189 results on '"Nucci MR"'
Search Results
2. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type
- Author
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Karnezis, AN, Wang, Y, Ramos, P, Hendricks, WPD, Oliva, E, D'Angelo, E, Prat, J, Nucci, MR, Nielsen, TO, Chow, C, Leung, S, Kommoss, F, Kommoss, S, Silva, A, Ronnett, BM, Rabban, JT, Bowtell, DD, Weissman, BE, Trent, JM, Gilks, CB, Huntsman, DG, Karnezis, AN, Wang, Y, Ramos, P, Hendricks, WPD, Oliva, E, D'Angelo, E, Prat, J, Nucci, MR, Nielsen, TO, Chow, C, Leung, S, Kommoss, F, Kommoss, S, Silva, A, Ronnett, BM, Rabban, JT, Bowtell, DD, Weissman, BE, Trent, JM, Gilks, CB, and Huntsman, DG
- Abstract
Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re-expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines.
- Published
- 2016
3. A candidate precursor to serous carcinoma that originates in the distal fallopian tube (J Pathol 2007; 211: 26–35)
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Lee, Y, primary, Miron, A, additional, Drapkin, R, additional, Nucci, MR, additional, Medeiros, F, additional, Saleemuddin, A, additional, Garber, J, additional, Birch, C, additional, Mou, H, additional, Gordon, RW, additional, Cramer, DW, additional, McKeon, FD, additional, and Crum, CP, additional
- Published
- 2007
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4. A candidate precursor to serous carcinoma that originates in the distal fallopian tube
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Lee, Y, primary, Miron, A, additional, Drapkin, R, additional, Nucci, MR, additional, Medeiros, F, additional, Saleemuddin, A, additional, Garber, J, additional, Birch, C, additional, Mou, H, additional, Gordon, RW, additional, Cramer, DW, additional, McKeon, FD, additional, and Crum, CP, additional
- Published
- 2006
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5. HMGIC expression as a diagnostic marker for vulvar aggressive angiomyxoma
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Nucci, MR, Giovanni Tallini, and Quade, Bj
6. Lesions sub-diagnostic of endometrioid intra-epithelial neoplasia/atypical hyperplasia: value of morphology and immunohistochemistry in predicting neoplastic outcome.
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Wyvekens N, Mutter GL, Nucci MR, Kolin DL, and Parra-Herran C
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- Humans, Female, Middle Aged, Adult, Aged, beta Catenin metabolism, PTEN Phosphohydrolase metabolism, PAX2 Transcription Factor metabolism, PAX2 Transcription Factor analysis, Aged, 80 and over, Immunohistochemistry, Carcinoma, Endometrioid pathology, Carcinoma, Endometrioid diagnosis, Carcinoma, Endometrioid metabolism, Biomarkers, Tumor analysis, Biomarkers, Tumor metabolism, Endometrial Neoplasms pathology, Endometrial Neoplasms diagnosis, Endometrial Neoplasms metabolism, Endometrial Hyperplasia pathology, Endometrial Hyperplasia diagnosis, Endometrial Hyperplasia metabolism
- Abstract
Aims: Areas of gland crowding that do not fulfil diagnostic criteria of endometrioid intra-epithelial neoplasia (EIN) are often encountered in endometrial biopsies. In this study, we document the prevalence of neoplastic outcome in patients with these subdiagnostic lesions (SL) and assess the utility of morphological features and a three-marker immunohistochemistry panel (PAX2, PTEN, beta-catenin) to predict outcome., Methods and Results: Of 430 women with SL on endometrial sampling at Brigham and Women's Hospital between 2001 and 2021 with available follow-up biopsy, 72 (17%) had a neoplastic outcome (EIN or endometrioid carcinoma). Multilayered epithelium and mitoses in SL were statistically associated with a neoplastic outcome. Abnormal three-marker staining was observed in 93% (53 of 57) of SL with neoplastic outcome and 60% (37 of 62) of a control group with benign outcome. Among the 72 patients with neoplastic outcome, EIN/carcinoma tissue was available in 33; of these, 30 (91%) showed abnormal staining for one or more markers. Remarkably, in 84% of these cases the EIN/carcinoma had the aberrant expression seen in the preceding SL. Based on a prevalence of 17%, the positive and negative predictive values of abnormal staining in one or more markers were 24 and 97%, respectively., Conclusions: The presence of SL warrants clinical surveillance and repeat sampling because it is followed by endometrioid neoplasia in a significant subset of patients. Normal three-marker staining identifies women with a very low risk of neoplastic outcome. Conversely, abnormal staining is frequent in SL with benign outcome leading to poor specificity and positive predictive value., (© 2024 John Wiley & Sons Ltd.)
- Published
- 2024
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7. Myxoid Inflammatory Myofibroblastic Sarcoma: Clinicopathologic Analysis of 25 Cases of a Distinctive Sarcoma With Deceptively Bland Morphology and Aggressive Clinical Behavior.
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Papke DJ Jr, Odintsov I, Dickson BC, Nucci MR, Agaimy A, and Fletcher CDM
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- Humans, Male, Female, Adult, Middle Aged, Aged, Adolescent, Young Adult, Child, Soft Tissue Neoplasms pathology, Soft Tissue Neoplasms genetics, Soft Tissue Neoplasms mortality, Soft Tissue Neoplasms therapy, Sarcoma pathology, Sarcoma genetics, Sarcoma chemistry, Sarcoma mortality, Immunohistochemistry, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, Myofibroblasts pathology, Myofibroblasts chemistry
- Abstract
The number of recognized sarcoma types harboring targetable molecular alterations continues to increase. Here we present 25 examples of a distinctive myofibroblastic tumor, provisionally termed "myxoid inflammatory myofibroblastic sarcoma," which might be related to inflammatory myofibroblastic tumor, and which occurred in 13 males (52%) and 12 females at a median age of 37 years (range: 7 to 79 years). Primary tumor sites were peritoneum (18 patients; 72%), paratesticular (2; 8%), chest wall (1), upper extremity (1), esophagus (1), retroperitoneum (1), and uterus (1). Nine peritoneal tumors (50%) were multifocal at presentation; all other tumors were unifocal. Tumors showed bland-to-mildly-atypical neoplastic myofibroblasts in a myxoid stroma, with prominent inflammatory infiltrates in 22 cases (88%). Most tumors showed delicate branching stromal vessels like those of myxoid liposarcoma, and most showed infiltrative growth through non-neoplastic tissue. Immunohistochemistry demonstrated expression of SMA (19/25 tumors; 76%), desmin (13/22; 59%), and CD30 (5/11; 45%), while ALK was expressed in 1 tumor (of 25; 4%) that was negative for ALK rearrangement. Sequencing of 11 tumors showed seven to harbor tyrosine kinase fusions (4 PDGFRB , 2 PML :: JAK1 , 1 SEC31A :: PDGFRA ). Two instead harbored hot spot KRAS mutations (G12V and Q61H), and 2 were negative for known driving alterations. Clinical follow-up was available for 18 patients (72%; median: 2.7 years; range: 4 mo-12.3 years). Nine patients (50%) were alive with no evidence of disease, 5 (28%) died of disease, and 4 (22%) were alive with disease. Seven patients (39%) experienced peritoneal relapse or distant metastasis. Two patients showed disease progression on conventional, nontargeted chemotherapy. The patient whose tumor harbored SEC31A :: PDGFRA was treated after multiple relapses with imatinib and sunitinib therapy, with progression-free periods of 5 and 2 years, respectively. Despite its bland appearance, myxoid inflammatory myofibroblastic sarcoma harbors a significant risk for disseminated disease, particularly when it occurs in the peritoneum. Targeted therapy could be considered for patients with disseminated disease., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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8. Ewing Sarcoma of the Female Genital Tract: Clinicopathologic Analysis of 21 Cases With an Emphasis on the Differential Diagnosis of Gynecologic Round Cell, Spindle, and Epithelioid Neoplasms.
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Sharma AE, Wepy CB, Chapel DB, Maccio L, Irshaid L, Al-Ibraheemi A, Dickson BC, Nucci MR, Crum CP, Fletcher CDM, and Kolin DL
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- Humans, Female, Adult, Diagnosis, Differential, Adolescent, Young Adult, Middle Aged, Child, Retrospective Studies, Immunohistochemistry, In Situ Hybridization, Fluorescence, Homeobox Protein Nkx-2.2, Transcription Factors genetics, Homeodomain Proteins genetics, Predictive Value of Tests, Gene Rearrangement, 12E7 Antigen metabolism, Epithelioid Cells pathology, Epithelioid Cells chemistry, Nuclear Proteins, Sarcoma, Ewing genetics, Sarcoma, Ewing pathology, Sarcoma, Ewing diagnosis, Sarcoma, Ewing chemistry, Genital Neoplasms, Female pathology, Genital Neoplasms, Female genetics, Genital Neoplasms, Female diagnosis, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, RNA-Binding Protein EWS genetics
- Abstract
Ewing sarcoma is an uncommon neoplasm considered in the differential diagnosis of tumors with "small round cell" morphology, but its occurrence in the gynecologic tract has only been sporadically documented. Herein, we describe the largest cohort of Ewing sarcoma localized to the female genital tract to date, and emphasize their clinicopathologic resemblance to more common gynecologic neoplasms. Ewing sarcoma (n=21) was retrospectively identified from 5 institutions. The average patient age was 35 (range 6-61) years. Tumor sites included uterus (n=8), cervix (n=4), vulva (n=5), vagina (n=1), broad ligament (n=1), inguinal area (n=1), and pelvis (n=1). Nine of 18 cases in which slides were available for review demonstrated only classic round cell morphology, with the remainder showing a variable combination and prominence of variant ovoid/spindle or epithelioid appearance. Tumors showed diffuse membranous reactivity for CD99 (20/20) and were positive for NKX2.2 (8/8, diffuse) and cyclin D1 (7/7, of which 3/7 were patchy/multifocal and 4/7 were diffuse). They were negative for ER (0/6) and CD10 (0/6). Three cases were initially diagnosed as endometrial stromal sarcomas. EWSR1 rearrangement was confirmed in 20/21 by fluorescence in situ hybridization (n=15) and/or sequencing (n=8). Of the eight tumors that underwent sequencing, 6 harbored FLI1 , 1 ERG, and 1 FEV as the fusion partner. Of 11 patients with available follow-up, 5 died of disease, 1 developed lung metastases and 5 are alive with no evidence of disease. Ewing sarcoma of the gynecologic tract is a rare, aggressive entity that shares some morphologic and immunohistochemical features with other more common gynecologic neoplasms. In addition to the typical round cell appearance, variant spindled/ovoid to epithelioid morphology may also be observed and should prompt consideration of this entity with appropriate immunohistochemical and/or molecular studies., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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9. STK11 (LKB1) immunohistochemistry is a sensitive and specific marker for STK11 adnexal tumours.
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Dehghani A, Sharma AE, Siegmund SE, Carreon CK, Stewart CJR, Medeiros F, Mirkovic J, Nucci MR, Crum CP, Hornick JL, Howitt BE, McCluggage WG, and Kolin DL
- Subjects
- Humans, Female, Diagnosis, Differential, Sensitivity and Specificity, Adult, Peutz-Jeghers Syndrome diagnosis, Peutz-Jeghers Syndrome pathology, Peutz-Jeghers Syndrome genetics, Peutz-Jeghers Syndrome metabolism, Adnexal Diseases diagnosis, Adnexal Diseases pathology, Adnexal Diseases metabolism, Ovarian Neoplasms pathology, Ovarian Neoplasms diagnosis, Immunohistochemistry, AMP-Activated Protein Kinase Kinases, Biomarkers, Tumor analysis, Biomarkers, Tumor metabolism, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism
- Abstract
Aims: STK11 adnexal tumour is a rare, recently described malignant neoplasm that is associated with Peutz-Jeghers syndrome. [Correction added on 3 October 2024, after first online publication: 'ST11' in preceding sentence has been corrected to 'STK11' in this version.] It predominantly originates from the para-adnexal soft tissues and often shows secondary involvement of the fallopian tube and ovary. STK11 adnexal tumours have a broad differential diagnosis due to their variable morphology and non-specific immunoprofile, and diagnostic confirmation currently requires sequencing to identify an STK11 mutation. We investigate the diagnostic utility of STK11 (LKB1) immunohistochemistry (IHC) in a cohort of STK11 adnexal tumours and morphological mimics., Methods and Results: IHC for STK11 was performed on 122 tumours, including 17 STK11 adnexal tumours and 105 morphological mimics (10 female adnexal tumours of Wolffian origin, 22 adult granulosa cell tumours, 10 juvenile granulosa cell tumours, four Sertoli-Leydig cell tumours, two Leydig cell tumours, one Sertoli cell tumour, one steroid cell tumour, four extra-ovarian sex cord-stromal tumours, 16 ovarian endometrioid carcinomas, eight tubo-ovarian high-grade serous carcinomas, five ovarian mesonephric-like adenocarcinomas, 14 ovarian carcinosarcomas, five peritoneal malignant mesotheliomas, two pelvic plexiform leiomyomata and one ovarian solid pseudopapillary tumour). All STK11 adnexal tumours showed complete loss of cytoplasmic staining for STK11. All other tumour types showed retained cytoplasmic staining, except for one endometrioid carcinoma with mucinous differentiation which showed complete loss of STK11 expression and a high-grade serous carcinoma with subclonal loss., Conclusions: STK11 is a highly sensitive and specific immunohistochemical marker for distinguishing STK11 adnexal tumour from its histological mimics, and can obviate the need for confirmatory molecular studies in the appropriate morphological context., (© 2024 John Wiley & Sons Ltd.)
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- 2024
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10. Practical guidance for assessing and reporting lymphovascular space invasion (LVSI) in endometrial carcinoma.
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Peters EEM, Nucci MR, Gilks CB, McCluggage WG, and Bosse T
- Abstract
Lymphovascular space invasion (LVSI) is an important prognostic parameter in endometrial carcinoma (EC) and has gained increasing interest in recent years due to an expanding body of evidence of its independent prognostic value, especially when the presence of LVSI is quantified. A key strength of LVSI as a prognostic factor is that it can be detected on routine microscopic examination, without ancillary tests, and thus can be used in low-resource settings. A weakness, however, is the lack of uniformly applied criteria for assessment and quantification of LVSI, resulting in interobserver variation in diagnosis. This is confounded by artefacts and other morphological features that may mimic LVSI (commonly referred to as pseudo-LVSI). Despite these issues, multiple studies have shown that LVSI is strongly associated with lymph node (LN) metastasis and is an independent risk factor for LN recurrence and distant metastasis. Consequently, the presence of substantial/extensive LVSI has become an important consideration in formulating adjuvant treatment recommendations in patients with EC, and this has been incorporated in the recent International Federation of Gynecology and Obstetrics (FIGO) 2023 staging system. Herein, we review the current literature on LVSI in EC and discuss its role as a prognostic marker, the reproducibility of LVSI assessment and distinction between LVSI and its mimics. We provide illustrations of key diagnostic features and discuss the two-tiered (none/focal versus substantial) system of LVSI classification. This work is intended to provide guidance to practising pathologists and unify the approach towards LVSI assessment in EC., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)
- Published
- 2024
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11. Uterine Leiomyosarcoma Associated With Perivascular Epithelioid Cell Tumor: A Phenomenon of Differentiation/Dedifferentiation and Evidence Suggesting Cell-of-Origin.
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Katsakhyan L, Shahi M, Eugene HC, Nonogaki H, Gross JM, Nucci MR, Vang R, and Xing D
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- Humans, Female, Middle Aged, Immunohistochemistry, Cell Dedifferentiation, Adult, Cell Lineage, Aged, Cell Differentiation, Leiomyosarcoma pathology, Leiomyosarcoma chemistry, Leiomyosarcoma genetics, Perivascular Epithelioid Cell Neoplasms pathology, Perivascular Epithelioid Cell Neoplasms chemistry, Perivascular Epithelioid Cell Neoplasms genetics, Uterine Neoplasms pathology, Uterine Neoplasms chemistry, Uterine Neoplasms genetics, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics
- Abstract
Perivascular epithelioid cell tumor (PEComa) is a mesenchymal tumor thought to originate from perivascular epithelioid cells (PECs). The normal counterpart to PEC, however, has not been identified in any human organ, and the debate as to whether PEComa is related to smooth muscle tumors has persisted for many years. The current series characterizes 4 cases of uterine leiomyosarcoma (LMS) coexisting with PEComas. All cases exhibited an abrupt transition from the LMS to PEComa components. The LMS component displayed typical spindled morphology and fascicular growth pattern and was diffusely positive for desmin and smooth muscle myosin heavy chain, completely negative for HMB-45 and Melan A, and either negative or had focal/weak expression of cathepsin K and GPNMB. In contrast, the PEComa tumor cells in case 1 contained glycogen or lipid-distended cytoplasm with a foamy appearance (low grade), and in cases 2, 3, and 4, they displayed a similar morphology characterized by epithelioid cells with eosinophilic and granular cytoplasm and high-grade nuclear atypia. Different from the LMS component, the epithelioid PEComa cells in all cases were focally positive for HMB-45, and diffusely immunoreactive for cathepsin K and GPNMB. Melan A was focally positive in cases 1 and 3. Loss of fumarate hydratase expression (case 1) and RB1 expression (cases 2, 3, 4) was identified in both LMS and PEComa components, indicating that they are clonally related. In addition, both components showed an identical TP53 p.R196* somatic mutation and complete loss of p53 and ATRX expression in case 2 and complete loss of p53 expression in case 3. We hypothesize that LMSs containing smooth muscle progenitor cells may give rise to divergent, lineage-specific PEComatous lesions through differentiation or dedifferentiation. While we do not dispute the recognition of PEComas as a distinct entity, we advocate the hypothesis that modified smooth muscle cells represent the origin of a subset of PEComas, and our case series provides evidence to suggest this theory., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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12. FIGO 2023 endometrial cancer staging: too much, too soon?
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McCluggage WG, Bosse T, Gilks CB, Howitt BE, McAlpine JN, Nucci MR, Rabban JT, Singh N, Talia KL, and Parra-Herran C
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- Humans, Female, Endometrial Neoplasms pathology, Neoplasm Staging
- Abstract
An updated International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial carcinoma was introduced in June 2023. The new system represents a significant departure from traditional endometrial and other gynecological carcinoma staging systems which are agnostic of parameters such as tumor type, tumor grade, lymphovascular space invasion, and molecular alterations. The updated system, which incorporates all of these 'non-anatomical' parameters, is an attempt to make staging more personalized and relevant to patient prognostication and management, and to align with the European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) risk stratification. Herein, we present a critical review of the new staging system and discuss its advantages and disadvantages. The authors propose that the new FIGO staging system should be first appraised at a multi-institutional and global level with the input of all relevant societies (gynecology, pathology, gynecologic oncology, medical oncology, radiation oncology) to understand the impact, scope, and supporting evidence of the proposed changes. Such a process is fundamental to produce a robust system that pathologists and treating clinicians can adopt., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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13. Targeted RNA Sequencing Highlights a Diverse Genomic and Morphologic Landscape in Low-grade Endometrial Stromal Sarcoma, Including Novel Fusion Genes.
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Kolin DL, Nucci MR, Turashvili G, Song SJ, Corbett-Burns S, Cesari M, Chang MC, Clarke B, Demicco E, Dube V, Lee CH, Rouzbahman M, Shaw P, Cin PD, Swanson D, and Dickson BC
- Subjects
- Female, Humans, Young Adult, Adult, Middle Aged, Aged, Aged, 80 and over, Transcription Factors genetics, Genomics, Sequence Analysis, RNA, Sarcoma, Endometrial Stromal pathology, Endometrial Neoplasms pathology, Endometrial Stromal Tumors genetics
- Abstract
Low-grade endometrial stromal sarcoma (LGESS) represents a morphologically and genetically heterogenous mesenchymal neoplasm. Previous work has shown that approximately half of LGESS are characterized by JAZF1::SUZ12 gene fusions, while a smaller proportion involves rearrangement of other genes. However, a subset of cases has no known genetic abnormalities. To better characterize the genomic landscape of LGESS, we interrogated a cohort with targeted RNA sequencing (RNA-Seq). Cases previously diagnosed as low-grade endometrial stromal neoplasia (n=51) were identified and re-reviewed for morphology and subjected to RNA-Seq, of which 47 were successfully sequenced. The median patient age was 49 years (range: 19 to 85). The most commonly detected fusions were JAZF1::SUZ12 (n=26, 55%) and BRD8::PHF1 (n=3, 6%). In addition to the usual/typical LGESS morphology, some JAZF1::SUZ12 fusion tumors showed other morphologies, including fibrous, smooth muscle, sex-cord differentiation, and myxoid change. Novel translocations were identified in 2 cases: MEAF6::PTGR2 and HCFC1::PHF1 . Ten tumors (21%) had no identifiable fusion, despite a similar morphology and immunophenotype to fusion-positive cases. This suggests that a subset of cases may be attributable to fusion products among genes that are not covered by the assay, or perhaps altogether different molecular mechanisms. In all, these findings confirm that RNA-Seq is a potentially useful ancillary test in the diagnosis of endometrial stromal neoplasms and highlight their diverse morphology., Competing Interests: Conflicts of Interest and Source of Funding: Funding of this study was, in part, provided by the Martin E. Blackstein research fund and the Panov 2 Research Program. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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14. Pattern A endocervical adenocarcinomas with ovarian metastasis are indolent and molecularly distinct from destructively invasive adenocarcinomas.
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Neil AJ, Li YY, Hakam A, Nucci MR, and Parra-Herran C
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- Female, Humans, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms diagnosis, Papillomavirus Infections complications, Adenocarcinoma pathology, Adenocarcinoma in Situ, Ovarian Neoplasms genetics, Ovarian Neoplasms secondary
- Abstract
Aims: The invasive pattern in HPV-associated endocervical adenocarcinoma (HPVA) has prognostic value. Non-destructive (pattern A) HPVA has excellent prognosis mirroring adenocarcinoma in-situ (AIS). However, the rare occurrence of ovarian spread in these tumours suggests aggressiveness in a subset of patients with these otherwise indolent lesions. We hypothesise that AIS/pattern A HPVA with ovarian metastases are biologically different than metastatic destructively invasive HPVA., Methods and Results: Samples from patients with HPVA and synchronous or metachronous metastases were retrieved and reviewed to confirm diagnosis and determine the Silva pattern in the primary lesion. For each case, normal tissue, cervical tumour and at least one metastasis underwent comprehensive sequencing using a 447-gene panel. Pathogenic single-nucleotide variants and segmental copy-number alterations (CNA), tumour mutational burden and molecular signatures were evaluated and compared between primary and metastases and among invasive pattern categories. We identified 13 patients: four had AIS/pattern A primaries, while nine had pattern B/C tumours. All AIS/pattern A lesions had metastasis only to ovary; 50% of patients with ovarian involvement, regardless of invasive pattern, also had involvement of the endometrium and/or fallopian tube mucosa by HPVA. In the ovary, AIS/pattern A HPVA showed deceptive well-differentiated glands, often with adenofibroma-like appearance. Conversely, pattern C HPVAs consistently showed overt infiltrative features in the ovary. Sequencing confirmed the genetic relationship between primary and metastatic tumours in each case. PIK3CA alterations were identified in three of four AIS/pattern A HPVAs and three of eight pattern B/C tumours with sequenced metastases. Pattern C tumours showed a notably higher number of CNA in primary tumours compared to pattern A/B tumours. Only one metastatic AIS/pattern A HPVA had a novel pathogenic variant compared to the primary. Conversely, five of eight pattern B/C tumours with sequenced metastases developed novel pathogenic variants in the metastasis not seen in the primary. All four AIS/pattern A patients were alive and free of disease at 31, 47, 58 and 212 months after initial diagnosis. Conversely, cancer-related death was documented in five of nine pattern B/C patients with follow-up at 7, 20, 20, 43 and 87 months., Conclusion: Morphologically and genomically, AIS/pattern A HPVA with secondary ovarian involvement appears distinct from destructively invasive tumours. In at least a subset of these cases, ovarian spread appears to occur via trans-Mullerian superficial extension, different from the stromal and lymphatic vascular spread typical of more aggressive tumours (pattern C). These differences may explain the indolent outcome observed in the rare subset of patients with AIS/pattern A HPVA and ovarian metastasis. Our data underscore the potential for conservative surgical management approaches to pattern A HPVA., (© 2023 John Wiley & Sons Ltd.)
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- 2024
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15. Atypical Endometriosis: Comprehensive Characterization of Clinicopathologic, Immunohistochemical, and Molecular Features.
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Wepy C, Nucci MR, and Parra-Herran C
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- Female, Humans, Tumor Suppressor Protein p53 genetics, Endometrium pathology, Receptors, Estrogen, Endometriosis diagnosis, Endometriosis genetics, Endometriosis pathology, Carcinoma pathology, Precancerous Conditions pathology, Ovarian Neoplasms diagnosis, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
- Abstract
Atypical endometriosis (A-EMS), defined by cytologic atypia and/or crowded glands resembling endometrial intraepithelial neoplasia, remains poorly understood. We aimed to refine the morphologic, immunohistochemical, and molecular features of A-EMS in an institutional series. Cases were identified through a structured search and reviewed by 2 pathologists. Immunohistochemistry and comprehensive sequencing using a panel 447-gene coverage were performed in suitable cases. A-EMS with synchronous and/or subsequent EMS-related neoplasia were compared with those without. Of 4598 EMS cases over an 11-yr period, 36 A-EMS were identified. The mean age at presentation was 46 (range 26-68) yr. Locations included the ovary (24, 66%), tubo-ovary (6, 17%), fallopian tube (3, 8%), and peritoneum (3, 8%). The mean size was 6.5 (range 0.5-40) mm. Cytologic atypia was mild in 4 (11%), moderate in 21 (58%), and severe in 11 (31%). Most lesions were partially or completely flat (28, 78%); of these, 66% showed hobnail nuclei. Crowded/cribriform and micropapillary/papillary patterns were seen in 11 (31%) and 16 (44%) A-EMS, respectively. Immunohistochemistry, performed in 33 A-EMS, showed wildtype p53 (100%) retained PMS2/MSH6 (100%), and positive estrogen receptor (97%, mean 65% cells), progesterone receptor (76%, mean 30% cells), and Napsin A (39%). Ki67 labelling was <1% to 10% (median 5%). Nine (25%) patients presented with concurrent or subsequent ipsilateral endometrioid, seromucinous, or clear cell neoplasia (4 borderline tumors and 4 carcinomas). The only A-EMS feature statistically more frequent in this subset was crowded/glands (6/9 vs. 2/27 A-EMS without, P =0.001 Fisher exact test). Sequencing showed pathogenic variants in 5 of 6 cases analyzed, involving ATM , BRCA2 , KRAS , AKT , CTNNB1 , PTEN , and ARID1A among other genes. In 2 cases, synchronous neoplasia showed an accumulation of additional variants. A-EMS is characterized by cytologic atypia and crowded architecture but low proliferation index, positive estrogen receptor, and normal p53 and MMR, which can be helpful in the distinction from malignancy. The prevalence of synchronous/subsequent tubo-ovarian neoplasia in our series was 25%, significantly higher than the reported 1% in conventional EMS. Moreover, A-EMS harbors genomic alterations seen in EMS-related tumors and shares pathogenic variants with synchronous ipsilateral neoplasia. Therefore, it is important to report A-EMS as currently defined and describe its architectural features, especially gland crowding as this appears to increase the risk of EMS-related epithelial neoplasia. Napsin-A is often positive in A-EMS and should be interpreted with caution., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)
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- 2024
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16. Malignant female genital tract smooth muscle tumors with adipocytic differentiation: A morphologic, immunohistochemical, MDM2 fluorescence in situ hybridization and molecular genetic study of 6 lipoleiomyosarcomas.
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Swanson AA, Michal M, Xing D, Dashti NK, Židlík V, Cheek-Norgan EH, Keeney ME, Keeney GL, Sukov WR, Gupta S, Nucci MR, and Schoolmeester JK
- Subjects
- Humans, Female, Adult, Middle Aged, In Situ Hybridization, Fluorescence, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, Immunohistochemistry, Genitalia, Female chemistry, Genitalia, Female pathology, Molecular Biology, Proto-Oncogene Proteins c-mdm2 genetics, Leiomyosarcoma pathology, Smooth Muscle Tumor pathology
- Abstract
Leiomyosarcoma with adipocytic differentiation or lipoleiomyosarcoma is an uncommon sarcoma of the female genital tract with only a few individual reports in the literature. We therefore performed a morphologic, immunohistochemical, MDM2 gene amplification and RNA and DNA sequencing analysis of a series of gynecologic lipoleiomyosarcoma to better define the clinicopathologic spectrum. Six tumors from 6 patients were identified and classified as spindled lipoleiomyosarcoma (n = 2), mixed spindled and myxoid lipoleiomyosarcoma (n = 1), epithelioid lipoleiomyosarcoma with focal myxoid features (n = 1) and mixed spindled and epithelioid lipoleiomyosarcoma (n = 2). Patient age ranged from 41 to 64 years (mean: 49; median: 50). Primary location included uterine corpus (3), uterine corpus/cervix (2) and broad ligament (1). Tumor size ranged from 4.5 to 22 cm (mean: 11.2; median: 9.8). Four patients had metastasis at presentation or subsequently developed recurrent or distant disease. Patient status was known for 5: 2 dead of disease, 2 alive with disease and 1 alive without evidence of disease. Immunohistochemical expression of smooth muscle markers, ER, PR and WT-1 showed patterns similar to non-adipocytic gynecologic leiomyosarcomas. MDM2 amplification fluorescence in situ hybridization performed on 2 tumors was negative in 1 and equivocal in 1. Sequencing studies performed on 3 tumors found TP53 mutations in 3, with 1 tumor also having an ATRX alteration. No gene fusions were identified. Although lipoleiomyosarcomas have a diverse morphologic spectrum, our findings suggest the smooth muscle component shares morphologic and immunohistochemical features with female genital tract non-adipocytic leiomyosarcomas. Lipoleiomyosarcomas also have genetic alterations associated with non-adipocytic gynecologic leiomyosarcomas., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2024
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17. Benign female genital tract smooth muscle tumors with adipocytic differentiation: A morphologic, immunohistochemical and MDM2 fluorescence in situ hybridization study of 44 conventional lipoleiomyomas and lipoleiomyoma variants.
- Author
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Swanson AA, Michal M, Xing D, Židlík V, Cheek-Norgan EH, Keeney ME, Keeney GL, Sukov WR, Gupta S, Nucci MR, and Schoolmeester JK
- Subjects
- Female, Humans, Adult, Middle Aged, Aged, Aged, 80 and over, In Situ Hybridization, Fluorescence, Uterus pathology, Proto-Oncogene Proteins c-mdm2 genetics, Smooth Muscle Tumor, Leiomyoma pathology, Lipoma genetics, Lipoma pathology, Uterine Neoplasms pathology
- Abstract
Leiomyomas with adipocytic differentiation typically occur in the uterus although they may arise at several sites in the female genital tract. While these are most commonly spindled leiomyomas with a component of adipocytic tissue ("conventional lipoleiomyomas"), there is a relatively ill-defined assortment of leiomyoma variants with adipocytic differentiation. We performed a morphologic, immunohistochemical and MDM2 gene amplification analysis of a large series of gynecologic leiomyomas with adipocytic differentiation to better define the clinicopathologic spectrum. Forty four tumors from 44 patients were identified and classified as conventional lipoleiomyoma (n = 21), adipocyte-rich lipoleiomyoma (defined as tumor volume >80 % adipocytes, n = 9); cellular lipoleiomyoma (n = 9); hydropic lipoleiomyoma (n = 3); and lipoleiomyoma with bizarre nuclei (n = 2). Patient age ranged from 32 to 83 years (mean 63; median 63). Primary location included uterine corpus (35), uterine cervix (3), uterine corpus/cervix (1), broad ligament (2), parametrium (2), and round ligament (1). Tumor size was 0.6-30 cm (mean 8; median 6). None of the 34 patients with follow up developed further disease (range 1-311 months; mean 65; median 41). Immunohistochemical expression of ER, PR, HMB45, Melan A, Cathepsin K and WT-1 in lipoleiomyomas and variants was similar to patterns in non-adipocytic gynecologic leiomyomas. MDM2 amplification fluorescence in situ hybridization performed on 14 tumors was negative in all. Our findings suggest female genital tract conventional lipoleiomyomas and lipoleiomyoma variants largely parallel their non-adipocytic counterparts in morphology and immunophenotype, and may be categorized using non-adipocytic leiomyoma histologic criteria., Competing Interests: Declaration of competing interest The authors have no conflicts of interest or sources of research funding to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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18. Expanding the Clinicopathologic and Molecular Spectrum of Lipoblastoma-Like Tumor in a Series of 28 Cases.
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Anderson WJ, Mariño-Enríquez A, Trpkov K, Hornick JL, Nucci MR, Dickson BC, and Fletcher CDM
- Abstract
Lipoblastoma-like tumor (LLT) is a rare adipocytic neoplasm with a predilection for the vulva. Since 2002, <30 cases have been reported, characterizing it as an indolent tumor that may sometimes recur locally. Diagnosis can be challenging due to its rarity and morphologic overlap with other adipocytic tumors. Thus far, there are no specific molecular or immunohistochemical features to aid in the diagnosis of LLT. Recent case reports have described LLT arising at other sites, including the spermatic cord and gluteal region, suggesting wider anatomical distribution. We present a large series of LLT to further characterize its clinicopathologic and molecular features. Twenty-eight cases of LLT were retrieved from departmental and consult archives (including 8 from a prior series). The cohort comprised 28 patients (8 males, 20 females) with a median age of 28 years (range: 1-80 years). There were 17 primary LLT of the vulva. Other anatomical sites included the scrotum (n = 3), spermatic cord (n = 2), inguinal region (n = 2), limbs (n = 2), pelvis (n = 1), and retroperitoneum (n = 1). Median tumor size was 6.0 cm (range: 1.8-30.0 cm). The tumors had a lobulated architecture and were typically composed of adipocytes, lipoblasts, and spindle cells in a myxoid stroma with prominent thin-walled vessels. Using immunohistochemistry, a subset showed loss of Rb expression (12/23 of samples). Follow-up in 15 patients (median: 56 months) revealed 8 patients with local recurrence and 1 patient with metastases to the lung/pleura and breasts. Targeted DNA sequencing revealed a simple genomic profile with limited copy number alterations and low mutational burden. No alterations in RB1 were identified. The metastatic LLT showed concurrent pathogenic PIK3CA and MTOR activating mutations, both in the primary and in the lung/pleural metastasis; the latter also harbored TERT promoter mutation. One tumor had a pathogenic TSC1 mutation, and one tumor showed 2-copy deletion of CDKN2A, CDKN2B, and MTAP. No biologically significant variants were identified in 8 tumors. No gene fusions were identified by RNA sequencing in 4 tumors successfully sequenced. This study expands the clinicopathologic spectrum of LLT, highlighting its wider anatomical distribution and potential for occasional metastasis. Molecularly, we identified activating mutations in the PI3K-MTOR signaling pathway in 2 tumors, which may contribute to exceptional aggressive behavior., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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19. Genomic profiling of dedifferentiated endometrial carcinomas arising in the background of high-grade carcinoma: a targeted next-generation sequencing study.
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Olkhov-Mitsel E, Busca A, Parra-Herran C, Amemiya Y, Nofech-Mozes S, Djordjevic B, Nucci MR, Seth A, and Mirkovic J
- Subjects
- Female, Humans, Biomarkers, Tumor analysis, Immunohistochemistry, High-Throughput Nucleotide Sequencing, DNA Helicases, Nuclear Proteins genetics, Transcription Factors genetics, Endometrial Neoplasms pathology, Carcinoma pathology
- Abstract
Aims: Our understanding of dedifferentiated endometrial carcinoma (DEC), a rare and aggressive malignancy, mainly reflects undifferentiated carcinomas (UC) arising in the setting of low-grade endometrial cancer (DEC-LG). However, cases of UC arising in the setting of high-grade EC (DEC-HG) have been noted in the literature. Our knowledge of the genomics of DEC-HG is limited. To characterise the molecular landscape of DEC-HC, targeted genomic sequencing and immunohistochemical analysis was carried out on seven DEC-HG and four DEC-LG., Methods and Results: DEC-HG and DEC-LG, including undifferentiated and differentiated components, both showed a similar frequency and spectrum of mutations. ARID1A mutations were identified in 6/7 (86%) DEC-HG and 4/4 (100%) DEC-LG, while SMARCA4 mutations were present in 4/7 (57%) DEC-HG and in 1/4 (25%) DEC-LG. Concurrent SMARCA4/BRG1 protein loss by immunohistochemistry was observed in 3/4 and 1/1 SMARCA4 mutated DEC-HG and DEC-LG, respectively. Neither genomic alterations nor protein loss in SMARCB1/INI1 were observed in any of our cases. TP53 mutations were detected in 4/7 (57%) DEC-HG and in 2/4 (50%) DEC-LG, while mutation-pattern p53 immunohistochemistry expression was observed in 2/7 (29%) DEC-HG and none of the DEC-LG. MLH1 mutations were observed in 1/7 (14%) DEC-HG and 1/4 (25%) DEC-LG. MSH2 and MSH6 mutations were each detected in 1/7 (14%) DEC-HG, but neither was associated with corresponding loss of protein expression., Conclusion: The findings support expanding the definition of DEC to include DEC-HG, a previously under-recognised phenomenon with genomic similarities to DEC-LG., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)
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- 2023
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20. Localized Endometrial Proliferations of Pregnancy are Clonal Glandular Outgrowths Characterized by PTEN Loss and PIK3CA Pathogenic Variants.
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Wepy C, Chapel DB, Mutter GL, Quade BJ, Nucci MR, and Parra-Herran C
- Subjects
- Female, Pregnancy, Humans, Adult, Receptors, Progesterone metabolism, Receptors, Estrogen metabolism, Endometrium metabolism, PTEN Phosphohydrolase genetics, Class I Phosphatidylinositol 3-Kinases genetics, Class I Phosphatidylinositol 3-Kinases metabolism, Endometrial Neoplasms pathology, Endometrial Hyperplasia pathology
- Abstract
Gestational endometrium can demonstrate a spectrum of atypical but benign changes. One such lesion is localized endometrial proliferation of pregnancy (LEPP), first described in a series of 11 cases. To understand its biological and clinical importance, we explore the pathologic, immunophenotypic, and molecular features of this entity. Nine cases of LEPP identified in 15 years were retrieved from departmental archives and reviewed. Immunohistochemistry and next-generation sequencing using a comprehensive 446-gene panel were performed when the material was available. Eight cases were identified in curettage specimens performed after first-trimester pregnancy loss, and 1 in the basal plate of a mature placenta. The mean patient age was 35 (range 27-41) years. The mean lesion size was 6.3 (range 2-12) mm. Architectural patterns, often coexisting in the same case, included cribriform (n = 7), solid (n = 5), villoglandular (n = 2), papillary (n = 2), and micropapillary (n = 1). Cytologic atypia was mild in 7 cases and moderate in 2. Mitotic activity was low (up to 3 per 2.4 mm
2 ). All lesions were associated with neutrophils. Background Arias-Stella phenomenon was present in 4 cases. Immunohistochemistry was performed in 7 LEPP, all of which demonstrated wildtype p53, retained MSH6 and PMS2, membranous beta-catenin, and positive estrogen receptor (mean 71%) and progesterone receptor (mean 74%). All were negative for p40 except 1 case (focal weak positivity). PTEN was markedly reduced in background secretory glands in all cases; in 5/7, LEPP foci showed a complete absence of PTEN expression. PIK3CA pathogenic variants were identified in 4/4 cases sequenced; 3/4 had inactivating PTEN mutations. Follow-up, available in 8 patients (mean length = 51 months, range 7-161), was conservative with observation only and showed no persistence or adverse outcomes. LEPP is characterized by intraglandular cribriform/solid architecture, positive estrogen receptor/progesterone receptor, PTEN loss, and PIK3CA and PTEN mutations. Although our findings indicate that LEPP is neoplastic, for now, we advise against diagnosing LEPP as endometrial carcinoma or hyperplasia because LEPP has a particular clinicopathologic context (concurrent gestation), distinct morphology (purely intraepithelial complex growth), and indolent outcome. Thus, it should be distinguished from endometrial intraepithelial neoplasia and carcinoma for which therapeutic interventions are indicated., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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21. Molecular correlates of invasion pattern in HPV-associated endocervical adenocarcinoma: emergence of two distinct risk-stratified tiers.
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Sharma AE, Hodgson AJ, Howitt BE, Olkhov-Mitsel E, Djordevic B, Park KJ, Nucci MR, and Parra-Herran C
- Subjects
- Female, Humans, Human Papillomavirus Viruses, Biomarkers, Tumor, Prognosis, Neoplasm Invasiveness, Papillomavirus Infections complications, Papillomavirus Infections pathology, Adenocarcinoma genetics, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms pathology
- Abstract
Background: The pattern-based (Silva) classification of invasive human papilloma virus (HPV)-associated endocervical adenocarcinomas (HPVA) is an established and reproducible method to predict outcomes for this otherwise stage-dependent group of tumours. Previous studies utilising targeted sequencing have shown a correlation between mutational profiles and an invasive pattern. However, such correlation has not been explored using comprehensive molecular testing., Design: Clinicopathologic data including invasive pattern (Silva groups A, B, and C) was collected for a cohort of invasive HPVA, which previously underwent massive parallel sequencing using a panel covering 447 genes. Pathogenic alterations, molecular signatures, tumour mutational burden (TMB), and copy number alterations (CNA) were correlated with pattern of invasion., Results: Forty five HPVA (11 pattern A, 17 pattern B, and 17 pattern C tumours) were included. Patients with pattern A presented at stage I with no involved lymph nodes or evidence of recurrence (in those with >2 months of follow-up). Patterns B and C patients also mostly presented at stage I with negative lymph nodes, but had a greater frequency of recurrence; 3/17 pattern B and 1/17 pattern C HPVAs harboured lymphovascular space invasion (LVI). An APOBEC mutational signature was detected only in Silva pattern C tumours (5/17), and pathogenic PIK3CA changes were detected only in destructively invasive HPVA (patterns B and C). When cases were grouped as low-risk (pattern A and pattern B without LVI) and high-risk (pattern B with LVI and pattern C), high-risk tumours were enriched in mutations in PIK3CA, ATRX, and ERBB2. There was a statistically significant difference in TMB between low-risk and high-risk pattern tumours (P = 0.006), as well as between Pattern C tumours with and without an APOBEC signature (P = 0.002). CNA burden increased from pattern A to C., Conclusion: Our findings further indicate that key molecular events in HPVA correlate with the morphologic invasive properties of the tumour and their aggressiveness. Pattern B tumours with LVI clustered with pattern C tumours, whereas pattern B tumours without LVI approached pattern A genotypically. Our study provides a biologic foundation for consolidating the Silva system into low-risk (pattern A + B without LVI) and high-risk (pattern B with LVI and pattern C) categories., (© 2023 John Wiley & Sons Ltd.)
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- 2023
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22. Molecular Landscape of Mullerian Clear Cell Carcinomas Identifies The Cancer Genome Atlas-like Prognostic Subgroups.
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Irshaid L, Costigan DC, Dong F, Matulonis UA, Nucci MR, and Kolin DL
- Subjects
- Female, Humans, Prognosis, Retrospective Studies, Biomarkers, Tumor genetics, Class I Phosphatidylinositol 3-Kinases genetics, Mutation, Endometrial Neoplasms pathology, Carcinoma, Endometrioid genetics, Carcinoma, Endometrioid pathology
- Abstract
Mullerian clear cell carcinoma (CCC) is often aggressive and chemoresistant. The prognostic significance of molecular subclassification of endometrioid carcinomas is well established. However, less is known about the molecular landscape of CCC. The aim of this study was to better characterize the genetic landscape of a large cohort of CCC and correlate these findings with clinicopathologic features. CCC of the ovary (n = 72), endometrium (n = 24), and peritoneum/abdominal wall (n = 5) were retrospectively identified. Tumors had undergone tumor-only targeted sequencing using a hybrid capture next-generation sequencing panel. Median tumor mutational burden was 6.8 mutations/megabase (range, 1.3-185, 21% were ≥10 mutations/Mb). The most frequently mutated genes were ARID1A (48%), PIK3CA (45%), TP53 (23%), and PTEN (10%). ERBB2 amplification occurred in 4%. When classified according to the Cancer Genome Atlas/the Proactive Molecular Risk Classifier for Endometrial Cancer endometrial carcinoma molecular subgroups, 3 (3%) were POLE ultramutated, 5 (5%) were microsatellite instability-high (MSI-H), 20 (20%) were TP53-mutant subgroup, and 73 (72%) were no specific molecular profile (NSMP). Immunohistochemical expression of estrogen receptor, progesterone receptor, and programmed death-ligand 1 were not associated with the molecular subgroup. POLE and MSI-H tumors were characterized by an excellent prognosis, and the TP53-mutant subgroup had a worse disease-free survival than NSMP. NSMP tumors could be further substratified as high-risk NSMP if they lacked PIK3CA, PIK3R1, and ARID1A mutations, and/or harbored a TERT-promoter mutation. The Cancer Genome Atlas and NSMP-specific stratifications were prognostic for both the entire cohort and the subset of stage I ovarian tumors. On multivariable analysis, stage, lymphovascular invasion, and tumor mutational burden were prognostic for disease-free survival, whereas advanced stage and TP53-mutant subgroup - but not a TP53 mutation in isolation - were negative prognostic factors for overall survival. These data suggest that routine molecular profiling of Mullerian CCC may be warranted for both prognosis and identification of potential targeted treatments, such as immunotherapy and anti-HER2 agents., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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23. Dedifferentiated leiomyosarcoma of the uterus: a clinicopathologic and immunohistochemical analysis of 23 cases.
- Author
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Chapel DB, Maccio L, Bragantini E, Zannoni GF, Quade BJ, Parra-Herran C, and Nucci MR
- Subjects
- Female, Humans, Prospective Studies, Uterus pathology, Biomarkers, Tumor analysis, Leiomyosarcoma diagnosis, Smooth Muscle Tumor, Leiomyoma, Uterine Neoplasms pathology
- Abstract
Aims: To morphologically and immunophenotypically characterize dedifferentiated uterine leiomyosarcoma (LMS)., Methods and Results: We identified 23 dedifferentiated uterine LMS, defined as a malignant uterine smooth muscle tumour containing discrete differentiated and dedifferentiated components (i.e. with and without morphologic and immunophenotypic evidence of smooth muscle differentiation, respectively). The differentiated component was leiomyosarcoma in most cases (17/23), though some arose from a leiomyoma (n = 4) or smooth muscle tumour of uncertain malignant potential (n = 2). The dedifferentiated tumour component showed noncohesive polygonal cells with moderate to abundant cytoplasm, pleomorphic nuclei with coarse vesicular to smudged chromatin, one or more macronucleoli, frequent multinucleation, and atypical mitoses. Three cases showed heterologous osteosarcomatous or chondrosarcomatous differentiation. Immunohistochemistry revealed alterations characteristic of uterine LMS, including Rb loss (18/19); strong diffuse p16 (17/19); strong diffuse (9/19) or complete absence of (5/19) p53; and ATRX loss (6/16). Compared to a control cohort of uterine LMS without dedifferentiation, dedifferentiated uterine LMS showed significantly shorter disease-specific (median, 54 versus 20 months; 5-year DSS, 46% versus 36%; P = 0.04) and disease-free (median, 31 versus 8 months; 5-year DFS, 42% versus 8%; P = 0.002) survival. Of 19 dedifferentiated uterine LMS with follow-up, 12 had died of disease at median 14 (range, 2-73) months; four were alive with disease at 4, 12, 44, and 50 months; and three were alive with no evidence of disease at 56, 109, and 114 months., Conclusion: Routine prospective recognition of dedifferentiated uterine LMS and distinction from mimics is advocated for accurate prognostication and for further characterisation of these tumours., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)
- Published
- 2023
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24. A Clinicopathologic and Molecular Characterization of Uterine Sarcomas Classified as Malignant PEComa.
- Author
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Anderson WJ, Dong F, Fletcher CDM, Hirsch MS, and Nucci MR
- Subjects
- Female, Humans, Adult, Middle Aged, Aged, Aged, 80 and over, Immunohistochemistry, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, Uterine Neoplasms genetics, Uterine Neoplasms pathology, Perivascular Epithelioid Cell Neoplasms genetics, Perivascular Epithelioid Cell Neoplasms pathology, Sarcoma genetics, Neoplasms, Connective and Soft Tissue, Pelvic Neoplasms, Soft Tissue Neoplasms, Neuroendocrine Tumors
- Abstract
Perivascular epithelioid cell tumors (PEComas) are a distinctive group of mesenchymal neoplasms that demonstrate features of smooth muscle and melanocytic differentiation. Here, we present the clinicopathologic, immunohistochemical, and molecular features of 15 uterine sarcomas diagnosed as malignant PEComa. The median patient age was 56 years (range: 27 to 86 y). The median tumor size was 8.0 cm (range: 5.0 to 14.0 cm). All tumors were classified as malignant based on the presence of mitoses (15/15; 100%), necrosis (15/15; 100%), lymphovascular invasion (8/15; 53%), and high nuclear grade (13/15; 87%). Molecular analysis revealed the mammalian target of rapamycin pathway gene mutations in 7 cases (47%), including mutually exclusive variants in TSC1 (27%) and TSC2 (20%). Recurrent alterations were also identified in TP53 (53%), RB1 (30%), ATRX (33%), and BRCA2 (13%). Tumors with inactivating ATRX mutations all demonstrated loss of ATRX expression by immunohistochemistry. Loss of expression was also observed in 2 tumors without demonstrable ATRX alterations. Clinical follow-up was available for 14 patients (range: 5 to 92 mo; median: 15 mo). Five patients developed local recurrence and 9 developed metastases; 2 patients died of their disease. Our series expands the spectrum of molecular events in tumors diagnosed as malignant PEComa and further highlights the important role of targeted sequencing in tumors with focal melanocytic marker expression., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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25. Fumarate Hydratase and S-(2-Succinyl)-Cysteine Immunohistochemistry Shows Evidence of Fumarate Hydratase Deficiency in 2% of Uterine Leiomyosarcomas: A Cohort Study of 348 Tumors.
- Author
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Chapel DB, Sharma A, Maccio L, Bragantini E, Zannoni GF, Yuan L, Quade BJ, Parra-Herran C, and Nucci MR
- Subjects
- Female, Humans, Fumarate Hydratase genetics, Cysteine, Cohort Studies, Immunohistochemistry, Leiomyosarcoma, Uterine Neoplasms pathology, Pelvic Neoplasms, Leiomyomatosis genetics, Kidney Neoplasms pathology, Carcinoma, Renal Cell pathology
- Abstract
Approximately 1% to 1.5% of uterine leiomyomas are fumarate hydratase (FH)-deficient (FHd). A subset of these are associated with germline FH mutations. However, the prevalence and clinicopathologic characteristics of FHd uterine leiomyosarcoma (uLMS) remain unknown. Clinicopathologic data were collected for 348 uLMS. Morphologic features associated with FH deficiency (staghorn-type vessels, alveolar-pattern edema, macronucleoli with perinucleolar clearing, eosinophilic cytoplasmic inclusions, and chain-like nuclear arrangement) were documented. All 348 tumors were studied by FH immunohistochemistry. Eighty-nine were also studied by S-(2-succinyl)-cysteine (2SC) immunohistochemistry. Seven (2%) FHd uLMS were identified. Five showed uniformly negative FH and diffusely positive 2SC immunostaining; 1 showed variably negative to weak to strong FH and diffusely positive 2SC immunostaining; and 1 showed retained FH staining alongside positive 2SC confined to a morphologically distinct subclone. Three of 7 patients had extrauterine disease at presentation, and 3 of 6 had persistent disease or died from disease. Macronucleoli with perinucleolar clearing were significantly more common in FHd uLMS (7/7) than in uLMS with retained FH (182/341; P =0.017). Disease-specific survival, disease-free survival, and other morphologic features of FH deficiency did not differ significantly between FHd and FH-retained tumors. Our data emphasize that immunohistochemical FH deficiency does not preclude malignancy in uterine smooth muscle tumors. However, the biological significance and molecular basis of FH deficiency in uLMS, including any relationship to germline FH mutation, remain unknown, and a larger multi-institutional effort is necessary to gather sufficient FHd uLMS for more robustly powered clinicopathologic and for molecular characterization., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)
- Published
- 2023
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26. Reply to Comment on HPV-independent, p53-Wild-type Vulvar Intraepithelial Neoplasia: A Review of Nomenclature and the Journey to Characterize Acanthotic Precursor Lesions of the Vulva.
- Author
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Parra-Herran C, Nucci MR, Singh N, Rakislova N, Howitt BE, Hoang L, Gilks CB, Bosse T, and Watkins JC
- Subjects
- Female, Humans, Tumor Suppressor Protein p53, Vulva, Papillomavirus Infections complications, Vulvar Neoplasms
- Published
- 2023
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27. Ovarian Signet-ring Stromal Tumor: A Morphologic, Immunohistochemical, and Molecular Study of 7 Cases With Discussion of the Differential Diagnosis.
- Author
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Tchrakian N, Oliva E, Chong AS, Rivera-Polo B, Bennett JA, Nucci MR, Sah S, Schoolmeester JK, van der Griend RA, Foulkes WD, Clarke BA, Young RH, and McCluggage WG
- Subjects
- Female, Humans, beta Catenin analysis, Diagnosis, Differential, DNA Mutational Analysis, Biomarkers, Tumor analysis, Sex Cord-Gonadal Stromal Tumors pathology, Ovarian Neoplasms diagnosis, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
- Abstract
Signet-ring stromal tumor (SRST) is a rare ovarian stromal neoplasm characterized by a population of bland signet-ring cells, devoid of mucin or lipid, in a generally cellular fibromatous stroma. Previous reports have described heterogenous immunohistochemical and molecular genetic findings, including occasional nuclear β-catenin expression and/or CTNNB1 mutations. We report 10 ovarian stromal neoplasms originally diagnosed as SRST. All but 1 tumor underwent detailed immunohistochemical analysis (including β-catenin) and 5 of 10 had CTNNB1 mutation analysis performed. All tumors contained a population of morphologically bland signet-ring cells that ranged from 15% to 95% of the neoplasm, characterized by a single large empty intracytoplasmic vacuole, mostly with nuclear indentation. Six of the 10 tumors contained cellular fibroma-like areas, comprising from 10% to 85% of the neoplasm. Three of the 10 tumors were reclassified as microcystic stromal tumor with signet-ring cells on the basis of the microcyst formation and hyalinized stroma, beta-catenin and cyclin D1 nuclear expression and/or CTNNB1 mutation, CD10 staining and largely absent expression of inhibin and calretinin. In the remaining 7 tumors, the diagnosis of SRST remained, constituting the largest series of SRST reported in the literature to date. The results of our study suggest that a subset of tumors diagnosed as ovarian SRST, especially those which show β-catenin nuclear positivity and/or CTNNB1 mutation, likely represent microcystic stromal tumor with variant morphology. We also suggest that at least a subset of SRSTs without evidence of Wnt/β-catenin pathway abnormalities may be related to ovarian fibromas. We discuss the differential diagnosis of ovarian neoplasms containing signet-ring cells., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
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28. Data Set for Reporting of Uterine Malignant and Potentially Malignant Mesenchymal Tumors: Recommendations From the International Collaboration on Cancer Reporting (ICCR).
- Author
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Nucci MR, Webster F, Croce S, George S, Howitt BE, Ip PPC, Lee CH, Rabban JT, Soslow RA, van der Griend R, Lax SF, and McCluggage WG
- Subjects
- Female, Humans, Pathologists, Research Report, Pathology, Clinical, Carcinoma pathology, Sarcoma
- Abstract
The International Collaboration on Cancer Reporting (ICCR) seeks to produce standardized, evidence-based protocols for the reporting of tumors with the aim of ensuring that all cancer reports generated worldwide will be of similar high quality and record the same elements. Herein, we describe the development of the data set for the reporting of uterine malignant and potentially malignant mesenchymal tumors by a panel of expert pathologists and a single clinician and provide the commentary and rationale for the inclusion of core and noncore elements. This data set, which incorporates the recent updates from the 5th edition of the World Health Organization Classification of Female Genital Tumors, addresses several subjects of debate including which mesenchymal tumors should be graded, how to document extent of invasion, mitotic counts, and the role of ancillary testing in tumor diagnosis and patient management. The inclusion of elements is evidence-based or based on consensus of the expert panel with clinical relevance being the guiding standard., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)
- Published
- 2022
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29. Well-developed Cerebellum in an Ovarian Mature Teratoma From a Pregnant Female.
- Author
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Sauer MA, Coy S, Quade BJ, and Nucci MR
- Subjects
- Humans, Female, Pregnancy, Cerebellum pathology, Teratoma pathology, Ovarian Neoplasms pathology, Dermoid Cyst
- Abstract
Teratomas are the most common neoplasm of the ovary, comprising over half of all diagnosed tumors in patients under 50. Most lesions are classified as benign mature teratomas and are histologically defined by the presence of mature tissues from one or more of the embryological germ layers: ectoderm, mesoderm, and endoderm. Neuroectodermal derivatives, including glia, neurons, ependymal cells, and meninges are present in a third to half of mature teratomas. Although teratomatous tissue elements are typically arranged in a haphazard fashion, well-developed and organized embryonic organ structures have been rarely reported and often with limited histologic, clinical, or gross characterization. In this report, we describe the case of an ovarian mature cystic teratoma identified in a pregnant female which exhibited remarkably well-developed posterior fossa structures including lobated and foliated cerebellum with appropriate anatomic organization and associated brainstem, ventricular, and meningeal structures., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)
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- 2022
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30. NTRK -Rearranged Uterine Sarcomas: Clinicopathologic Features of 15 Cases, Literature Review, and Risk Stratification.
- Author
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Costigan DC, Nucci MR, Dickson BC, Chang MC, Song S, Sholl LM, Hornick JL, Fletcher CDM, and Kolin DL
- Subjects
- Adolescent, Adult, Biomarkers, Tumor genetics, Female, Humans, Middle Aged, Neoplasm Recurrence, Local, Oncogene Proteins, Fusion genetics, RNA, Receptor, trkA genetics, Risk Assessment, Young Adult, Pelvic Neoplasms, Sarcoma genetics, Sarcoma pathology, Sarcoma therapy, Soft Tissue Neoplasms pathology, Uterine Cervical Neoplasms, Uterine Neoplasms genetics, Uterine Neoplasms pathology, Uterine Neoplasms therapy
- Abstract
NTRK -rearranged uterine sarcomas are rare spindle cell neoplasms that typically arise in the uterine cervix of young women. Some tumors recur or metastasize, but features which predict behavior have not been identified to date. Distinguishing these tumors from morphologic mimics is significant because patients with advanced stage disease may be treated with TRK inhibitors. Herein, we present 15 cases of NTRK- rearranged uterine sarcomas, the largest series to date. Median patient age was 35 years (range: 16 to 61). The majority arose in the uterine cervix (n=14) and all but 2 were organ-confined at diagnosis. Tumors were composed of an infiltrative, fascicular proliferation of spindle cells and most showed mild-to-moderate cytologic atypia. All were pan-TRK positive by immunohistochemistry (13/13); S100 (11/13) and CD34 (6/10) were usually positive. RNA or DNA sequencing found NTRK1 (10/13) and NTRK3 (3/13) fusions with partners TPR , TPM3 , EML4 , TFG , SPECC1L , C16orf72 , and IRF2BP2 . Unusual morphology was seen in 2 tumors which were originally diagnosed as unclassifiable uterine sarcomas, 1 of which also harbored TP53 mutations. Follow up was available for 9 patients, of whom 3 died of disease. By incorporating outcome data of previously reported tumors, adverse prognostic features were identified, including a mitotic index ≥8 per 10 high-power fields, lymphovascular invasion, necrosis, and NTRK3 fusion. Patients with tumors which lacked any of these 4 features had an excellent prognosis. This study expands the morphologic spectrum of NTRK -rearranged uterine sarcomas and identifies features which can be used for risk stratification., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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31. HPV-independent, p53-wild-type vulvar intraepithelial neoplasia: a review of nomenclature and the journey to characterize verruciform and acanthotic precursor lesions of the vulva.
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Parra-Herran C, Nucci MR, Singh N, Rakislova N, Howitt BE, Hoang L, Gilks CB, Bosse T, and Watkins JC
- Subjects
- Class I Phosphatidylinositol 3-Kinases metabolism, Female, Humans, Papillomaviridae, Tumor Suppressor Protein p53 metabolism, Vulva metabolism, Vulva pathology, Biological Products, Carcinoma in Situ pathology, Carcinoma, Squamous Cell pathology, Papillomavirus Infections pathology, Precancerous Conditions pathology, Squamous Intraepithelial Lesions, Vulvar Neoplasms pathology
- Abstract
Vulvar squamous cell carcinomas and their precursors are currently classified by the World Health Organization based on their association with high-risk human papillomavirus (HPV). HPV independent lesions often harbor driver alterations in TP53, usually seen in the setting of chronic vulvar inflammation. However, a group of pre-invasive vulvar squamous lesions is independent from both HPV and mutant TP53. The lesions described within this category feature marked acanthosis, verruciform growth and altered squamous maturation, and over the last two decades several studies have added to their characterization. They have a documented association with verrucous carcinoma and conventional squamous cell carcinoma of the vulva, suggesting a precursor role. They also harbor recurrent genomic alterations in several oncogenes, mainly PIK3CA and HRAS, indicating a neoplastic nature. In this review, we provide a historical perspective and a comprehensive description of these lesions. We also offer an appraisal of the terminology used over the years, going from Vulvar Acanthosis with Altered Differentiation and Verruciform Lichen Simplex Chronicus to Differentiated Exophytic Vulvar Intraepithelial Lesion and Vulvar Aberrant Maturation, the latter term having been recently proposed by the International Society for the Study of Vulvovaginal Diseases. In line with the recognition of these lesions by the 2020 World Health Organization Classification of Tumours as a neoplastic precursor, we herein propose the term HPV-independent, p53-wild-type verruciform acanthotic Vulvar Intraepithelial Neoplasia (HPVi(p53wt) vaVIN), which better conveys not only the pathology but also the neoplastic nature and the biologic risk inherent to these uncommon and challenging lesions. We outline strict morphologic and immunohistochemical criteria for its diagnosis and distinction from mimickers. Immunohistochemistry for p16 and p53 should be performed routinely in the diagnostic work-up of these lesions, and the morphologic alternative term vaVIN should be reserved for instances in which p16/HPV/p53 status is unknown. We also discuss management considerations and the need to further explore precursors within and beyond the spectrum of verruciform acanthotic vulvar intraepithelial neoplasia., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)
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- 2022
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32. Addressing the diagnostic and therapeutic dilemmas of ovarian immature teratoma: Report from a clinicopathologic consensus conference.
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Pashankar F, Hanley K, Lockley M, Stoneham S, Nucci MR, Reyes-Múgica M, Elishaev E, Vang R, Veneris J, Rytting H, Olson T, Hazard K, Covens A, Arora R, Billmire D, Al-Ibraheemi A, Ulbright TM, Frazier L, and Hirsch MS
- Subjects
- Adult, Child, Consensus Development Conferences as Topic, Female, Humans, Endodermal Sinus Tumor drug therapy, Endodermal Sinus Tumor therapy, Neoplasms, Germ Cell and Embryonal diagnosis, Neoplasms, Germ Cell and Embryonal therapy, Ovarian Neoplasms drug therapy, Ovarian Neoplasms therapy, Teratoma drug therapy, Teratoma therapy
- Abstract
Ovarian immature teratoma is a rare subtype of germ cell tumour that can be pure or associated with non-teratomatous germ cell tumour elements and is graded based on extent of the immature neuroectodermal component. Immature teratoma (IT) can also be associated with somatic differentiation in the form of sarcoma, carcinoma, or extensive immature neuroectodermal elements and may produce low levels of serum alpha-fetoprotein. Variable interpretation of these issues underlies diagnostic and management dilemmas, resulting in substantial practice differences between paediatric and adult women with IT. The Malignant Germ Cell International Consortium (MaGIC) convened oncologists, surgeons, and pathologists to address the following crucial clinicopathologic issues related to IT: (1) grading of IT, (2) definition and significance of 'microscopic' yolk sac tumour, (3) transformation to a somatic malignancy, and (4) interpretation of serum tumour biomarkers. This review highlights the discussion, conclusions, and suggested next steps from this clinicopathologic conference., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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33. Low-grade Fibromyxoid Sarcoma of the Vulva and Vagina: Clinical, Pathologic, and Molecular Characterization of 7 Cases and Review of the Literature.
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Costigan D, Dal Cin P, Fletcher CDM, Nucci MR, Parra-Herran C, and Chapel DB
- Subjects
- Adult, Biomarkers, Tumor genetics, Female, Humans, In Situ Hybridization, Fluorescence, Neoplasm Recurrence, Local pathology, Vagina pathology, Vulva pathology, Fibrosarcoma pathology, Myxosarcoma, Soft Tissue Neoplasms pathology
- Abstract
Low-grade fibromyxoid sarcoma (LGFMS) is a malignancy with propensity for late relapse that principally affects deep soft tissues of the extremities and trunk. Its occurrence in the lower female genital tract is rare, and thus it may not be always considered in the differential diagnosis. We describe the salient features of 7 vulvovaginal LGFMS identified in the authors' consultation files. Clinical information was obtained from referring pathologists. Archival slides were reviewed, and immunohistochemistry and fluorescence in situ hybridization were performed in cases with available material. Median age was 40 years (range, 34 to 58 y). Primary sites included vulva (n=6) and vagina (n=1). Tumors were 1.2 to 8.7 cm (median, 5.0 cm) in size and grossly circumscribed with firm to focally gelatinous cut surfaces. Microscopically, 5/7 had infiltrative edges. All tumors showed fibrous and myxoid areas, with lobulated myxoid foci in 5/7, comprising storiform, patternless, or (less often) fascicular arrangement of spindled to stellate cells with bland, slender to ovoid nuclei. In all cases, mitoses were <1/2.4 mm 2 , and necrosis was absent. Capillary "arcades" were seen in 3/7. Margins were positive in 3/6. Immunohistochemistry showed positive epithelial membrane antigen in 4/6 and MUC4 in 5/6. Fluorescence in situ hybridization detected FUS rearrangement in 5/7. Both tumors without FUS rearrangement were also negative for EWSR1 rearrangement. All 5 patients with available follow-up were alive and disease-free 10 to 150 months (median, 57 mo) after diagnosis. However, a review of vulvovaginal/pelvic LGFMS previously reported shows recurrences as late as 45 years after initial diagnosis. Pathologists need to be aware that LGFMS can arise in the vulvovaginal region. Tumor lobulation, capillary arcades, and positive MUC4 are helpful features distinguishing LGFMS from other bland myxoid spindle cell neoplasms in the lower female genital tract. Molecular testing can be useful in challenging cases. Complete excision is feasible for most vulvovaginal LGFMS. Long-term surveillance is required as local and/or distant spread can occur decades after diagnosis., Competing Interests: Conflicts of Interest and Source of Funding: D.B.C.’s work is supported by the Ovarian Cancer Research Alliance (Ann Schreiber Mentored Investigator Award; grant no. 650320). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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34. Evaluation of Treatment With Talazoparib and Avelumab in Patients With Recurrent Mismatch Repair Proficient Endometrial Cancer.
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Konstantinopoulos PA, Gockley AA, Xiong N, Krasner C, Horowitz N, Campos S, Wright AA, Liu JF, Shea M, Yeku O, Castro C, Polak M, Lee EK, Sawyer H, Bowes B, Moroney J, Cheng SC, Tayob N, Bouberhan S, Spriggs D, Penson RT, Fleming GF, Nucci MR, and Matulonis UA
- Subjects
- Aged, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, DNA Mismatch Repair, Diphosphates therapeutic use, Female, Humans, Immune Checkpoint Inhibitors, Ligands, Neoplasm Recurrence, Local drug therapy, Phthalazines, Ribose therapeutic use, B7-H1 Antigen, Endometrial Neoplasms drug therapy, Endometrial Neoplasms genetics
- Abstract
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.
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- 2022
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35. A novel morphology-based risk stratification model for stage I uterine leiomyosarcoma: an analysis of 203 cases.
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Chapel DB, Sharma A, Lastra RR, Maccio L, Bragantini E, Zannoni GF, George S, Quade BJ, Parra-Herran C, and Nucci MR
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- Female, Humans, Necrosis pathology, Neoplasm Staging, Prognosis, Risk Assessment, Leiomyosarcoma pathology, Uterine Neoplasms pathology
- Abstract
Uterine leiomyosarcoma is the most common uterine mesenchymal malignancy. The majority present at stage I, and clinical outcomes vary widely. However, no widely accepted risk stratification system for stage I uterine leiomyosarcoma is currently available. We studied 17 routinely evaluated clinicopathologic parameters in 203 stage I uterine leiomyosarcoma from three institutions to generate a novel risk stratification model for these tumors. Mitoses >25 per 2.4 mm
2 (10 high-power fields), atypical mitoses, coagulative necrosis, lymphovascular invasion, and serosal abutment were significantly associated with disease-free and disease-specific survival in univariate and multivariate analyses. These prognostic parameters were each scored as binary ("yes" or "no") variables and fitted to a single optimized algebraic risk model:Risk score = (coagulative necrosis)(1) + (mitoses > 25 per 2.4 mm2 )(2) + (atypical mitoses)(2) + (lymphovascular invasion)(3) + (serosal abutment)(5)By logistic regression, the risk model was significantly associated with 5-year disease-free (AUC = 0.9270) and 5-year disease-specific survival (AUC = 0.8517). Internal and external validation substantiated the model. The continuous score (range, 0-13) was optimally divided into 3 risk groups with distinct 5-year disease-free and disease-specific survival: low risk (0-2 points), intermediate risk (3-5 points), and high risk (6-13 points) groups. Our novel risk model performed significantly better than alternative uterine leiomyosarcoma risk stratification systems in predicting 5-year disease-free and disease-specific survival in stage I tumors. A simplified risk model, omitting terms for serosal abutment and lymphovascular invasion, can be accurately applied to myomectomy or morcellated specimens. We advocate routine application of this novel risk model in stage I uterine leiomyosarcoma to facilitate patient counseling and proper risk stratification for clinical trials., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)- Published
- 2022
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36. Epithelioid Leiomyosarcoma of the Uterus: Modern Outcome-based Appraisal of Diagnostic Criteria in a Large Institutional Series.
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Chapel DB, Nucci MR, Quade BJ, and Parra-Herran C
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- Biomarkers, Tumor, Female, Humans, Middle Aged, Necrosis, Uterus pathology, Leiomyoma pathology, Leiomyosarcoma chemistry, Smooth Muscle Tumor diagnosis, Smooth Muscle Tumor pathology, Smooth Muscle Tumor therapy
- Abstract
Epithelioid leiomyosarcoma of the uterus is rare and poorly understood. Herein, we characterize a large institutional series of epithelioid leiomyosarcomas aiming to define outcome-determinant diagnostic pathologic features. We also retrieved epithelioid smooth muscle tumors of unknown malignant potential and evaluated a consecutive cohort of leiomyomas for epithelioid subtypes. Of a total of 1177 uterine leiomyosarcomas, 81 (7%) were categorized as epithelioid after review. Epithelioid leiomyosarcoma was strictly defined as having round to polygonal cells with visible pink cytoplasm and round to ovoid nuclei in ≥50% of the tumor volume. Average age was 55 years (range: 26 to 81 y). Median tumor size was 11 cm; tumor was >5 cm in 93% of subjects; 47% were stage 1 at presentation. An infiltrative tumor border was observed, grossly and/or microscopically, in 89% of cases; necrosis was noted in 80%, and vascular invasion in 47%. Mitotic count in 2.4 mm2 (totalling 10 high-power fields, each field 0.55 mm in diameter) ranged from 3 to 100 (median: 26). All cases had moderate, severe or highly pleomorphic atypia. All cases had 2 or 3 of the following: necrosis, at least moderate atypia and ≥4 mitoses in 2.4 mm2. Immunohistochemistry revealed frequent expression of smooth muscle markers including SMA (96%), desmin (95%), and caldesmon (81%). HMB45 and Melan-A were negative in 92% and 100% of cases, respectively. Estrogen and progesterone receptors were expressed by 65% and 54% of tumors, respectively. Follow-up information was available in 68 subjects (median: 23 mo, range: 1 to 254); cancer-related death occurred in 63%, and an additional 15% had recurrent or metastatic disease at last follow-up. Disease-specific survival was shorter in epithelioid leiomyosarcoma patients (median: 44 mo; 35% at 5-y) than in a matched cohort of nonepithelioid leiomyosarcoma (median: 55 mo; 46% at 5-y) (P=0.03). Three epithelioid smooth muscle tumors of unknown malignant potential were evaluated, all <5 cm in size and with atypia and/or irregular borders but mitotic count below the threshold for malignancy. Two of these had follow-up available, which was uneventful. Of 142 consecutive leiomyomas assessed, none had epithelioid morphology as defined. Epithelioid leiomyosarcoma is an aggressive neoplasm, sometimes with a remarkably low mitotic count. In the setting of an epithelioid smooth muscle tumor of the uterus, we postulate that the diagnosis of malignancy is made in the presence of ≥2 of the following: moderate or severe atypia, ≥4 mitoses/2.4 mm2 and tumor cell necrosis. In their absence, the finding of tumor size ≥5 cm, vascular invasion, infiltrative edges or atypical mitoses should be treated with caution, and designation as of at least uncertain malignant potential is warranted., Competing Interests: Conflicts of Interest and Source of Funding: D.B.C. work is supported by the Ovarian Cancer Research Alliance (Ann Schreiber Mentored Investigator Award; grant number 650320). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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37. Atypical uterine polyps show morphologic and molecular overlap with mullerian adenosarcoma but follow a benign clinical course.
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Chapel DB, Howitt BE, Sholl LM, Dal Cin P, and Nucci MR
- Subjects
- Adenosarcoma genetics, Adult, Aged, Cohort Studies, Female, Follow-Up Studies, Humans, Middle Aged, Mitosis, Polyps genetics, Uterine Diseases genetics, Young Adult, Adenosarcoma pathology, Polyps pathology, Uterine Diseases pathology
- Abstract
A subset of clinically benign uterine polyps shows atypical morphologic features worrisome for, but not diagnostic of, Mullerian adenosarcoma. We report clinicopathologic data for 63 polyps from 58 women with atypical morphologic features including abnormal architecture, abnormal periglandular stroma, stromal atypia, and mitoses >2 per 10 hpf. Four (11%) of 36 women with follow-up tissue sampling had residual/recurrent atypical polyp. Twelve (27%) of 44 women underwent hysterectomy subsequent to a diagnosis of atypical polyp. No patient developed adenosarcoma over median follow-up of 150 months. Twenty-one primary atypical polyps underwent molecular profiling. Five (24%) harbored chr 12q13-15 gain or amplification, 9/20 (45%) harbored chr 6q25.1 gain, and 7/21 (33%) had no significant copy number alterations. Gains of chr 1q, chr 8p12, and chr 10q11.21-23, amplifications of chr 12q24.12-13, chr 15p24.1-26.1, and chr 18q21.33, and loss of chr 7 and chr 11q21 were each seen in a single polyp. Mean tumor mutational burden was 3.1 (range, 0.76-8.365) mutations/Mb. Pathogenic point mutations were identified in 12/20 (60%) primary atypical polyps. We propose the term "atypical uterine polyps" for these lesions, which show biologic overlap with early Mullerian adenosarcoma but lack molecular alterations characteristic of clinically aggressive adenosarcoma and appear to follow a benign clinical course. Conservative management with close clinical follow-up and repeat sampling can be considered for these lesions, when clinically appropriate., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)
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- 2022
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38. Interobserver reproducibility of the diagnosis of differentiated exophytic vulvar intraepithelial lesion (DEVIL) and the distinction from its mimics.
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Neville G, Chapel DB, Crum CP, Song SJ, Yoon JY, Lee KR, Kolin DL, Hirsch MS, Nucci MR, and Parra-Herran C
- Subjects
- Diagnosis, Differential, Female, Humans, Observer Variation, Precancerous Conditions diagnosis, Precancerous Conditions pathology, Vulvar Diseases diagnosis, Vulvar Diseases pathology
- Abstract
Aims: Most vulvar squamous cell carcinomas are human papillomavirus (HPV)-associated or TP53-mutant. A third category of HPV-independent TP53-wild-type lesions is uncommon and not fully understood. Differentiated exophytic vulvar intraepithelial lesion (DEVIL) has been characterised as a precursor of this latter category. The reproducibility of the diagnosis of DEVIL and its distinction from lesions with overlapping morphology has not been studied. Our aim was to establish the interobserver agreement in the diagnosis of DEVIL and its distinction from neoplastic and reactive conditions of the vulva on haematoxylin and eosin evaluation., Methods and Results: A set of 35 slides was evaluated by eight reviewers (two trainees and six practising gynaecological pathologists). The set included DEVIL, condyloma, established vulvar precursors [high-grade squamous intraepithelial lesion (HSIL) and differentiated vulvar intraepithelial neoplasia (dVIN)] with superimposed acanthosis or verruciform growth, lichen simplex chronicus (LSC), and psoriasis. Kappa (κ) values were calculated. Overall, interobserver agreement was moderate (κ = 0.56), improving to substantial (κ = 0.7) when evaluation was performed by practising pathologists. Agreement was strong for the diagnosis of HSIL (κ = 0.88), and substantial for the diagnosis of DEVIL (κ = 0.61), condyloma (κ = 0.79), and LSC (κ = 0.72). Agreement was moderate for the diagnosis of dVIN (κ = 0.59) and psoriasis (κ = 0.53). Perfect agreement (6/6) among practising pathologists was observed in 43% of cases, and majority agreement (5/6 or 4/6) was observed in 48% of cases., Conclusions: Reproducibility in the diagnosis of verruciform vulvar lesions, including the novel DEVIL, is acceptable overall. Reproducibility is higher for well-known lesions such as HSIL and condyloma than for more challenging diagnoses such as DEVIL, dVIN, and psoriasis. Agreement is higher among practising gynaecological pathologists, suggesting that training and experience improve reproducibility. Our findings support the inclusion of DEVIL as a diagnostic entity in the classification of vulvar squamous lesions., (© 2021 John Wiley & Sons Ltd.)
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- 2021
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39. EWSR1-WT1 gene fusions in neoplasms other than desmoplastic small round cell tumor: a report of three unusual tumors involving the female genital tract and review of the literature.
- Author
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Schoolmeester JK, Folpe AL, Nair AA, Halling K, Sutton BC, Landers E, Karnezis AN, Dickson BC, Nucci MR, and Kolin DL
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- Adult, Female, Genital Neoplasms, Female genetics, Humans, Middle Aged, Young Adult, Genital Neoplasms, Female pathology, Oncogene Fusion genetics, RNA-Binding Protein EWS genetics, WT1 Proteins genetics
- Abstract
Desmoplastic small round cell tumor (DSRCT) is a high-grade round cell sarcoma that typically arises in the abdominopelvic cavity of young males, co-expresses keratins and desmin, and carries a pathognomonic EWSR1-WT1 gene fusion. The EWSR1-WT1 gene fusion is generally considered specific for DSRCT, although there are two reports of this fusion in tumors otherwise lacking features of DSRCT. We report three female genital tract tumors with EWSR1-WT1 fusions but showing morphologic and immunohistochemical features incompatible with DSRCT. The tumors occurred in the uterine cervix, uterine corpus/ovaries, and vagina, respectively, of 46, 30, and 20-year-old women. Two tumors consisted of a sheet-like to fascicular proliferation of relatively uniform spindled to occasionally more epithelioid cells arrayed about thick-walled, hyalinized, and capillary-sized vessels, with distinctive areas of pseudovascular change, and absence of desmoplastic stroma. The third tumor resembled a monomorphic spindle cell sarcoma with necrosis. All had diffuse desmin and variable but more limited keratin expression, two of three expressed smooth muscle actin, and all were negative for h-caldesmon, CD10, estrogen receptor, myogenin, N-terminus WT-1, and S100 protein. One patient received neoadjuvant chemotherapy and radiation therapy followed by resection and is disease-free 42 months after diagnosis. Another patient was managed by resection only and is disease-free 9 months after initial diagnosis. The remaining patient recently underwent resection of multifocal pelvic disease. Comprehensive differential gene expression analysis on two tumors compared to two classic DSRCTs with known EWSR1-WT1 fusions resulted in 1726 genes that were differentially expressed (log2 fold change >2 or < -2) and statistically significant (FDR < 5%). In combination with previous reports, our findings suggest pleiotropy of the EWSR1-WT1 fusion is possible and not limited to DSRCT. Subsets of non-DSRCT EWSR1-WT1 positive tumors may represent discrete entities, but further study is necessary., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)
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- 2021
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40. Mixed Endometrioid Adenocarcinoma and Müllerian Adenosarcoma of the Uterus and Ovary: Clinicopathologic Characterization With Emphasis on its Distinction From Carcinosarcoma.
- Author
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El Hallani S, Arora R, Lin DI, Måsbäc A, Mateoiu C, McCluggage WG, Nucci MR, Otis CN, Parkash V, Parra-Herran C, and Longacre TA
- Subjects
- Adenosarcoma genetics, Adenosarcoma mortality, Adenosarcoma therapy, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Biopsy, Carcinoma, Endometrioid genetics, Carcinoma, Endometrioid mortality, Carcinoma, Endometrioid therapy, Diagnosis, Differential, Europe, Female, Humans, Middle Aged, Neoplasm Grading, Neoplasm Staging, North America, Ovarian Neoplasms genetics, Ovarian Neoplasms mortality, Ovarian Neoplasms therapy, Predictive Value of Tests, Uterine Neoplasms genetics, Uterine Neoplasms mortality, Uterine Neoplasms therapy, Adenosarcoma pathology, Carcinoma, Endometrioid pathology, Carcinosarcoma pathology, Ovarian Neoplasms pathology, Uterine Neoplasms pathology
- Abstract
Mullerian adenosarcoma is a biphasic neoplasm composed of benign or atypical Müllerian epithelium and a malignant mesenchymal component that is usually, but not always, of low grade. Focal architectural or cytologic atypia of the epithelial component resembling atypical hyperplasia may uncommonly be present and foci of adenocarcinoma have been rarely reported. Whether the coexistence of these 2 tumor components is a result of independent primaries (collision tumor), adenocarcinoma arising from the epithelial component of the adenosarcoma, an unusual form of carcinosarcoma or some other mechanism is uncertain. To establish the diagnostic criteria and clinical significance of the coexistence of adenocarcinoma in close association with Müllerian adenosarcoma, we conducted a multi-institutional study of these rare tumors. Twenty-six patients were identified with "mixed" adenosarcoma and adenocarcinoma; they ranged in age from 43 to 87 years (median: 66 y). Tumors occurred in the uterine corpus (n=22), ovary (n=2), and the pelvis (n=2). All but 6 had International Federation of Gynecology and Obstetrics (FIGO) stage I disease. All extrauterine tumors were associated with endometriosis. The tumor size ranged from 2 to 25 cm (median: 7.9 cm). The sarcomatous component was of low grade in 18 and high grade in 8 (the majority demonstrating rhabdomyoblastic differentiation); 9 had stromal overgrowth. Twenty-five carcinomas were endometrioid in type (23 FIGO grade 1; 3 FIGO grade 2) and 1 carcinoma was dedifferentiated with FIGO grade 1 endometrioid adenocarcinoma component; 33% of the uterine neoplasms were associated with adjacent endometrial hyperplasia. Next-generation sequencing in 2 tumors identified similar molecular abnormalities in the sarcomatous and carcinomatous components supporting a clonal relationship. Of 10 patients with available follow-up (median: 18 mo), 8 had no evidence of disease and 2 died of recurrent sarcoma at 7 and 8 months. Endometrioid adenocarcinomas that arise in close spatial association with Müllerian adenosarcoma appear to be clonally related to the sarcoma. Unlike carcinosarcomas, these tumors are usually early stage at presentation. The prognosis appears to be driven by the sarcomatous component. These tumors should be distinguished from carcinosarcomas, dedifferentiated endometrial carcinomas, and corded and hyalinized endometrioid carcinomas., Competing Interests: Conflicts of Interest and Source of Funding: D.I.L. reports current full-time employment at Foundation Medicine which is a whole subsidiary of Roche. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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41. Detection of ERBB2 amplification in uterine serous carcinoma by next-generation sequencing: an approach highly concordant with standard assays.
- Author
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Robinson CL, Harrison BT, Ligon AH, Dong F, Maffeis V, Matulonis U, Nucci MR, and Kolin DL
- Subjects
- Carcinoma pathology, DNA Copy Number Variations, Endometrial Neoplasms pathology, Female, Gene Dosage, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Neoplasms, Cystic, Mucinous, and Serous pathology, Predictive Value of Tests, Reproducibility of Results, Retrospective Studies, Biomarkers, Tumor genetics, Carcinoma genetics, Endometrial Neoplasms genetics, Gene Amplification, High-Throughput Nucleotide Sequencing, Neoplasms, Cystic, Mucinous, and Serous genetics, Receptor, ErbB-2 genetics
- Abstract
Uterine serous carcinoma is an aggressive subtype of endometrial cancer that accounts for fewer than 10% of endometrial carcinomas but is responsible for about half of deaths. A subset of cases has HER2 overexpression secondary to ERBB2 gene amplification, and these patients may benefit from anti-HER2 therapies, such as trastuzumab. HER2 protein overexpression is currently assessed by immunohistochemistry (IHC) and ERBB2 gene amplification by fluorescence in situ hybridization (FISH). Targeted next-generation sequencing (NGS) is increasingly used to routinely identify predictive and prognostic molecular abnormalities in endometrial carcinoma. To investigate the ability of a targeted NGS panel to detect ERBB2 amplification, we identified cases of uterine serous carcinoma (n = 93) and compared HER2 expression by IHC and copy number assessed by FISH with copy number status assessed by NGS. ERBB2 copy number status using a combination of IHC and FISH was interpreted using the 2018 ASCO/CAP guidelines for breast carcinoma. ERBB2 amplification by NGS was determined by the relative number of reads mapping to ERBB2 in tumor DNA compared to control nonneoplastic DNA. Cases with copy number ≥6 were considered amplified and copy number <6 were non-amplified. By IHC, 70 specimens were classified as negative (0 or 1+), 19 were classified as equivocal (2+), and 4 were classified as positive (3+). Using combined IHC/FISH, ERBB2 amplification was observed in 8 of 93 cases (9%). NGS identified the same 8 cases with copy number ≥6; all 85 others had copy number <6. In this series, NGS had 100% concordance with combined IHC/FISH in identifying ERBB2 amplification. NGS is highly accurate in detecting ERBB2 amplification in uterine serous carcinoma and provides an alternative to measurement by IHC and FISH.
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- 2021
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42. Mural nodules in mucinous ovarian tumors represent a morphologic spectrum of clonal neoplasms: a morphologic, immunohistochemical, and molecular analysis of 13 cases.
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Chapel DB, Lee EK, Da Silva AFL, Teschan N, Feltmate C, Matulonis UA, Crum CP, Sholl LM, Konstantinopoulos PA, and Nucci MR
- Subjects
- Adolescent, Adult, Aged, Biopsy, Female, Humans, Microtubule-Associated Proteins analysis, Microtubule-Associated Proteins genetics, Middle Aged, Predictive Value of Tests, Prognosis, Tumor Suppressor Protein p53 analysis, Tumor Suppressor Protein p53 genetics, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, High-Throughput Nucleotide Sequencing, Immunohistochemistry, Neoplasms, Cystic, Mucinous, and Serous chemistry, Neoplasms, Cystic, Mucinous, and Serous genetics, Neoplasms, Cystic, Mucinous, and Serous pathology, Neoplasms, Cystic, Mucinous, and Serous therapy, Ovarian Neoplasms chemistry, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Ovarian Neoplasms therapy
- Abstract
Mucinous ovarian tumors rarely harbor mural nodules, which have historically been classified as sarcoma-like, anaplastic carcinomatous, or sarcomatous on the basis of predominant morphologic features. The molecular relationship between mural nodules and associated mucinous ovarian tumors remains poorly characterized, as does the molecular pathogenesis of these mural nodules. Thus, we analyzed the morphological, immunohistochemical, and genetic features of 13 mucinous ovarian tumors and associated mural nodule(s). Three harbored sarcoma-like mural nodules and ten contained anaplastic carcinomatous nodules, including 1 tumor with spatially discrete anaplastic carcinomatous and sarcomatous nodules. Twelve of 13 cases showed genetic evidence of clonality between the mural nodule(s) and associated mucinous ovarian tumor, including all three tumors with sarcoma-like morphology. Mural nodules were genetically identical in the five cases in which there were multiple discrete mural nodules that were sequenced separately. MTAP and p53 immunohistochemistry confirmed the distribution of neoplastic cells in a subset of sarcoma-like and anaplastic carcinomatous nodules. No single recurrent genetic alteration was associated with mural nodule development. No recurrent genetic differences were identified between mural nodules with sarcoma-like, anaplastic carcinomatous, and sarcomatous morphology. Of 11 patients with clinical follow-up, three died of disease 3, 8, and 9 months after diagnosis, but no recurrent genetic events were associated with poor outcome. These molecular data suggest that sarcoma-like, anaplastic carcinomatous, and sarcomatous nodules represent a morphologic spectrum of clonal neoplasms arising in mucinous ovarian tumors rather than three discrete biological entities.
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- 2021
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43. Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer.
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Wan C, Keany MP, Dong H, Al-Alem LF, Pandya UM, Lazo S, Boehnke K, Lynch KN, Xu R, Zarrella DT, Gu S, Cejas P, Lim K, Long HW, Elias KM, Horowitz NS, Feltmate CM, Muto MG, Worley MJ Jr, Berkowitz RS, Matulonis UA, Nucci MR, Crum CP, Rueda BR, Brown M, Liu XS, and Hill SJ
- Subjects
- Animals, Apoptosis, Biomarkers, Tumor genetics, Biomarkers, Tumor immunology, CD8-Positive T-Lymphocytes immunology, Cell Proliferation, Cystadenocarcinoma, Serous immunology, Cystadenocarcinoma, Serous pathology, Female, Humans, Killer Cells, Natural immunology, Lymphocytes, Tumor-Infiltrating immunology, Mice, Neoplasm Grading, Ovarian Neoplasms immunology, Ovarian Neoplasms pathology, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, B7-H1 Antigen antagonists & inhibitors, Biomarkers, Tumor metabolism, Cystadenocarcinoma, Serous drug therapy, Gene Expression Regulation, Neoplastic, Immune Checkpoint Inhibitors therapeutic use, Ovarian Neoplasms drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo , validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. SIGNIFICANCE: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states., (©2020 American Association for Cancer Research.)
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- 2021
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44. Genomic Characterization of HPV-related and Gastric-type Endocervical Adenocarcinoma: Correlation With Subtype and Clinical Behavior.
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Hodgson A, Howitt BE, Park KJ, Lindeman N, Nucci MR, and Parra-Herran C
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- Adenocarcinoma pathology, Adult, DNA chemistry, DNA isolation & purification, DNA Mutational Analysis, DNA, Viral analysis, Female, Humans, Middle Aged, Papillomaviridae genetics, Sequence Analysis, DNA, Uterine Cervical Neoplasms pathology, Adenocarcinoma genetics, Adenocarcinoma virology, Papillomavirus Infections, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms virology
- Abstract
The majority of endocervical adenocarcinomas (EAs) are caused by human papillomavirus (HPV). Gastric-type EA, the second most common EA and unrelated to HPV, is biologically different with a more aggressive clinical course. Our knowledge of the molecular fingerprint of these important EA types and its role in diagnosis, prognosis and management is still evolving. Thus, we sought to evaluate the genomic profile of HPV-related and gastric EA. Clinical information including patient outcome was gathered for 56 tumors (45 HPV-associated and 11 gastric-type) surveying evaluated by a targeted massively parallel sequencing assay (OncoPanel platform) which surveys exonic DNA sequences of 447 cancer genes and 191 regions across 60 genes for rearrangement detection. KRAS, TP53, and PIK3CA were the most commonly mutated genes (10, 10, and 9 cases, respectively). Alterations in TP53, STK11, CDKN2A, ATM, and NTRK3 were significantly more common in gastric-type EA (P<0.05, Fisher exact test). Disease recurrence and/or death occurred in 14/49 (29%) cases with clinical information available 7 HPV-related (18% of HPV-related cases with clinical information available) and 7 gastric-type (64% of gastric-type cases with clinical information available). Tumors associated with adverse outcome, regardless of histotype, more commonly had alterations in KRAS (2 HPV-related, 4 gastric-type), GNAS (3 HPV-related, 1 gastric-type), and CDKN2A (0 HPV-related, 3 gastric type) compared with indolent-behaving cases (P<0.05, Fisher exact test). A total of 8/56 (14%) tumors harbored at least one actionable mutation; of these, 6 (75%) were associated with recurrence and/or cancer-related death. Copy number variations were detected in 45/56 cases (80%). The most frequent were chromosome 20 gain and 16q loss, identified in 7 cases each (all HPV-associated EA). The mutational profile of EA is diverse and correlates with clinical behavior and EA subtype. Thus, targeted sequencing assays can potentially serve as a diagnostic and prognostic tool. It can also identify targetable alterations, which may benefit patients with recurrent/metastatic disease.
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- 2020
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45. Undifferentiated endometrial carcinoma arising in the background of high-grade endometrial carcinoma - Expanding the definition of dedifferentiated endometrial carcinoma.
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Busca A, Parra-Herran C, Nofech-Mozes S, Djordjevic B, Ismiil N, Cesari M, Nucci MR, and Mirkovic J
- Subjects
- Aged, Aged, 80 and over, Biomarkers, Tumor analysis, Female, Humans, Middle Aged, Neoplasm Grading, Carcinoma, Endometrioid pathology, Endometrial Neoplasms pathology
- Abstract
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.)
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- 2020
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46. Molecular Characterization of Neuroendocrine Carcinomas of the Endometrium: Representation in All 4 TCGA Groups.
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Howitt BE, Dong F, Vivero M, Shah V, Lindeman N, Schoolmeester JK, Baltay M, MacConaill L, Sholl LM, Nucci MR, and McCluggage WG
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Neuroendocrine pathology, DNA Mutational Analysis, Endometrial Neoplasms pathology, Female, Humans, Middle Aged, Carcinoma, Neuroendocrine genetics, Endometrial Neoplasms genetics
- Abstract
High-grade neuroendocrine carcinomas (NEC) of the endometrium are rare and account for <1% of all endometrial carcinomas. Both small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) morphologies have been reported. Little is known regarding the molecular features of endometrial NEC including how they compare to pulmonary NEC (the most common site for these neoplasms) and the more common endometrial carcinoma histotypes. In this study, we investigated the molecular alterations in a series of endometrial NEC using a targeted next generation sequencing panel (Oncopanel). Fourteen NEC were sequenced; pure NEC (n=4) and mixed (n=10) with endometrioid adenocarcinoma (n=9) or carcinosarcoma (n=1). The NEC components of mixed tumors comprised LCNEC (n=6) and SCNEC (n=4). The 4 pure NEC comprised LCNEC (n=2) and SCNEC (n=2). Molecular analysis classified tumors into the 4 The Cancer Genome Atlas groups: (1) POLE-mutated/ultramutated (1/14; 7%), (2) microsatellite instability/hypermutated (6/14; 43%), (3) TP53 mutated/copy number high (2/14; 14%), or (4) no specific molecular profile (5/14; 36%). Overall, 50% of cases were ultramutated or hypermutated. In 8 cases of mixed carcinomas, the different histologic components were macrodissected and separately sequenced; molecular alterations were nearly identical among the 2 components, with the non-NEC component harboring slightly increased tumor mutational burden. Only 2 carcinomas (both with pure SCNEC morphology) had a molecular profile that would be expected in typical pulmonary SCNEC (RB1 deletion and TP53 mutations). Our findings, similar to data from NECs of other anatomic sites, suggest that the molecular context may be important when selecting therapies for women with endometrial NEC. Immune checkpoint inhibition may be a reasonable approach to treatment of microsatellite instability-NEC and we thus recommend that all endometrial NEC be tested for mismatch repair abnormalities, either molecularly or by mismatch repair protein immunohistochemistry.
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- 2020
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47. Synovial Sarcoma of the Female Genital Tract: A Protean Mimic of Müllerian Neoplasia.
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Kolin DL, Crum CP, Baranov E, Cin PD, Chang MC, Colgan TJ, Dickson BC, Hornick JL, and Nucci MR
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- Adult, Female, Humans, Middle Aged, Sarcoma, Synovial diagnosis, Vaginal Neoplasms diagnosis, Vulvar Neoplasms diagnosis, Young Adult, Diagnosis, Differential, Sarcoma, Synovial pathology, Vaginal Neoplasms pathology, Vulvar Neoplasms pathology
- Abstract
Synovial sarcoma most commonly occurs in the extremities but has rarely been described in the female genital tract. In this series, we describe the clinical, morphologic, immunohistochemical, and molecular features of 7 cases of vulvovaginal synovial sarcoma (vulva, n=6; vagina, n=1). We emphasize their wide morphologic spectrum, which can overlap significantly with other more common tumors at these sites, as highlighted by 2 cases initially diagnosed as other entities (endometrioid carcinoma and malignant peripheral nerve sheath tumor). The average patient age was 41 (range: 23 to 62) years and tumor size ranged from 0.8 to 7 cm. Histologically, the tumors were biphasic (n=6) and monophasic (n=1). All cases were confirmed with fluorescence in situ hybridization or sequencing, and 5/5 cases were positive for the novel immunohistochemical markers SSX and SS18-SSX. In 3 cases with follow-up, 2 patients died of disease and 1 was alive with no evidence of disease. Previously described cases arising in the female genital tract are also reviewed. Vulvovaginal monophasic synovial sarcoma raises a broad differential diagnosis, including smooth muscle tumors, spindled carcinomas, and melanoma. Biphasic synovial sarcoma may mimic Müllerian carcinosarcoma, endometrioid carcinoma with spindled, corded, and hyalinized elements, and mesonephric-like adenocarcinoma. Awareness that synovial sarcoma can occur in the female genital tract with a wide variety of histologic appearances is critical for correctly diagnosing this rare entity. In particular, synovial sarcoma should be considered for any deeply situated "adenocarcinoma" in the vulva, with attention to subtle spindle cell differentiation.
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- 2020
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48. PNL2: A Useful Adjunct Biomarker to HMB45 in the Diagnosis of Uterine Perivascular Epithelioid Cell Tumor (PEComa).
- Author
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Valencia-Guerrero A, Pinto A, Anderson WJ, Trevisan G, Nucci MR, and Hirsch MS
- Subjects
- Antibodies, Monoclonal analysis, Antigens, Neoplasm, Female, Humans, Immunohistochemistry, MART-1 Antigen analysis, Perivascular Epithelioid Cell Neoplasms chemistry, Perivascular Epithelioid Cell Neoplasms pathology, Receptors, Somatostatin immunology, Smooth Muscle Tumor chemistry, Smooth Muscle Tumor pathology, Uterine Neoplasms chemistry, Uterine Neoplasms pathology, gp100 Melanoma Antigen, Antibodies, Monoclonal, Humanized analysis, Biomarkers, Tumor analysis, Melanoma-Specific Antigens analysis, Perivascular Epithelioid Cell Neoplasms diagnosis, Smooth Muscle Tumor diagnosis, Uterine Neoplasms diagnosis
- Abstract
Perivascular epithelioid cell tumors (PEComa) are rare neoplasms characterized by co-expression of melanocytic and muscle markers. HMB45 and Melan-A are used to confirm a PEComa diagnosis; however, both are often focally expressed and sensitivity for Melan-A is low. PNL2 is a reliable biomarker for epithelioid melanoma and renal angiomyolipoma/PEComa. The objective of this study was to determine PNL2 utility in diagnosing uterine PEComas as well as distinguishing PEComas from uterine smooth muscle tumors (SMTs). Twenty-one uterine PEComas and 45 SMTs were analyzed for PNL2; a subset was also stained for HMB45, Melan-A, Cathepsin-K, Desmin, and h-Caldesmon. Cases were scored as negative (0), focal (<10% of tumor cells), or patchy to diffusely positive (>10% of tumor cells). PEComas were positive for PNL2, HMB45, and Melan-A in 86%, 100%, and 57% of cases, respectively. In PEComas, PNL2 was patchy to diffusely positive more frequently (10/18, 56%) than Melan-A (4/12, 33%). In contrast, 2 of 45 (4%) SMTs were focally PNL2 positive; HMB45 was focally positive in 4 SMTs (11%) and all were negative for Melan-A. Desmin and h-Caldesmon were positive in 90% and 57% of PEComas, and 91% and 82% of SMTs. Cathepsin-K was positive in 100% of PEComas and 93% of SMTs. PNL2 is a useful biomarker for the diagnosis of uterine PEComa, with comparable sensitivity and specificity to HMB45. In contrast, PNL2 stains more PEComas when compared with Melan-A. Cathepsin-K, Desmin, and h-Caldesmon are of little utility for distinguishing PEComas and SMTs; however, lack of Cathepsin-K argues against PEComa. These results suggest that PNL2 should be used in conjunction with HMB45 in the diagnosis of PEComa of the uterine corpus.
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- 2020
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49. Malignant tumours of the uterus and ovaries with Mullerian and germ cell or trophoblastic components have a somatic origin and are characterised by genomic instability .
- Author
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Acosta AM, Sholl LM, Cin PD, Howitt BE, Otis CN, and Nucci MR
- Subjects
- Adenosarcoma genetics, Adenosarcoma pathology, Adult, Aged, Carcinoma, Endometrioid genetics, Carcinoma, Endometrioid pathology, Cystadenocarcinoma, Serous genetics, Cystadenocarcinoma, Serous pathology, Endodermal Sinus Tumor genetics, Endodermal Sinus Tumor pathology, Female, Genomic Instability, Humans, Middle Aged, Neoplasms, Complex and Mixed pathology, Ovarian Neoplasms pathology, Trophoblastic Neoplasms genetics, Trophoblastic Neoplasms pathology, Uterine Neoplasms pathology, Neoplasms, Complex and Mixed genetics, Ovarian Neoplasms genetics, Uterine Neoplasms genetics
- Abstract
Aims: Tumours of the female genital tract with a combination of malignant Mullerian and germ cell or trophoblastic tumour (MMGC/T) components are usually diagnosed in postmenopausal women, and pursue an aggressive clinical course characterised by poor response to therapy and early relapses. These clinical features suggest that MMGC/T are somatic in origin, but objective molecular data to support this interpretation are lacking. This study evaluates the molecular features of nine MMGC/T, including seven tumours containing yolk sac tumour (YST), one tumour containing choriocarcinoma and one tumour containing epithelioid trophoblastic tumour. The objectives were to: (i) investigate whether MMGC/T show a distinct genetic profile and (ii) explore the relationship between the different histological components., Methods and Results: Next-generation sequencing of paired samples demonstrated that the mutational profile of the Mullerian and non-Mullerian components of the tumour were almost identical in all cases. Moreover, the driver mutations identified were those expected in the specific subtype of Mullerian component present in each case. In contrast, variants expected in postpubertal germ cell tumours and gestational trophoblastic tumours were not identified, and FISH for i(12p) was negative in all cases tested. In this study, mismatch repair-proficient MMGC/T (eight of nine) were characterised by a complex copy-number variant profile, including numerous focal, regional, arm-level and chromosome-level events., Conclusions: Comparison of paired samples supports that the YST and trophoblastic tumour components of MMGC/T have a somatic origin and often show numerous copy-number variants, suggestive of underlying genomic instability., (© 2020 John Wiley & Sons Ltd.)
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- 2020
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50. Retrospective detection of isolated tumor cells by immunohistochemistry in sentinel lymph node biopsy performed for endometrial carcinoma: is there clinical significance?
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Goebel EA, St Laurent JD, Nucci MR, and Feltmate CM
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- Adult, Aged, Aged, 80 and over, Female, Humans, Immunohistochemistry methods, Middle Aged, Retrospective Studies, Sentinel Lymph Node Biopsy methods, Endometrial Neoplasms pathology, Sentinel Lymph Node pathology
- Abstract
Introduction: Several studies have reported optimizing ultrastaging protocols using immunohistochemistry for sentinel lymph node (SLN) biopsy in endometrial carcinoma; however, the clinical significance of isolated tumor cells (ITCs) detected by ultrastaging is unknown. This study aimed to: (1) determine the frequency of retrospective ITC detection in patients with endometrial carcinoma and reported negative SLNs determined by hematoxylin and eosin (H&E) examination only; and (2) determine the clinicopathological features and outcomes of patients with endometrial carcinoma and previously undetected ITCs., Methods: 474 SLNs from 155 patients with endometrial carcinoma and reported negative SLNs were subjected to an immunohistochemistry protocol which included staining slides with cytokeratin at 1, 10, 20, and 50 µm levels, to examine for ITCs. Clinicopathological data of patients with ITCs detected by this method were analyzed to determine patient outcomes., Results: Using immunohistochemistry, ITCs were detected in 5.7% (27/474) of SLNs and 13.5% (21/155) of patients with previously reported negative SLNs. In this patient cohort, 95.2% (20/21) had endometrioid histology, with the remaining case being carcinosarcoma. 38.1% (8/21) received adjuvant therapy (either brachytherapy alone (4/8) or chemotherapy and radiation (4/8)) based on other parameters, while 61.9% (13/21) had no adjuvant therapy. Of the patients who did not receive adjuvant therapy, all had endometrioid histology and 84.6% (11/13) were International Federation of Gynecology and Obstetrics (FIGO) stage IA. No patients (0/13) recurred after a median follow-up of 31.5 (range 2-84.4) months., Discussion: In this study, 38.1% of patients with previously undetected ITCs had adjuvant treatment based on other high risk factors; as such, reporting ITCs would not have altered patient management for those who received adjuvant chemotherapy. To date, no patients with previously undetected ITCs without adjuvant treatment had a recurrence, suggesting that ITC detection may not be clinically relevant., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2020
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