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Objective: To review the results of patients with high-grade Stage I ovarian cancer managed without adjuvant treatment. Materials and Methods: A retrospective chart review identified patients with newly diagnosed Stage I high-grade ovarian cancer, who underwent comprehensive surgical staging. Results: Thirty-three patients with FIGO surgical Stage I high-grade ovarian cancer were identified. After a median follow-up of 40 months, nine patients (27%) recurred. The median time to recurrence was 19 months. Of the nine patients with recurrences, four (44%) are alive with disease, three (33%) patients have no evidence of disease, and two have died of disease (22%). The two- and five-year overall survival is 100% and 90%, respectively. Conclusions: It would appear the recurrence rates of Stage I high risk epithelial ovarian cancer completely staged, without adjuvant treatment are comparable to those of treatment arms reported in the literature. A proportion of these patients can be salvaged at recurrence, yielding a high overall survival. [ABSTRACT FROM AUTHOR]

Background:The histology and grade of endometrial cancer are important predictors of disease outcome and of the likelihood of nodal involvement. In most centres, however, surgical staging decisions are based on a preoperative biopsy. The objective of this study was to assess the concordance between the preoperative histology and that of the hysterectomy specimen in endometrial cancer.Methods:Patients treated for endometrial cancer during a 10-year period at a tertiary cancer centre were identified from a prospectively collected pathological database. All pathology reports were reviewed to confirm centralised reporting of the original sampling or biopsy specimens; patients whose biopsies were not reviewed by a dedicated gynaecological pathologist at the treating centre were excluded. Surgical pathology data including histology, grade, depth of myometrial invasion, cervical stromal involvement and lymphovascular space invasion (LVSI) as well as preoperative histology and grade were collected. Preoperative and final tumour cell type and grade were compared and the distribution of other high-risk features was analysed.Results:A total of 1329 consecutive patients were identified; 653 patients had a centrally reviewed epithelial endometrial cancer on their original biopsy, and are included in this study. Of 255 patients whose biopsies were read as grade 1 (G1) adenocarcinoma, 45 (18%) were upgraded to grade 2 (G2) on final pathology, 6 (2%) were upgraded to grade 3 (G3) and 5 (2%) were read as a non-endometrioid high-grade histology. Overall, of 255 tumours classified as G1 endometrioid cancers on biopsy, 74 (29%) were either found to be low-grade (G1-2) tumours with deep myometrial invasion, or were reclassified as high-grade cancers (G3 or non-endometrioid histologies) on final surgical pathology. Despite these shifts, we calculate that omitting surgical staging in preoperatively diagnosed G1 endometrioid cancers without deep myometrial invasion would result in missing nodal involvement in only 1% of cases.Conclusions:Preoperative endometrial sampling is only a modest predictor of surgical pathology features in endometrial cancer and may underestimate the risk of disease spread and recurrence. In spite of frequent shifts in postoperative vs preoperative histological assessment, the predicted rate of missed nodal metastases with a selective staging policy remains low. [ABSTRACT FROM AUTHOR]

Abstract Colorectal small cell carcinoma (SmCC) is a rare tumor with an aggressive course. The aim of this study is to summarize our experience with this tumor and to highlight its immunohistochemical profile. Ten cases of colorectal SmCC were identified in our files and a panel of immunostains was performed. Follow up was available for the average of 3 years, during which 7 patients died and 3 were alive with disease. All cases were positive for LMWK, CK 19 and pancytokeratin but were negative for TTF-1 and CA 125. EGFR was positive in 7 cases. TTF-1 negative staining may be valuable in differentiating it from its pulmonary counterpart. CDX2, mCEA, CD56, synaptophysin, NSE and chromogranin can help differentiate it from non-endocrine poorly differentiated adenocarcinoma. The expression of EGFR in a subset of patients has not been reported earlier and has to be evaluated in larger series to assess its role in the planning of targeted biologic therapy.

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.

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., (© 2020 John Wiley & Sons Ltd.)

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.

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.

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.

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.

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.

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.

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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.

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.

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.

Hydatidiform moles are gestational diseases with abnormal development of the villous trophoblast and characterized by an excess of paternal to maternal genetic material. Complete moles are usually diploid and androgenetic, and are thought to develop after the fertilization of an "empty ovum" by either a haploid spermatozoon or two spermatozoa. We report a case of a complete mole in which fluorescence in situ hybridization (FISH) incidentally disclosed trisomy 13. Microsatellite genotyping showed a single allele at each of the markers tested on the chorionic villi, and comparison with parental peripheral blood specimens revealed that the markers were all of paternal origin. These results confirmed the paternal origin of all three copies of chromosome 13, and the isodisomy for each chromosome was consistent with duplication of a monospermic fertilization event and subsequent non-disjunction. To the best of our knowledge, this is the only case of an androgenetic complete mole with trisomy 13 described in the scientific literature. We present a review of the literature and hypothesize that the trisomy 13 in our case likely resulted from non-disjunction of chromosome 13., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

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.

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.

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.

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., (2009 Wiley-Liss, Inc.)

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."

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.

To evaluate the value of lymphovascular invasion (LVI) in endometrial endometrioid adenocarcinoma (EEA) as a predictor for distant recurrence, we analyzed the histopathologic features of 513 consecutive cases of nonsurgically staged EEA limited to the uterus. Grade, myoinvasion, cervical involvement, and LVI were evaluated. With a median follow-up of 28 months (range, 2-144 months), 67 cases (13.1%) recurred, 37 (7.2%) had locoregional recurrence, and 30 (5.8%) developed distant recurrence. LVI was identified in 116 cases (22.6%) cases and was the only adverse histopathologic finding in 23 cases; 5 (22%) of the 23 recurred. Multivariate analysis demonstrated a significant association between any type of recurrence and cervical involvement (hazard ratio [HR], 2.760; 95% confidence interval [CI], 1.621-4.698) and LVI (HR, 2.717; CI, 1.568-4.707). Multivariate analysis revealed LVI as the only independent predictor for distant recurrence (HR, 2.841; CI, 1.282-6.297). Studies to examine the role of adjuvant systemic therapy in patients with early-stage disease should be considered.

We reviewed 827 consecutive cases of pure endometrial endometrioid adenocarcinoma (EEA) treated by hysterectomy to update the distribution of pathologic features. Tumor grade (reported in a 2-tiered system), depth of myometrial invasion, presence of cervical involvement, lymphovascular invasion (LVI), and evidence of extrauterine disease were recorded.The median age at diagnosis was 62 years (range, 30-94 years). The tumor was high grade in 94 cases (11.4%), invaded into the outer half of the myometrium in 249 (30.1%), was positive for cervical involvement in 171 (20.7%), and was positive for LVI in 182 (22.0%). Lymph nodes (sampled in 85 cases) were positive in 13 (1.6%), and ovarian metastases were present in 15 cases (1.8%). High tumor grade was significantly associated with deep myometrial invasion (P > .0001), cervical involvement (P = .0065), and LVI (P > .0001).EEA manifests most commonly with low tumor grade and without deep myometrial invasion. High tumor grade is significantly associated with deep myometrial invasion, cervical involvement, and LVI.

Colorectal small cell carcinoma (SmCC) is a rare tumor with an aggressive course. The aim of this study is to summarize our experience with this tumor and to highlight its immunohistochemical profile. Ten cases of colorectal SmCC were identified in our files and a panel of immunostains was performed. Follow up was available for the average of 3 years, during which 7 patients died and 3 were alive with disease. All cases were positive for LMWK, CK 19 and pancytokeratin but were negative for TTF-1 and CA 125. EGFR was positive in 7 cases. TTF-1 negative staining may be valuable in differentiating it from its pulmonary counterpart. CDX2, mCEA, CD56, synaptophysin, NSE and chromogranin can help differentiate it from non-endocrine poorly differentiated adenocarcinoma. The expression of EGFR in a subset of patients has not been reported earlier and has to be evaluated in larger series to assess its role in the planning of targeted biologic therapy.

Adenomyosis is commonly seen in association with endometrial adenocarcinoma where it may or may not be involved by malignancy. This study of grade 1 endometrioid adenocarcinoma investigates whether patients with cancer-positive adenomyosis are at a different risk for deep myometrial invasion compared with those with cancer-negative adenomyosis. Ninety-three hysterectomy specimens with FIGO (International Federation of Gynecologists and Obstetricians) grade 1 endometrial endometrioid adenocarcinoma associated with adenomyosis were studied. Four experienced gynecologic pathologists retrospectively reviewed all hematoxylin and eosin-stained sections. Myometrial invasion was confirmed by CD10-negative staining around glands with jagged outline surrounded by inflamed desmoplastic stroma. Adenomyosis was involved by adenocarcinoma in 46 cases, whereas it was carcinoma-negative in 47 cases. Myometrial invasion was found in significantly more carcinoma-positive adenomyosis cases (n = 42, 91.3%) than with carcinoma-negative adenomyosis cases (n = 30, 63.8%) (chi(2) = 12.10; P = .0005). Moreover, myometrial invasion in the outer half was also seen in significantly more carcinoma-positive adenomyosis cases (n = 16, 34.8%) than with carcinoma-negative adenomyosis cases (n = 3, 6.4%) (chi(2) = 11.53; P = .0007). Among all cases of FIGO grade 1 endometrial endometrioid adenocarcinoma associated with adenomyosis, the ones that extend in the adenomyosis gain more invasive advantage, probably through increasing the surface area of its interface with the adjacent myometrium. When compared with tumors that do not involve adenomyosis, these tumors are not only more likely to invade the myometrium but are significantly more prone to achieve deep invasion into the outer half.

Objective: The cyclooxygenase-2 (COX-2) enzyme is up-regulated in inflammatory and neoplastic conditions. In the last decade, its biological role has been investigated in various pre-invasive and invasive cancers with the hope that it can serve as a target for cancer prevention and treatment., Methods: We evaluated the expression of COX-2 in vulvar biopsies to determine its relationship to the degree of dysplasia. COX-2 expression was studied by immunohistochemistry in 62 consecutive vulvar biopsies divided into four diagnostic groups. Group 1 included inflamed vulva (n = 14); group 2, vulvar intraepithelial neoplasia (VIN) I and VIN II (n = 20); group 3, VIN III and carcinoma in situ (n = 18); and group 4, invasive squamous cell carcinoma (n = 10). Representative sections were immunostained using polyclonal anti-COX-2 antibodies at concentration 1:25 without pretreatment. Immunostaining was scored according to the proportion of positive epithelial cells in the vulvar mucosa as 0 (no positive cells), 1(< 5% positive), 2 (6-50% positive), or 3 (> 50% positive)., Results: Mean immunostaining scores were 1.6, 1.4, 0.7, and 1.2 for groups 1, 2, 3, and 4, respectively. Scores were different between the groups (chi(2) = 9.908, P = 0.019) as shown by Cochran-Mantel-Haenszel statistical analysis (modified ridit scores), but did not correlate with age or the degree of dysplasia. The strongest staining for COX-2 was in the inflammatory group., Conclusion: COX-2 staining in inflamed, dysplastic, and malignant vulvar epithelium is variable but, as shown in this study, does not correlate with the degree of vulvar dysplasia or malignancy.

A 46-year-old woman presented with increasing abdominal girth. Investigations revealed bilateral ovarian tumors but no evidence of systemic disease. A total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. There was no evidence of extraovarian tumor at the time of the operation. A diagnosis of precursor B cell lymphoblastic lymphoma was established by histologic examination, immunohistochemical staining, and molecular analysis. After a 6-month follow-up, there was evidence of focal bony involvement that improved after chemotherapy. Although non-Hodgkin's lymphoma may involve the female genital tract, particularly the ovaries, primary ovarian lymphoma is rare and its definition controversial. To the best of our knowledge, this is only the third reported case of a primary lymphoblastic lymphoma of the ovary.