Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer.

BACKGROUND: Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence. METHODS: In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life. RESULTS: Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group. CONCLUSIONS: Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.).

Evaluating agreement, histological features, and relevance of separating pleomorphic and florid lobular carcinoma in situ subtypes.

Morphological variants of lobular carcinoma in situ (LCIS) include classical (CLCIS), pleomorphic (PLCIS) and florid type (FLCIS). Treatment guidelines suggest managing PLCIS and FLCIS like ductal carcinoma in situ (DCIS); therefore accurate identification of LCIS subtypes is critical. However, the significance of separating PLCIS from FLCIS is not clear. Also, interobserver agreement in identifying LCIS subtypes, using contemporary criteria, is not known. We aimed to evaluate interobserver agreement amongst breast pathologists in diagnosing LCIS subtypes and use the agreement data to justify LCIS classification for management purposes. Six breast pathologists independently reviewed 50 hematoxylin and eosin-stained slides comprised of a mix of LCIS subtypes. After reviewing published criteria, participants diagnosed PLCIS, CLCIS and apocrine change in a marked region of interest and FLCIS based on entire section. PLCIS was identified in 8 to 37 slides with overall moderate agreement (Fleiss' κ = 0.565) and pairwise κ (Cohen's) ranging from -.008 to 0.492. FLCIS was diagnosed in 15-26 slides with overall substantial agreement (Fleiss' κ = 0.687) and pairwise κ ranging from -.068 to 0.706. Both FLCIS and PLCIS coexisted in 45% of slides with consensus on non-classical LCIS. Comedo-type necrosis (odds ratio = 5.5) and apoptosis (odds ratio = 1.8) predicted FLCIS. We found moderate and substantial agreement in diagnosing PLCIS and FLCIS respectively. Objective histological features linked with aggressive behavior were more frequent with FLCIS. PLCIS and FLCIS patterns frequently coexist, contain similar molecular aberrations, and are managed similarly (like DCIS); therefore, combining FLCIS and PLCIS into one category (non-classical LCIS) should be considered.

Comparison of estrogen receptor, progesterone receptor and HER2 results in concurrent ipsilateral samples with invasive breast carcinoma: a retrospective study of 246 biopsies from 119 patients.

There is no consensus regarding biomarker testing on the ipsilateral breast carcinomas present in separate biopsies, irrespective of whether the biopsies are performed concurrently or consecutively. We aimed to investigate estrogen receptor (ER), progesterone receptor (PR) and HER2 concordance in ipsilateral concurrent biopsies with invasive breast tumors. Consecutive ipsilateral concurrent biopsies with invasive breast tumors were identified retrospectively. Biomarker results, histologic grade and histologic subtype among the tumors in concurrent samples were compared. ER, PR, and HER2 expression was different in 3 (2.5%), 11 (9.2%) and 7 (5.9%) cases, respectively. All ER-discordant cases were sets of ER-negative (ER-) and weak-low ER-positive (ER+), ductal subtype and histologic grade 2 or 3 tumors. All PR-discordant cases were ER+, and comprised of histologic grades 1 to 3 ductal as well as lobular tumors. All HER2 discordant cases were histologic grade 2 to 3 ductal tumors. Biomarker discordance was independent of grade and subtype discordance. We found very low biomarker discordance among tumors in concurrent samples from ipsilateral breast. Our results suggest that ER and HER2 discordance in concurrent samples is predictable. ER discordance is present only in a setting of low ER+ tumors. Low-grade ductal and/or lobular tumors are ER and HER2 concordant. HER2 discordance is noted in grade 2 to 3 ductal tumors only. Histologic subtype and grade may guide extent of biomarker testing in concurrent ipsilateral breast biopsies.

Fibroadenoma With Pleomorphic Stromal Giant Cells: It's Not as Bad as It Looks!

Clinically relevant histological categorization of fibroepithelial lesions can be a daunting task, especially in a core needle biopsy. Assessment of stromal nuclear atypia, including nuclear pleomorphism and mitotic activity, is a key morphological feature employed to classify fibroepithelial lesions. We describe a case of fibroadenoma with markedly atypical nuclear features in the stromal cells that led to misclassification as phyllodes tumor in the core needle biopsy. Excision showed a fibroadenoma containing pleomorphic stromal giant cells, with occasional mitotic figures, including atypical forms. Aforementioned nuclear findings in a fibroepithelial lesion raise a legitimate question of phyllodes tumor. Knowledge of this pitfall may help avoid overtreatment of an otherwise benign fibroepithelial lesion.

Incidental gynecologic neoplasms in morcellated uterine specimens: a case series with follow-up.

Laparoscopic hysterectomy with morcellation (LHM) is considered a safe and less invasive alternative to other hysterectomy techniques by shortening postoperative hospital stay and patient recovery. Sparse incidental gynecologic neoplasms after LHM have been reported; however, the frequency and subsequent follow-up have not been systematically investigated in a large case series. We aimed to determine the frequency and types of incidental findings after LHM with clinical outcomes. An electronic chart review was conducted searching all cases of LHM performed within 5 years to determine the incidence of unexpected gynecologic neoplasms and subsequent peritoneal disease. Patient demographics, prior preoperative investigation, and subsequent follow-up were investigated. For comparison, the overall frequency of pertinent uterine neoplasms was noted during the study period. Of the 352 cases of LHM identified, 3 harbored unsuspected malignancies, an incidence of 0.9%. Four variant smooth muscle tumors (1.1%) and 5 benign non-smooth muscle neoplasms (1.4%) were identified at the time of initial morcellation. Two cases of subsequent peritoneal "implanted" leiomyoma were identified (0.6%). Of malignant or atypical mesenchymal neoplasms diagnosed at our institution during the study period, 8.6% were diagnosed in a morcellated specimen. There is a clinically important risk of occult malignant or atypical neoplasms in morcellated uterine specimens. Proper pathologic evaluation of malignant or atypical uterine neoplasms is limited when a uterus is morcellated. Patients undergoing morcellation procedures are also potentially at risk for dissemination of disease. Clinicians and patients should be aware of these risks when discussing surgical options for hysterectomy.

Phase III randomized trial of weekly cisplatin and irradiation versus cisplatin and tirapazamine and irradiation in stages IB2, IIA, IIB, IIIB, and IVA cervical carcinoma limited to the pelvis: a Gynecologic Oncology Group study.

PURPOSE: This prospective, randomized phase III intergroup trial of the Gynecologic Oncology Group and National Cancer Institute of Canada Clinical Trials Group was designed to test the effectiveness and safety of adding the hypoxic cell sensitizer tirapazamine (TPZ) to standard cisplatin (CIS) chemoradiotherapy in locally advanced cervix cancer. PATIENTS AND METHODS: Patients with locally advanced cervix cancer were randomly assigned to CIS chemoradiotherapy versus CIS/TPZ chemoradiotherapy. Primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and tolerability. RESULTS: PFS was evaluable in 387 of 402 patients randomly assigned over 36 months, with enrollment ending in September 2009. Because of the lack of TPZ supply, the study did not reach its original target accrual goal. At median follow-up of 28.3 months, PFS and OS were similar in both arms. Three-year PFS for the TPZ/CIS/RT and CIS/RT arms were 63.0% and 64.4%, respectively (log-rank P = .7869). Three-year OS for the TPZ/CIS/RT and CIS/RT arms were 70.5% and 70.6%, respectively (log-rank P = .8333). A scheduled interim safety analysis led to a reduction in the starting dose for the TPZ/CIS arm, with resulting tolerance in both treatment arms. CONCLUSION: TPZ/CIS chemoradiotherapy was not superior to CIS chemoradiotherapy in either PFS or OS, although definitive commentary was limited by an inadequate number of events (progression or death). TPZ/CIS chemoradiotherapy was tolerable at a modified starting dose.

Prevalence, distribution, and viral burden of all 15 high-risk human papillomavirus types in adenosquamous carcinoma of the uterine cervix: a multiplex real-time polymerase chain reaction-based study.

Human papillomavirus (HPV) 16 and 18 are the types most commonly found in cervical adenosquamous carcinoma. Multiple HPV types have been found in cervical adenocarcinoma but not in the adenosquamous variant. Type-specific detection of high-risk (HR) HPV allows the detection of co-infection by multiple HPV types and assessment of viral load per cell. Our aim was to identify and quantify all HR HPV types in cervical adenosquamous carcinoma and to correlate viral loads with prognosis-related histologic features. All 15 HR HPV types were tested for by multiplex real-time polymerase chain reaction, and standard curves were created for each type. Viral loads were determined retrospectively. Prognosis-related histologic features were correlated with specific HPV types and the viral loads. A total of 80% of the tumors examined expressed HPV. Types 16/18 were detected in 86% of these cases, whereas the remaining 14% of the positive cases were infected by other types. A single type of virus was detected in 67% of cases, 2 in 29%, and 3 in 4%. Poor prognostic features were seen in 84.6% of the tumors infected with HPV 16, 46% of those infected with HPV 18, and 100% of those infected with other types. As expected, HPV 16, HPV 18, or both were the most frequent viral types; HPV 73 was the next most frequent type. Multiple HPV types were detected in 33% of the tumors. Non-HPV 16/18 cases had low viral loads, but all of these had poor prognosis-related histologic features. Two of the three recurrent cases had multiple viral types.

Endometrial carcinomas with significant mucinous differentiation associated with higher frequency of k-ras mutations: a morphologic and molecular correlation study.

OBJECTIVES: K-ras gene product in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway is critical in the development of certain types of malignancies. K-ras mutation-associated pancreatic and ovarian carcinomas often display mucinous differentiation. Previous studies have shown that k-ras mutation is found in 10% to 30% of endometrial carcinomas. We investigated k-ras mutations in several morphologic subtypes of endometrial carcinomas with particular emphasis on various degrees of mucinous differentiation. METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue sections. Polymerase chain reaction amplification for k-ras codons 12 and 13 were performed, followed by sequencing using capillary electrophoresis. The Fisher exact test is used to compare the prevalent difference of k-ras mutation among the groups. P < 0.05 was considered significant. RESULTS: K-ras mutations were detected in 8 (80%) of 10 mucinous carcinomas, 12 (67%) of 18 endometrioid carcinomas (ECs) with significant mucinous differentiation (ECMD), 4 (25%) of 16 ECs, and 1 (9%) of 11 serous carcinomas. The differences were statistically significant between mucinous carcinomas versus EC (P < 0.01) and ECMD versus EC (P < 0.05). CONCLUSION: The findings suggest that mucinous carcinoma and endometrioid carcinoma with significant mucinous component are more likely to be associated with k-ras mutation. Potential clinical implications of k-ras mutation lies in the management of recurrent or higher-stage endometrial mucinous tumors, which would not be responsive to treatment protocols containing epidermal growth factor receptor inhibitors.

Utility of the Thin Prep Imaging System® in the detection of squamous intraepithelial abnormalities on retrospective evaluation: can we trust the imager?

Prospective studies analyzing the ThinPrep Imaging System (TIS) have demonstrated a significant decrease in screening time and detection rates comparable or better than manual screening. We retrospectively analyzed the accuracy of the TIS in detecting cervical abnormalities. Our study included all new HSIL diagnoses in 2007 with previous negative (NIL) pap tests screened with TIS. The original 22 fields of view (FOV) were reviewed by 2 blinded screeners followed by manual screening of all slides. Any ASC-US or above was considered "abnormal." Of a total of 111,080 pap tests performed in 2007, 180 were reported as HSIL. Of these, 45 cases had a previous NIL pap diagnosed within the last year, screened with TIS. Following re-examination of the NIL pap, 31 diagnoses remained unchanged and 9 were reclassified as abnormal on the basis of cells present within the original FOV. When manually reviewed, all nine cases were confirmed as abnormal. Four cases were reclassified as abnormal on the basis of the manual screen (abnormal cells absent in the FOV). The sensitivity of TIS for the detection of abnormality was 99.95% (false-negative rate FNR: 0.05%) and the sensitivity for detection of HSIL was 99.07% (FNR: 0.92%). When analyzing the cytotechnologist interpretation of the FOV, the sensitivity for detection of abnormality and HSIL was 99.89% (FNR: 0.1%), and 99.53% (FNR: 0.4%), respectively. On retrospective analysis based on newly diagnosed HSIL cases, the sensitivity of TIS was comparable to that of manual screening with a slightly decreased rate of false negatives.

Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders.

OBJECTIVE: The human epididymis protein 4 (HE4) is a novel biomarker for ovarian cancer. This study measured the HE4 and CA125 levels in women with benign gynecological disorders. STUDY DESIGN: Sera were obtained from women prior to surgery for a pelvic mass and HE4 and CA125 levels were determined. The proportions of patients with elevated biomarker levels were compared. RESULTS: There were 1042 women with benign disease. HE4 levels were less often elevated than CA125 (8% vs 29%, P < .001). A marked difference was observed in patients with endometriosis in which HE4 was elevated in 3% of patients and CA125 in 67% (P < .0001). Serous ovarian tumors were associated with elevated levels of HE4 in 8% of patients and CA125 in 20% (P = .0002); uterine fibroids in 8% vs 26% (P = .0083); dermoids in 1% vs 21% (P = .0004); and inflammatory disease in 10% vs 37% (P = .014). CONCLUSION: HE4 is elevated less frequently than CA125 in benign disease, particularly in premenopausal patients.

The presence and location of epithelial implants and implants with epithelial proliferation may predict a higher risk of recurrence in serous borderline ovarian tumors: a clinicopathologic study of 188 cases.

Serous borderline ovarian tumors have a favorable prognosis, and recurrences are uncommon. The factors influencing recurrence are not fully understood. Epithelial inclusions are identified in serous borderline ovarian tumors and are traditionally referred to as epithelial implants, which often show epithelial proliferation. We investigated whether the presence of epithelial implant and epithelial proliferation portends a higher risk for recurrence of serous borderline ovarian tumors in patients who underwent surgical removal of these tumors. Also examined was whether the anatomical site of epithelial implant and epithelial proliferation was associated with a higher risk of recurrence. One hundred eighty-eight cases of pure serous or predominantly serous borderline ovarian tumors were studied for the presence of epithelial implant and epithelial proliferation, and subsequent recurrences were recorded. The anatomical sites of epithelial implant and epithelial proliferation were compared between serous borderline ovarian tumors with or without recurrence. Statistical analysis was performed using the χ(2) test. Epithelial implant was noted in 106 cases (56%), and epithelial proliferation, in 26 cases (14%). Recurrence was identified in 10.4% cases with epithelial implant and 23% cases with epithelial proliferation. Statistical analyses of patients with recurrence showed significant differences in the following groups: epithelial implant versus no epithelial implant (P < .025) and epithelial proliferation versus no epithelial implant (P < .001). Recurrence rates were higher in the epithelial implant and epithelial proliferation groups as compared with no epithelial implant or epithelial proliferation groups. Epithelial implant and epithelial proliferation appear to pose a statistically significantly higher risk of recurrence in serous borderline ovarian tumors as compared with the absence of epithelial implant. Although the anatomical location of such implants was not significantly associated with a higher risk, the presence of epithelial proliferation at multiple sites was more frequently seen in recurrent serous borderline ovarian tumors.

Tubal metaplasia of the endometrium with cytologic atypia: analysis of p53, Ki-67, TERT, and long-term follow-up.

Tubal metaplasia of the endometrium may occasionally display cytologic atypia (atypical tubal metaplasia) resembling serous carcinoma or endometrial intraepithelial carcinoma. Although atypical tubal metaplasia is presumed to be reactive or degenerative in etiology, its clinical significance is unknown. In this study, we investigated atypical tubal metaplasia in regard to its immunoexpression of p53, Ki-67, and human telomerase reverse transcriptase (TERT), and its long-term clinical outcome. A total of 63 cases of atypical tubal metaplasia and 200 cases of endometrial samples with typical tubal metaplasia were followed for a mean of 64 and 61 months, respectively. Of the 63 atypical tubal metaplasia cases, formalin-fixed, paraffin-embedded tissue sections from 16 cases were immunostained with antibodies to p53, Ki-67, and TERT. Sections from 13 cases of uterine serous carcinoma were also stained for TERT as control. After long-term follow-up, 5% of patients in the atypical tubal metaplasia group developed hyperplasia without atypia compared with 4% of patients in the control group (P=0.44), whereas 3% in the atypical tubal metaplasia group developed atypical hyperplasia or carcinoma compared with 2% in the control group (P=0.44). p53 immunoreactivity was either focal and weak or negative in all cases of both atypical and typical tubal metaplasia (P>0.05). Ki-67 immunoreactivity was present in 0-5% of cells in 94% of both atypical and typical tubal metaplasia (P>0.05). TERT immunoexpression was absent in all 16 cases of atypical tubal metaplasia, but present in all 13 cases of uterine serous carcinoma (P<0.0001). Our study indicates that atypical tubal metaplasia displays an immunostaining pattern similar to otherwise typical tubal metaplasia of the endometrium, and distinct from uterine serous neoplasms. The presence of atypical tubal metaplasia in endometrial samplings does not increase the risk of developing endometrial hyperplasia or malignancy.

Progressive loss of selenium-binding protein 1 expression correlates with increasing epithelial proliferation and papillary complexity in ovarian serous borderline tumor and low-grade serous carcinoma.

Ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma often show a spectrum of histologic components with increasing epithelial proliferation and papillary complexity from flat cyst wall, hierarchical structures (with primary papillae branching into secondary papillae), micropapillae, and invasive carcinoma. Although tremendous research has been carried out to elucidate the causes of these tumors, the pathogenesis remains unclear. Literature has described a relationship between insufficient selenium intake and increased risk of cancer. The anticancer action of selenium has been suggested to be mediated by selenium-binding protein 1 as selenium-binding protein 1 is decreased in several cancers. The aim of the study was to examine by immunohistochemistry the expression of selenium-binding protein 1 in the various histologic components within ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma. Our study consisted of 62 cases of ovarian serous borderline tumor, 11 of micropapillary serous borderline tumor, and 7 of low-grade serous carcinoma. Review of archival slides showed flat cyst wall in 69 cases, primary and secondary papillae of hierarchical structures in 75 cases, micropapillae in 26 cases, microinvasion in 1 case, and frankly invasive carcinoma in 7 cases. The strongest immunoreactivity of selenium-binding protein 1 was seen in epithelial cells of flat cyst wall and primary papillae, followed by secondary papillae of the hierarchical structures. Micropapillae and invasive carcinoma (including microinvasion) exhibited a near complete loss of selenium-binding protein 1 expression. Selenium-binding protein 1 immunoreactivity remained the same regardless of the size of the micropapillae. Similar selenium-binding protein 1 expression was seen in the same histologic components from either ovarian serous borderline tumor or micropapillary serous borderline tumor. The gradual loss of selenium-binding protein 1 associated with increasing epithelial proliferation and papillary complexity indicates that selenium-binding protein 1 is involved in tumorigenesis of ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma. Our findings may provide a basis for future studies concerning the molecular mechanisms of selenium-binding protein 1 in tumorigenesis as well as a possible role of selenium in chemoprevention and treatment of ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma.

A case of Peutz-Jeghers syndrome with breast cancer, bilateral sex cord tumor with annular tubules, and adenoma malignum caused by STK11 gene mutation.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder, and women with this syndrome are at an increased risk of developing intestinal and extraintestinal malignancies including breast and gynecologic malignancies. This case report presents a patient with PJS with a concomitant breast cancer, bilateral stromal tumors with annular tubules of the ovaries, and adenoma malignum of the cervix. CASE: A 43-year-old woman presented with an advanced-stage breast cancer and a pelvic mass. The patient was treated with neoadjuvant chemotherapy followed by laparotomy with a hysterectomy and oophorectomy. Final pathologic examination revealed a concomitant breast cancer with metastasis to the ovaries, bilateral stromal tumors with annular tubules of the ovaries, and adenoma malignum of the cervix. CONCLUSIONS: Patients with PJS are at a high risk for intestinal and extraintestinal malignancies and can present with multiple concomitant malignancies.

Does the ThinPrep Imaging System increase the detection of high-risk HPV-positive ASC-US and AGUS? The Women and Infants Hospital experience with over 200,000 cervical cytology cases.

BACKGROUND: Published reports have demonstrated that introduction of the ThinPrep Imaging System (Imager) to the cytology screening services has increased the detection rate of high-grade squamous intraepithelial lesions (HSILs). In accordance with recent clinical treatment guidelines, patients with atypical squamous or glandular cells of undetermined significance (ASC-US or AGUS) are often tested for high-risk HPV infection using the Hybrid Capture HPV DNA test. We took the opportunity to investigate whether the Imager had resulted in any significant differences in our diagnostic categories, as well as whether the Imager increased the detection of high-risk HPV-DNA-positive (HRHPV+) ASC-US or AGUS. MATERIALS AND METHODS: Cytology cases with the diagnosis of ASC-US and AGUS were retrieved from the archival files of our institution during periods of 11 months prior to and 11 months after the introduction of the Imager. The total number of cases in each category was correlated with results of reflex high-risk HPV DNA testing when the latter were available. All AGUS diagnoses were correlated with subsequent biopsy follow-up. Statistical analyses were performed using the chi-Square test with Yate's Correction and Fisher's Exact test. RESULTS: A total of 108,371 and 104,555 of ThinPrep Pap Test (TPPT) cases were reviewed during 11 months pre- and post-imager introduction. The ASC-US rate was 5.4% in the pre-Imager and 5.3% in the post-Imager period. The HPV reflex test was 38% and 34% positive respectively in the pre- and post-Imager period (P>0.124). Similarly, 0.14% and 0.12% AGUS were found in the pre- and post-Imager period. The positive HPV reflex test was 14% versus 23% (P = 0.1690). The abnormal biopsy follow-up rate in the AGUS category was increased from 20.9% in the pre-Imager period to 31% in the post-Imager period (P = 0.1471). The ASCUS/SIL ratios were 1.9 and 1.6 respectively. CONCLUSIONS: The ASC-US and AGUS rates did not change statistically before and after the introduction of the Imager in our cytology laboratory. Although use of the Imager did not increase detection of HPV+ ASC-US, it did appear to increase the detection rate of HPV+ AGUS and subsequent abnormal biopsy follow-up rates in all categories. However, the increase in the detection rate did not reach the point of statistical significance.

Utility of PTEN expression of endometrial "surface epithelial changes" and underlying atypical endometrial hyperplasia.

Surface epithelial changes (SECs) have been reported to be associated with endometrial carcinoma in about 49% of cases. They have also been seen to be associated with endometrial hyperplasia. Although morphologically benign, these lesions are considered a marker for underlying malignancy. Their true biologic nature, however, is not known. PTEN has been reported to be altered in endometrial carcinomas and endometrial precancers where no morphologic changes are appreciated. The current study aims to investigate PTEN status in the endometrial SECs. Thirty-two cases of endometrial biopsy are divided into 2 groups: group 1 had 18 cases of SEC and underlying endometrial atypical hyperplasia and group 2 had 14 cases of SEC alone. Four-micron sections were cut from each block and stained with antibodies to PTEN. One section was stained with hematoxylin and eosin to confirm the presence of the area of interest. Positive and negative control slides were run with each batch of staining. All 32 cases were followed for a median period of 54 (range, 21 to 84) months. Overall, PTEN alteration (NULL) was found in 12 of the 32 cases of endometrial samples (37.5%) examined. In group 1, 10 of the 18 cases (56%) of atypical endometrial hyperplasia with "SECs" showed PTEN NULL. Of these 10 cases, 6 (60%) cases showed FIGO grade 1 endometrioid carcinoma in subsequent hysterectomy specimens. Two other cases (20%) had atypical endometrial hyperplasia only. In group 2, two of the 14 (14%) cases of SECs alone showed PTEN NULL phenotype. These 2 patients were followed for 26 and 63 months, respectively, and subsequent endometrial biopsies and pap smears were negative. Of the remaining 12 cases that retained PTEN, 9 cases (75%) were negative when followed for a median of 54 months (range, 21 to 84 mo). SECs seem to be a heterogeneous entity. Presence of PTEN NULL phenotype in SECs and associated endometrial hyperplasia does not necessarily predict an increased incidence of endometrioid carcinoma in subsequent follow-up. However, absence of PTEN NULL phenotype in SECs alone may predict a benign follow-up.

Ewing's sarcoma/peripheral primitive neuroectodermal tumor (ES/PNET) differentiation in endometrial serous carcinomas.

The association of Ewing's sarcoma/peripheral neuroectodermal tumor and endometrioid type endometrial carcinoma has been reported relatively recently. We have recently identified Ewing's sarcoma/peripheral neuroectodermal tumor differentiation in uterine serous carcinomas and undertook this study to evaluate the frequency of both serous and endometrioid carcinomas expressing Ewing's sarcoma/peripheral neuroectodermal tumor differentiation. Seventy cases of uterine serous carcinoma were retrieved from the archival files and stained with antibodies to CD99. Positive and negative control slides were run with each staining batch. Perinuclear dot-like and/or membranous staining was regarded as positive. The frequency of Ewing's sarcoma/peripheral neuroectodermal tumor differentiation in 56 FIGO grade 3 endometrioid carcinomas was also determined and 7% uterine serous and 12.5% of FIGO grade 3 endometrioid endometrial carcinomas showed Ewing's sarcoma/peripheral neuroectodermal tumor differentiation. Given the worse prognosis associated with Ewing's sarcoma/peripheral neuroectodermal tumor differentiation, even in neoplasms already at high risk for recurrence and metastasis, a high index of suspicion for Ewing's sarcoma/peripheral neuroectodermal tumor should be maintained in high-grade uterine serous carcinomas.

Primary peritoneal anaplastic giant cell carcinoma: case report of an unusual and highly malignant müllerian neoplasm.

Virtually all primary peritoneal carcinomas (PPCs) are of serous papillary type. We report an unusual histologic type of PPC composed of anaplastic giant cells, which exhibited an aggressive clinical course. A 72-year-old woman presented with lower abdominal pain. Computed tomography showed a diffuse omental thickening. The patient underwent an exploratory laparotomy with omentectomy, total hysterectomy, bilateral salpingo-oophorectomy, and appendectomy. Pathologic examination revealed extensive omental replacement by tumor but only superficial surface cortical involvement of both ovaries, a disease distribution consistent with a typical müllerian-derived PPC. However, this neoplasm was composed of diffuse anaplastic tumor giant cells, rather than serous carcinoma, which is the usual histologic type encountered in PPC. The patient died within 1 month after surgery. We report this unusual histologic variant of PPC to raise awareness that anaplastic giant cell carcinoma may arise in the pelvic peritoneum as a primary tumor.

Axillary lymph nodes: US-guided fine-needle aspiration for initial staging of breast cancer--correlation with primary tumor size.

PURPOSE: To retrospectively assess the sensitivity and specificity of ultrasonographic (US)-guided fine-needle aspiration (FNA) of axillary lymph nodes for preoperative staging of breast cancer across a range of primary tumor sizes, by using histologic findings as a reference standard. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant study; informed consent was waived. US-guided FNA results in 74 patients with breast cancer (75 axillae) were compared with final pathologic results. Lymph nodes were classified as benign, indeterminate, or suspicious on the basis of US characteristics at retrospective review. US-guided FNA in the most suspicious node at US, or the largest node if all appeared benign, was performed. Final pathologic results (sentinel lymph node biopsy [SNB] or axillary lymph node dissection [ALND]) were compared with US and preoperative US-guided FNA results. Results were assessed according to tumor size. Sensitivity, specificity, and positive predictive value of US and US-guided FNA were calculated. RESULTS: Primary tumor sizes were 0.3-12 cm (mean, 3 cm). Patient age range was 31-81 years (mean age, 51 years). Sensitivity of US-guided FNA for predicting positive results at ALND or SNB was 71%-75%. Specificity was 100%. Sensitivity of US-guided FNA increased with primary tumor size. CONCLUSION: US-guided FNA of axillary lymph nodes in patients with newly diagnosed breast cancer had a sensitivity that increased with increasing size of the primary tumor.

Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression.

PURPOSE: The seven transmembrane receptor, GPR30, is linked to estrogen binding and heparan-bound epidermal growth factor release. Here, the significance of GPR30 in human breast cancer was evaluated by comparing its relationship to steroid hormone receptor expression and tumor progression variables. EXPERIMENTAL DESIGN: Immunohistochemical analysis of a National Cancer Institute-sponsored tumor collection comprised of 361 breast carcinomas obtained at first diagnosis (321 invasive and 40 intraductal tumors). Biopsies from 12 reduction mammoplasties served as controls. The distribution pattern of GPR30, estrogen receptor (ER), and progesterone receptor (PR) was correlated with clinicopathologic variables obtained at diagnosis. RESULTS: GPR30, ER, and PR were positive in all 12 normal controls. In contrast, GPR30 expression varied in breast tumors, in which 62% (199 of 321) of invasive tumors and 42% (17 of 40) of intraductal tumors were positive. Codistribution of ER and GPR30 was measured in 43% (139 of 321) of invasive breast tumors, whereas both receptors were lacking (ER-GPR30-) in 19% (61 of 321) of the tumors analyzed, indicating a significant association between ER and GPR30 (P<0.05). The coexpression of PR and ER did not influence GPR30 expression, yet coexpression of GPR30 and ER was linked to PR positivity. Unlike ER, which varied inversely with HER-2/neu and tumor size, GPR30 positively associated with HER-2/neu and tumor size. In addition, GPR30 showed a positive association with metastasis (P=0.014; odds ratio, 1.9). CONCLUSIONS: GPR30 and ER exhibited distinct patterns of association with breast tumor progression variables, including HER-2/neu, tumor size, and metastatic disease. Thus, these results support the hypothesis that GPR30 and ER have an independent influence on estrogen responsiveness in breast carcinoma.