Debra A. Bell

Origins and molecular pathology of ovarian cancer.

Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. Current data indicate that each of these histologic subtypes is associated with distinct morphologic and molecular genetic alterations: high-grade serous and possibly endometrioid carcinomas most probably arise from surface epithelial inclusion glands with TP53 mutations and dysfunction of BRCA1 and/or BRCA2; low-grade serous carcinomas probably arise in a stepwise fashion in an adenoma–borderline tumor–carcinoma sequence from typical to micropapillary borderline tumors to low-grade invasive serous carcinoma via activation of the RAS–RAF signaling pathway secondary to mutations in KRAS and BRAF; mucinous carcinomas arise via an adenoma–borderline tumor–carcinoma sequence with mutations in KRAS; low-grade endometrioid carcinomas arise from endometriosis via mutations in CTNNB1 (the gene encoding β-catenin) and PTEN. Although the morphologic data strongly support an origin of clear cell carcinoma from endometriosis, there is limited data on the genetic alterations in these uncommon tumors. Thus it is likely that most low-grade, relatively indolent ovarian carcinomas of serous, mucinous and endometrioid type arise from pre-existing cystadenomas or endometriosis whereas most high-grade serous carcinomas arise without an easily identifiable precursor lesion.

Peritoneal implants of ovarian serous borderline tumors: Histologic features and prognosis

The clinicopathologic features of 56 cases of ovarian serous borderline tumors (SBT) associated with peritoneal implants were reviewed. Data from 368 person‐years of follow‐up (median follow‐up, 6.0 years) were analyzed to investigate the possibility that the histologic features of implants of this type of tumor may correlate with the prognosis. Eighty‐five percent of the 56 patients were clinically free of tumor at the time of death or at last contact. Thirteen percent of the patients died of tumor, and one patient (2%) was alive with widespread progressive tumor. The product‐limit estimate of the probability of death from tumor (± standard error) was 4% (±3%) at 5 years and 23% (±9%) at 10 years. The following three histologic features of the implants correlated with an adverse prognosis: (1) invasion (P = 0.0004), (2) severe cytologic atypia in both invasive and noninvasive implants (P = 0.0008) and in noninvasive implants alone (P = 0.02), and (3) the presence of mitotic activity in both types of implants (P = 0.02) and in noninvasive implants alone (P = 0.02). The only other feature that correlated with the prognosis was the presence of residual tumor postoperatively as assessed by the surgeon (P ± 0.01). The product‐limit estimate of death of tumor in patients with at least one of these four adverse prognostic factors was 56% (±20%) at 10 years. Whether or not the patients received radiation therapy, chemotherapy, or both had no statistically significant effect on the outcome. These data and the results of a stratified analysis suggest that patients may benefit from additional therapy if adverse prognostic factors are present, especially invasiveness or severe cytologic atypia. It is unlikely that additional therapy is necessary in patients without adverse prognostic features, because no deaths occurred in this group.

Signal Transducers and Activators of Transcription 3 Pathway Activation in Drug-Resistant Ovarian Cancer

Purpose: One of the major obstacles in the treatment of ovarian cancer is the development of multidrug resistance. Recent evidence shows that high-grade ovarian cancer often shows activation of the signal transducers and activators of transcription 3 (Stat3) pathway with subsequent transcription of genes that support tumor growth and survival. Less studied is the role of the Stat3 pathway in acquired drug resistance. There is no information on Stat3 expression in chemotherapy naïve ovarian cancer as compared with tumors collected later in the natural history of the disease. To further clarify the significance of Stat3 activation in ovarian cancer, here we investigated the Stat3 expression and activation in ovarian cancer and ovarian cancer multidrug resistance cell lines. Experimental Design: Western blotting, electrophoretic mobility shift assay, luciferase assays, ELISA assay, and real-time reverse transcription-PCR determined interleukin-6 and Stat3 pathway expression and activation in cell lines. Stat3 expression in ovarian cancer tissue microarray was evaluated by immunohistochemistry. Results: Activated (phosphorylated) Stat3 is overexpressed in most paclitaxel-resistant ovarian cancer cells. Inhibition of Stat3 activation results in significant decreases in paclitaxel resistance and enhanced apoptosis. Drug-resistant recurrent tumors have significantly greater phosphorylated Stat3 (pStat3) expression as compared with matched primary tumors. Tumors with associated inflammatory cell infiltrates also have a higher proportion of cells staining intensely for nuclear phosphorylated Stat3 as compared with tumors without inflammatory infiltrates, consistent with paracrine activation of the Stat3 pathway by immune-mediated cytokines. Conclusions: These data support the hypothesis that interruption of Stat3 signaling could reverse resistance to paclitaxel and perhaps other chemotherapy agents in human cancer.

Serous borderline tumors of the peritoneum

The clinicopathological features of 25 cases of peritoneal serous neoplasms histologically identical to noninvasive implants of ovarian serous borderline tumors but with minimal or no ovarian surface involvement were reviewed. The patients ranged in age from 19 to 53 (mean, 31) years; 18 of them were under 35 years of age. Infertility and abdominal pain were the most common presenting complaints. An extraovarian mass was present in two patients; adhesions or granularity of peritoneal surfaces were described in 23 of them. In 21 cases only the pelvic peritoneum was involved; the upper abdominal peritoneum was involved additionally in four cases. Most of the women were treated by hysterectomy, bilateral salpingoophorectomy, and omentectomy; six of them received chemotherapy postoperatively and two received both chemotherapy and radiation therapy. Nine women had a more limited operation to preserve their fertility. The 25 patients were followed for 4 to 13.9 (mean, 8) years. There was no clinical evidence of recurrence in 21 women. Borderline tumor recurred in two patients, who remained well for 1.7 and 2 years after excision of the recurrent tumor. Invasive low-grade serous carcinoma of the peritoneum developed in one woman who was living with extensive intra-abdominal tumor at the last followup examination. One women died of disseminated SBT, which was diagnosed cytologically but not confirmed by biopsy.

Bcl-2 and p53 Protein Expression, Apoptosis, and p53 Mutation in Human Epithelial Ovarian Cancers

Bcl-2 and p53 gene products have been both linked to cell death by apoptosis. In the present study, we examined the relationship of Bcl-2 and p53 protein expression, p53 mutation and apoptosis in normal human ovaries and different types of human ovarian epithelial tumors by immunohistochemical localization, in situ terminal transferase-mediated dUTP nick end labeling and polymerase chain reaction-single strand conformation polymorphism. It was found that Bcl-2 expressed strongly in the surface epithelium of normal ovaries and benign and borderline ovarian tumors but weakly in the malignant tumors. On the contrary, strong protein expression of p53 was found in 54% (25/46) of the malignant epithelial tumors examined but similar expression of p53 was not observed in borderline and benign tumors and normal ovarian surface epithelium. A significant inverse correlation between Bcl-2 and p53 expression was found in the malignant ovarian tumors examined. p53 gene mutation at exons 5-11 was however not a pre-requisite for p53 expression in both borderline and malignant tumors. Apoptotic activities, as reflected by apoptotic indices, were low in normal ovarian surface epithelium and benign tumors but were increased in borderline and malignant tumors, with the highest average apoptotic index found in grade III malignant tumors. Statistical analyses showed a positive correlation between apoptosis and p53 expression, but similar correlation was not found between apoptosis and Bcl-2 expression. Our results also indicate that although expression of Bcl-2 is important during ovarian carcinogenesis, the Bcl-2 protein may have other roles to play apart from being a modulator of apoptosis in human ovarian epithelial cancers.

Ovarian serous borderline tumors with stromal microinvasion: a report of 21 cases.

The clinicopathologic features of 21 cases of otherwise typical serous borderline tumors that contained small foci of stromal invasion were reviewed. The mean age of the patients was 43 years and six of them were pregnant at the time of diagnosis. Nineteen tumors were stage I, one was stage III (para-aortic lymph node involvement) and one was stage IV (parenchymal liver metastasis). The tumor invaded the stroma predominantly as individual cells or nests or clusters of cells with abundant eosinophilic cytoplasm (17 cases), as small confluent nests with a cribriform pattern (two cases) and as rounded aggregates of papillae (two cases). Seven women were treated with bilateral salpingo-oophorectomy and hysterectomy; 13 had less than bilateral oophorectomy. Of the 17 patients for whom followup data were available, 16 were without evidence of disease 1 to 11 (mean, 5.2) years postoperatively, and one patient had a serous borderline tumor with microinvasion in a conserved contralateral ovary 2.8 years postoperatively, but was well 6 months after a partial oophorectomy. These data suggest that serous borderline tumors with microinvasion have a prognosis similar to that of the usual serous borderline tumor, and that conservation of the contralateral ovary and uterus may be acceptable therapy in young women who wish to preserve their fertility.

Galactose consumption and metabolism in relation to the risk of ovarian cancer.

In a case-control study, consumption of dairy foods by 235 white women with epithelial ovarian cancer and by 239 control women, and activity of red blood cell galactose-1-phosphate uridyl transferase (transferase) in a subset of 145 cases and 127 controls were determined. Yogurt was consumed at least monthly by 49% of cases and 36% of controls. The mean transferase activity of cases was significantly lower than that of controls. When a ratio of lactose consumption to transferase (L/T) was calculated, cases had a mean L/T of 1.17 compared with 0.98 for controls; there was a highly significant trend for increasing ovarian cancer risk with increasing L/T ratio. Lactose consumption may be a dietary risk factor and transferase a genetic risk factor for ovarian cancer.

Borderline tumors of the ovary: correlation of frozen and permanent histopathologic diagnosis

Objective To evaluate the correlation between the diagnosis of borderline tumor of the ovary by frozen and permanent pathology. Methods All pathology reports with diagnoses of borderline tumor of the ovary between 1980 and 1998 at Massachusetts General Hospital were reviewed. Univariate and multivariable logistic regression models were constructed for patient age, tumor size, histology, presence of bilateral or extraovarian disease, and concurrent diagnosis of endometriosis or endosalpingiosis. Results We reviewed 140 cases. The average age of patients was 52.3 years. Eighty tumors were serous, 47 mucinous, 11 mixed, and two endometrioid. The mean diameter overall was 13.7 cm (range 1–70 cm), 10.2 cm for serous, and 20.1 cm for mucinous. Diagnoses of borderline tumors by frozen and permanent pathology were consistent in 60% of cases. Frozen section interpreted a benign lesion as malignant (overdiagnosed) in 10.7% of cases, and interpreted a malignant lesion as benign (underdiagnosed) in 29.3%. No variable was a significant predicator of overdiagnosis. In univariate analysis, underdiagnosis was more likely for other types of tumors than serous (P < .001), tumors larger than 20 cm (P = .039), and tumors confined to the ovaries (P = .009). When all variables were included in a multiple regression model, only histology was a significant predictor of underdiagnosis (P = .039). Conclusion Frozen or permanent pathology reports of diagnoses of borderline tumor were consistent 60% of the time, whereas the positive predictive value of borderline by frozen section was 89.3%. Tumors other than serous are more likely to be misinterpreted.

Ovarian surface epithelial-stromal tumors

The two decades since the publication of Dr Scully’s review for this journal, entitled “Recent Progress in Ovarian Cancer,“’ have been a time of intense investigative effort facilitated by the standardization of diagnostic criteria and terminology that resulted from widespread acceptance of the original World Health Organization (WHO) Classification of Ovarian Tumors.’ During this period, research on surface epithelialstromal tumors, formerly referred to as common “epithelial” tumors,2*3 has focused on the possible prognostic importance of the histologic appearance of peritoneal implants in borderline tumors, development of more precise histologic criteria for the diagnosis of borderline tumors, the miillerian neoplastic potential of the ovarian surface epithelium and female peritoneum, the division of mutinous tumors into those of endocervital-like (miillerian) and gastrointestinal type, and the separation of transitional cell carcinomas from malignant Brenner tumors. This review will concentrate primarily on these advances, which, among others, are the basis of the recent revision of the WHO Classification of Ovarian Tumors chaired by Dr Scully (Scully RE, personal communication).

p53 gene analysis of ovarian borderline tumors and stage I carcinomas

Mutations of the p53 gene are common in human ovarian carcinomas; however, their role in the early development of ovarian cancer is unclear. Twelve ovarian borderline tumors (BTs; eight of them p53 immunopositive) and 10 stage I carcinomas (four of them p53 immunopositive) were studied for genetic alterations in the p53 gene. The study was based on single-strand conformation polymorphism (SSCP) analysis and DNA sequencing of exons 2 through 11 of the p53 gene using DNA preparations from microdissected tumors. Mutations were found in 40% of the carcinomas (including a borderline component adjacent to carcinoma in one lesion) but in none of the pure BTs. These findings suggest that p53 mutations may not be commonly associated with the borderline phenotype of ovarian epithelial tumors but may occur during malignant transformation.