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Dedifferentiated and undifferentiated ovarian carcinomas (DDOC/UDOC) are rare neoplasms defined by the presence of an undifferentiated carcinoma. In this study, we detailed the clinical, pathological, immunohistochemical, and molecular features of a series of DDOC/UDOC. We collected a multi-institutional cohort of 23 DDOC/UDOC and performed immunohistochemistry for core switch/sucrose nonfermentable (SWI/SNF) complex proteins (ARID1A, ARID1B, SMARCA4, and SMARCB1), mismatch repair (MMR) proteins, and p53. Array-based genome-wide DNA methylation and copy number variation analyses were performed on a subset of cases with comparison made to a previously reported cohort of undifferentiated endometrial carcinoma (UDEC), small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), and tubo-ovarian high-grade serous carcinoma (HGSC). The age of all 23 patients with DDOC/UDOC ranged between 22 and 71 years (with an average age of 50 years), and a majority of them presented with extraovarian disease (16/23). Clinical follow-up was available for 19 patients. Except for 2 patients, the remaining 17 patients died from disease, with rapid disease progression resulting in mortality within a year in stage II-IV settings (median disease-specific survival of 3 months). Eighteen of 22 cases with interpretable immunohistochemistry results showed loss of expression of core SWI/SNF protein(s) that are expected to result in SWI/SNF complex inactivation as 10 exhibited coloss of ARID1A and ARID1B, 7 loss of SMARCA4, and 1 loss of SMARCB1. Six of 23 cases were MMR-deficient. Two of 20 cases exhibited mutation-type p53 immunoreactivity. Methylation profiles showed coclustering of DDOC/UDOC with UDEC, which collectively were distinct from SCCOHT and HGSC. However, DDOC/UDOC showed an intermediate degree of copy number variation, which was slightly greater, compared with SCCOHT but much less compared with HGSC. Overall, DDOC/UDOC, like its endometrial counterpart, is highly aggressive and is characterized by frequent inactivation of core SWI/SNF complex proteins and MMR deficiency. Its molecular profile overlaps with UDEC while being distinct from SCCOHT and HGSC.
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Neoplasias Encefálicas , Carcinoma de Células Pequenas , Carcinoma , Neoplasias Colorretais , Neoplasias do Endométrio , Síndromes Neoplásicas Hereditárias , Neoplasias Ovarianas , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Adulto , Idoso , Proteína Supressora de Tumor p53/genética , Variações do Número de Cópias de DNA , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Carcinoma/patologia , Carcinoma Epitelial do Ovário , Neoplasias do Endométrio/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
In the last two decades or so, a spectrum of benign, premalignant and malignant cervical glandular lesions exhibiting gastric differentiation has been described, with gastric-type adenocarcinoma representing the most common human papillomavirus (HPV)-independent cervical adenocarcinoma. More recently, limited literature has reported a variety of gastric-type glandular lesions at other sites within the female genital tract and, as in the cervix (the most common site for these lesions), a spectrum of benign, premalignant and malignant lesions has been proposed. We provide an update and review of the emerging spectrum of gastric-type glandular lesions at female genital tract sites other than the cervix. In the endometrium, putative gastric-type glandular lesions include mucinous metaplasia of gastric-type, atypical mucinous proliferation of gastric-type and gastric-type adenocarcinoma. Similarly in the vagina, gastric-type adenosis, atypical adenosis and adenocarcinoma have been described. There have also been occasional reports of gastric-type lesions involving the ovary and fallopian tube. We provide guidance on how to recognise gastric-type lesions morphologically and immunophenotypically and stress that sometimes these lesions occur at more than one site within the female genital tract (synchronous/multifocal gastric-type lesions of the female genital tract), sometimes in association with Peutz-Jeghers syndrome.
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Adenocarcinoma , Humanos , Feminino , Adenocarcinoma/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias dos Genitais Femininos/patologia , Neoplasias do Colo do Útero/patologia , Metaplasia/patologiaRESUMO
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.
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AIMS: Ovarian Wilms tumour (WT)/nephroblastoma is an extremely rare neoplasm that has been reported to occur in pure form or as a component of a teratomatous neoplasm. We hypothesized that teratoma-associated and pure ovarian WT may represent different tumour types with diverging molecular backgrounds. To test this hypothesis, we comprehensively characterized a series of five tumours originally diagnosed as ovarian WT. METHODS AND RESULTS: The five cases comprised three teratoma-associated (two mature and one immature) and two pure WTs. Two of the teratoma-associated WTs consisted of small nodular arrangements of "glandular"/epithelial structures, while the third consisted of both an epithelial and a diffuse spindle cell/blastemal component. The pure WTs consisted of "glandular" structures, which were positive for sex cord markers (including inhibin and SF1) together with a rhabdomyosarcomatous component. The two pure WTs harboured DICER1 pathogenic variants (PVs), while the three associated with teratomas were DICER1 wildtype. Panel-based DNA sequencing of four of the cases did not identify PVs in the other genes investigated. Analysis of the HA19/IGF2 imprinting region showed retention of imprinting in the pure WTs but loss of heterozygosity with hypomethylation of the ICR1 region in two of three teratoma-associated WTs. Furthermore, copy number variation and clustering-based whole-genome DNA methylation analyses identified divergent molecular profiles for pure and teratoma-associated WTs. CONCLUSION: Based on the morphological features, immunophenotype, and molecular findings (DICER1 PVs, copy number, and DNA methylation profiles), we suggest that the two cases diagnosed as pure primary ovarian WT represent moderately to poorly differentiated Sertoli Leydig cell tumours (SLCTs), while the tumours arising in teratomas represent true WTs. It is possible that at least some prior cases reported as pure primary ovarian WT represent SLCTs.
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Neoplasias Renais , Neoplasias Ovarianas , Tumores do Estroma Gonadal e dos Cordões Sexuais , Teratoma , Tumor de Wilms , Masculino , Feminino , Humanos , Variações do Número de Cópias de DNA , Tumor de Wilms/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Teratoma/genética , Teratoma/patologia , Neoplasias Renais/genética , Ribonuclease III/genética , RNA Helicases DEAD-box/genéticaRESUMO
AIMS: NTRK-rearranged sarcomas of the female genital tract mainly occur in the uterus (more commonly cervix than corpus) and are characterized by a "fibrosarcoma-like" morphology and NTRK gene rearrangements. These neoplasms may exhibit histological overlap with other entities and can present diagnostic difficulties without molecular confirmation. Pan-TRK immunohistochemistry was developed to identify tumours harbouring NTRK rearrangements. The aim of this study was to characterize pan-TRK immunohistochemical expression in a large cohort of gynaecological mesenchymal neoplasms and investigate the utility of pan-TRK immunohistochemistry to distinguish NTRK-rearranged sarcoma from its mimics. METHODS AND RESULTS: A total of 473 gynaecological mesenchymal tumours (461 without known NTRK fusions and 12 NTRK-rearranged sarcomas) were selected. Pan-TRK immunohistochemistry (EPR17341, Abcam) was performed on whole tissue sections and tissue microarrays. Molecular interrogation of pan-TRK positive tumours was performed by RNA sequencing or fluorescence in situ hybridization (FISH). Of the 12 NTRK-rearranged sarcomas, 11 (92%) exhibited diffuse (≥70%) cytoplasmic pan-TRK staining with moderate/marked intensity, while the other was negative. Eleven (2.4%) additional tumours also exhibited pan-TRK immunohistochemical expression: three low-grade endometrial stromal sarcomas, seven high-grade endometrial stromal sarcomas, and an undifferentiated uterine sarcoma. Molecular confirmation of the absence of NTRK rearrangements was possible in nine of these tumours. Of these nine neoplasms, seven exhibited focal/multifocal (<70%) pan-TRK cytoplasmic staining with weak/moderate intensity. CONCLUSION: Even though pan-TRK immunohistochemical expression is not entirely sensitive or specific for NTRK-rearranged sarcomas, these neoplasms tend to exhibit diffuse staining of moderate/strong intensity, unlike its mimics. Pan-TRK should be performed in monomorphic uterine (corpus and cervix) spindle cell neoplasms that are negative for smooth muscle markers and hormone receptors and positive for CD34 and/ or S100. Ultimately, the diagnosis requires molecular confirmation.
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Neoplasias do Endométrio , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Sarcoma do Estroma Endometrial , Sarcoma , Neoplasias de Tecidos Moles , Feminino , Humanos , Biomarcadores Tumorais/genética , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Proteínas de Fusão Oncogênica/genética , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/patologia , Receptor trkARESUMO
Leiomyomas are common hormone-responsive uterine neoplasms which can exhibit a variety of morphologic changes secondary to hormonal agents such as progestogens. They may increase in size during pregnancy as a result of hormonal stimulation but surprisingly the morphologic features of leiomyomas in pregnancy are not well described in the literature. In this report, we describe the morphologic features of a series of 29 uterine leiomyomas in pregnancy. The features include in decreasing order of frequency infarct-type necrosis, decidualization of the serosal surface, hyalinization, myxoid alteration of the stroma, edema (sometimes with cyst formation), and dystrophic calcification. We also report a feature which we term "deciduoid" change (seen in 10 of 29 leiomyomas) which takes the form of altered smooth muscle cells with an epithelioid morphology with abundant eosinophilic or clear cytoplasm. Furthermore, we show that the "deciduoid" cells commonly exhibit expression of sex cord markers inhibin and calretinin. We speculate on the pathogenesis of the "deciduoid" change which together with its "aberrant" immunophenotype may result in diagnostic problems and consideration of other neoplasms.
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Leiomioma , Neoplasias Uterinas , Feminino , Gravidez , Humanos , Calbindina 2 , Leiomioma/diagnóstico , Leiomioma/patologia , Neoplasias Uterinas/patologia , Necrose , ImunofenotipagemRESUMO
Benign and malignant neoplasms of the vagina are rare. We report 3 primary vaginal polypoid lesions involving the upper or mid-vagina in patients aged 40, 60, and 67 years. The lesions bore a striking morphologic resemblance to benign endocervical or endometrial polyps and we suggest the designation Mullerian polyp of the vagina. As far as we are aware, similar cases have not been reported previously in the literature. Follow-up ranging from 6 to 21 months has been uneventful. In reporting these cases, we discuss the possible origin and differential diagnosis and review vaginal lesions with a benign glandular component.
Assuntos
Pólipos , Neoplasias Vaginais , Feminino , Humanos , Diagnóstico Diferencial , Vagina/patologia , Neoplasias Vaginais/diagnóstico , Neoplasias Vaginais/patologia , Colo do Útero/patologia , Pólipos/diagnóstico , Pólipos/patologiaRESUMO
Endometrial and endocervical polyps not uncommonly exhibit focal benign "hobnail" change/metaplasia within the glandular epithelium, sometimes in association with inflammation or infarction. In most cases, this is readily recognized as benign but occasionally, especially in endometrial polyps, this change prompts consideration of a premalignant or malignant lesion, including early serous or clear cell carcinoma. Herein we highlight the previously unreported phenomenon of positive staining of this hobnail epithelium with Napsin A which has the potential to exacerbate concern for clear cell carcinoma. Endometrial (n = 22) and endocervical (n = 17) polyps showing hobnail change were stained with Napsin A. Six cases were positive (4 of 22 endometrial and 2 of 17 endocervical polyps). In all cases, Napsin A positivity was confined to the hobnail epithelium. The hobnail epithelium was positive with estrogen receptor and hepatocyte nuclear factor 1- beta and exhibited wild-type immunoreactivity with p53 in all cases where these markers were performed. In addition, in 2 of 3 uterine adenosarcomas with focal hobnail change the epithelium was Napsin A positive. Pathologists should be aware that Napsin A may be expressed in benign/reactive hobnail epithelium in endometrial and endocervical polyps and should not consider positivity with this marker as a diagnostic of clear cell carcinoma.
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Cervical adenocarcinomas are now classified as human papillomavirus (HPV)-associated and HPV-independent types with the former being more common. However, population-based studies regarding the relative incidences of the 2 types are few. This study investigates the incidence of cervical adenocarcinomas in Northern Ireland (a country with a relatively stable population of ~1.8 million) over a recent 9-year period (2015-2023). Overall, there were 146 primary cervical adenocarcinomas, 130 HPV-associated (89%) and 16 HPV-independent (11%). The median age was 43 years (range: 24-82) for HPV-associated and 62.5 years (range: 31-84) for HPV-independent neoplasms; this was statistically significant (P < 0.001). The calculated age-adjusted incidence of the patients with HPV-associated and HPV-independent neoplasms was 1.68 and 0.20 per 100,000 person-years, respectively. The HPV-independent neoplasms were more often advanced stage at diagnosis; 97 of 130 (75.4%) of the HPV-associated cases were diagnosed at Stage I compared with 5 of 16 (31.3%) of the HPV-independent cases. The HPV-independent neoplasms were mostly gastric-type (56.3%) with smaller numbers of clear cells and mesonephric. Despite the relatively short follow-up, the mortality of patients with HPV-independent adenocarcinomas was significantly higher than patients with HPV-associated neoplasms (56.3% vs 5.4%) with a median survival of just over a year (13.2 mo) in the former for those who died.
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Human papillomavirus (HPV)-associated multiphenotypic sinonasal carcinoma is a rare and recently described epithelial neoplasm exhibiting myoepithelial differentiation and morphological overlap with salivary gland neoplasms, especially adenoid cystic carcinoma; it is commonly associated with HPV, especially type 33. It has mainly been reported in the nasal cavity and paranasal sinuses with a single case reported in the breast. Herein, we report the first vulval example in a 47-year-old patient who presented with a large craggy mass in the region of the Bartholin gland. The histologic features were of a high-grade carcinoma composed of basaloid cells arranged in sheets and nests, with occasional ductal formations, surrounded by densely hyalinised basement membrane-type material. There was diffuse block-type immunoreactivity with p16 and HPV genotyping revealed high-risk HPV type 16. In reporting this case, we highlight the propensity for "salivary gland-type" neoplasms to arise in the vulva, especially in the Bartholin gland, and stress that pathologists should consider salivary-type neoplasms when faced with a morphologically unusual vulval tumor.
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Pathogenic variants (mutations) and other molecular events involving subunits of the SWItch/Sucrose Non-Fermentable chromatin remodelling complex are common in a wide variety of malignancies. Many of these neoplasms are characterized by undifferentiated morphology. They arise at a variety of sites in the female genital tract but have rarely been reported in the uterine cervix. We report 2 primary cervical neoplasms arising in young women (ages 28 and 29 yr) exhibiting loss of nuclear immunoreactivity with SMARCB1 (INI1). In one case, which had a mixture of epithelioid and spindle cells, molecular studies revealed no SMARCB1 pathogenic variant, but showed a SPECCL1::NTRK 3 fusion, in keeping with an NTRK fusion sarcoma. The second case exhibited rhabdoid morphology and molecular testing confirmed a SMARCB1 pathogenic variant (c.425 T>G:p.(Leu142Ter) which, interpreted in conjunction with the morphology and immunohistochemistry, resulted in classification as a proximal-type epithelioid sarcoma. To our knowledge, this is the first reported cervical neoplasm exhibiting a SMARCB1 pathogenic variant and the first NTRK fusion sarcoma showing SMARCB1 protein loss. We discuss the diagnostic challenges and complexities of the molecular findings.
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Expression of neuroendocrine (NE) markers in primary ovarian non-NE epithelial tumors has rarely been evaluated. The aim of our study was to evaluate the expression of the most widely used NE markers in these neoplasms and to determine any prognostic significance of NE marker expression. The cohort consisted of 551 primary ovarian tumors, including serous borderline tumors, low-grade serous carcinomas, high-grade serous carcinomas (HGSC), clear cell carcinomas, endometroid carcinomas, mucinous borderline tumors, and mucinous carcinomas. Immunohistochemical analysis was performed using antibodies against INSM1, synaptophysin, chromogranin, and CD56 on tissue microarray. Positivity for INSM1, synaptophysin, chromogranin, and CD56 was most frequently observed in mucinous tumors (48.7%, 26.0%, 41.5%, and 100%, respectively). The positivity for these NE markers was mostly restricted to nonmucinous elements distributed throughout the tumor. The mucinous borderline tumor and mucinous carcinomas groups had similar proportions of positivity (mucinous borderline tumor: 53%, mucinous carcinomas: 39%). In the other tumor types, except for HGSC, there was only focal expression (5%-10%) or negativity for NE markers. HGSC showed high CD56 expression (in 26% of cases). Survival analysis was only performed for CD56 in HGSC as this was the only group with sufficient positive cases, and it showed no prognostic significance. Except for mucinous tumors, expression of NE markers in non-NE ovarian epithelial tumors is low. CD56 expression in HGSC occurs frequently but is without diagnostic or prognostic value.
Assuntos
Adenocarcinoma Mucinoso , Tumores Neuroendócrinos , Neoplasias Ovarianas , Feminino , Humanos , Sinaptofisina/metabolismo , Biomarcadores Tumorais/metabolismo , Cromograninas , Tumores Neuroendócrinos/patologia , Neoplasias Ovarianas/patologia , Adenocarcinoma Mucinoso/diagnóstico , Proteínas Repressoras/metabolismoRESUMO
Adult granulosa cell tumors (AGCTs) are a molecularly distinct group of malignant ovarian sex cord-stromal tumors (SCSTs) characterized by a nearly ubiquitous c.402C>G/p.C134W mutation in FOXL2 (hereafter referred to as "C134W"). In some cases, AGCT exhibits marked morphologic overlap with other SCSTs and has an identical immunophenotype, and molecular testing may be necessary to help confirm the diagnosis. However, molecular testing is time consuming, relatively expensive, and unavailable in many pathology laboratories. We describe the development and validation of an in situ hybridization (ISH) custom BaseScope assay for the detection of the FOXL2 C134W mutation. We evaluated 106 ovarian SCSTs, including 78 AGCTs, 9 juvenile granulosa cell tumors, 18 fibromas (cellular and conventional), and 1 SCST, not otherwise specified, as well as 53 epithelial ovarian tumors (42 endometrioid carcinomas and 11 carcinosarcomas) and 1 STK11 adnexal tumor for the presence or absence of FOXL2 wild-type and FOXL2 C134W RNA expression via BaseScope-ISH. Fifty-one tumors had previously undergone DNA sequencing of the FOXL2 gene. Across the entire cohort, the FOXL2 C134W probe staining was positive in 77 of 78 (98.7%) AGCTs. Two of 81 (2.5%) non-AGCTs also showed positive staining, both of which were epithelial ovarian tumors. The assay worked in tissue from blocks >20 years old. There was 100% concordance between the FOXL2 sequencing and BaseScope-ISH results. Overall, assessment of FOXL2 mutation status by custom BaseScope-ISH demonstrated 98.7% sensitivity and 97.5% specificity for the diagnosis of AGCT. BaseScope-ISH for FOXL2 C134W represents a reasonable alternative to sequencing, is quicker and less expensive, and is more easily incorporated than molecular testing into many pathology laboratories. It also has the advantage of requiring less tissue, and the neoplastic cells can be directly visualized on stained sections.
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Tumor de Células da Granulosa , Neoplasias Ovarianas , Feminino , Adulto , Humanos , Adulto Jovem , Tumor de Células da Granulosa/diagnóstico , Tumor de Células da Granulosa/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Proteína Forkhead Box L2/genética , Mutação , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Hibridização In SituRESUMO
Primary ovarian mucinous tumors represent a heterogeneous group of neoplasms, and their diagnosis may be challenging. We analyzed 124 primary ovarian mucinous tumors originally diagnosed as mucinous borderline tumors (MBTs) or mucinous carcinomas (MCs), with an emphasis on interobserver diagnostic agreement and the potential for diagnostic support by molecular profiling using a next-generation sequencing targeted panel of 727 DNA and 147 RNA genes. Fourteen experienced pathologists independently assigned a diagnosis from preset options, based on a review of a single digitized slide from each tumor. After excluding 1 outlier participant, there was a moderate agreement in diagnosing the 124 cases when divided into 3 categories (κ = 0.524, for mucinous cystadenoma vs MBT vs MC). A perfect agreement for the distinction between mucinous cystadenoma/MBT as a combined category and MC was found in only 36.3% of the cases. Differentiating between MBTs and MCs with expansile invasion was particularly problematic. After a reclassification of the tumors into near-consensus diagnostic categories on the basis of the initial participant results, a comparison of molecular findings between the MBT and MC groups did not show major and unequivocal differences between MBTs and MCs or between MCs with expansile vs infiltrative pattern of invasion. In contrast, HER2 overexpression or amplification was found only in 5.3% of MBTs and in 35.3% of all MCs and in 45% of MCs with expansile invasion. Overall, HER2 alterations, including mutations, were found in 42.2% of MCs. KRAS mutations were found in 65.5% and PIK3CA mutations in 6% of MCs. In summary, although the diagnostic criteria are well-described, diagnostic agreement among our large group of experienced gynecologic pathologists was only moderate. Diagnostic categories showed a molecular overlap. Nonetheless, molecular profiling may prove to be therapeutically beneficial in advanced-stage, recurrent, or metastatic MCs.
Assuntos
Adenocarcinoma Mucinoso , Cistadenoma Mucinoso , Neoplasias Císticas, Mucinosas e Serosas , Neoplasias Ovarianas , Humanos , Feminino , Cistadenoma Mucinoso/patologia , Reprodutibilidade dos Testes , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologiaRESUMO
High-grade endometrial stromal sarcomas (HGESSs) are aggressive uterine tumors harboring oncogenic fusion proteins. We performed a molecular study of 36 HGESSs with YWHAE::NUTM2 gene fusion, assessing co-occurring genetic events, and showed that these tumors frequently harbor recurrent events involving the CDKN2A locus on chromosome 9p. Using array-based copy number profiling and CDKN2A fluorescence in situ hybridization, we identified homozygous and hemizygous deletions of CDKN2A in 18% and 14% of tumors (n = 22 analyzed), respectively. While all YWHAE-rearranged HGESSs with retained disomy for CDKN2A were immunohistochemically positive for p16INK4 (p16), all tumors with homozygous deletion of CDKN2A showed complete absence of p16 staining. Of the 2 tumors with a hemizygous deletion of CDKN2A, 1 showed diffuse and strong p16 positivity, whereas the other showed complete absence of staining. In the p16-negative case, we did not find intragenic mutations or DNA promoter methylation to explain the p16 protein loss, implicating other mechanisms in the regulation of protein expression. In our cohort, subclonal or complete absence of p16 staining was associated with worse overall survival compared with positive p16 staining (1-year overall survival: 28.6% vs 90.7%, respectively; n = 32; P < .001), with all 7 patients in the p16-negative group having succumbed to their disease within 2 years of diagnosis. Our results suggested CDKN2A alterations as a cooperative driver of tumorigenesis in a subset of HGESSs with the YWHAE::NUTM2 gene fusion and showed p16 to be a potential prognostic marker.
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Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Sarcoma , Feminino , Humanos , Neoplasias do Endométrio/patologia , Prognóstico , Hibridização in Situ Fluorescente , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/patologia , Homozigoto , Deleção de Sequência , Sarcoma/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Fusão Gênica , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismoRESUMO
AIMS: To report novel observations in five mesonephric-like adenocarcinomas (MLAs) of the female genital tract. METHODS AND RESULTS: We report two endometrial MLAs in association with endometrioid carcinoma and atypical hyperplasia and three (one endometrial, two ovarian) cases with a sarcomatoid component (mesonephric-like carcinosarcoma). Pathogenic KRAS mutations, which are characteristic of MLA, were identified in all cases although interestingly, in one of the mixed carcinomas, this was confined to the endometrioid component. The concurrent MLA, endometrioid carcinoma and atypical hyperplasia components in one case harboured identical EGFR, PTEN and CCNE1 mutations, suggesting that the atypical hyperplasia gave rise to a Müllerian carcinoma with both endometrioid and mesonephric-like components. The carcinosarcomas all contained a component of MLA and a sarcomatous component with chondroid elements. In the ovarian carcinosarcomas, the coexisting epithelial and sarcomatous components shared some mutations including KRAS and CREBBP, suggesting that they are clonally related. Furthermore, in one case CREBBP and KRAS mutations detected in the MLA and sarcomatous components were also detected in an associated undifferentiated carcinoma component, suggesting that it was clonally related to the MLA and sarcomatous components. CONCLUSIONS: Our observations provide additional evidence that MLAs have a Müllerian origin and characterise mesonephric-like carcinosarcomas in which chondroid elements appear to be characteristic. In reporting these findings, we provide recommendations for distinction between a mesonephric-like carcinosarcoma and a MLA with a spindle cell component.
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Adenocarcinoma , Carcinoma Endometrioide , Carcinossarcoma , Feminino , Humanos , Carcinoma Endometrioide/patologia , Hiperplasia/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinossarcoma/genética , Carcinossarcoma/patologia , Endométrio/patologiaRESUMO
Microscopic sex cord proliferations are a rare incidental finding seen in association with ovarian and uterine stromal or epithelial neoplasms and more uncommonly non-neoplastic conditions such as endometriosis and adenomyosis. They may also occur in the absence of other pathology, as an incidental finding in the ovaries of pregnant women and in heterotopic locations such as the fallopian tube. Most reports of this phenomenon describe adult granulosa cell tumor-like morphology. Herein, we describe 4 cases of microscopic sex cord proliferations with Sertoliform features, occurring in the stromal component of endometriosis or in the wall of an epithelial ovarian neoplasm; 2 of the patients with endometriosis had concurrent endometrioid adenocarcinoma (1 uterine corpus, 1 ovary). The proliferations were positive with sex cord markers inhibin and calretinin. As far as we are aware, such Sertoliform proliferations have not been reported previously in endometriosis and have only rarely been described in association with ovarian epithelial neoplasia. It is likely that such proliferations represent a benign non-neoplastic phenomenon. Awareness of this phenomenon is important in order to avoid misdiagnosis as a sex cord or other neoplasm. In reporting this unusual phenomenon, we review incidental sex cord and sex cord-like proliferations in the female genital tract.
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Carcinoma Endometrioide , Endometriose , Tumor de Células da Granulosa , Neoplasias Ovarianas , Tumores do Estroma Gonadal e dos Cordões Sexuais , Gravidez , Adulto , Feminino , Humanos , Tumor de Células da Granulosa/patologia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Endometriose/complicações , Endometriose/diagnóstico , Endometriose/patologia , Carcinoma Endometrioide/complicações , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/patologia , Tubas Uterinas/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/complicações , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologiaRESUMO
Special AT-rich sequence-binding protein 2 (SATB2) is a nuclear transcription factor that shows consistent nuclear staining in colorectal adenocarcinoma and osteosarcoma. Following the observation of cytoplasmic staining with this marker in luteinized ovarian stromal cells, we studied the expression of SATB2 in ovarian stromal cells, various types of follicular cysts, and sex cord-stromal tumors. Eighty-five cases were stained for SATB2. Ovarian hilar Leydig cells (n = 12), luteinized stromal cells (n = 10), corpora lutea (n = 4), luteinized follicular cysts (n = 4), and stromal hyperthecosis (n = 6) exhibited consistent, usually diffuse, granular cytoplasmic staining. In addition, Leydig cell tumors (n = 1) and steroid cell tumors (n = 4) showed diffuse cytoplasmic staining. SATB2 also exhibited cytoplasmic staining in most Sertoli-Leydig cell tumors (n = 16) and gynandroblastomas (n = 3) confined to the Leydig cell component. Adult granulosa cell tumors (n = 14), juvenile granulosa cell tumors (n = 3), sex cord tumors with annular tubules (n = 3), cellular fibromas (n = 3), sclerosing stromal tumors (n = 1), and thecomas (n = 1) were negative apart from cytoplasmic staining in associated luteinized stromal cells. SATB2 cytoplasmic staining has not been previously described in these lesions but is characteristic of a variety of ovarian stromal cells and sex cord-stromal tumors, in particular, those exhibiting luteinization or a Leydig or steroid cell component. SATB2 staining may be of value in identifying luteinized or Leydig cells when these are morphologically inconspicuous.
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Microscopic sex cord proliferations are an uncommon finding, most often associated with ovarian or uterine stromal, epithelial, or mixed epithelial and stromal neoplasms. Rarely they occur in conjunction with a non-neoplastic process such as endometriosis or adenomyosis, and occasionally in the absence of concurrent pathology in locations such as the fallopian tube. Most reports of this phenomenon document adult granulosa cell tumor-like morphology but more uncommonly the proliferations exhibit Sertoliform features. We report a case of a multifocal sex cord proliferation (inhibin and calretinin positive; BerEP4 and epithelial membrane antigen negative) with Sertoliform features occurring in the pelvic peritoneum and associated with endosalpingiosis, a previously unreported phenomenon. We discuss the differential diagnosis and speculate that this represents a non-neoplastic phenomenon.
Assuntos
Tumor de Células da Granulosa , Neoplasias Ovarianas , Tumores do Estroma Gonadal e dos Cordões Sexuais , Adulto , Feminino , Humanos , Neoplasias Ovarianas/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Peritônio/patologia , Tumor de Células da Granulosa/patologia , Proliferação de CélulasRESUMO
Gastric-type adenocarcinoma is the commonest human papillomavirus (HPV)-independent adenocarcinoma of the cervix. We report a rare case of a primary cervical gastric-type adenocarcinoma with malignant squamous elements (gastric-type adenosquamous carcinoma) in a 64-yr-old female. This is only the third report of a cervical gastric-type adenosquamous carcinoma. The tumor was p16 negative and molecular studies for HPV were negative. Next-generation sequencing showed pathogenic variants in BRCA1 and KRAS , as well as variants of unknown significance in CDK12 and ATM and homozygous deletion of CDKN2A/CDKN2B . Pathologists should be aware that not all cervical adenosquamous carcinomas are HPV-associated and the term gastric-type adenosquamous carcinoma is recommended when malignant squamous elements are present within a gastric-type adenocarcinoma. In reporting this case, we discuss the differential and the possible therapeutic options raised by the presence of pathogenic variants in BRCA1 .