Pathology of stage I versus stage III ovarian carcinoma with implications for pathogenesis and screening.

The progression of ovarian carcinoma from stage I when it is confined to the ovaries and curable to disseminated abdominal disease, which is usually fatal, is poorly understood. An accurate understanding of this process is fundamental to designing, testing, and implementing an effective screening program for ovarian cancer. Pathologic features of the primary ovarian tumors in 41 FIGO stage I ovarian carcinomas were compared with those in 40 stage III carcinomas. The primary ovarian tumors in stage I cases, when compared with stage III, respectively, were significantly larger (15.4 versus 9.8 cm), were less frequently bilateral (12% versus 75%), more frequently contained a noninvasive component (88% versus 30%), had a higher proportion of a noninvasive component (42% versus 8%), and were more often nonserous (83% versus 20%) (P < 0.001 for all five comparisons). There are significant pathologic differences between the primary ovarian tumors in stage I and III ovarian carcinomas that are very difficult to explain by a simple temporal progression. These findings along with the growing body of literature suggest that early- and advanced-stage ovarian cancers are in many instances biologically different entities. This knowledge may have significant implications for our understanding of the biology of early- and advanced-stage ovarian cancer and therefore on the development of screening strategies for ovarian cancer.

Serous borderline tumours of the ovary.

Serous borderline tumours of the ovaryIn this Expert Opinion we have invited articles from two leading groups, to discuss serous borderline tumours (serous tumours of low malignant potential) of the ovary from their own perspectives. Controversy remains over heterogeneity within this group of tumours and their relationship to ovarian cancer. Our authors discuss the histopathological classification of these tumours in relation to morphological appearances, molecular and clinical data. The significance of a micropapillary pattern is discussed, and issues related to extra-ovarian implants.

Uterine adenosarcoma with sarcomatous overgrowth versus uterine carcinosarcoma: comparison of treatment and survival.

OBJECTIVE: Uterine adenosarcoma with sarcomatous overgrowth (ASSO) is a rare variant of uterine sarcoma first described in 1989. This clinicopathologic study was undertaken to compare the treatment and survival of uterine adenosarcoma with sarcomatous overgrowth to that of uterine carcinosarcomas. METHODS: A review of uterine sarcomas diagnosed at Washington Hospital Center from January 1988 to December 1998 was performed. Records were reviewed for demographic data, surgical staging, primary and adjuvant therapy, metastatic site, disease recurrence, and survival. All pathology was reviewed and diagnosis confirmed. Statistical analysis included chi(2) test and Student's t test. Kaplan-Meier survival curves were plotted to estimate the median and 5-year survival times. The log-rank test was used to compare survival times. A P value <0.05 was considered significant. RESULTS: Sixty patients were diagnosed with uterine sarcoma at Washington Hospital Center. Of these, 33 (55%) were uterine carcinosarcomas, 11 (18%) ASSOs, 6 (10%) adenosarcomas, and 10 (17%) leiomyosarcomas. Of the patients diagnosed with uterine ASSO, 3 (27%) were stage I, 3 (27%) stage II, 1 (9%) stage III, and 4 (36%) stage IV. All 11 patients with uterine ASSO underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and tumor debulking. Postoperative adjuvant therapy included chemotherapy (n = 4), radiation (n = 4), combination radiation and chemotherapy (n = 1), and no adjuvant therapy (n = 2). The overall median survival time of patients with uterine ASSO was 13 months. Nine of eleven patients are dead of disease, and two patients (both with stage I) are alive without evidence of disease at 18 and 19 months. Thirty-three patients with carcinosarcoma were identified, with follow-up available on 29 patients. Of these, 10 (34%) were stage I, 6 (22%) stage II, 3 (10%) stage III, and 10 (34%) stage IV. Twenty-seven of the twenty-nine patients diagnosed with carcinosarcoma underwent surgical therapy to include total abdominal hysterectomy, bilateral salpingo-oophorectomy, staging and tumor debulking. Two patients died prior to treatment. Postoperative adjuvant therapy included chemotherapy (n = 9), radiation (n = 13), combination (n = 1), and no further therapy (n = 4). Twenty of the twenty-nine patients are dead of disease; there were nine surviving patients at the time of this report (stage I-5, stage II-3, stage III-1). The median survival of these patients was 31 months, with an overall 5-year survival of 22%. Comparison of the Kaplan-Meier survival curves using the log-rank test suggests a worse prognosis for uterine ASSO. However, this did not reach statistical significance (P = 0.0522). CONCLUSIONS: Patients diagnosed with uterine ASSO have a poor prognosis similar to that of carcinosarcoma. Management should include complete surgical staging. Additional therapy in the form of radiation, chemotherapy, or both has been reported; however, the superiority of one modality could not be determined from our data.

A serologically identified tumor antigen encoded by a homeobox gene promotes growth of ovarian epithelial cells.

Ovarian carcinomas are thought to arise from cells of the ovarian surface epithelium by mechanisms that are poorly understood. Molecules associated with neoplasia are potentially immunogenic, but few ovarian tumor antigens have been identified. Because ovarian carcinomas can elicit humoral responses in patients, we searched for novel tumor antigens by immunoscreening a cDNA expression library with ovarian cancer patient serum. Seven clones corresponding to the homeobox gene HOXB7 were isolated. ELISAs using purified recombinant HOXB7 protein revealed significant serologic reactivity to HOXB7 in 13 of 39 ovarian cancer patients and in only one of 29 healthy women (P < 0.0001). Ovarian carcinomas were found to express HOXB7 at markedly higher levels than normal ovarian surface epithelium, suggesting that immunogenicity of HOXB7 in patients could be associated with its elevated expression in ovarian carcinomas. Overexpression of HOXB7 in immortalized normal ovarian surface epithelial cells dramatically enhanced cellular proliferation. Furthermore, HOXB7 overexpression increased intracellular accumulation and secretion of basic fibroblast growth factor, a potent angiogenic and mitogenic factor. These results reveal HOXB7 as a tumor antigen whose up-regulated expression could play a significant role in promoting growth and development of ovarian carcinomas.

Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators.

BACKGROUND: The behavior of ovarian serous borderline tumors (SBTs) and significance of various prognostic factors are unclear and difficult to evaluate because of inconsistencies and confusion in the literature. Recent studies have suggested that the morphological features of the primary tumor (presence or absence of micropapillary features) and the peritoneal "implants" (presence or absence of invasive features) can reliably subclassify SBTs into benign and malignant types. The aim of the current review was to test two hypotheses. First, that the alleged malignant behavior of SBTs is poorly documented, and second, that the morphological features of the primary ovarian tumors and the associated peritoneal implants are sufficient to separate SBTs into benign and malignant types, thereby obviating the need for the category. METHODS: 245 studies reporting approximately 18,000 patients with borderline ovarian tumors were reviewed. After excluding series that lacked clinical follow-up or were not analyzable for other reasons, there remained 97 reports that included 4,129 patients. In addition to recurrences and survival, we evaluated the type of peritoneal implants, microinvasion, lymph node involvement, late recurrences, and progression to carcinoma, as these features have served as the underpinning of the concept of "borderline malignancy" or "low malignant potential." RESULTS: Among 4,129 patients with SBTs reviewed, the recurrence rate after a mean follow-up of 6.7 years was 0.27% per year for stage I tumors, the disease-free survival was 98.2%, and the overall disease-specific survival rate was 99.5%. For patients with advanced-stage tumors, the recurrence rate was 2.4% per year. However, the majority (69%) of reported recurrences were not pathologically documented, and only 26 cases (8.4% of all recurrences) were documented to have recurred from an adequately sampled ovarian tumor. The most reliable prognostic indicator for advanced stage tumors was the type of peritoneal implant. After 7.4 years of follow-up, the survival of patients with noninvasive peritoneal inplants was 95.3%, as compared with 66% for invasive implants (P < .0001). Microinvasion in the primary ovarian tumor was associated with a 100% survival rate at 6.7 years, and lymph node involvement was associated with a 98% survival rate at 6.5 years. The few reported cases of stage IV disease, progression to invasive carcinoma, and very late (>20 years) recurrences were poorly documented. The survival for all stages among approximately 373 patients in 6 prospective randomized trials followed for a mean of 6.7 years was 100%. CONCLUSION: Surgical pathological stage and subclassification of extraovarian disease into invasive and noninvasive implants are the most important prognostic indicators for SBTs. Survival for stage I tumors is virtually 100%. Survival for advanced stage tumors with noninvasive implants is 95.3%, whereas survival for tumors with invasive implants is 66%. Invasive implants behave as carcinomas and are most likely metastatic. The precise nature of so-called noninvasive implants is not clear, but they behave in a benign fashion. The presence of a micropapillary architecture in the primary ovarian tumor is a strong predictor of invasive implants. These data support the recommendation that ovarian tumors with a micropapillary architecture be designated "micropapillary serous carcinomas," and those lacking these features, "atypical proliferative serous tumors."

Cluster of uterine mullerian adenosarcoma in the Washington, DC metropolitan area with high incidence of sarcomatous overgrowth.

Mullerian adenosarcoma is an uncommon variant of uterine sarcoma. Twelve uterine adenosarcomas were diagnosed during a 42-month period at the Washington Hospital Center in Washington, DC. Based on estimated incidence data derived from the US Department of Defense beneficiary population, an estimated relative risk of 15.4 (95% confidence interval, 7.7-31.0) was calculated, indicating a significantly increased incidence of adenosarcoma in the population studied (p<0.0000001). Among 10 patients who underwent hysterectomy, six (60%) of their tumors had sarcomatous overgrowth. In comparison with the previously reported proportion of adenosarcomas with sarcomatous overgrowth, approximately 16%, the proportion with sarcomatous overgrowth was significantly higher than expected (p<0.01). Mullerian adenosarcoma with sarcomatous overgrowth was first described in 1989 and suggests that the cluster of adenosarcomas reported herein may be due in part to the current classification of some uterine tumors as adenosarcoma with sarcomatous overgrowth that previously would have been classified as other types of uterine sarcoma. Nonetheless, even after reviewing and updating the classification of all sarcomas diagnosed at the Washington Hospital Center from 1985 to 1998, the ratio of adenosarcomas to uterine adenocarcinomas during the 1994-1998 period was 4.7 times (p<0.005) that of the 1985-1993 period, suggesting a more modest but real increase in the occurrence of this tumor. Correct classification of mullerian adenosarcomas with sarcomatous overgrowth is important because the limited available data suggest that the prognosis is notably worse than that for adenosarcomas without sarcomatous overgrowth.

Placental site nodule and characterization of distinctive types of intermediate trophoblast.

Both placental site nodule and exaggerated placental site are described as being composed of intermediate trophoblast (IT), yet their morphological features and clinical presentation differ significantly. This study was undertaken to evaluate the morphological and immunohistochemical features of trophoblastic cells in placental site nodules and compare them with the trophoblastic cells in exaggerated placental sites as well as in different anatomic locations in the developing placenta to evaluate these differences. Forty-two placental site nodules, 20 abortus specimens ranging from 3 to 13 weeks, 8 second- and 10 third-trimester placentas, and 12 exaggerated placental sites were studied by conventional light microscopy and immunohistochemistry. This analysis showed that the trophoblastic cells in the placental site nodule closely resemble those in the chorion laeve. We have designated these cells "chorionic-type IT cells." They are composed of two populations of cells, one with eosinophilic and the other with clear (glycogen-rich) cytoplasm. The eosinophilic cells tended to be larger with more pleomorphic nuclei, whereas the clear cells were smaller with more uniform nuclei. Chorionic-type IT cells in the chorion laeve and placental site nodule were diffusely positive for placental alkaline phosphatase but were only focally positive or negative for human placental lactogen (hPL), Mel-CAM (CD146), and oncofetal fibronectin. In contrast, hPL, Mel-CAM, and oncofetal fibronectin were diffusely expressed in IT cells in the placental site, both normal and exaggerated. The chorionic-type IT cells in placental site nodule and chorion laeve showed mild proliferative activity as indicated by an increased Ki-67 labeling index (3% to 10%). In contrast, the Ki-67 labeling index in normal and exaggerated implantation sites was zero. The morphological and immunohistochemical features of chorionic-type IT cells contrast with the IT cells in the implantation site that we have designated "implantation site IT cells." Both types of IT cells develop from a population of trophoblastic cells in the trophoblastic columns that we have tentatively termed "villous IT cells." Four of 42 placental site nodules were larger (>5 mm) than the remainder and showed transitional features between a typical placental site nodule and an epithelioid trophoblastic tumor, a recently described distinctive gestational trophoblastic tumor. There were no recurrences among the placental site nodules regardless of size. All placental site nodules were immunoreactive for inhibin-alpha and cytokeratin 18, whereas 33 squamous cell carcinomas of the cervix, which can at times be confused with placental site nodules, were negative. In conclusion, there appear to be three subpopulations of IT cells with distinctive morphological and immunohistochemical features. Different subpopulations can be related to different trophoblastic lesions: implantation site IT cells to an exaggerated placental site and its neoplastic counterpart, placental site trophoblastic tumor and chorionic-type IT cells to a placental site nodule and its neoplastic counterpart, epithelioid trophoblastic tumor.

Inhibin and epithelial membrane antigen immunohistochemistry assist in the diagnosis of sex cord-stromal tumors and provide clues to the histogenesis of hypercalcemic small cell carcinomas.

Ovarian sex cord-stromal tumors are a morphologically diverse group of neoplasms that can mimic the appearance of other ovarian tumors. Because the treatment and prognosis of sex cord-stromal tumors differs substantially from those of other ovarian neoplasms, the development of an immunohistochemical panel to support the diagnosis of the former group of tumors would be useful. In this report, the utility of immunostaining for inhibin alpha, epithelial membrane antigen, MIC2 gene protein product, and keratin in the differential diagnosis of sex cord-stromal tumors was assessed in formalin-fixed, paraffin-embedded sections. In addition, the immunohistochemical staining pattern of ovarian small cell carcinomas (SCCs), hypercalcemic type, was analyzed in an attempt to clarify the histogenesis of these tumors. Thirty-two (97%) of 33 granulosa cell tumors (GCTs), 10 (91%) of 11 Sertoli-Leydig cell tumors (SLCTs), and 4 (8%) of 51 carcinomas showed inhibin alpha immunopositivity. None of the 3 lymphomas, 5 carcinoids, 6 dysgerminomas, or 12 SCCs showed inhibin alpha positivity. Eighteen (55%) GCTs, 6 (55%) SLCTs, 6 (12%) carcinomas, and 7 (58%) SCCs showed MIC2 gene expression. None of the GCTs and only one SLCT showed epithelial membrane antigen (EMA) positivity, although 92% of surface epithelial carcinomas and 75% of SCCs were immunoreactive. These data suggest that detection of inhibin immunoreactivity in an ovarian tumor that is EMA-negative provides both sensitive and specific support for the diagnosis of a sex cord-stromal tumor. Because SCCs generally stain for EMA but not for inhibin, it appears that SCCs probably represent a variant of surface epithelial tumor rather than a type of sex cord-stromal tumor.

Subclassification of serous borderline tumors of the ovary into benign and malignant types. A clinicopathologic study of 65 advanced stage cases.

Poor outcome in serous borderline tumors (SBT) of the ovary is limited to patients with advanced stage disease. This study was designed to determine whether there are histologic features among advanced-stage SBTs (International Federation of Gynecology and Obstetrics [FIGO] stages II and III) that predict behavior. The 65 cases in the study were divided into three groups: typical SBTs, with noninvasive implants (51 cases), SBTs with invasive implants (three cases), and a recently described tumor, designated micropapillary serous carcinoma (MPSC) (11 cases), a proliferative serous ovarian neoplasm that often lacks destructive infiltrative growth but appears to behave as a low-grade invasive carcinoma. When the tumor lacks infiltrative growth, as it did in the 11 cases in this series, it qualifies as a borderline tumor. After censoring nontumor deaths, the 5- and 10-year actuarial survival rates were 98% for SBTs with noninvasive implants, 33% for SBTs with invasive implants, and 81% at 5 years and 71% at 10 years for MPSCs. The mean follow-up was 100 months. Two (4%) of 51 patients with SBTs with noninvasive implants subsequently developed invasive carcinoma, and one (2%) died of carcinoma. In contrast, two (67%) of three women with SBTs accompanied by invasive implants developed invasive carcinoma, and both died of disease. Finally, of the 11 patients with MPSC, seven (64%), all of whom had invasive implants, developed recurrences of invasive carcinoma and/or died of tumor. MPSCs had significantly higher rates of mortality (p < 0.001) and recurrence as invasive carcinoma (p < .002) than SBTs with noninvasive implants. The recognition that SBTs can be divided into benign and malignant subtypes provides the basis for replacing the borderline category. The benign subgroup is composed of typical SBTs, including those with noninvasive implants for which the term atypical proliferative serous tumor is appropriate. In contrast, tumors displaying a micropapillary growth pattern (MPSC) and SBTs with invasive implants should be classified as carcinomas and treated accordingly.

Uterine leiomyomas. Racial differences in severity, symptoms and age at diagnosis.

OBJECTIVE: To investigate racial differences in the presence of leiomyomas, condition severity, associated symptoms and age at diagnosis between black and white hysterectomy patients. STUDY DESIGN: This study included 409 black women and 836 white women aged 18 or older who underwent hysterectomy for noncancerous conditions at 28 hospitals in Maryland. Patients were interviewed shortly before surgery, and hospital records were abstracted after discharge. RESULTS: Overall, 89% of the black women and 59% of the white women were found to have leiomyomas. Among those with a confirmed presurgical diagnosis of leiomyomas, the average age at diagnosis was 37.5 years for black women and 41.6 for white women, and the average age at hysterectomy was 41.7 for black women and 44.6 for white women. The average uterine weight for black women with leiomyomas was 420.8 g and for white women was 319.1 g. Black women were more likely to have seven or more leiomyomas (57%) in comparison to white women (36%). Black women with leiomyomas were more likely to be anemic (56%) than white women (38%) and more likely to report having very severe or severe pelvic pain (59%) than white women (41%). CONCLUSION: Black women having hysterectomy had larger and more numerous leiomyomas, and the leiomyomas were more symptomatic than in white women despite a younger age at diagnosis and hysterectomy.

Pathologic findings from the Maryland Women's Health Study: practice patterns in the diagnosis of adenomyosis.

Criteria for the diagnosis of adenomyosis vary widely in practice. The reported frequency of adenomyosis in hysterectomy specimens varies from 5-70% in published series. In this study, 1252 pathology reports on hysterectomy specimens from women enrolled in the Maryland Women's Health Study were reviewed. The frequency of adenomyosis was calculated based on two subgroups: 1114 reports from 15 hospitals, and 705 reports signed by 25 pathologists. The frequency of diagnosis of adenomyosis ranged from 12% to 58% among the 15 hospitals, and 10% to 88% among the 25 pathologists. This wide variation could not be explained by differences in patient age or number of pregnancies, factors known to correlate with the frequency of adenomyosis. These data suggest that adenomyosis may be overdiagnosed. Stringent and widely accepted criteria for the diagnosis of adenomyosis are needed, as epidemiologic studies of this common condition would be facilitated by the use of standard criteria in practice.

Unclassified ovarian gonadal stromal tumors. A clinicopathologic study of 32 cases.

Approximately 10% of gonadal stromal (sex cord-stromal) tumors of the ovary are difficult to classify. In most of these cases, the differential diagnosis is between granulosa and Sertoli-Leydig types. We studied 32 such neoplasms. The tumors were divided into two groups: Group 1 consisted of tumors with a predominance of a primitive spindle-cell stroma without specific differentiation, and group 2 consisted of tumors with a predominance of cords, trabecula, or tubules with features suggestive of or characteristics of both granulosa and Sertoli-Leydig cell differentiation in different areas. All tumors had overall features that did not permit definitive placement into granulosa or Sertoli-Leydig categories. There were 18 group 1 tumors and 14 group 2 tumors. The mean patient age was 49 years. The International Federation of Gynecology and Obstetrics (FIGO) stage was known in 12 patients, all of whom were in stage I. Survival data were available for 17 patients, whose follow-up was a mean of 8 years of until death. There were three deaths, one of which was of unrelated causes. the 5- and 10-year corrected actuarial survival rates were 92% and 74%. The number of patients was too small to make meaningful comparisons between the two groups. We concluded that the behavior of these unclassified tumors is similar to that of granulosa and Sertoli-Leydig tumors, with a favorable prognosis when confined to the ovaries.

Atypical apocrine adenosis of the breast: a clinicopathologic study of 37 patients with 8.7-year follow-up.

BACKGROUND: Apocrine metaplasia is occasionally superimposed on sclerosing adenosis (apocrine adenosis) in breast biopsies, and cytologic atypia is sometimes present (atypical apocrine adenosis). The long term risk of patients developing breast carcinoma subsequent to the diagnosis of this lesion is unknown. METHODS: Atypical apocrine adenosis was defined as apocrine adenosis with enlarged nucleoli and a greater than threefold variation in nuclear area. Lesions with recognizable cytoarchitectural patterns of intraductal carcinoma were excluded. Surveillance, Epidemiology and End Results (SEER) data were used as the reference population for calculations of relative risk. RESULTS: Thirty-seven women with atypical apocrine adenosis had a mean follow-up of 8.7 years. Four patients developed invasive ductal carcinoma of the breast (3 ipsilateral, 1 contralateral) after a mean of 5.6 years. The relative risk of developing carcinoma was 5.5 (95% confidence interval [CI], 1.9-16). All patients who developed carcinoma were older than age 60 at the time of breast biopsy showing atypical apocrine adenosis, and carcinoma developed at a mean age of 70 years. In the older than 60 years age group (11 patients), the relative risk of developing carcinoma was 14 (95% CI, 4.1-48). CONCLUSIONS: Atypical apocrine adenosis confers an increased risk of developing breast carcinoma in women older than age 60, and the risk in younger women is probably low. Some cases of atypical apocrine adenosis may represent in situ apocrine carcinomas that are difficult to diagnose because of the absence of the usual architectural features of intraductal carcinoma.