with follow-up information all died within 1 year of the ovarian metastases. Although information is limited, our results suggest that metastatic spread to the ovary by intestinal-type gastric adenocarcinoma is usually seen in patients older than those with Krukenberg tumors, with a known history of gastric carcinoma, and with concomitant widespread disease. Involvement of the ovary by intestinal-type gastric carcinoma produces a microscopic picture distinctly different from that of a Krukenberg tumor.
These metastatic intestinal-type tumors may be confused with metastases from other gastrointestinal sites that are more frequently the cause of pseudoendometrioid or mucinous metastases, and like such tumors may be confused with primary ovarian endometrioid and mucinous neoplasms.*ADAPTED FROM SEMINARS IN DIAGNOSTIC PATHOLOGY 2001;18(3)
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS
- Analysis of gene amplification and prognostic markers in ovarian cancer using comparative genomic hybridization for microarrays and immunohistochemical analysis for tissue microarrays.
Mayr D, Kanitz V, Anderegg B, Luthardt B, Engel J, Lohrs U, Amann G, Diebold J.
Institute of Pathology, Ludwig-Maximilians University Munich, Munich, Germany.
Am J Clin Pathol. 2006 Jul;126(1):101-9. Abstract quote
To identify oncogene amplification involved in ovarian carcinogenesis, we studied 21 ovarian carcinomas and 5 serous borderline tumors using conventional comparative genomic hybridization (CGH) and CGH to a genomic DNA microarray. Immunohistochemical analysis of the proteins encoded by the genes that were amplified frequently (FGF3/4, FGFR1, CCNE1, PAK1, JUNB, and MDM2) was performed on a tissue microarray comprising 254 cases of ovarian neoplasms.
Regarding histologic type, characteristic patterns of copy number changes were revealed. They correlated with histologic tumor type and with intratumoral heterogeneity. Gain of FGF3/4 and CCNE1 was found in all serous carcinomas. Endometrioid carcinomas most frequently showed gain of JUNB (83%), KRAS2 (67%), MYCN (50%), ESR (50%), and CCND2 (50%). Of the serous borderline tumors, 80% harbored amplification of FGFR1 and MDM2 and a 75% gain of PIK3CA. Only CCNE1 immunoreactivity was significantly correlated with CGH results (P < .05) and postoperative survival (P < .05).
Microarray-based genomic analysis in combination with immunohistochemical analysis was found to be a powerful technique for identification of clinically relevant gene amplification in human ovarian cancer.
Clinicopathologic Analysis of Early-stage Sporadic Ovarian Carcinoma
Leitao, Mario M Jr MD*; Boyd, Jeff PHD†‡; Hummer, Amanda MS§; Olvera, Narciso BS†; Arroyo, Crispinita D BS†; Venkatraman, Ennapadam PHD§; Baergen, Rebecca N MD¶; Dizon, Don S MD ? ; Barakat, Richard R MD*; Soslow, Robert A MD**
From the *Gynecology Service, Department of Surgery; †Gynecology and Breast Research Laboratory, Department of Surgery; ‡Clinical Genetics Service, Department of Medicine; §Department of Biostatistics, Memorial Sloan-Kettering Cancer Center; the ¶Department of Pathology, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, NY; and ^ Developmental Chemotherapy Service, Department of Medicine and **Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 147-159 Abstract quote The reported experience with early-stage (FIGO stage I/II) ovarian carcinoma (OC) is limited given that the majority of women with OC are diagnosed at an advanced stage. There has not been an extensive review of these tumors, and since the pathologic criteria differentiating invasive and borderline tumors have evolved over time, the issue of whether a proportion of these tumors should be reclassified has not been addressed.
We identified patients with stage I/II invasive OC who underwent primary surgical management at Memorial Sloan-Kettering Cancer Center from 1980 to 2000. Patients known to have a BRCA mutation or a family history of breast/ovarian cancer were excluded. Hematoxylin and eosin slide review, blinded to clinical outcomes, using current diagnostic criteria for ovarian carcinomas and borderline ovarian tumors, was performed. Progression-free survival (PFS) and disease-specific survival (DSS) were estimated and compared. Hematoxylin and eosin slides were reviewed for 140 of the 145 patients identified. The diagnosis was changed to borderline (low malignant potential) in 41 cases (29.3%). Twenty-nine (70.7%) of 41 changes in diagnosis involved endometrioid and mucinous tumors. This was attributable to the application of recently revised criteria for distinguishing borderline tumors from carcinomas. None of the originally diagnosed clear cell carcinomas was reclassified as borderline. The distribution of histologic subtypes among the 94 carcinomas included 26 serous (27.7%), 25 clear cell (26.6%), 22 endometrioid (23.4%), 10 mixed (10.6%), 6 mucinous (6.4%), 2 malignant Brenner (2.1%), and 3 adenocarcinomas, not otherwise specified (3.2%). Adjuvant therapy was given to 84 (89.4%) of the 94 patients with carcinomas. The 5-year PFS and DSS were significantly greater for the group of cases that was reclassified as borderline (4.5% vs. 26.2% progressed [ P = 0.006]; 4.5% vs. 25.6% died [ P = 0.003]). The 5-year PFS and DSS were significantly worse for carcinomas with a TP53 mutation (22.6% vs. 41.2% progressed [ P = 0.04]; 21.7% vs. 24.7% died [ P = 0.04]). There were no statistically significant differences in outcome between stages I versus II, tumor grades, clear cell histology versus other, and stage IC preoperative versus intraoperative rupture.
We concluded that a large number of cases originally diagnosed as early-stage sporadic OC were borderline tumors. Clear cell histology does not confer a worse prognosis compared with other histologies. The presence of a TP53 mutation was an adverse prognostic indicator.Relationship between age, histological type, and size of ovarian tumors.
Okugawa K, Hirakawa T, Fukushima K, Kamura T, Amada S, Nakano H.
Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Int J Gynaecol Obstet 2001 Jul;74(1):45-50 Abstract quote
OBJECTIVE: To clarify the relationship between age, histological type, and size of ovarian tumors.
METHOD: A review was made of 1648 cases of histopathologically diagnosed ovarian tumors and tumor-like lesions, and information on the age of the patients and size of the tumor was obtained. Statistical analysis was performed using Kruskal-Wallis tests or Mann-Whitney U-tests.
RESULTS: There were 840 (51%) cases of benign tumors, 73 (4%) cases of tumors of low malignant potential (LMP), 268 (16%) cases of malignant tumors and 467 (28%) cases of tumor-like lesions. The age of the patients was significantly different among tumor-like lesions (34.6+/-8.1 years), benign tumors (39.8+/-16.4 years), LMP tumors (45.2+/-18.3 years) and malignant tumors (51.9+/-13.0 years) (P<0.0001). The maximum diameter of the tumors was significantly different among tumor-like lesions (7.1+/-3.3 cm), benign tumors (10.9+/-5.6 cm), malignant tumors (13.6+/-6.5 cm) and LMP tumors (18.5+/-6.8 cm) (P<0.0001).
CONCLUSION: The distribution of tumor histological type (tumor-like lesions, benign, LMP and malignant) was correlated against patient age and lesion diameter, with tumors in older patients or larger tumors more likely to be malignant.
SURVIVIN
Survivin expression in ovarian carcinoma: correlation with apoptotic markers and prognosis.Cohen C, Lohmann CM, Cotsonis G, Lawson D, Santoianni R.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Mod Pathol. 2003 Jun;16(6):574-83. Abstract quote Survivin is a novel inhibitor of apoptosis commonly detected in tissues during fetal development and in cancer, but not usually in normal tissues. Expression of this protein may be of prognostic significance and therapeutically relevant in many cancers.
We assessed survivin expression in ovarian carcinoma, correlating results with expression of other anti-apoptotic (bcl-2, bcl-x, mutant p53) and pro-apoptotic (bax) markers, with prognostic parameters, and prognosis. Paraffin-embedded sections of 49 ovarian carcinoma were immunostained for survivin, bcl-2, bcl-x, bax, and p53.Expression was evaluated in nuclei and cytoplasm, as intensity (0-3+), and percentage of positive cells was scored on a four-tiered system with <10% as negative. Frequency of survivin, bcl-2, bcl-x, bax, and p53 was 73.5%, 36.7%, 93.9%, 77.6%, and 60.4%, respectively. There was significant correlation between nuclear survivin expression and grade (P =.0014), histologic type (P =.0376), and mutant p53 (P =.0414). Survivin expression did not correlate with bcl-2, bcl-x, or bax expression, stage, or overall or disease-free survival.
The majority (74%) of ovarian carcinoma show survivin expression, which correlates with poor prognostic parameters (high grade, histologic type, p53 mutation) but not with survival. Therapeutic targeting of survivin in ovarian carcinoma is a future possibility.TREATMENT Occult Carcinoma in Prophylactic Oophorectomy Specimens Prevalence and Association With BRCA Germline Mutation Status
Terence J. Colgan, M.D.; Joan Murphy, M.D.; David E. C. Cole, M.D., Ph.D.; Steven Narod, M.D.; Barry Rosen, M.D.
From Mount Sinai Hospital and the Department of Laboratory Medicine and Pathobiology (T.J.C.), University of Toronto; the Division of Gynecologic Oncology, University Health Network, and the Department of Obstetrics and Gynecology (J.M.), University of Toronto; the Adult Genetics Program, University Health Network, and the Department of Laboratory Medicine and Pathobiology (D.E.C.C.), University of Toronto; Breast Cancer Research, Center for Research in Women's Health (S.N.), University of Toronto, and Public Health Sciences; and the Familial Ovarian Cancer Clinic, University Health Network, (B.R.) and the Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada.
Am J Surg Pathol 2001;25:1283-1289 Abstract quote
Prophylactic oophorectomy (PO) is an option for women at increased risk for ovarian carcinoma.
In this study the value of intensive pathologic examination of PO specimens and accompanying resected tissues in the identification of occult carcinoma and any association of occult carcinoma with BRCA germline mutation status were ascertained.
Specimens from 60 consecutive PO patients, who were not suspected of having any ovarian tumor at the time of surgery, were subjected to standardized, complete pathologic examination in a prospective study over an 8-year period. Extra-ovarian tissues were examined as well, but they were not subject to the same standardized protocol. Any occult carcinoma of the ovaries or fallopian tubes was noted. The BRCA status and follow-up of patients were obtained, if available.
Fifty-five of the 60 PO specimens did not show any evidence of malignancy. Of the 32 patients in this group followed for >1 year, all are alive and well. The remaining five patients, all BRCA1 mutation positive, showed occult carcinoma of the ovaries and/or in situ or invasive carcinoma of a fallopian tube. One of these five patients has died of abdominal carcinomatosis; four continue to be well, but follow-up is <4 years in all cases.
Occult carcinoma is present in a small proportion of BRCA-positive or unknown PO patients and may be of prognostic significance. The entire ovaries and tubes from PO patients should be submitted for histologic examination to identify malignancy.
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Borderline (Low Malignant Potential)-This is a category of ovarian cancers which have subtle features of malignancy but have an indolent prognosis and only rarely progress to a more advanced stage.
Capsule-This is the surface epithelial covering of the ovary. The majority of ovarian cancers arise from this epithelium. If a cancer penetrates through this capsule, it is considered a poor prognostic factor.
Sex-Cord Stroma-The ovarian stoma is derived from the primitive embyronic tissue which gives rise to the ovary and testis. This tissue is known as sex cords and have the potential to give rise to tumors found in both males and females. In addition, this stroma may secrete estrogens and androgens producing feminizing or masculinizing features.
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