An Unusual Endometrial Stromal Neoplasm With JAZF1-BCORL1 Rearrangement.

Endometrial stromal tumors represent the second most common category of uterine mesenchymal tumors. Several different histologic variants and underlying genetic alterations have been recognized, one such being a group associated with BCORL1 rearrangements. They are usually high-grade endometrial stromal sarcomas, often associated with prominent myxoid background and aggressive behavior. Here, we report an unusual endometrial stromal neoplasm with JAZF1-BCORL1 rearrangement and briefly review the literature. The neoplasm formed a well-circumscribed uterine mass in a 50-yr-old woman and had an unusual morphologic appearance that did not warrant a high-grade categorization. It was characterized by a predominant population of epithelioid cells with clear to focally eosinophilic cytoplasm growing in interanastomosing cords and trabeculae set in a hyalinized stroma as well as nested and fascicular growths imparting focal resemblance to a uterine tumor resembling ovarian sex-cord tumor, PEComa, and a smooth muscle neoplasm. A minor storiform growth of spindle cells reminiscent of the fibroblastic variant of low-grade endometrial stromal sarcoma was also noted but conventional areas of low-grade endometrial stromal neoplasm were not identified. This case expands the spectrum of morphologic features seen in endometrial stromal tumors, especially when associated with a BCORL1 fusion and highlights the utility of immunohistochemical and molecular techniques in the diagnosis of these tumors, not all of which are high grade.

Hot Seat Diagnosis.

CONTEXT.­: Competency-based medical education relies on frequent formative in-service assessments to ascertain trainee progression. Currently at our institution, trainees receive a summative end-of-rotation In-Training Evaluation Report based on feedback collected from staff pathologists. There is no method of simulating report sign-out. OBJECTIVE.­: To develop a formative in-service assessment tool that is able to simulate report sign-out and provide case-by-case feedback to trainees. Further, to compare time- versus competency-based assessment models. DESIGN.­: Twenty-one pathology trainees were assessed for 20 months. Hot Seat Diagnosis by trainees and trainee assessment by pathologists were recorded in the laboratory information system. In the first iteration, trainees were assessed by using a time-based assessment scale on their ability to diagnose, report, use ancillary tests, comment on clinical implications, and provide intraoperative consultation and/or gross cases. The second iteration used a competency-based assessment scale. Trainees and pathologists completed surveys on the effectiveness of the In-Training Evaluation Report versus the Hot Seat Diagnosis tool. RESULTS.­: Scores from both iterations correlated significantly with other assessment tools including the Resident In-Service Examination (r = 0.93, P = .04 and r = 0.87, P = .03). The competency-based model was better able to demonstrate improvement over time and stratify junior versus senior trainees than the time-based model. Trainees and pathologists rated Hot Seat Diagnosis as significantly more objective, detailed, and timely than the In-Training Evaluation Report, and effective at simulating report sign-out. CONCLUSIONS.­: Hot Seat Diagnosis is an effective tool for the formative in-service assessment of pathology trainees and simulation of report sign-out, with the competency-based model outperforming the time-based model.

Undifferentiated endometrial carcinoma arising in the background of high-grade endometrial carcinoma - Expanding the definition of dedifferentiated endometrial carcinoma.

Dedifferentiated endometrial adenocarcinoma (DEC) is defined by the coexistence of undifferentiated carcinoma with low-grade (FIGO grade 1 or 2) endometrioid carcinoma. Few cases of DEC arising in the background of high-grade carcinoma (DEC-HG) have been reported, however, this phenomenon is poorly characterized. In this study we describe the morphologic, immunohistochemical and clinico-pathologic characteristics of DEC-HG. 18 DECs were diagnosed at our institution between 2008-2019, and in 11 (61%), the undifferentiated component was associated with high-grade carcinoma (8 endometrioid FIGO grade 3, 2 with ambiguous features, 1 serous). The remaining 7 (39%) represented DEC-LG (3 FIGO grade 1 and 4 FIGO grade 2). 7/11 (64%) patients with DEC-HG presented with advanced stage (FIGO stage III/IV), whereas most with DEC-LG (6/7, 86%) were stage I. On follow up, 2 patients in the DEC-HG group died of disease and 2 had progressive disease within 2 months of surgery. There was only one recurrence in the DEC-LG, 6 months post-surgery. The DEC component in both groups showed similar morphology and immunophenotype, with predominantly focal or complete loss of expression of pan-keratin, EMA, E-cadherin, CK8/18, PAX8 and ER. The DEC component in the DEC-HG group had wild-type p53 expression in 8/11 (73%) cases, loss of MLH1 and PMS2 in 6/11 (55%) and loss of SMARCA4 in 3/9 (33%). Although numbers are small, we show that DEC-HG is a previously under-recognized phenomenon, with morphologic and immunophenotypic similarities to DEC-LG, which supports expanding the definition of DEC to include DEC-HG. DEC-HG may be more aggressive than DEC-LG.

p53, Mismatch Repair Protein, and POLE Abnormalities in Ovarian Clear Cell Carcinoma: An Outcome-based Clinicopathologic Analysis.

The PROMISE diagnostic algorithm, which uses p53, mismatch repair (MMR) protein immunohistochemistry, and DNA polymerase ε (POLE) exonuclease domain mutation testing, is a reliable surrogate of the molecular group in endometrial carcinoma. Its prognostic value has been validated in endometrial carcinoma and ovarian endometrioid carcinoma. Moreover, a similar prognostic grouping has been recently documented in endometrial clear cell carcinoma. Thus, we aimed to explore the role of these markers in ovarian clear cell carcinoma, another endometriosis-associated malignancy. A total of 90 cases were identified and confirmed after secondary review. Immunohistochemistry for p53, MLH1, MSH2, MSH6, and PMS2 was performed in formalin-fixed, paraffin-embedded tissue. POLE mutational analysis was performed in 47 cases. Results were correlated with clinicopathologic variables including disease-free survival (DFS), overall survival, and disease-specific survival (DSS). Endometriosis was found in 67 (74%) cases. Six (7%) tumors were p53 abnormal, 82 (91%) were p53 normal, and 2 (2%) tumors had MMR deficiency (1 MSH6 loss and 1 MSH2/6 loss; both were p53 normal). Several POLE variants of unknown significance were detected, but no pathogenic mutations. The mean follow-up period was 43 months (median: 34, range: 1 to 189). Abnormal p53 status was associated with advanced Federation of Gynecology and Obstetrics stage, lymph node metastases, DFS and DSS (P<0.05, Fisher exact test). In univariate analysis, abnormal p53 and positive lymph node status had worse DFS, whereas bilaterality, surface involvement, and advanced stage were associated with worse DFS, overall survival and DSS (P<0.05, Cox regression). On multivariate analysis, only stage retained statistical association with survival. Using a molecular-based approach designed for endometrial carcinoma, most ovarian clear cell carcinomas fall into the copy-number-low molecular subgroup. However, a small but important subset has an abnormal p53 expression (copy-number-high group). This subset is associated with adverse features including extrapelvic disease, nodal metastases, and recurrence similar to endometrial and ovarian endometrioid cancer. Thus, testing for this marker has potential prognostic significance. The role of other markers in the PROMISE algorithm remains to be elucidated, as we found a low frequency of MMR abnormalities and no pathogenic POLE mutations in our series.

Myxoid smooth muscle neoplasia of the uterus: comprehensive analysis by next-generation sequencing and nucleic acid hybridization.

Uterine myxoid smooth muscle tumors, including myxoid leiomyosarcoma, are rare and their genomic profile has not been fully characterized. With the discovery of uterine sarcomas with ZC3H7B-BCOR fusion and BCOR internal tandem duplications, the differential diagnosis of myxoid smooth muscle lesions is expanding to include molecularly-defined tumors. Thus, we aimed to explore the genomic landscape of myxoid smooth muscle tumor using comprehensive tools. We performed whole exome next-generation sequencing and a pan-sarcoma RNA fusion assay in tumoral paraffin-embedded tissue from nine well-characterized uterine myxoid smooth muscle tumors (seven myxoid leiomyosarcomas and two myxoid smooth muscle tumors of unknown malignant potential). By immunohistochemistry, all tumors were strongly positive for smooth muscle markers and negative for BCOR staining; 4/6 expressed PLAG1. None of the tumors harbored known fusions including ZC3H7B-BCOR, TRPS1-PLAG1, and RAD51B-PLAG1. None harbored exon 15 BCOR internal tandem duplications; however, four tumors contained BCOR internal tandem duplications of unknown significance (mostly intronic). Mutational burden was low (median 3.8 mutations/megabase). DNA damage repair pathway gene mutations, including TP53 and BRCA2, were found. Copy number variation load, inferred from sequencing data, was variable with genomic indexes ranging from 2.2 to 74.7 (median 25.7), with higher indexes in myxoid leiomyosarcomas than myxoid smooth muscle tumors of unknown malignant potential. The absence of clear driver mutations suggests myxoid smooth muscle tumors to be genetically heterogeneous group of tumours and that other genetic (eg., undiscovered translocation) or epigenetic events drive the pathogenesis of uterine myxoid smooth muscle neoplasia.

FIGO Versus Silverberg Grading Systems in Ovarian Endometrioid Carcinoma: A Comparative Prognostic Analysis.

The International Federation of Obstetrics and Gynecology (FIGO) grading system for endometrial carcinoma is currently applied to ovarian endometrioid carcinoma (OEC) in many practices. However, previous reports claim superior prognostication by using the Silverberg grading system for ovarian carcinoma. Thus, a thorough comparison between FIGO and Silverberg in OEC is still warranted. A total of 72 OECs diagnosed at our institution were independently graded using both systems. Grade (G) following Silverberg was based on combined scores for architecture, nuclear atypia, and mitotic activity. FIGO grading was based on the % of nonsquamous solid component; severe atypia warranted upgrade to the architectural FIGO grade (G1 to G2 or G2 to G3). Case grouping by grade was correlated with disease-free (DFS), disease-specific (DSS), and overall (OS) survival. Eleven (15.3%) OECs were bilateral, 26 (36.1%) had ovarian surface involvement, and 12 (16.7%) had lymphovascular space invasion. Forty-seven OECs were stage I (65%), 16 (22%) stage II, and 9 (13%) stage III. Median follow-up period was 62 months (range: 1 to 179 mo). Median DFS was 60.5 months (1 to 179 mo); median OS was 61 months (1 to 179 mo). Sixteen (22%) OECs recurred and 9 (13%) patiets died of disease. In univariate analysis, both FIGO and Silverberg correlated significantly with DFS, DSS, and OS (all with P<0.05). However, when compared in multivariate analysis, only Silverberg retained statistical correlation with survival (P<0.05). G1+G2 OEC by Silverberg had significantly better DFS, DSS, and OS compared with G3; such separation was not seen with FIGO. Survival was similar in Silverberg G1 and G2 tumors even 5 years after diagnosis, whereas FIGO G2 tumors had survival approaching G1 in the first 5 years, but declined after the 5-year mark approaching G3 tumors. Tumor laterality, lymphovascular space invasion, and stage also correlated with outcome. Stage showed prognostication superior to all other variables in multivariate analysis. As currently defined, the Silverberg grading system is a better predictor of survival than FIGO. Such differences may be explained by the G2 OEC groups, with G2 Silverberg clustering with G1 tumors, and having a more favorable behavior compared with G2 FIGO. Thus, Silverberg may be preferable in order to stratify patients in low and high-risk categories for prognosis and disease management.

Endometriosis-associated Ovarian Cancer is a Subset With a More Favorable Outcome and Distinct Clinical-pathologic Characteristics.

There is a controversy about whether endometriosis-associated ovarian cancer (EAOC) might represent a different entity from the corresponding ovarian cancer occurring de novo, in the absence of endometriosis. This study investigated the clinical-pathologic characteristics and outcome of EAOC compared with other ovarian carcinomas that are not associated with endometriosis (non-EAOC) in a large cohort. Seven hundred two patients meeting the inclusion criteria were further subclassified as group I when patients had ovarian carcinoma associated with or arising within endometriosis (EAOC) and group II when patients had non-EAOC. Age, gross features, histologic type, International Federation of Gynecology and Obstetrics stage, and disease-free survival (DFS) were compared between the groups. One hundred sixty-eight (23.9%) patients had EAOC, whereas 534 (76.1%) patients had non-EAOC. EAOCs were mostly endometrioid and clear cell type. Patients with EAOC were younger, present early, and had a lower rate of recurrence when compared with patients with non-EAOC, P<0.001. Patients with EAOC had longer DFS time, 51.9 mo (95% confidence interval, 44.9-58.8) versus 30.5 mo (95% confidence interval, 27.7-33.3) in non-EAOC patients. The 5 yr Kaplan-Meier estimate of DFS rate was 70% in 166 patients of group I and was 39.3% in 532 patients of group II, P<0.001. On multivariate analysis, International Federation of Gynecology and Obstetrics staging, histologic type, and treatment were the only significant factors affecting the hazards of recurrence. Patients with tumors associated with endometriosis are usually, younger, present early, have lower rate of recurrence, longer DFS, and their tumors are of lower grade and are more likely endometrioid or clear cell carcinoma.

Comprehensive Clinicopathologic and Updated Immunohistochemical Characterization of Primary Ovarian Mucinous Carcinoma.

The distinction of primary mucinous ovarian carcinoma (PMOC) from other primaries or secondaries is essential for selecting therapeutic options and prognostication. We aimed to characterize the immunohistochemical profile of 36 PMOCs using an extended immunohistochemical panel, with clinicopathologic features and outcome. PAX8 was negative in 30 (83.3%), and SATB2 was negative in 32/35. HNF1B, AMACR, and napsin-A were detected in 33 (91.7%), 35 (97.2%), and 0 (0%), respectively. MMR proteins and ARID1A were retained in 100%; PTEN was lost in 4 (11.1%). P53 was aberrant in 10 (27.8%); none overexpressed p16. HER2 was positive in 6/35 (17.1%). Most PMOCs had a favorable outcome. However, recurrence is usually fatal. The typical tumor profile was CK7+, CK20+/-, CDX2+/-, PAX8-, ER-, PgR-, and SATB2-. HER2 positivity suggests a possible target for therapy in advanced disease.

Molecular-based classification algorithm for endometrial carcinoma categorizes ovarian endometrioid carcinoma into prognostically significant groups.

The Cancer Genome Atlas classification divides endometrial carcinoma in biologically distinct groups, and testing for p53, mismatch repair proteins (MMR), and polymerase ɛ (POLE) exonuclease domain mutations has been shown to predict the molecular subgroup and clinical outcome. While abnormalities in these markers have been described in ovarian endometrioid carcinoma, their role in predicting its molecular profile and prognosis is still not fully explored. Patients with ovarian endometrioid carcinomas treated surgically in a 14-year period were selected. Only tumors with confirmation of endometrioid histology and negative WT1 and Napsin-A were included. POLE mutational analysis and immunohistochemistry for p53, MLH1, MSH2, MSH6, and PMS2 was performed in formalin-fixed, paraffin-embedded tissue. Following the molecular classifier proposed for endometrial carcinoma (Br J Cancer2015;113:299-310), cases were classified as POLE mutated, MMR abnormal, p53 abnormal, and p53 wild type. Clinicopathologic information was recorded, including patient outcome. In all, 72 cases were included, distributed as follows: 7 (10%) POLE mutated; 6 (8%) MMR abnormal; 17 (24%) p53 abnormal; and 42 (58%) p53 wild type. The molecular classification correlated with disease-free survival in multivariate analysis (P=0.003), independently of tumor grade and stage. Correlation with overall survival approached statistical significance (P=0.051). POLE-mutated and MMR-abnormal tumors had excellent survival, whereas p53-abnormal tumors had significantly higher rates of recurrence and death. Ovarian endometroid carcinoma can be classified in clinically meaningful subgroups by testing for molecular surrogates, akin to endometrial cancer. MMR and POLE alterations seem to identify a subset of ovarian endometrioid carcinomas with excellent outcome; conversely, abnormal p53 carries a worse prognosis. In the era of personalized medicine, the use of these markers in the routine evaluation of ovarian endometrioid tumors should be considered.

Performance of residents using digital images versus glass slides on certification examination in anatomical pathology: a mixed methods pilot study.

BACKGROUND: It is anticipated that many licensing examination centres for pathology will begin fully digitizing the certification examinations. The objective of our study was to test the feasibility of a fully digital examination and to assess the needs, concerns and expectations of pathology residents in moving from a glass slide-based examination to a fully digital examination. METHODS: We conducted a mixed methods study that compared, after randomization, the performance of senior residents (postgraduate years 4 and 5) in 7 accredited anatomical pathology training programs across Canada on a pathology examination using either glass slides or digital whole-slide scanned images of the slides. The pilot examination was followed by a post-test survey. In addition, pathology residents from all levels of training were invited to participate in an online survey. RESULTS: A total of 100 residents participated in the pilot examination; 49 were given glass slides instead of digital images. We found no significant difference in examination results between the 2 groups of residents (estimated marginal mean 8.23/12, 95% confidence interval [CI] 7.72-8.87, for glass slides; 7.84/12, 95% CI 7.28-8.41, for digital slides). In the post-test survey, most of the respondents expressed concerns with the digital examination, including slowly functioning software, blurring and poor detail of images, particularly nuclear features. All of the respondents of the general survey (n = 179) agreed that additional training was required if the examination were to become fully digital. INTERPRETATION: Although the performance of residents completing pathology examinations with glass slides was comparable to that of residents using digital images, our study showed that residents were not comfortable with the digital technology, especially given their current level of exposure to it. Additional training may be needed before implementing a fully digital examination, with consideration for a gradual transition.

Fertility sparing treatment of complex atypical hyperplasia and low grade endometrial cancer using oral progestin.

OBJECTIVE: Oral progestin is an alternative to hysterectomy for women with complex atypical hyperplasia (CAH) or grade one endometrial cancer (G1EC) who wish fertility preservation. We evaluated treatment efficacy and fertility outcomes in this population. METHODS: Women <45 y treated with oral progestin for CAH or G1EC were identified from two cancer centers. Data were obtained from medical records and telephone questionnaires. Time until complete response (CR), and from CR until recurrence was censored for patients without events and analyzed for associations with patient and treatment characteristics; cumulative incidence functions were used to estimate event probability over time. RESULTS: 44 patients were identified, 19 (43%) with CAH and 25 (57%) with G1EC. Median age was 36.5 y (26-44). 24 (55%) achieved CR (median time: 5.7 months). Older age was associated with a lower likelihood of CR (HR 0.84, p=0.0003, 95% CI, 0.8-0.9). CR probability appeared to plateau after 12 months of therapy. Among those with CR, 13 (54%) recurred (median time 3.5 y). 24 patients (55%) underwent hysterectomy; 3 (13%) were upstaged. 11 (25%) underwent fertility treatment with the following outcomes: 6 (55%) no pregnancy, 2 (18%) at least one live infant, and 3 (27%) spontaneous abortion. One achieved a live birth without intervention. CONCLUSION: Oral progestin is an effective temporizing fertility-sparing treatment for women with CAH/G1EC. Fertility specialist involvement is recommended due to the low live birth rate without intervention. Progestin therapy should be re-evaluated at 1 year in non-responders due to a low probability of success. Hysterectomy is recommended after childbearing due to a high recurrence rate.

Is routine appendectomy at the time of primary surgery for mucinous ovarian neoplasms beneficial?

UNLABELLED: The question whether the appendix should be removed at the time of surgery for apparent early-stage ovarian cancer is controversial. Removal of the appendix in the setting of mucinous histologic type is primarily driven by the existing challenge to distinguish between primary ovarian mucinous neoplasm and metastatic appendiceal carcinoma to the ovary. OBJECTIVES: To evaluate the value of an appendectomy at the time of surgery for ovarian mucinous borderline tumors or carcinoma. METHODS: A retrospective single institute-based study was conducted. We identified patients who were operated on by a gynecologic oncologist for an abnormal pelvic mass, which was diagnosed as mucinous adenocarcinoma or mucinous borderline tumor between January 2000 and December 2010. Cases were included in the study if an appendectomy was performed at the time of initial surgery. RESULTS: Seventy-seven cases meeting the inclusion criteria were identified. The ovarian mass of 11 patients (14%) was diagnosed as metastatic appendiceal carcinoma involving the ovary. Evidence of metastatic disease, abnormal-looking appendix, or pseudomyxoma peritonei, were identified at the time of surgery for all of these cases. The condition of 30 patients (39%) and 36 patients (47%) were diagnosed as mucinous borderline ovarian tumor and invasive or microinvasive mucinous ovarian carcinoma, respectively. Evidence of metastasis from the ovary to the appendix was not identified in any of the cases. CONCLUSIONS: Our data suggest that in cases of apparent early-stage mucinous ovarian borderline tumors and cancer, adding an appendectomy at the time of surgery is not warranted in the absence of a grossly abnormal appendix or evidence of metastatic disease.

P16INK4a expression in undifferentiated carcinoma of the uterus does not exclude its endometrial origin.

Undifferentiated carcinoma of the endometrium is a rare neoplasm, which, when involving the cervix, raises a question about its origin. Diffuse p16 positivity of uterine cancers is usually interpreted as a surrogate marker for high-risk human papilloma virus and favors cervical origin. In this study, we investigated the expression of cytokeratin 7 (CK7), monoclonal carcinoembryonic antigen (mCEA), estrogen receptor (ER), vimentin, and p16 in 28 cases of undifferentiated endometrial carcinoma, 20 high-grade endometrioid adenocarcinomas, and 50 cervical adenocarcinomas. Staining was considered positive when it was cytoplasmic for CK7, mCEA, and vimentin, nuclear for ER, and both nuclear and cytoplasmic for p16. Percentages of cells staining were recorded as follows: negative (0%-5%), 1+ (6%-25%), 2+ (26%-50%), 3+ (51%-75%), and 4+ (>75%). P16 was considered positive if it stained more than 75% of the tumor cells. Diffuse/strongly positive staining for p16 was seen in 40/50 (80%) cases of cervical adenocarcinoma and 14/28 (50%) cases of undifferentiated endometrial carcinoma. In high-grade endometrioid adenocarcinoma, staining was mainly patchy. CK7, mCEA, ER, progesterone receptor, and vimentin staining in undifferentiated endometrial carcinoma was as follows: 10/28 (36%), 4/28 (14%), 21/28 (75%), 23/28 (82%), and 26/28 (93%), respectively; for high-grade endometrioid carcinoma: 20/20 (100%), 1/20 (5%), 17/20 (85%), 18/20 (90%), and 19/20 (95%); for endocervical adenocarcinoma: 50/50 (100%), 45/50 (90%), 9/50 (18%), 8/50 (16%), and 6/50 (12%), respectively. Our data indicate that p16 may play a role in the tumorigenesis of a subset of undifferentiated endometrial carcinoma. In the setting of p16 positivity, undifferentiated endometrial carcinomas are more likely to be ER, progesterone receptor, and vimentin positive and mCEA negative when compared with endocervical adenocarcinomas. Distinction between undifferentiated endometrial carcinoma and endocervical adenocarcinoma, both of which can share diffuse p16 expression, should rely on detection of human papilloma virus in the latter.

Immunohistochemical characterization of primary and recurrent adult granulosa cell tumors.

Adult granulosa cell tumors are usually diagnosed at an early stage. However, most patients with advanced or recurrent disease will die of the disease due to limited treatment options. Data on the immunohistochemical characteristics of recurrent granulosa cell tumors are limited. The aim of this study was to compare the immunohistochemical profile of primary and recurrent adult granulosa cell tumors. Special emphasis is given to epidermal growth factor receptor expression because it represents a potential marker for targeted therapy with monoclonal antibodies.Inhouse granulosa cell tumor cases accessioned between 1999 and 2008 were retrieved and reviewed according to the WHO classification. Cases were studied by immunohistochemistry using a panel of 11 antibodies. Immunostaining was semiquantitatively recorded.We have studied 20 cases of primary and 20 cases of recurrent adult granulosa cell tumors from 31 patients. Immunohistochemistry showed that primary tumors were positive for inhibin in 100%, calretinin 100%, CD56 90%, CD99 40%, D2-40 35% and low molecular weight keratin 30%. Recurrences were positive for inhibin 90%, calretinin 85%, CD56 95%, CD99 65%, D2-40 55% and low molecular weight keratin 10%. Recurrences were positive for inhibin 90%, calretinin 85%, CD56 95%, CD99 65%, D2-40 55%, and low molecular weight keratin 10%. All primary and recurrent tumors were negative for melan-A, CD10, and epithelial membrane antigen. Epidermal growth factor receptor was positive in 65% of primary tumors and 85% of recurrences. Ki67 index was higher in recurrence specimens. The immunoprofile of primary and recurrent adult granulosa cell tumors is highly concordant. Similar to primary tumors, almost all recurrent cases exhibited evidence of sex cord lineage. The lack of specific markers emphasizes the need for evaluation using a panel of antibodies. Special attention should be paid when low molecular-weight keratin is used as part of a panel differentiating granulosa cell tumors from carcinomas, as a significant proportion of the former are positive. Although targeted therapies directed against epidermal growth factor receptor have not been tested yet in the setting of advanced or recurrent granulosa cell tumors, the high level of epidermal growth factor receptor expression is important as we step to an era of advanced biolabeled imaging techniques.

Lymphatic vessel density as a prognostic marker in clinical stage I endocervical adenocarcinoma.

There are limited data evaluating the significance of lymphatic vessel density (LVD) as a prognostic marker in cervical adenocarcinoma. In this study, we investigated intratumoral and peritumoral LVD, using the lymphatic marker D2-40, as a prognostic marker in endocervical adenocarcinoma. Surgical specimens from 50 consecutive patients with endocervical adenocarcinoma treated with complete staging surgical procedures were reviewed. Selected tumor blocks were immunostained for D2-40 and CD31. Positively stained microvessels (MVs) were counted in densely vascular/lymphatic foci (hot spots) at 400x field in each specimen (0.17 mm). Results were expressed as the highest MV count identified within any single field. Both intratumoral CD31 MV and peritumoral D2-40 LVD showed significant correlation with depth of invasion (r=0.39, 0.37, respectively), percentage of circumferential involvement (r=0.36, 0.48, respectively), and lymphovascular invasion detected by D2-40 (r=0.45, 0.51, respectively; P<0.01). Only peritumoral D2-40 LVD showed a significant correlation with lymph node metastases (r=0.40; P<0.01), disease-free and overall survivals. Using univariate analysis, peritumoral D2-40 LVD showed significant correlation with lymphovascular invasion detected by D20-40 and lymph node metastases (P<0.05), which was maintained on multivariate analysis. D2-40 detected lymphovascular invasion in 16 of 50 (32%) cases, and showed a significant correlation with depth of invasion, lymph node metastases, involvement of parametrium (r=0.41, 0.38, 0.32, respectively; P<0.01), and disease-free survival. Our study showed that both angiogenesis and lymphangiogenesis play an important role in the progression of endocervical adenocarcinoma, and that peritumoral D2-40 LVD is an independent predictor of lymph node metastasis.

Detection of HPV-DNA by a PCR-based method in formalin-fixed, paraffin-embedded tissue from rare endocervical carcinoma types.

High-risk human papilloma virus (HPV) seems to play a role in the pathogenesis of cervical squamous neoplasia and adenocarcinomas of the mucinous and endometrioid cell types. Cervical serous, clear cell, and small cell carcinomas differ from the conventional endocervical adenocarcinoma in their clinical characteristics. The data on the role of HPV in their pathogenesis are limited. In this study, we examined the presence of high-risk HPV-DNA in rare types of cervical carcinoma using polymerase chain reaction-based test. In-house cervical serous, clear cell, and small cell carcinoma cases accessioned between 2000 and 2008 were tested for HPV by polymerase chain reaction amplification of DNA extracted from deparaffinized sections using Roche AMPLICOR HPV Amplification Detection and Control Kits. The kit detects all 13 high-risk HPV-DNA genotypes. The positive cut-off point for AMPLICOR HPV Test was A450 = 0.2. We identified 4 serous, 3 clear cell, 1 mixed clear cell and serous, and 5 small cell carcinomas. High-risk HPV-DNA tested positive in 3 out of 4 serous carcinomas, 2 out of 3 cervical clear cell carcinomas, and all 5 cases of small cell carcinoma and the mixed cell type. Our report documents HPV status in a series of archival unusual types of adenocarcinoma of the uterine cervix. It suggests a robust association between high-risk HPV and these rare subtypes. Despite their unique clinical setting and morphologic appearance, the majority of these tumors likely share a common HPV-mediated carcinogenic pathway. Our observation is particularly significant in cervical cancer prevention as we enter the HPV vaccination era.

CDX-2 expression is a common event in primary intestinal-type endocervical adenocarcinoma.

We studied the expression of cytokeratin (CK) 7, CK20, CDX-2, and p16 in 119 cervical adenocarcinomas (65 usual type [50 invasive; 15 in situ], 37 intestinal type [21 invasive; 16 in situ], 10 endometrioid, 5 adenosquamous, and 2 signet-ring carcinomas) in comparison with 55 cases of rectal adenocarcinomas. The percentage of cells staining was considered negative if 0% to 5% stained; more than 5% was considered positive. For p16, staining of more than 50% was considered positive. CK7 was expressed in all cervical cases and in 12 rectal adenocarcinomas (22%). CK20 was expressed in 17 cervical adenocarcinomas (14.3%) and in 48 rectal adenocarcinomas (87%). CK20 immunostaining was diffuse in the majority of rectal tumors but focal in most cervical tumors. CDX-2 was expressed in all cases of rectal adenocarcinoma and in 46 cervical adenocarcinomas (38.7%): usual type, 10 (15%); intestinal type, 31 (84%); endometrioid type, 5 (50%); adenosquamous and signet-ring types, 0 (0%). CDX-2 is a marker for intestinal differentiation irrespective of a rectal or cervical origin. Therefore, it should not be used as the sole basis to confirm the colorectum as the primary origin in metastatic cases.

Intraoperative consultation in gynecologic pathology: a 6-year audit at a tertiary care medical center.

BACKGROUND: Most of the literature on intraoperative consultation (IOC) in gynecologic pathology focuses on the accuracy of this technique. This study addresses a wide range of quality assurance issues regarding this practice through a comprehensive audit of our experience. DESIGN: The anatomic pathology database was searched between 1999 and 2005 for all gynecologic cases who received IOCs. Seven hundred thirty-one IOCs rendered were identified and analyzed. The accuracy of IOC by gynecologic pathologists was comparable to that of surgical pathologists. RESULTS: Patient care was potentially negatively impacted in 14 IOCs; 2 were conducted by the former and 12 by the latter group. Management of ovarian tumors with borderline features significantly improved when the terminology of "at least borderline" was used. Intraoperative consultation by gross inspection only had a low accuracy of 94.7%. Intraoperative consultation was able to definitively and correctly answer the question of whether an ovarian tumor was primary or metastatic in only 35% of patients. As a result of the IOC, the surgical procedure proceeded as originally intended in 96% of patients, was modified in 2%, and was terminated in 2%. CONCLUSIONS: This audit identifies certain procedural and communication strategies that can increase accuracy. It also highlights the situations where IOC could be less reliable. Patient's safety can increase by improving the communication between the surgeons and the consultant pathologist, consulting with gynecologic pathologists in oncology cases whenever feasible, and using the term of "at least borderline" rather than "borderline."

Postradical vaginal trachelectomy follow-up by isthmic-vaginal smear cytology: a 13-year audit.

Radical trachelectomy is a fertility preserving alternative for early cervical cancer patients. This audit assesses the role of isthmic-vaginal smear in postoperative follow-up. A total of 94 patients were identified generating 913 smears. The final surgical margin was at the lower uterine segment in 37 cases (39.4%) and significantly correlated with the presence of lower uterine segment endometrial cells (LUSEC) in smears (P = 0.035). The most common abnormal diagnoses in the presence of LUSEC were ASC-US and AGUS seen in 14.2% and 11.9% of positive smears, respectively. The most common follow-up pattern was initial positive smears, which converted to negative (45.7% of patients), showing that reactive changes are another potential overcall pitfall. The only 2 central recurrences were successfully diagnosed by smears. This study summarizes our experience, emphasizing the role of isthmic-vaginal smears for early detection of central recurrence and highlighting the role of LUSEC and reactive changes as potential overcall pitfalls.

Immunophenotyping of serous carcinoma of the female genital tract.

To update the data on the expression of 'mesothelioma markers' by serous carcinomas of various sites we have studied cases from ovary (n=56), endometrium (n=37), fallopian tube (n=6), primary peritoneum (n=5) and cervix (n=3) using a panel of antibodies (WT1, P53, estrogen receptors, HER2/neu, D2-40, cytokeratin 5/6 and E-cadherin). Ovarian carcinomas demonstrated D2-40 and cytokeratin 5/6 immunoreactivity in 23.2 and 55.4% of cases, respectively. Endometrial carcinomas demonstrated D2-40 and cytokeratin 5/6 immunoreactivity in 43.2 and 37.8% of cases, respectively. D2-40 staining pattern was predominantly focal; however, strong reactivity was identified in 16.2% of endometrial and 10.7% of ovarian carcinomas. HER2/neu oncoprotein overexpression was demonstrated in 7 of 37 (18.9%) uterine serous carcinomas. In contrast, all the serous carcinomas of the other sites were HER2/neu negative. The proportion of positive cases was significantly different in ovarian vs endometrial carcinomas regarding WT1 (P=0.0458), estrogen receptors (P<0.001) reactivity and HER2/neu overexpression (P=0.0025). D2-40 and cytokeratin 5/6 are expressed in a considerable proportion of serous carcinomas and should be used cautiously in a 'mesothelioma panel' in situations where serous carcinoma is in the differential diagnosis. HER2/neu was exclusively overexpressed in serous carcinomas of endometrial origin.