Combined BRCA2 and MAGEC3 Expression Predict Outcome in Advanced Ovarian Cancers.

Like BRCA2, MAGEC3 is an ovarian cancer predisposition gene that has been shown to have prognostic significance in ovarian cancer patients. Despite the clinical significance of each gene, no studies have been conducted to assess the clinical significance of their combined expression. We therefore sought to determine the relationship between MAGEC3 and BRCA2 expression in ovarian cancer and their association with patient characteristics and outcomes. Immunohistochemical staining was quantitated on tumor microarrays of human tumor samples obtained from 357 patients with epithelial ovarian cancer to ascertain BRCA2 expression levels. In conjunction with our previously published MAGEC3 expression data, we observed a weak inverse correlation of MAGEC3 with BRCA2 expression (r = −0.15; p < 0.05) in cases with full-length BRCA2. Patients with optimal cytoreduction, loss of MAGEC3, and detectable BRCA2 expression had better overall (median OS: 127.9 vs. 65.3 months, p = 0.035) and progression-free (median PFS: 85.3 vs. 18.8 months, p = 0.002) survival compared to patients that were BRCA2 expressors with MAGEC3 normal levels. Our results suggest that combined expression of MAGEC3 and BRCA2 serves as a better predictor of prognosis than each marker alone.

The Role of Castration-Resistant Bmi1+Sox2+ Cells in Driving Recurrence in Prostate Cancer.

BACKGROUND: Recurrence following androgen-deprivation therapy is associated with adverse clinical outcomes in prostate cancer, but the cellular origins and molecular mechanisms underlying this process are poorly defined. We previously identified a population of castration-resistant luminal progenitor cells expressing Bmi1 in the normal mouse prostate that can serve as a cancer cell-of-origin. Here, we investigate the potential of Bmi1-expressing tumor cells that survive castration to initiate recurrence in vivo. METHODS: We employed lineage retracing in Bmi1-CreER; R26R-confetti; Ptenf/f transgenic mice to mark and follow the fate of emerging recurrent tumor clones after castration. A tissue recombination strategy was used to rescue transgenic mouse prostates by regeneration as grafts in immunodeficient hosts. We also used a small molecule Bmi1 inhibitor, PTC-209, to directly test the role of Bmi1 in recurrence. RESULTS: Transgenic prostate tumors (n = 17) regressed upon castration but uniformly recurred within 3 months. Residual regressed tumor lesions exhibited a transient luminal-to-basal phenotypic switch and marked cellular heterogeneity. Additionally, in these lesions, a subpopulation of Bmi1-expressing castration-resistant tumor cells overexpressed the stem cell reprogramming factor Sox2 (mean [SD] = 41.1 [3.8]%, n = 10, P < .001). Bmi1+Sox2+ cells were quiescent (BrdU+Bmi1+Sox2+ at 3.4 [1.5]% vs BrdU+Bmi1+Sox2- at 18.8 [3.4]%, n = 10, P = .009), consistent with a cancer stem cell phenotype. By lineage retracing, we established that recurrence emerges from the Bmi1+ tumor cells in regressed tumors. Furthermore, treatment with the small molecule Bmi1 inhibitor PTC-209 reduced Bmi1+Sox2+ cells (6.1 [1.4]% PTC-209 vs 38.8 [2.3]% vehicle, n = 10, P < .001) and potently suppressed recurrence (retraced clone size = 2.6 [0.5] PTC-209 vs 15.7 [5.9] vehicle, n = 12, P = .04). CONCLUSIONS: These results illustrate the utility of lineage retracing to define the cellular origins of recurrent prostate cancer and identify Bmi1+Sox2+ cells as a source of recurrence that could be targeted therapeutically.

Subsequent breast and high grade serous carcinomas after risk-reducing salpingo-oophorectomy in BRCA mutation carriers and patients with history of breast cancer.

Risk-reducing salpingo-oophorectomy (RRSO) is a procedure to reduce the risk of adnexal cancer in BRCA mutation carriers and for hormonal manipulation in women with breast cancer (BC). The goal of the study is to report the frequency of subsequent BC and high-grade serous carcinoma (HGSC) following RRSO in BRCA1 and BRCA2 mutation carriers and in patients with personal history of BC with or without BRCA mutation. A series of 147 consecutive patients who received a RRSO were reviewed. Patient's age, clinical history, BC histotype, gene mutation data, incidence of post-RRSO BC and HGSC and time intervals were analyzed. The cases were followed for a mean of 49 months. Group 1 consists of 97 cases with pathogenic or likely pathogenic "deleterious" mutation BRCA1 (n = 49) or BRCA2 (n = 48). Group 2 consists of 50 cases with history of BC and no documented BRCA gene mutation. Prior to RRSO, 42 (43%) cases in group 1 had a history of BC and all cases in group 2 had a history of BC. There was no difference between the groups in the age at diagnosis for BC (Mean of 44 years). Following RRSO, 2/49 cases (4%) with BRCA1 mutation were found to have occult HGSC and none in BRCA2 cases. There were also 1 BC recurrence and 1 primary BC with BRCA1 mutation compared to 5 recurrent BC in Group 2 (10%). In conclusion, the risk of subsequent recurrent BC after RRSO appears to be higher (10%) in patients with history of BC with no BRCA mutation when compared to (2%) in BRCA mutation carriers.

Trends in High-Grade Cervical Cancer Precursors in the Human Papillomavirus Vaccine Era.

INTRODUCTION: The 2006 introduction of human papillomavirus vaccine targeted against genotypes 6, 11, 16, and 18 should result in decreased cervical dysplasia in vaccinated women. However, new cervical cancer guidelines to increase screening intervals complicate interpretation of trends. The hypothesis is that cervical dysplasia would decrease only in young vaccine-eligible women, and not older women. METHODS: The authors identified Davidson County, Tennessee, women aged 18-39 years with cervical intraepithelial neoplasia (CIN) grade 2 or greater and adenocarcinoma in situ, denoted as CIN2+, through pathology reports from laboratories serving this population. Biopsy specimens for human papillomavirus genotyping were collected. Trends in CIN2+ rates and associated human papillomavirus genotypes, 2008 through 2013, were examined. RESULTS: The authors identified 2,031 women with CIN2+. Rates of CIN2+ fell from 188.9 to 58.7 per 100,000 women aged 18-20 years (annual percentage change= -24.2, 95% CI= -41.4, -2.1) and from 495.6 to 332.4 per 100,000 women aged 21-24 years (annual percentage change= -10.2%, 95% CI= -16.3, -3.4). There was no significant change in CIN2+ rates for women aged 25-29 or 30-39 years. In biopsy specimens from 1,319 of 2,031 (65%) women, at least one human papillomavirus genotype was identified in 1,270 (96%). The prevalence of at least one of four vaccine human papillomavirus genotypes (6, 11, 16, and 18) declined from 59% in 2008 to 52% in 2013 (p=0.003). CONCLUSIONS: Diagnosis of CIN2+ decreased in women aged 18-24 years, but not in older women. Both changes in screening and human papillomavirus vaccination could have contributed to the decline of CIN2+ in young women.

The role of skin ulceration in breast carcinoma staging and outcome.

Breast carcinoma with skin ulceration (SU) is considered a locally advanced disease. The purpose of the study is to investigate if SU is an independent adverse factor. Breast carcinoma patients with SU (n=111) were included in the study. A subset (n=38, study cohort) was matched with cases that had no SU (n=38, matched cohort); the survival analyses were compared between these groups. Then, cases (n=80) were staged independent from SU into stage I, II or III. Disease free survival (DFS) and overall survival (OS) were analyzed. Patients with larger tumors tended to present with distant metastases more often than patients with smaller tumors (P=.004). In the matched cases, the 5-year DFS probability was 53% for the study cohort and 58% for the matched cohort; and for OS 75% for the study cohort and 84% for the matched cohort with no statistical significant difference. However, there was a trend towards worse DFS for the patients whose tumors had SU. When the cases were staged based on tumor size and node status (I, II or III), the OS was statistically significant (P=.047) but not the DFS (P=.195). Relatively small tumors with SU had an extent of disease similar to that observed in patients with early stages disease. The survival analysis suggests that SU may not be an adverse factor. However, more cases are needed to further examine this finding.

Clear Cell Renal Cell Carcinoma Metastatic to the Gynecologic Tract: A Clinicopathologic Analysis of 17 Cases.

Clear cell renal cell carcinomas (CCRCC) rarely metastasizes to the gynecologic tract. In this study, we analyzed a multi-institutional data set to provide insights into the clinical, morphologic, and immunophenotypic features of this phenomenon. Seventeen metastatic CCRCC involving the gynecologic tract [ovary/fallopian tube (n=9), vulva (n=2), uterine corpus (n=3), cervix (n=2), uterine serosa (n=1)] were analyzed. Mean patient age was 62 yr (range: 45-79 yr). Most cases (15/17) presented as a recurrence 6 to 72 mo postnephrectomy, 1 case was concurrently diagnosed, and 1 case (a cervical metastasis) was diagnosed prenephrectomy. In 10 cases, metastases to other locations were identified within 6 wk of the gynecologic tract lesion. The adnexa were the most common site of metastases and the mean tumor size of adnexal metastases was 3.7 cm; in only 2 of 9 cases were metastases bilateral and only 1 had external surface nodules. The morphologic and immunohistochemical features of metastatic CCRCC were compared with those of 102 müllerian clear cell carcinomas (müllerian CCC: 49 endometrial, 53 ovarian). Although CCRCC and müllerian CCC displayed extensive morphologic overlap, a higher mitotic index and a higher frequency of an alveolar pattern were seen in CCRCC, whereas diffuse hobnail cells, hyaline globules, tubulocystic pattern, or any papillary pattern were more frequently seen in müllerian CCC. CA-IX, CD10, and renal cell carcinoma antigen were more frequently expressed in CCRCC than müllerian CCC, whereas Napsin-A, CK7, and p504S showed the reverse. PAX8 and HNF1ß did not significantly distinguish between the 2 groups. In summary, gynecologic tract metastases most often occur as a relapse of a previously resected CCRCC, and these relapses may occur many years postnephrectomy. Gynecologic tract metastases are often accompanied by concurrent metastases to other organs. The gross pathology of metastatic CCRCC in the ovary may potentially overlap with primary neoplasia. However, the expected morphology and immunophenotype of CCRCC are maintained in most gynecologic tract metastases. As such, although metastatic CCRCC and müllerian CCC may display significant overlap in pathologic features, several morphologic and immunophenotypic features are useful in their distinction.

Atypical mucinous glandular proliferations in endometrial samplings: follow-up and other clinicopathological findings in 41 cases.

The 2014 World Health Organization classification calls for endometrial mucinous proliferations that display "confluent or cribriform architecture with even minimal atypia" in sampling specimens to be classified as carcinoma, and others whose features are not diagnostic of carcinoma to be categorized as atypical mucinous glandular proliferations (AMGPs). Herein, we evaluate follow-up findings in 41 cases that were classified as AMGP from our files. The average patient age was 46years (range, 37-59 years). Postbiopsy follow-up duration ranged from 15 to 109weeks (mean, 40 weeks). There was no follow-up resection in 12 patients (9 with repeat biopsies, all 9 with no clinical evidence of disease, mean follow-up of 43weeks), and 29 patients underwent a hysterectomy an average of 2.4months after the index biopsy. The distribution of pathologic findings in the uteri was as follows: no residual AMGP or carcinoma (5/29; 17%), AMGP (11/29; 38%), and adenocarcinoma (13/29; 45%). All adenocarcinomas were grade I and stage I, and histotypes were endometrioid (n=8), mucinous (n=3), and endometrioid with mucinous differentiation (n=2). Only 3 (23%) carcinomas were myoinvasive, of which 1 case, a mucinous carcinoma with a 40% endometrioid component, showed greater than 50% myometrial invasion. None of a wide array of morphologic features was significantly associated with a hysterectomy diagnosis of carcinoma (versus AMGP) on univariate analyses. In conclusion, our cohort of AMGP represents a biologically variable spectrum of lesions that includes mucinous hyperplastic proliferations as well as endometrioid and mucinous adenocarcinomas that are occasionally myoinvasive. Morphologic features that optimally stratified AMGP cases into clinically relevant subgroups were not identified.

Bmi1 marks distinct castration-resistant luminal progenitor cells competent for prostate regeneration and tumour initiation.

Identification of defined cell populations with stem/progenitor properties is key for understanding prostate development and tumorigenesis. Here we show that the polycomb repressor protein Bmi1 marks a population of castration-resistant luminal epithelial cells enriched in the mouse proximal prostate. We employ lineage tracing to show that these castration-resistant Bmi1-expressing cells (or CARBs) are capable of tissue regeneration and self-renewal. Notably, CARBs are distinct from the previously described luminal castration-resistant Nkx3.1-expressing cells (CARNs). CARBs can serve as a prostate cancer cell-of-origin upon Pten deletion, yielding luminal prostate tumours. Clonal analysis using the R26R-confetti allele indicates preferential tumour initiation from CARBs localized to the proximal prostate. These studies identify Bmi1 as a marker for a distinct population of castration-resistant luminal epithelial cells enriched in the proximal prostate that can serve as a cell of origin for prostate cancer.

Core Breast Biopsies Showing Lobular Carcinoma In Situ Should Be Excised and Surveillance Is Reasonable for Atypical Lobular Hyperplasia.

OBJECTIVE: The purpose of this article is to determine the upgrade rate to ductal carcinoma in situ (DCIS) or invasive carcinoma at excision at the same site after percutaneous breast biopsy findings of atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS) using current imaging and strict pathologic criteria. MATERIALS AND METHODS: From January 2006 through September 2013, 32,960 breast core biopsies were performed; 1084 (3.3%) core biopsies found ALH or classic LCIS. For 447 lesions in 433 women, this was the only high-risk lesion at that site, with no ipsilateral malignancy, and results of excision were available. RESULTS: Among the 447 lesions, 22 (4.9%) were malignant at excision, including 10 invasive carcinomas (two grade 2 and eight grade 1; all node negative) and 12 DCIS. The upgrade rate of LCIS was 9.3% (10/108; 95% CI, 5.1-16.2%) and that of ALH was 3.5% (12/339; 95% CI, 2.0-6.1%; p = 0.02). After excluding five cases with radiologic-pathologic discordance and reclassifying one core from ALH to LCIS at review, the upgrade rate for LCIS remained higher (8.4%; 9/107; 95% CI, 4.5-15.2%) than that for ALH (2.4%; 8/335; 95% CI, 1.2-4.6%; p = 0.01). CONCLUSION: Excision is recommended for LCIS on core biopsy because of its 8.4-9.3% upgrade rate. Excluding discordant cases, patients with other high-risk lesions or concurrent malignancy, the risk of upgrade of ALH was 2.4%. Surveillance at 6, 12, and 24 months can be performed in lieu of excision because a short delay in diagnosis of the few malignancies is not expected to cause harm.

The risk of upgrade for atypical ductal hyperplasia detected on magnetic resonance imaging-guided biopsy: a study of 100 cases from four academic institutions.

AIMS: To identify variables that can predict upgrade for magnetic resonance imaging (MRI)-detected atypical ductal hyperplasia (ADH). METHODS AND RESULTS: We reviewed 1655 MRI-guided core biopsies between 2005 and 2013, yielding 100 (6%) cases with ADH. The pathological features of ADH and MRI findings were recorded. An upgrade was considered when the subsequent surgical excision yielded invasive carcinoma (IC) or ductal carcinoma in situ (DCIS). The rate of ADH between institutions was 3.3-7.1%, with an average of 6%. A total of 15 (15%) cases had upgrade, 12 DCIS and three IC. When all cases were included, only increased number of involved cores was statistically significant (P = 0.02). When cases with concurrent lobular neoplasia (LN) were excluded (n = 14), increased number of ADH foci and increased number of involved cores were statistically significant (P = 0.002, P = 0.009). We analysed the data separately from a single institution (n = 61). Increased number of foci, increased number of total cores and involved cores and larger ADH size predicted upgrade with statistical significance. CONCLUSIONS: The incidence of ADH in MRI-guided core biopsy is rare. The rate of upgrade is comparable to mammographically detected ADH, warranting surgical excision. Similar to mammographically detected lesions, the volume of the ADH predicts the upgrade.

Are clear cell carcinomas of the ovary and endometrium phenotypically identical? A proteomic analysis.

Phenotypic differences between otherwise similar tumors arising from different gynecologic locations may be highly significant in understanding the underlying driver molecular events at each site and may potentially offer insights into differential responses to treatment. In this study, the authors sought to identify and quantify phenotypic differences between ovarian clear cell carcinoma (OCCC) and endometrial clear cell carcinoma (ECCC) using a proteomic approach. Tissue microarrays were constructed from tumor samples of 108 patients (54 ECCCs and 54 OCCCs). Formalin-fixed samples on microarray slides were analyzed by matrix-assisted laser desorption/ionization mass spectrometry, and 730 spectral peaks were generated from the combined data set. A linear mixed-effect model with random intercept was used to generate 93 (12.7%) peaks that were significantly different between OCCCs and ECCCs at the fold cutoffs of 1.5 and 0.667 and an adjusted P value cutoff of 1.0 × 10(-10). Liquid chromatography-tandem mass spectrometry was performed on selected cores from each group, and peptides identified therefrom were compared with lists of statistically significant peaks from the aforementioned linear mixed-effects model to find matches within 0.2 Da. A total of 53 candidate proteins were thus identified as being differentially expressed in OCCCs and ECCCs, 45 (85%) of which were expressed at higher levels in ECCCs than OCCCs. These proteins were functionally diverse and did not highlight a clearly dominant cellular theme or molecular pathway. Although ECCCs and OCCCs are very similar, some phenotypic differences are demonstrable. Additional studies of these differentially expressed proteins may ultimately clarify the significance of these differences.

An immunohistochemical analysis of stathmin 1 expression in uterine smooth muscle tumors: differential expression in leiomyosarcomas and leiomyomas.

The oncogenic phosphatidylinositol 3-kinase-AKT-mammlian target of rapamycin pathway (PI3K-AKT-mTOR) pathway is known to be activated in uterine smooth muscle tumors, and Stathmin 1 (STMN1) expression has been identified as a marker of PI3K-AKT-mTOR pathway activation. We hypothesized that STMN1 may have some diagnostic utility and explored how well STMN1 expression correlated with histologic classifications of uterine smooth muscle tumors into benign and malignant groupings. 84 smooth muscle tumors were assessed for STMN1 expression by immunohistochemistry. These included spindle cell leiomyosarcoma (n=32), conventional spindle cell leiomyomas (n=30), atypical (symplastic) leiomyoma (n=5), cellular leiomyoma (n=7), smooth muscle tumor of uncertain malignant potential (n=4), mitotically active leiomyomas (n=2), benign metastasizing leiomyoma (n=3), and cotyledonoid dissecting leiomyoma (n=1). All spindle cell leiomyosarcomas were positive (32/32 positive; 100%) as compared with conventional leiomyomata (11/30; 37%) (P<0.0001). The average immunohistochemical score (0-12+, reflective of intensity and extent) for leiomyosarcomas was 8.7 (±1.43) whereas the conventional leiomyomata average score was 1.6 (±1.07) (P<0.0001). This difference in scores was reflected in the patterns of expression: leiomyosarcomas were predominantly strongly and diffusely positive whereas leiomyomata were predominantly weakly, albeit diffusely positive when expression was present. The sensitivity of STMN1 expression for leiomyosarcomas was 100%. However, the specificity was found to be only 55% (CI=43-68%). The negative and positive predictive values for leiomyosarcomas were 100% and 52% respectively. The odds ratio (OR) for any STMN1 expression in predicting a spindle cell leiomyosarcoma diagnosis from this dataset was highly significant (OR=144, P=0.0006). Thirteen non-smooth muscle tumors that involved the uterus all showed at least focal STMN1 immunoreactivity. In summary, STMN1 is a highly sensitive marker for leiomyosarcoma but is suboptimally specific for diagnostic purposes. The 100% negative predictive value for leiomyosarcoma may offer some diagnostic utility in a small sample, since the absence of STMN1 immunoreactivity in a putative leiomyosarcoma is a strong argument against this diagnostic possibility.

Comparative analysis of Napsin A, alpha-methylacyl-coenzyme A racemase (AMACR, P504S), and hepatocyte nuclear factor 1 beta as diagnostic markers of ovarian clear cell carcinoma: an immunohistochemical study of 279 ovarian tumours.

Napsin A and α-methylacyl-coenzyme A racemase (AMACR, P504S) have recently been described as being frequently expressed in clear cell carcinomas (CCC) of the gynecological tract. The present study was conducted to assess the test performance of these newer markers relative to the more traditional marker, hepatocyte nuclear factor 1ß (HNF1ß), in a large and histotypically diverse dataset. A total of 279 ovarian tumours in tissue microarrays were immunohistochemically assessed for the expression of Napsin A, AMACR and HNF1ß. HNF1ß, Napsin A and AMACR were expressed in 92%, 82% and 63% of 65 CCC, 7%, 1% and 1% of 101 serous carcinomas, 37%, 5.3% and 0% of 19 endometrioid carcinomas, 60%, 0% and 0% of 45 mucinous tumours, 100%, 0% and 0% of seven yolk sac tumours, and 0%, 16.7% and 16.7% of six steroid cell tumours NOS, respectively. All other tumours, including 18 adult-type granulosa cell tumours, eight dysgerminomas and nine other miscellaneous tumour types were negative for all three markers. Using a benchmark of ≥1% of tumour cells for positivity and CCC as the diagnostic end-point, the sensitivity, specificity, negative predictive value and positive predictive value of Napsin A expression were 0.82, 0.99, 0.94, and 0.98, respectively (odds ratio 439, p < 0.0001). Respective parameters were 0.92, 0.79, 0.97, and 0.58 (odds ratio 44, p < 0.0001) for HNF1ß and 0.63, 0.99, 0.89, and 0.5 (odds ratio 112, p < 0.0001) for AMACR. The combination of any two positive markers, irrespective of the staining pattern of the third, significantly predicted the CCC histotype in every analytic scenario. In summary, HNF1ß is highly sensitive but is suboptimally specific in isolation, whereas AMACR is highly specific but is suboptimally sensitive. Napsin A is specific but of intermediate sensitivity. Napsin A, AMACR and HNF1ß are all viable markers of CCC that can be deployed as components of larger panels when CCC is a diagnostic consideration.

Ovarian mucinous tumor with malignant mural nodules: dedifferentiation or collision?

Ovarian mucinous tumors with mural nodules are rare surface epithelial-stromal tumors. The mural nodules are divergent neoplasms that may be benign or malignant. The latter may be in the form of a sarcoma, carcinosarcoma, anaplastic carcinoma, or a variety of other recognized histotypes of carcinoma, which raises the question of whether malignant mural nodules represent a form of dedifferentiation in ovarian mucinous tumors or whether they represent collision tumors. We recently reported the K-RAS gene mutation status in a case of ovarian mucinous adenocarcinoma with mural nodule of high-grade sarcoma. The mucinous and sarcomatous components revealed a mutation in codon 12 of the K-RAS gene of a different nucleotide substitution, indicating that these 2 tumor components were different clones of the same tumor. Herein, we are reporting another case of a 20-yr-old woman who presented with 22 cm pelvic mass, omental caking, and ascites. A diagnosis of invasive mucinous carcinoma with mural nodules of anaplastic carcinoma was rendered. K-RAS gene mutation studies revealed p.G12V, c.35G>T mutation in the 2 components of the tumor, which is the most common mutation reported in mucinous tumors of the ovary. The fact that sarcomatous or anaplastic carcinomatous mural nodules in ovarian mucinous tumors display the same K-RAS mutations as their underlying mucinous neoplasms provides supportive evidence that at least some malignant mural nodules represent a form of dedifferentiation in ovarian mucinous tumors, rather than a collision of 2 divergent tumor types.

Incidental placenta increta at the time of prophylactic hysterectomy for Lynch syndrome: Insights into individualized decision-making and surgical timing.

•Increta in a prophylactic hysterectomy specimen for Lynch syndrome is rare.•Individualizing risk-reducing procedures after childbearing is important.•Shared decision making should include the timing of prophylactic surgery.•Minimizing surgical risks in the postpartum period should be discussed.

Differential vimentin expression in ovarian and uterine corpus endometrioid adenocarcinomas: diagnostic utility in distinguishing double primaries from metastatic tumors.

This study aimed to assess the diagnostic value of vimentin expression in differentiating endometrioid adenocarcinoma of primary uterine corpus and ovarian origin. Immunohistochemical analyses for the expression of vimentin in tumoral epithelial cells were performed on 149 endometrioid adenocarcinomas wherein the primary sites were not in question, including whole tissue sections of 27 carcinomas of uterine corpus origin (and no synchronous ovarian tumor), 7 carcinomas of ovarian origin (and no synchronous uterine corpus tumor) and a tissue microarray (TMA) containing 91 primary uterine corpus and 24 primary ovarian carcinomas. We also assessed 15 cases that synchronously involved the uterine corpus and ovary, 15 cases of metastasis to organs/tissues other than uterine corpus or ovary as well as 7 lymph node metastases. Vimentin was negative in 97% (30/31) of primary ovarian carcinomas. In contrast, 82% (97/118) of primary uterine corpus carcinomas were vimentin-positive. Vimentin expression was discordant in 53% of synchronous tumors. The sensitivity and specificity of negative vimentin staining in predicting an ovarian primary were 97% and 82%, respectively, whereas parallel values for positive vimentin staining in predicting a primary uterine tumor were 82% and 97%, respectively. The pattern of vimentin expression in all cases was maintained in their respective regional lymph nodes and distant metastases. In conclusion, ovarian and uterine corpus endometrioid adenocarcinomas have different patterns of vimentin expression. If validated in larger and/or different data sets, these findings may have diagnostic value in distinguishing metastatic lesions from double primary tumors involving both sites.

Immunophenotype and K-RAS mutation in mucinous ovarian adenocarcinoma with mural nodule of high-grade sarcoma: case report.

Ovarian mucinous tumors with mural nodules are rare. The mural nodules are microscopically divergent neoplasms of varying sizes that may be benign (eg, sarcoma-like and carcinosarcoma-like), or malignant (eg, anaplastic carcinoma and sarcoma). The K-RAS gene mutation in ovarian mucinous neoplasms with mural nodules has not been previously reported. This is a case report of a 25-year-old female diagnosed with ovarian invasive mucinous adenocarcinoma with mural nodule of high-grade sarcoma. The mucinous tumor component demonstrated a K-RAS codon 12/13 mutation (p.G12V, c.35 G>T), whereas the sarcomatous component demonstrated a K-RAS codon 12/13 mutation (p.G12D, c.35 G>A). Although both tumor components revealed a mutation in codon 12 of K-RAS, they were of different nucleotide substitutions, indicating that these 2 tumor components were of different clonal origins. However, the fact that the 2 mutations identified in the tumor components are the most common mutations reported in mucinous tumors of the ovary, raises the possibility that sarcomatous mural nodules simply represent a form of dedifferentiation in mucinous tumors.

Frequent expression of napsin A in clear cell carcinoma of the endometrium: potential diagnostic utility.

The histotyping of high-grade endometrial carcinomas with clear cells may be subject to significant interobserver variability, which suggests that a biomarker that can distinguish endometrial clear cell carcinoma (CCC) from its mimics would be of diagnostic utility. This study assessed the usefulness of napsin A immunohistochemistry in the diagnosis of CCC, on the basis of an analysis of 77 cases diagnosed as such at 9 institutions. After being independently reviewed by a subset of 3 pathologists, cases for which there was diagnostic consensus among all 3 reviewers in agreement with the primary contributor (n=60) were used to establish a "consensus group" that served as a gold standard relative to which napsin A performance was assessed. Duplicate, 1.0-mm-core tissue microarrays were constructed from the 54 cases in the consensus group for which requisite materials were available, as well as from 49 endometrial endometrioid carcinomas (all grades) and 17 endometrial serous carcinomas. Napsin A immunohistochemical analysis was performed on the microarrays and on the 17 cases for which there was no diagnostic consensus, with scoring based on the proportion of immunoreactive cells (0, 1+, 2+, and 3+ indicative of 0, 1% to 25%, 26% to 49%, and ≥50% immunoreactive cells, respectively). The distribution of scores for the 49 CCC cases with evaluable cores was as follows: 0, n=6; 1+, n=6; 2+, n=8; 3+, n=29. Among the evaluable cases, the frequency of ≥1+ napsin A immunoreactivity was significantly higher in CCCs (43/49, 88%) than in endometrial serous carcinomas (1/13, 7.7%; P<0.0001) and endometrial endometrioid carcinomas (0/49, 0%; P<0.0001). The sensitivity, specificity, negative predictive value, and positive predictive value of ≥1+ napsin A expression in predicting the consensus clear cell histotype were 0.88 (95% confidence interval [CI], 0.75-0.95), 0.98 (95% CI, 0.9-1), 0.91 (95% CI, 0.86-0.96), and 0.98 (95% CI, 0.86-1), respectively. Napsin A expression was not associated with survival or clinicopathologic factors. In the group of cases without diagnostic consensus for CCC, 50% showed ≥1+ napsin A expression; all napsin A-negative cases had previously been classified as non-CCC by ≥2 reviewers, whereas only 37.5% of the napsin A-positive cases had been classified as CCC by 2 of the 3 reviewers. In conclusion, napsin A is a sensitive and specific biomarker of the clear cell histotype in endometrial carcinomas and accordingly may have diagnostic utility in their histotyping.

Pleomorphic lobular carcinoma in situ of the breast: clinicopathological review of 47 cases.

AIMS: Pleomorphic lobular carcinoma in situ (PLCIS) of the breast is a distinctive entity, but its behaviour and management are unclear. The purpose of this study was to review a relatively large number of cases and to evaluate the risk of recurrence. METHODS AND RESULTS: Cases of PLCIS (n = 47) from a 12-year period were reviewed. The clinical, radiological and pathological findings were recorded. Immunohistochemistry for oestrogen receptor (ER), progesterone receptor (PR) and HER2 was performed. Thirty-one patients had no concurrent breast cancer or past history of breast cancer, and six (19.4%) of these had local recurrence; all tumours (four invasive carcinoma and two PLCIS) were ipsilateral. Younger age at presentation was a risk factor for local recurrence: patients with recurrence had a mean age (range) of 52.5 years (44-59 years), versus 60.6 years (40-81 years) for those without (P = 0.03). Three of 31 patients were treated with radiation therapy (RT), and none of these developed local recurrence. PLCIS had an adverse ER/PR/HER2 molecular profile, with at least 41.2% of the cases overexpressing HER2. Moreover, at least 11.7% of the cases were triple-negative. CONCLUSIONS: This study included the largest number of patients who had no concurrent breast cancer or past history of breast cancer with the longest clinical follow-up, providing insights into management practices for PLCIS and the risk of recurrence.