Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Risk-scoring system for the individualized prediction of lymphatic dissemination in patients with endometrioid endometrial cancer.

OBJECTIVE: To develop a risk-scoring system (RSS) for the prediction of lymphatic dissemination after hysterectomy in endometrioid endometrial carcinoma (EC). METHODS: Patients who underwent surgery from 1/1/1999-12/31/2008 were evaluated. Patients with non-endometrioid histology, stage IV with macroscopic extrauterine disease, or receiving adjuvant therapy (excluding brachytherapy) without pelvic and/or paraaortic (P/PA) lymphadenectomy (LND) were excluded. Lymph node dissemination was defined as nodal metastasis when P/PA LND was performed or P/PA lymph node recurrence after negative LND or when LND was not performed. Logistic regression analysis was used to identify predictors for lymphatic dissemination and develop a RSS and nomogram. The RSS was assessed for calibration and verified for discrimination. RESULTS: Overall, 883 patients were assessed of which 521 (59.0%) underwent P/PA LND and 57 (10.9%) had positive lymph nodes. Of patients who did not undergo P/PA LND (N=362) or had negative nodes (N=464), 10 (1.2%) patients had P/PA lymph node recurrence. Myometrial invasion, tumor diameter (TD), FIGO grade, cervical stromal invasion and lymphovascular space invasion were significant on univariable analysis. All preceding variables were included in a multivariable logistic model. A parsimonious model and an alternative full model not including TD were considered. The full model with TD (illustrated in nomogram) had the highest predictive ability (concordance index 0.88). CONCLUSION: Our RSS allows accurate quantification of the probability of lymphatic dissemination and can be used as an adjunct to clinical decision-making after hysterectomy in the absence of staging. TD is an important component of the RSS and should be routinely assessed.

Risk factors that mitigate the role of paraaortic lymphadenectomy in uterine endometrioid cancer.

OBJECTIVE: Paraaortic lymph node (PA) dissemination in endometrial cancer (EC) is uncommon and a systematic infrarenal PA dissection carries morbidity. Our objective was to identify a subgroup of EC patients who may potentially forego PA lymphadenectomy (LND). METHODS: The study endpoint (PA Metastasis or Recurrence; PAMR) was defined as detection of metastasis to PA nodes (among those with any type of PA LND) or PA recurrence within 2 years (among patients without PA LND or those with negative nodes in the context of an inadequate (<5 nodes) PA LND). Patients with non-endometrioid histology, stage IV disease, synchronous cancers, gross extrauterine or gross adnexal disease, neoadjuvant therapy, or insufficient follow-up were excluded. Multivariable logistic regression analysis identified predictors of PAMR. RESULTS: Of the 946 patients, PAMR was observed in 4% (36/946). Multivariable analysis identified positive pelvic nodes (odds ratio (OR) 24.2; p<0.001), >50% MI (OR 5.3; p<0.001) and lymphovascular space invasion (LVSI) (OR 3.7; p=0.005) as the only three independent predictors of PAMR. When all three factors were absent (77% of study cohort), the predicted probability of PAMR was 0.6%. If intraoperative frozen section is not available on pelvic lymph nodes and LVSI, omitting PA LND in all patients with ≤ 50% MI would affect 84% (792/946) of the total cohort, with a 1.1% risk of PAMR (9/792). CONCLUSION: The majority of patients with endometrioid EC may potentially forgo PA LND with expected reductions in surgical morbidity and cost. This cohort may be identified by a combined absence of: positive pelvic nodes, >50% MI and LVSI.

Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer.

OBJECTIVE: Since 1999, patients with low risk endometrial cancer (EC) as defined by the Mayo criteria have preferably not undergone lymphadenectomy (LND) at our institution. Here we prospectively assess survival, sites of recurrence, morbidity, and cost in this low risk cohort. METHODS: Cause-specific survival (CSS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Complications were graded per the Accordion Classification. Thirty-day cost analyses were expressed in 2010 Medicare dollars. RESULTS: Among 1393 consecutive surgically managed cases, 385 (27.6%) met inclusion criteria, accounting for 34.1% of type I EC. There were 80 LND and 305 non-LND cases. Complications in the first 30 days were significantly more common in the LND cohort (37.5% vs. 19.3%; P<0.001). The prevalence of lymph node metastasis was 0.3% (1/385). Over a median follow-up of 5.4 years only 5 of 31 deaths were due to disease. The 5-year CSS in LND and non-LND cases was 97.3% and 99.0%, respectively (P=0.32). None of the 11 total recurrences occurred in the pelvic or para-aortic nodal areas. Median 30-day cost of care was $15,678 for LND cases compared to $11,028 for non-LND cases (P<0.001). The estimated cost per up-staged low-risk case was $327,866 to $439,990, adding an additional $1,418,189 if all 305 non-LND cases had undergone LND. CONCLUSION: Lymphadenectomy dramatically increases morbidity and cost of care without discernible benefits in low-risk EC as defined by the Mayo criteria. In these low-risk patients, hysterectomy with salpingo-oophorectomy alone is appropriate surgical management and should be standard of care.

Incidence and factors associated with synchronous ovarian and endometrial cancer: a population-based case-control study.

OBJECTIVE: To estimate the incidence of synchronous endometrial cancer (EC) and ovarian cancer (OC) in the female population, among all women with EC, and in women under 50 years of age with EC, and to identify factors associated with synchronous EC/OC. METHODS: All cases of synchronous EC/OC and EC diagnosed in women residing in Olmsted County, Minnesota between 1/1/1945 and 12/31/2008 were identified. Incidence was estimated using the population denominator from decennial census data, corrected for hysterectomy prevalence. A case-control study using 15 identified cases (EC/OC) and 45 controls (EC alone) was performed. RESULTS: The incidence of synchronous EC/OC and EC (age-adjusted to the 2000 US female total and corrected for hysterectomy prevalence) in 1945-2008 was 0.88 and 30.3 per 100,000 person-years, respectively. Among women under 50 years of age, the corrected incidence of EC/OC and EC was 0.51 and 5.1 per 100,000 person-years, respectively. Among all women with EC, 3.1% had a synchronous OC compared to 9.4% of women under 50 years of age with EC. Patients with synchronous EC/OC were more likely than those with EC alone to present with a pelvic mass (57.1% vs. 8.9%, p<0.001). Patients with EC alone were more likely to have used oral contraceptive pills (OCPs) than synchronous EC/OC cases (22.7% vs 0%; Odds ratio, 0.10; 95% CI, <0.01-0.87). CONCLUSION: Although the incidence of synchronous EC/OC in the general population is lower than previously reported, nearly 1 in 10 women diagnosed with EC under 50 years of age will have a synchronous OC.

Referral and ascertainment bias in patients with synchronous and metachronous endometrial malignancy.

The purpose of this study was to evaluate the frequency in patients with endometrial cancer of other malignancies and the influence of referral and ascertainment biases on these associations. Analysis of 1,028 local and referred patients who had a hysterectomy for endometrial cancer was based on residence at the time of diagnosis. Altogether, 208 patients had a history of another malignancy, most frequently breast, colon, and ovary. At the time of surgery for endometrial cancer, the prevalence of lymphoma and breast and ovarian cancers was greater than expected although the higher prevalence of lymphoma was limited to referred patients. During follow-up after hysterectomy, the incidence of lung cancer was lower than expected, whereas the incidence of lymphoma was higher. Breast, colorectal, and bladder cancers were more common than expected although this finding was limited to local patients. We concluded that results of epidemiologic studies from tertiary care centers may be misleading if they do not account for referral and ascertainment biases.

Phase I trial of autologous hematopoietic SCT with escalating doses of topotecan combined with CY and carboplatin in patients with relapsed or persistent ovarian or primary peritoneal carcinoma.

We designed a phase I clinical trial of escalating doses of topotecan with CY and carboplatin in combination with autologous hematopoietic SCT (AHSCT) for the treatment of relapsed or persistent platinum sensitive ovarian or primary peritoneal carcinoma. After stem cell collection, 16 patients received topotecan at 1.5, 2.5, 3.5, 4.5 or 6.0 mg/m(2)/d combined with CY 1.5 g/m(2)/d and carboplatin 200 mg/m(2)/d, all by 4-day continuous infusion. Steady state pharmacokinetics of topotecan and carboplatin were examined. Pre-treatment biopsies were examined for the expression of topoisomerase (topo) I, Ki67 and Bcl-2 family members by immunohistochemistry. One of six patients at a topotecan dose of 4.5 mg/m(2)/d and two of three patients at 6.0 mg/m(2)/d had dose-limiting toxicity of grade 3 stomatitis lasting >2 weeks. There was no treatment-related mortality. As topotecan clearance was constant over the dose range examined, topotecan steady state plasma concentrations increased with dose. Median progression-free survival and overall survival were 6.5 months and 2.7 years, respectively. Shorter progression-free survival was observed in tumors with low topo expression (P=0.04). Topotecan can safely be dose escalated to 4.5 mg/m(2)/d in combination with CY, carboplatin and AHSCT. This trial is registered at ClinicalTrials.gov as NCT00652691.

HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer.

Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare but highly aggressive variants of endometrial cancer (EC). HER2 and EGFR may be differentially expressed in type II EC. Here, we evaluate the clinical role of HER2 and EGFR in a large cohort of surgically staged patients with type II (nonendometrioid) EC and compare the findings with those seen in a representative cohort of type I (endometrioid) EC. In this study HER2 gene amplification was studied by fluorescence in situ hybridisation (FISH) and EGFR expression by immunohistochemistry. Tissue microarrays were constructed from 279 patients with EC (145 patients with type I and 134 patients with type II EC). All patients were completely surgically staged and long-term clinical follow up was available for 258 patients. The rate of HER2 gene amplification was significantly higher in type II EC compared with type I EC (17 vs 1%, P<0.001). HER2 gene amplification was detected in 17 and 16% of the cases with uterine serous papillary and clear cell type histology, respectively. In contrast, EGFR expression was significantly lower in type II compared with type I EC (34 vs 46%, P=0.041). EGFR expression but not HER2 gene amplification was significantly associated with poor overall survival in patients with type II EC, (EGFR, median survival 20 vs 33 months, P=0.028; HER2, median survival 18 vs 29 months, P=0.113) and EGFR expression retained prognostic independence when adjusting for histology, stage, grade, and age (EGFR, P=0.0197; HER2, P=0.7855). We conclude that assessment of HER2 gene amplification and/or EGFR expression may help to select type II EC patients who could benefit from therapeutic strategies targeting both HER2 and EGFR.

Aggressive angiomyxoma of the female pelvis and perineum: a case series.

Aggressive angiomyxoma (AA) was first described in 1983, and fewer than 150 cases have been reported in the world medical literature. These tumors are benign, locally infiltrative mesenchymal neoplasms with a predilection for the female pelvis and perineum and a tendency to recur. The size of AAs at presentation varies considerably; however, these tumors often achieve large dimensions before becoming clinically symptomatic. Surgical excision remains the mainstay of treatment, but whether clear, tumor-free surgical margins are necessary is controversial. We report a cohort of six patients treated surgically during the past 20 years for primary or recurrent AA. Treatment, surgical margin status, estrogen and progesterone receptor status, and outcomes are reviewed.

Lipoblastoma-like tumour of the vulva: report of three cases of a distinctive mesenchymal neoplasm of adipocytic differentiation.

AIMS: We sought to delineate and describe three cases of a distinctive mesenchymal neoplasm of the vulva showing adipocytic differentiation and affecting young patients. METHODS AND RESULTS: In three patients between 13 and 38 years of age, the vulvar tumours had well-circumscribed borders and ranged in size from 35 to 100 mm. Histologically, they were well circumscribed and lobulated. The lobules were separated by thin fibroconnective tissue septa and were composed of slender spindle cells showing slightly eosinophilic cytoplasm with indistinct boundaries, uniform nuclei with finely granular chromatin, and no nucleoli. The cells were embedded in a richly myxoid stroma. The background in all three tumours was a 'chicken-wire', capillary vascular network resembling that seen in myxoid liposarcomas. Two tumours had scattered signet-ring-type lipoblasts and the third a large number of such lipoblasts. Clusters of mature adipocytes were entrapped in the tumours. None had mitotic figures, necrosis, or pleomorphism. The neoplastic cells stained positively for vimentin and were negative for other immunohistochemical markers. Treatment for all three tumours was enucleation alone. After follow-up of 10 years, 7 years, and 1 year, all patients are well with no evidence of disease. CONCLUSIONS: The benign behaviour of these neoplasms militates against the diagnosis of liposarcoma. We believe these are benign lesions of adipocytic differentiation akin to infantile lipoblastomas.

Role of wide/radical hysterectomy and pelvic lymph node dissection in endometrial cancer with cervical involvement.

OBJECTIVE: The goal of this work was to assess retrospectively the role of wide/radical hysterectomy (RH) and pelvic lymph node dissection (LND) in endometrial cancer with cervical involvement. METHODS; From 1984 to 1993, 82 patients with endometrial cancer and cervical involvement were surgically managed at our institution. Of 57 patients with stage II (59%) or III (41%) disease receiving no preoperative therapy, 22 (39%) had simple hysterectomy (SH) and 35 (61%) had RH. Forty-four patients (77%) had pelvic LND, and 38 (67%) had adjuvant radiotherapy (RT). Median follow-up was 70 months. RESULTS: The 5-year disease-related survival (DRS) and recurrence-free survival (RFS) were 73 and 63%, respectively. Five-year DRS and RFS were 68 and 50%, respectively, in the SH group compared with 76% (P = 0.1) and 71% (P = 0.04) in the RH group. Distant recurrences occurred in 45% of patients with SH and in 23% with RH (P = 0.08). Local recurrence rates did not differ significantly. Considering only stage II tumors, we did not observe any recurrence among patients with negative nodes who had RH, irrespective of the administration of adjuvant RT. By contrast, adjuvant RT improved local control (even if not significantly) in stage II patients who had SH. Five-year DRS of stage III patients was 47%, but it was improved by adjuvant RT in the subgroup of patients who had RH. Independent variables associated with prognosis were stage III disease, deep myometrial invasion, RH, and adjuvant RT. CONCLUSION: RH and adjuvant RT appear to improve prognosis in endometrial cancer with cervical involvement. In particular, radical surgery alone is therapeutic in stage II patients with negative nodes, irrespective of the administration of RT. By contrast, RT can possibly improve local control in stage II patients who previously had SH. Overall, stage III patients have a poor prognosis that can be improved by a combination of radical surgery and adjuvant RT; however, associated therapy directed to extrapelvic sites is probably needed in patients with extrauterine disease.

Telomerase activity in sex cord-stromal tumors of the ovary.

OBJECTIVE: Telomerase is a ribonucleoprotein that protects chromosomes from degradation and end-to-end fusions by maintaining telomere length. Studies have shown that telomerase is present in 95% of gynecologic malignancies and in 88% of epithelial ovarian carcinomas but undetectable in benign tissue. The aim of this investigation was to determine whether telomerase is present in sex cord-stromal tumors and whether telomerase activity is indicative of patient outcomes. METHODS: Forty-five consecutive sex cord-stromal ovarian tumors were analyzed by using reverse transcription-polymerase chain reaction for expression of human telomerase, human telomerase reverse transcriptase, and telomerase activity. RESULTS: Of the 29 patients with malignant cell types (granulosa cell, Sertoli-Leydig cell, and steroid cell tumors), 21 of the 28 patients (75%) available for follow-up had recurrence, with a mean follow-up of 86 months (95% CI, 36-157 months). The telomerase repeat amplification protocol assay had a sensitivity of 74% and specificity of 94% for malignancy. Patients with telomerase-positive tumors had a mean disease-free interval of 66.5 months; for those with telomerase-negative tumors the interval was 90 months. In addition, patients with telomerase-positive tumors were more likely to be dead from disease or alive with disease than those without telomerase activity, and they showed trends toward requiring a larger number of surgical procedures for the treatment of their disease. However, these trends were not statistically significant. CONCLUSION: Although activation of telomerase is clearly an important step in carcinogenesis, it is unlikely to be helpful in the clinical management of sex cord-stromal tumors of the ovary.

Solitary fibrous tumor: a study of cytologic features of six cases diagnosed by fine-needle aspiration.

Solitary fibrous tumor (SFT) is a spindle-cell neoplasm most often presenting as a pleural-based tumor but increasingly recognized in other locations. Few reports have described the cytologic features of SFTs. Six cases of SFT diagnosed by fine-needle aspiration (3 pleura, 2 retroperitoneum, and 1 orbit) were identified in the Mayo Clinic files. The smears (Papanicolaou-stained) and corresponding histologic specimens were reviewed. Immunohistochemical staining for CD34 was performed in all cases. The cytologic findings were similar in all cases. The tumor cells were oval to polygonal, with cellularity ranging from scant to moderate. The background contained irregular ropy fragments of collagen and a few inflammatory cells. Most cells were dispersed singly, but all cases contained irregular, loose aggregates of cells enmeshed in a collagenous matrix. The nuclei were uniformly bland, with evenly distributed, finely granular chromatin. All cases were immunoreactive for CD34. SFT has distinctive cytologic features that allow diagnosis in cytologic specimens with the help of appropriate immunocytochemical stains on accompanying tissue biopsy specimens. Distinctive cytologic findings predictive of clinical behavior were not identified.

Routes of lymphatic spread: a study of 112 consecutive patients with endometrial cancer.

OBJECTIVE: The goal of this work was to assess different patterns of lymphatic spread to pelvic and para-aortic lymph nodes (LNs) in endometrial cancer as a function of the location of tumor within the uterus. METHODS: Between 1984 and 1999, 625 patients with endometrial cancer were managed with hysterectomy and node dissection at our institution. The present study includes the 112 (18%) patients who had positive pelvic and/or para-aortic LNs; 41 (37%) of them had cervical involvement. RESULTS: The external iliac was the most commonly involved pelvic LN site both in patients with tumor limited to the corpus and in those with cervical invasion. Isolated pelvic LN metastases to a single site were more frequently observed in external iliac LNs and obturator LNs in patients with tumor confined to the uterine corpus, whereas they occurred more commonly in external iliac and common iliac LNs in patients with cervical involvement. Metastasis to the common iliac LNs was more frequent in patients with disease extension to the cervix. In fact, common iliac LNs were positive in 67% of patients with cervical invasion, compared with only 30% of those with tumor confined to the uterine corpus (P < 0.01). Para-aortic LN invasion was significantly associated with obturator LN status. In fact, para-aortic LNs were positive in 64% of patients with positive obturator LNs compared with 23% of patients with negative obturator LNs (P = 0.01). All patients with positive para-aortic LNs and tumor invading the cervix had positive common iliac LNs. By contrast, when tumor was limited to the corpus, common iliac LNs were involved in only 27% of patients with positive para-aortic LNs. CONCLUSION: External iliac LNs are the most commonly involved LNs in endometrial cancer. Compared with carcinomas limited to the uterine corpus, endometrial cancers invading the cervix spread more readily to the common iliac LNs. Furthermore, these data suggest that para-aortic LN metastases spread via a route shared by the common iliac LNs when tumor involves the cervix but spread predominantly via a route common to the obturator LNs (and/or external iliac LNs) when the primary tumor site is the corpus only.

Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading.

Prognostic value of histological grading of oligodendroglial tumors is controversial and interobserver reproducibility in grading of these tumors is unknown. Seven neuropathologists and 6 surgical pathologists experienced in brain tumor-diagnosis assessed 124 oligodendroglial tumors operated at the Mayo Clinic (1960-1990). Among histologic parameters upon which current oligodendroglioma grading systems are based, only high cellularity, presence of mitoses, microcalcifications, endothelial hypertrophy, endothelial proliferation, and necrosis appeared to be reproducible. Reproducible histologic features, based on consensus ratings among neuropathologists (defined as > 60%), were evaluated for the association with cause-specific survival by fitting Cox regression models. By univariate analysis, a significant association with survival was found for age, high cellularity, presence of mitoses, endothelial hypertrophy and proliferation and necrosis. On multivariable analysis with a stepwise variable selection method, only age and presence of endothelial proliferation were found to be independently associated with survival with a discriminatory index of the model of 0.68. Mitotic index was significantly associated with survival based on the grading from each separate neuropathologist, but it was not based on consensus, most likely because this was classified as indeterminate in 54% of cases. Alternatively, "models fit" considering the assessment of single neuropathologists, identified a model based on age and on mitotic index with similar discriminatory indices of 0.69-0.7. Our study found few factors independently associated with cause specific-survival among morphological parameters. These findings are consistent with the present WHO stratification of oligodendrogliomas into low- and high-grade variants.

Hematogenous dissemination in corpus cancer.

OBJECTIVE: The aim of this study was to assess the predictors of hematogenous dissemination (HD) in corpus cancer. METHODS: In 612 corpus cancer patients managed surgically, we defined HD as tumor spread to the lung, liver, or other sites via hematogenous routes. RESULTS: We observed 142 instances of tumor spread-71 nonhematogenous and 42 hematogenous to the lung, 9 to the liver, 5 to other sites (adrenals, breast, brain, bone, skin), 3 to both liver and lung, 1 to both lung and bone, and 11 to sites unknown. Stage IV disease, positive adnexae, deep myometrial invasion, primary tumor diameter, tumor involving the whole uterine cavity, positive peritoneal cytology, adjuvant radiotherapy, adjuvant chemotherapy, grade 3 histology, histologic subtype, and lymph-vascular invasion significantly (P < or = 0.01) correlated with HD. However, deep myometrial invasion was the only independent predictor of HD. Only 5% of patients with < or = 50% myometrial invasion had HD compared with 23% with > 50% myometrial invasion. Considering separately recurrence in the lung and in the liver and recurrence in other sites, the only independent predictors of lung recurrence were stage IV disease and myometrial invasion, whereas independent predictors of HD to the liver/other sites were age and histologic grade. Considering only the 60 patients with a known site of HD, 67% with lung recurrence were > 65 years old compared with 17% with HD to the liver/other sites. Furthermore, grade 1-2 disease was observed in 65% of patients with lung recurrence compared with 27% with HD to the liver/other sites. CONCLUSIONS: The presence of deep myometrial invasion was the strongest predictor of HD in corpus cancer, and, together with stage IV disease, it independently predicted lung recurrence. Recurrence in the lung was more frequent in older patients with well or moderately differentiated tumors, whereas HD to the liver/other sites was more frequent in patients < or = 65 years of age harboring grade 3 tumors.

Serous borderline tumor of the paratestis: a report of seven cases.

We report the clinical, morphologic, immunophenotypic, and ploidy findings of seven cases of serous borderline tumor of the paratestis. Mean patient age was 56 years (range, 14-77 years), and the clinical presentation was that of a testicular mass. Tumors ranged in size from 1 to 6 cm (mean, 3.5 cm). Six tumors arose from the tunica albuginea, and two of these tumors were intratesticular. One tumor arose from the tunica vaginalis. Serous borderline tumor of the paratestis is histologically identical to its ovarian counterpart. The tumors were cystic with numerous intracystic blunt papillae lined by stratified epithelial cells with minimal to mild cytologic atypia. Psammoma bodies were present in two cases. In all cases, the neoplastic cells stained strongly and diffusely for cytokeratin 7, estrogen receptor, and CD15, and six of seven cases were positive for progesterone receptor and MOC-31. The cells did not stain for cytokeratin 20, carcinoembryonic antigen, calretinin, and HER2/neu. Proliferative activity, as assessed by MIB-1 staining, ranged from 1.3% to 10% (mean, 5.5%). Five of six tumors were diploid, and one was tetraploid. Patients were treated by radical orchiectomy and followed up from 4 months to 18 years (mean, 48 months; median, 8.5 months). No recurrences or metastases occurred. Serous borderline tumor of the paratestis is morphologically and immunophenotypically identical to ovarian serous borderline tumor. To date, no serous borderline tumor of the paratestis reported in the literature or in our series has recurred or metastasized after resection.

Benign tumors of the breast with multinucleated stromal giant cells. Immunohistochemical analysis of six cases and review of the literature.

The authors present six cases of benign tumors of the breast with numerous multinucleated stromal giant cells (MSGC). All six patients were women aged 37-70 years (mean 48 years), presenting clinically with a breast mass 1.0-3.8 cm in size (mean 1.9 cm; median 1.5 cm). By standard H&E examination, all cases showed the presence of numerous MSGC haphazardly dispersed within the tumor stroma. Three cases revealed MSGC merging into the surrounding adipose tissue simulating infiltrative growth. The MSGC appeared to have multiple nuclei (5 to 25) with fine chromatin and sporadic small nucleoli. Their cytoplasm was inconspicuous. The MSGC expressed vimentin only and to lesser extent CD34. These cells were negative for muscle markers, keratins, S-100 protein, vascular markers, CD68 and hormone receptors. Interestingly, the majority of MSGC and mononuclear stromal cells showed reactivity for p53 protein and Ki-67 proliferation antigen. All patients were treated by simple excision and remain free of recurrence (mean 70 months, median 48 months.). The reactivity of p53 in MSGC and mononuclear stromal cells may play a key role in linking these two cell types. Nonetheless, the presence of MSGC does not alter prognosis of otherwise typical benign lesions.

Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis.

OBJECTIVE: Endometriosis is extremely common in developed countries. Obesity is a major health concern and may cause hyperestrogenism. Hormonal replacement, particularly unopposed estrogens after hysterectomy, is becoming popular. Because endometriosis is ectopic endometrium, hyperestrogenism (either endogenous or exogenous) may cause hyperplasia or transformation into cancer. This study was conducted to describe the main clinical and pathologic features of malignancies in endometriosis and define the treatment and outcome and to compare patients who had cancer arising in endometriosis with patients who had endometriosis but no cancer. METHODS: Patients who had tumors from endometriosis diagnosed from 1986 to 1997 were analyzed retrospectively. Each patient was matched with two control patients (endometriosis without cancer) treated during the same study interval. Clinical and epidemiologic variables were compared to identify risk factors for the development of cancer. RESULT: We identified 31 patients with cancer developing from endometriosis. Fifteen women were obese, 9 had a history of endometriosis, and 9 were taking unopposed estrogen. Endometrioid adenocarcinoma was the most common histologic type (16 patients). When the patients with cancer were compared with controls, no significantly higher risk for the development of cancer was found with prolonged use of unopposed estrogens or with higher body mass index, but a trend was observed. When obesity and use of unopposed estrogens were considered together, the difference was statistically significant (P = 0.05). CONCLUSION: Hyperestrogenism, either endogenous or exogenous, is a significant risk factor for the development of cancer from endometriosis. The prevalences of endometriosis, obesity, and use of hormonal replacement therapy in women in developed countries are increasing, and this trend justifies the assumption that cancer developing in endometriosis might become more common in the future.

Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary?

OBJECTIVE: The objective of this study was to find readily ascertainable intraoperative pathologic indicators that would discriminate a subgroup of early corpus cancers that would not require lymphadenectomy or adjuvant radiotherapy. STUDY DESIGN: Between 1984 and 1993, a total of 328 patients with endometrioid corpus cancer, grade 1 or 2 tumor, myometrial invasion < or =50%, and no intraoperative evidence of macroscopic extrauterine spread were treated surgically. Pelvic lymphadenectomy was performed in 187 cases (57%), and nodes were positive in nine cases (5%). Adjuvant radiotherapy was administered to 65 patients (20%). Median follow-up was 88 months. RESULTS: The 5-year overall cancer-related and recurrence-free survivals were 97% and 96%, respectively. Primary tumor diameter and lymphatic or vascular invasion significantly affected longevity. No patient with tumor diameter < or =2 cm had positive lymph nodes or died of disease. CONCLUSION: Patients who have International Federation of Gynecology and Obstetrics grade 1 or 2 endometrioid corpus cancer with greatest surface dimension < or =2 cm, myometrial invasion < or =50%, and no intraoperative evidence of macroscopic disease can be treated optimally with hysterectomy only.