Evidence for a Novel Endometrioid Carcinogenic Sequence in the Fallopian Tube With Unique Beta-Catenin Expression

Epithelial proliferations in the fallopian tube have been characterized by some as stem cell outgrowths (SCOUTs) and divided into type I and type II. Type II SCOUTs exhibit diffuse cellular beta-catenin nuclear staining (β-catenin+), implying a CTNNB1 mutation. SCOUTs are more common in perimenopausal and postmenopausal women and are associated with ovarian cancer but have not been linked directly to malignancy. We analyzed type II SCOUTs in various gynecologic conditions, and searched for endometrioid atypical hyperplasias (tubal endometrioid intraepithelial neoplasia) or adenocarcinomas in the tube. β-catenin+ SCOUT frequency in cases of neoplasia was 66.7% per case and 30.7% per nonfimbrial cross-section for uterine endometrioid carcinomas versus 25% and 13.3% for controls, respectively (P=0.02 and 0.09). Multiple (3 or more) β-catenin+ SCOUTs in a single section were uncommon; 6 of 9 were associated with a carcinoma or proliferative lesion in the endometrium. Tubal endometrioid intraepithelial neoplasia/atypical hyperplasia displayed complex growth, including focal cribriform growth patterns and squamous morules. Two cases of type II SCOUTs associated with tubal endometrioid intraepithelial neoplasia/atypical hyperplasia and/or adenocarcinomas in the fallopian tube were identified, both of which coexisted with a separate endometrioid adenocarcinoma, one with bilateral ovarian endometrioid adenocarcinomas. Both benign and neoplastic tubal lesions were β-catenin+. This report is the first to link components of a unique β-catenin+ endometrioid carcinogenic sequence in the fallopian tube. It further emphasizes the multifocal nature of endometrioid neoplasia in the female genital tract and poses questions regarding the frequency and biologic underpinnings of β-catenin+ proliferations in the oviduct

Intravenous Leiomyomatosis: An Unusual Intermediate between Benign and Malignant Uterine Smooth Muscle Tumors

Intravenous leiomyomatosis is an unusual smooth muscle neoplasm with quasi-malignant intravascular growth but a histologically banal appearance. Herein, we report expression and molecular cytogenetic analyses of a series of 12 intravenous leiomyomatosis cases to understand better the pathogenesis of intravenous leiomyomatosis. All cases were analyzed for expression of HMGA2, MDM2 and CDK4 proteins by immunohistochemistry based on our previous finding of der(14)t(12;14)(q14.3;q24) in intravenous leiomyomatosis. Seven of 12 (58%) intravenous leiomyomatosis cases expressed HMGA2, and none expressed MDM2 or CDK4. Co-localization of hybridization signals for probes from the HMGA2 locus (12q14.3) and from 14q24 by interphase fluorescence in situ hybridization (FISH) was detected in a mean of 89.2% of nuclei in HMGA2-positive cases by immunohistochemistry, but in only 12.4% of nuclei in negative cases, indicating an association of HMGA2 expression and this chromosomal rearrangement (p=8.24×10−10). Four HMGA2-positive cases had greater than two HMGA2 hybridization signals per cell. No cases showed loss of a hybridization signal by interphase FISH for the frequently deleted region of 7q22 in uterine leiomyomata. One intravenous leiomyomatosis case analyzed by array comparative genomic hybridization revealed complex copy number variations. Finally, expression profiling was performed on three intravenous leiomyomatosis cases. Interestingly, hierarchical cluster analysis of the expression profiles revealed segregation of the intravenous leiomyomatosis cases with leiomyosarcoma rather than with myometrium, uterine leiomyoma of the usual histological type, or plexiform leiomyoma. These findings suggest that intravenous leiomyomatosis cases share some molecular cytogenetic characteristics with uterine leiomyoma, and expression profiles similar to that of leiomyosarcoma cases, further supporting their intermediate, quasi-malignant behavior

Evaluation of Treatment With Talazoparib and Avelumab in Patients With Recurrent Mismatch Repair Proficient Endometrial Cancer

Importance: Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration–approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC. Objective: To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC. Design, Settings, and Participants: This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies. Interventions: Talazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects. Main Outcomes and Measures: Statistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity. Results: Thirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit. Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02912572</p

Gynecologic pathology : a volume in the series foundation in diagnostic pathology/ Edit.: Marisa R. Nucci; Esther Oliva

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Concomitant opsoclonus ataxia and limbic encephalitis as a result of dual anti‐Ri and anti‐Yo antibodies in uterine carcinosarcoma: A case report

Background Paraneoplastic syndromes have become increasingly recognized as causing a number of neurological symptoms that can herald the presence of malignancy. A number of these antibodies have been identified. Few cases report paraneoplastic syndromes resulting from the presence of multiple antibodies in a single tumor source. Case presentation Here, we describe a case of simultaneous opsoclonus ataxia and limbic encephalitis from two concurrent paraneoplastic antibodies, anti‐Ri and anti‐Yo, in the presence of diagnosed uterine carcinosarcoma. Anti‐Ri (anti‐neuronal nuclear antibody type 2 or ANNA‐2) and anti‐Yo (anti‐Purkinje cell cytoplasmic antibody type 1) antibodies are known to be associated with opsoclonus myoclonus and cerebellar degeneration syndromes, respectively. Anti‐Ri has also been associated with limbic encephalitis. Conclusions This is a unique description of both anti‐Ri and anti‐Yo paraneoplastic antibodies with correlating syndromes in uterine carcinosarcoma. Although paraneoplastic syndromes are widely recognized and described, they are rare; but, as evidenced by this case, it is possible to have multiple concomitant syndromes and antibodies

Gynecologic pathology : a volume in the series Foundations in diagnostic pathology /

"Now fully revised to include recent advances in the field, the second edition of Gynecologic Pathology, a volume in the Foundations in Diagnostic Pathology series, is an essential foundation text for residents and pathologists. The popular template format makes it easy to use, and new information throughout brings you up to date with what's new in the field, including key molecular findings. Practical and affordable, this resource by Drs. Marisa R. Nucci and Esther Oliva is ideal for study and review as well as everyday clinical practice. Coverage of neoplastic and non-neoplastic conditions of the female reproductive tract to equip you to meet a wide range of diagnostic challenges"--Publisher's description."A volume in the series Foundations in diagnostic pathology."Includes bibliographical references.Inflammatory diseases of the vulva -- Squamous neoplasms of the vulva -- Extramammary Paget disease and vulvar melanocytic lesions -- Mesenchymal lesions of the vulva and vagina -- Nonneoplastic diseases of the vagina -- Neoplastic lesions of the vagina -- Nonneoplastic lesions of the cervix -- Neoplastic lesions of the cervix -- Nonneoplastic lesions of the endometrium -- Endometrial glandular neoplasia -- Mesenchymal and miscellaneous lesions of the uterus -- Diseases of the fallopian tube and broad ligament -- Nonneoplastic lesions of the ovary -- Epithelial neoplasms of the ovary -- Sex cord-stromal tumors of the ovary -- Germ cell neoplasms of the ovary -- Metastatic and miscellaneous primary neoplasms of the ovary -- Diseases of the peritoneum -- Gestational trophoblastic lesions -- Immunohistochemistry and molecular diagnostics in the differential diagnosis of female genital tract pathology -- Cytology in the practice of gynecologic pathology."Now fully revised to include recent advances in the field, the second edition of Gynecologic Pathology, a volume in the Foundations in Diagnostic Pathology series, is an essential foundation text for residents and pathologists. The popular template format makes it easy to use, and new information throughout brings you up to date with what's new in the field, including key molecular findings. Practical and affordable, this resource by Drs. Marisa R. Nucci and Esther Oliva is ideal for study and review as well as everyday clinical practice. Coverage of neoplastic and non-neoplastic conditions of the female reproductive tract to equip you to meet a wide range of diagnostic challenges"--Publisher's description.Description based on online resource; title from resource home page (ClinicalKey, viewed April 21, 2020).Elsevie

Giant Condyloma of the Cervix: An Uncommon Entity Associated With Low-risk Human Papilloma Virus Infection.

"Giant Condylomas" of the cervix are very uncommon, and have not been fully characterized in the English literature. We report 4 cases of cervical giant condyloma seen in our practice. Patients were predominantly young and presented with a cervical lesion producing bleeding or a mass effect. Biopsy/excision revealed a uniformly bland, exophytic squamous epithelial proliferation with viral cytopathic changes and absence of stromal invasion. Human papilloma virus types 6 and 11 were detected in all cases. Follow-up was uneventful without recurrence or spread. Giant condylomas of the cervix as defined in this report signify a benign albeit extensive variant of low-risk human papilloma virus infection. This term is proposed as a specific descriptor for such lesions and should be considered in the setting of any large well-differentiated exophytic cervical squamous lesion in young or immunosuppressed women. The term "giant condyloma of Buschke and Loewenstein" should be discontinued given the lack of specificity

Intestinal-type endocervical adenocarcinoma in situ: an immunophenotypically distinct subset of AIS affecting older women.

peer reviewedConventional endocervical adenocarcinoma in situ (cAIS) is typically strongly and diffusely positive for p16 with a high Ki67 index consistent with its frequent association with high-risk human papillomavirus (HPV) infection. The intestinal variant (iAIS) is less common, and its relationship to HPV infection has not been thoroughly examined. This study compares the clinicopathologic features, frequency of HPV infection, and expression of CDX2 and surrogate biomarkers of HPV infection (p16, Ki67) in cAIS with those of iAIS. A total of 86 cases with a diagnosis of AIS (49 iAIS, 37 cAIS) were identified from our multi-institutional files. Of these, 13 iAIS and 20 cAIS cases had slides and tissue available for histopathologic review, immunohistochemical analysis, and molecular tests. All 86 cases were used to evaluate clinical parameters; however, HPV DNA analysis and immunohistochemical analysis for p16, MIB-1, CDX2, and p53 were performed only on those cases with available slides or paraffin blocks. The average age at diagnosis was significantly higher in iAIS compared with that in cAIS (44.5 vs. 32.6 y) (P=0.0001). All 20 cAIS cases showed moderate to strong and diffuse p16 staining; however, only 9/13 iAIS cases showed this degree of p16 staining, whereas 4/13 (31%) iAIS cases showed weak and patchy distribution (P<0.02). Only 6/9 (67%) iAIS cases were positive for either HPV type 18 (5) or 33 (1), in contrast to 11/11 conventional cAIS (P=0.04). Similarly, 12/14 cAIS, but only 5/13 iAIS, cases showed a high Ki67 proliferative index. CDX2 was positive in all iAIS cases, whereas p53 was negative. Most iAIS cases are positive for high-risk HPV and show moderate to strong and diffuse p16 staining; however, a subset of iAIS shows variable staining with p16 and Ki67, is not associated with HPV, and occurs in a distinctly older age group suggesting an alternative pathogenesis. Awareness that iAIS can show variable staining for p16 and Ki67 is important when resolving problematic endocervical lesions, particularly in small biopsies with unusual p16 staining patterns

Differential expression of p-ERM, a marker of cell polarity, in benign and neoplastic oviductal epithelium.

Serous tubal intraepithelial carcinoma (STIC) is a noninvasive phase of pelvic serous cancer at risk for metastasizing. Because of its biologic significance, its accurate distinction from nonmalignant mimics is important. Loss of cell orientation is an important feature of STIC. We sought to determine whether the immunohistochemical localization of cytoskeletal-organizing proteins phospho-ezrin-radaxin-moesin (p-ERM) would be useful in making this distinction. The benign oviductal entities (normal and p53 signatures), premalignant atypias (tubal intraepithelial lesions in transition), serous intraepithelial carcinomas (STICs), and carcinomas were analyzed for 5 staining patterns and compared. Linear or uniform luminal p-ERM staining was strongly associated with benign mucosa in contrast to STICs, in which it was lost and often replaced by nonlinear or nonuniform patterns highlighting individually cell groups or single cells. Premalignant atypias were similar to benign mucosa by p-ERM staining and retained the linear luminal pattern. This study shows, for the first time, that patterns of staining for an immunohistochemical correlate of cell polarity (p-ERM) differ between STICs, their benign counterparts and premalignant atypias that do not fulfill the criteria for STICs. If confirmed, these findings warrant further analysis of indices of cell polarity as objective markers for the diagnosis and mapping of the evolution of pelvic serous precursors. Int J Gynecol Pathol 2013 Jul; 32(4):345-52