Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 97
Filtrar
1.
Am J Surg Pathol ; 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33534223

RESUMO

We describe 22 examples of a novel, usually paratubal, adnexal tumor associated with Peutz-Jeghers syndrome in nearly 50% of cases that harbored STK11 alterations in all tested (n=21). The patients ranged from 17 to 66 years (median=39 y) and the tumors from 4.5 to 25.5 cm (median=11 cm). Most (n=18) were paratubal, with metastases noted in 11/22 (50%) and recurrences in 12/15 (80%). Morphologically, they were characterized by interanastomosing cords and trabeculae of predominantly epithelioid cells, set in a variably prominent myxoid to focally edematous stroma, that often merged to form tubular, cystic, cribriform, and microacinar formations, reminiscent of salivary gland-type tumors. The tumor cells were uniformly atypical, often with prominent nucleoli and a variable mitotic index (median=9/10 HPFs). The tumors were usually positive to a variable extent for epithelial (CAM5.2, AE1/AE3, cytokeratin 7), sex cord (calretinin, inhibin, WT1), and mesothelial (calretinin, D2-40) markers, as well as hormone receptors. PAX8, SF1, and GATA-3 were rarely positive, while claudin-4, FOXL2, and TTF-1 were consistently negative. All sequenced tumors (n=21) harbored alterations in STK11, often with a loss of heterozygosity event. There were no other recurrently mutated genes. Recurrent copy number alterations included loss of 1p and 11q, and gain of 1q, 15q, and 15p. Despite an extensive morphologic, immunohistochemical, and molecular evaluation, we are unable to determine with certainty the histogenesis of this unique tumor. Wolffian, sex cord stromal, epithelial, and mesothelial origins were considered. We propose the term STK11 adnexal tumor to describe this novel entity and emphasize the importance of genetic counseling in these patients as a significant number of neoplasms occur in association with Peutz-Jeghers syndrome.

3.
Int J Gynecol Pathol ; 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33323857

RESUMO

Endometriosis is generally histopathologically defined as the presence of at least 2 of the following: endometrial stroma, Müllerian epithelium, and/or hemosiderin-laden macrophages (HLM). Despite clinically evident endometriotic lesions, biopsies are frequently nondiagnostic. In this study, we conducted a large-scale review of biopsies of lesions clinically thought to represent endometriosis and correlate the histologic findings with clinical appearance to expand sensitivity of the pathologic definition of endometriosis, particularly in patients on hormonal therapy. In all, 112 biopsies from 78 patients (mean age=25, range 18-39 yr) were reviewed for histopathologic features suggestive of or diagnostic for endometriosis including the presence of endometrial stroma, Müllerian epithelium, dystrophic calcifications, HLM, chronic inflammation, adhesions, and vascular proliferation. Endometriosis was confirmed by pathologic criteria in 37 of 78 patients (47%). Biopsies from patients on hormonal therapy (n=62, 80%) were significantly less likely to meet pathologic criteria for endometriosis (P=0.01). Nondiagnostic biopsies (70/112; 63%) frequently displayed HLM (20%), chronic inflammation (29%), dystrophic calcifications (26%), vascular proliferation (20%), or adhesions (20%) and were significantly more likely to have a vascular clinical appearance (P=0.01). Diagnostic biopsies (42/112; 38%) were more likely to have a blue/black clinical appearance (P=0.03), demonstrate HLM (P=0.004), and display pseudodecidualization (P=0.05). Patients with a high clinical suspicion of endometriosis have a range of histologic findings, with less than half meeting the current histopathologic criteria for diagnosing endometriosis. Given the heterogeneous histopathologic appearance, revision of the histologic criteria may be warranted with further exploration, particularly for lesions with predominantly vascular features.

4.
Am J Surg Pathol ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33165093

RESUMO

Mesonephric adenocarcinoma (MA) and mesonephric-like adenocarcinoma (MLA) are uncommon neoplasms of the gynecologic tract that have until recently been poorly understood. Although their morphologic, immunohistochemical, and molecular profiles have been recently defined, little is known about their clinical behavior. Small studies have demonstrated inconsistent findings and no large studies have examined the clinical behavior of these adenocarcinomas. In this multi-institutional study, representing the largest and most stringently defined cohort of cases to date, we examined the clinicopathologic features of 99 MAs and MLAs (30 MAs of the uterine cervix, 44 MLAs of the endometrium, and 25 MLAs of the ovary). Only tumors with characteristic mesonephric morphology and either immunohistochemical or molecular support were included. Our results demonstrate that the majority of mesonephric neoplasms presented at an advanced stage (II to IV) (15/25 [60%] MA of the cervix, 25/43 [58%] MLA of the endometrium, and 7/18 [39%] MLA of the ovary). The majority (46/89 [52%] overall, 12/24 [50%] MA of the cervix, 24/41 [59%] MLA of the endometrium, and 10/24 [42%] MLA of the ovary) developed recurrences, most commonly distant (9/12 [75%] MA of the cervix, 22/24 [92%] MLA of the endometrium, and 5/9 [56%] MLA of the ovary). The 5-year disease-specific survival was 74% (n=26) for MA of cervix, 72% (n=43) for MLA of endometrium, and 71% (n=23) for MLA of ovary. Our results confirm that mesonephric neoplasms are a clinically aggressive group of gynecologic carcinomas that typically present at an advanced stage, with a predilection for pulmonary recurrence.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33252159

RESUMO

Our knowledge regarding the role of genes encoding the chromatin remodeling switch/sucrose non-fermenting (SWI/SNF) complex in the initiation and progression of gynecologic malignancies continues to evolve. This review focuses on gynecologic tumors in which the sole or primary genetic alteration is in SMARCA4 or SMARCB1, two members of the SWI/SNF chromatin remodeling complex. In this review we present a brief overview of the classical example of such tumors, ovarian small cell carcinoma of hypercalcemic type, and then a detailed review and update of SMARCB1-deficient and SMARCA4-deficient tumors of the uterus and vulva. This article is protected by copyright. All rights reserved.

6.
Am J Surg Pathol ; 44(11): 1541-1548, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32773531

RESUMO

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.

7.
Hum Pathol ; 103: 83-94, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32687944

RESUMO

Data have shown that uterine diagnostic criteria are universal for smooth muscle tumors (SMTs) originating in the ovary, vulva, vagina, broad ligament, and other supportive connective tissue and that uterine criteria outperform site-specific criteria for vulvar and vaginal SMTs. Classic benign and malignant spindled SMTs were well represented in our recent study comparing uterine and site-specific criteria in vulvovaginal SMTs, but leiomyoma variants and smooth muscle tumors of uncertain malignant potential (STUMPs) were relatively few. Therefore, we evaluated additional leiomyoma variants, STUMPs, and leiomyosarcomas from 17 patients (10 vaginal and 7 vulvar). The 10 vaginal tumors (59%) comprised cellular leiomyoma (n = 2), leiomyoma with bizarre nuclei (n = 3), STUMP (n = 1), and leiomyosarcoma (n = 4). The 7 vulvar tumors (41%) comprised leiomyoma with bizarre nuclei (n = 3), STUMP (n = 1), and leiomyosarcoma (n = 3). Follow-up was available for 13 patients (76.5%) ranging from 1 to 97 months (mean: 17.3; median: 7). Follow-up for some patients with leiomyosarcoma was limited (≤4 months for 4 patients). One vaginal STUMP locally recurred after 19 months, and 2 patients diagnosed with leiomyosarcoma developed distant metastases. All remaining patients had either no evidence of disease at last follow-up (10 patients, 58.8%) or their status was unknown (4 patients, 23.5%). Uterine criteria are valid for vulvovaginal leiomyoma variants and STUMPs and more appropriately classified these tumors than site-specific criteria. Our combined findings from the current and previous studies support use of uterine diagnostic thresholds for the entire spectrum of vulvovaginal SMTs.

8.
Histopathology ; 77(5): 788-797, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32558949

RESUMO

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.

10.
Gynecol Oncol ; 157(1): 106-114, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31954538

RESUMO

OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and SMARCA4-deficient undifferentiated uterine sarcoma (SMARCA4-DUS) are rare and aggressive tumors, primarily affecting pre- and perimenopausal women. Inactivating SMARCA4 mutations are thought to be the driving molecular events in the majority of these tumors. Here, we report the clinical course of a family with germline SMARCA4 mutation and compare large cohorts of these rare tumor types. METHODS: We extracted clinico-pathological medical record data for the family with germline SMARCA4 mutation. Clinico-genomic data from SCCOHT and SMARCA4-DUS cohorts were retrospectively extracted from the archives of a large CLIA-certified reference molecular laboratory. RESULTS: We identified a single family with an inherited germline SMARCA4 mutation, in which two different family members developed either SCCOHT or SMARCA4-DUS, both of whom died within one year of diagnosis, despite aggressive surgical, chemotherapy and immunotherapy treatment. Retrospective comparative analysis of large SCCOHT (n = 48) and SMARCA4-DUS (n = 17) cohorts revealed that SCCOHT patients were younger (median age: 28.5 vs. 49.0) and more likely to have germline SMARCA4 alterations (37.5% vs. 11.8%) than SMARCA4-DUS patients. CONCLUSIONS: Growing understanding of the role SMARCA4 plays in the pathogenesis of these rare cancers may inform recommended genetic testing and counseling in families with these tumor types.


Assuntos
Carcinoma de Células Pequenas/genética , DNA Helicases/genética , Mutação em Linhagem Germinativa , Hipercalcemia/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Sarcoma/genética , Fatores de Transcrição/genética , Neoplasias Uterinas/genética , Adulto , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/terapia , Diferenciação Celular/fisiologia , Estudos de Coortes , DNA Helicases/deficiência , Feminino , Humanos , Hipercalcemia/patologia , Hipercalcemia/terapia , Pessoa de Meia-Idade , Proteínas Nucleares/deficiência , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Prognóstico , Estudos Retrospectivos , Sarcoma/patologia , Sarcoma/terapia , Fatores de Transcrição/deficiência , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia
11.
Int J Gynecol Pathol ; 39(2): 119-127, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30702464

RESUMO

Endometrial endometrioid carcinomas (EECs) with exon 3 CTNNB1 mutations characterize a more aggressive subset of tumors in patients with low-grade low-stage disease. Thus, prospectively identifying these cases may be clinically relevant. The aim of this study was to examine the feasibility of ß-catenin and Cyclin D1 immunohistochemistry to identify EECs harboring CTNNB1 mutations and to evaluate the clinicopathologic features of EECs with exon 3 CTNNB1 mutations. Thirty-nine CTNNB1 mutated EECs and 40 CTNNB1 wild-type EECs were identified from a cohort of previously sequenced endometrial carcinomas using a targeted next-generation sequencing panel. Immunohistochemistry for ß-catenin and Cyclin D1 was performed on all cases. Immunohistochemistry results were correlated with CTNNB1 mutation status and clinicopathologic parameters. Patients with CTNNB1 mutated EECs were younger than those with CTNNB1 wild-type (56.2 vs. 61.5 y; P=0.033). Nuclear ß-catenin expression correlated with exon 3 CTNNB1 mutation (P<0.0001) with a sensitivity of 91% and a specificity of 89%. Cyclin D1 expression correlated with CTNNB1 exon 3 mutation with relatively high specificity (90%) but low sensitivity (29%). Recurrence rate in patients with stage IA disease at diagnosis was significantly higher in patients whose tumors were CTNNB1 mutated compared with CTNNB1 wild-type (30% vs. 0%; P=0.025) and included distant metastases; all recurrent tumors in this group harbored exon 3 mutations and were histologically low grade (5 grade 1, 2 grade 2). Nuclear ß-catenin expression appears to be an acceptable proxy for CTNNB1 mutation.


Assuntos
Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , beta Catenina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação
12.
Am J Surg Pathol ; 44(2): 263-270, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31567195

RESUMO

Undifferentiated and dedifferentiated endometrial carcinomas (UDEC) are aggressive uterine tumors which may show loss of expression of SMARCA4 (BRG1) or SMARCB1 (INI-1). The recently described SMARCA4-deficient undifferentiated uterine sarcoma (SDUS) has a morphology which overlaps with UDEC. In this study, we compared clinical, morphologic, immunohistochemical, and molecular characteristics to identify features which differentiate SDUS from UDEC. Cases of SDUS (n=12) were compared with cases of UDEC (n=84, 55 of which were previously published). Immunohistochemistry was performed for p53, mismatch repair proteins, claudin-4, SMARCA4, and SMARCB1. Targeted molecular profiling was performed on 15 cases. Patients with SDUS were significantly younger than those with UDEC (mean 35.8 vs. 61.2 y, P=0.0001). UDEC and SDUS showed morphologic overlap; however, phyllodiform architecture favored a diagnosis of SDUS (36% vs. 0%, P=0.005), while prominent nuclear pleomorphism was only seen in some cases of UDEC (0% vs. 24%, P=0.15). Compared with SDUS, UDEC more frequently showed TP53 mutations (0% vs. 34%, P=0.03), microsatellite instability (0% vs. 44%, P=0.006), and intact SMARCA4 and SMARCB1 (0% vs. 80%); a panel combining these immunohistochemical markers had a sensitivity of 100% and specificity of 92% in distinguishing SDUS and UDEC. Cases of UDEC had mutations in genes associated with endometrial adenocarcinomas (eg, TP53, PTEN, PIK3CA) and occasionally SMARCA4, while SDUS was characterized solely by inactivating mutations in SMARCA4. Disease-specific survival was shorter in SDUS than UDEC (median survival 9 and 36 mo, P=0.01). In conclusion, SDUS occurs in younger patients than UDEC, has a worse prognosis, and in most cases has a distinct molecular and immunohistochemical profile.


Assuntos
Biomarcadores Tumorais/deficiência , DNA Helicases/deficiência , Neoplasias do Endométrio/diagnóstico , Proteínas Nucleares/deficiência , Proteína SMARCB1/deficiência , Sarcoma/diagnóstico , Fatores de Transcrição/deficiência , Neoplasias Uterinas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Sarcoma/metabolismo , Sarcoma/patologia , Sensibilidade e Especificidade , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
13.
Int J Gynecol Pathol ; 39(6): 578-586, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31855952

RESUMO

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.

14.
Histopathology ; 76(5): 707-713, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31811787

RESUMO

AIMS: Hobnail variant of papillary thyroid carcinoma (PTC) is an aggressive PTC subtype characterised by a hobnail cytomorphology. However, some classic PTC have a 'hobnail-like' cytomorphology associated with thick, hyalinised, variably oedematous fibrovascular cores that appears to be a form of ischaemic/degenerative atypia. METHODS AND RESULTS: We studied three cohorts to compare the histopathological characteristics and clinical outcome of 'hobnail-like' classic PTC and true hobnail variant of PTC: cohort 1, PTC consecutively resected between 2016 and 2017 (to assess frequency of 'hobnail-like' cytomorphology); cohort 2, 20 'hobnail-like' classic PTC resected between 2005 and 2007 (to assess clinical outcome); and cohort 3, seven true hobnail variant of PTC. A 'hobnail-like' cytomorphology was identified in 16% of consecutively resected PTC. Compared with true hobnail variant, 'hobnail-like' classic PTC occurred in younger patients (mean age 40 years versus 68 years, P < 0.001), were smaller tumours (mean tumour size 2.1 cm versus 4.4 cm, P < 0.001), had a lower rate of gross extrathyroidal extension (0% versus 71%, P < 0.001), had a lower proliferative rate (≥3 mitoses per 10 high-power fields seen in 0% versus 71%, P < 0.001; Ki67 index ≥5% in 0% versus 86%, P < 0.001), a lower rate of secondary pathogenic mutations (for cases with molecular data, 0% versus 100%, P = 0.0061) and improved survival (for cases with sufficient clinical outcome data, 10-year disease-free survival of 93% versus 0%, P = 0.0016). CONCLUSION: Classic PTC can show ischaemic/degenerative atypia that mimics the hobnail cytomorphology of true hobnail variant; however, these tumours lack aggressive histopathological features and pursue an indolent clinical course.

15.
Clin Cancer Res ; 25(24): 7517-7526, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31492746

RESUMO

PURPOSE: Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in gBRCA carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship. EXPERIMENTAL DESIGN: Thirty-eight gBRCA carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gynecologic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the gBRCA-wild-type allele (gBRCA/LOHpos) were defined "gBRCA-associated," those without LOH (gBRCA/LOHneg) were defined "sporadic." RESULTS: LOH could be assessed for 40 ECs (30 gBRCA1, 10 gBRCA2), of which 60% were gBRCA/LOHpos. gBRCA/LOHpos ECs were more frequently of nonendometrioid (58%, P = 0.001) and grade 3 histology (79%, P < 0.001). All but two were in the TP53-mutated TCGA-subgroup (91.7%, P < 0.001). In contrast, gBRCA/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: POLE-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and TP53-mutated (6.3%). CONCLUSIONS: We provide novel evidence in favor of EC being part of the gBRCA-associated HBOC-syndrome. gBRCA-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of gBRCA carriers.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Mutação em Linhagem Germinativa , Perda de Heterozigosidade , Adulto , Idoso , Estudos de Coortes , Neoplasias do Endométrio/classificação , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores
16.
Gynecol Oncol ; 154(2): 441-448, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31118141

RESUMO

OBJECTIVE: There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT. METHODS: We established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS). RESULTS: 877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5-65) and 28 months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45-0·66; P < 0·001) and 0·65 (95% CI 0·50-0·85, P = 0·002) respectively; no heterogeneity was identified (PFS: Q = 6·42, P = 0·698, I2 = 0·0%; OS: Q = 6·89, P = 0·648, I2 = 0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0·027). CONCLUSIONS: CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos , Biomarcadores Tumorais/análise , Intervalo Livre de Doença , Neoplasias das Tubas Uterinas/mortalidade , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Terapia Neoadjuvante , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Resultado do Tratamento
17.
Surg Pathol Clin ; 12(2): 363-396, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31097109

RESUMO

The spectrum of mesenchymal neoplasia in the uterus has expanded in recent years. First, the identification of prevalent, recurrent molecular alterations has led to a more biologically and clinically congruent classification of endometrial stromal tumors. Likewise, the diagnostic criteria of several rare and miscellaneous tumor types have been refined in recent case series (Perivascular Epithelioid Cell tumor, inflammatory myofibroblastic tumor). Pure mesenchymal tumors are still broadly classified based on morphology according to the tumor cell phenotype. Smooth muscle tumors predominate in frequency, followed by tumors of endometrial stromal derivation; the latter are covered in depth in this article with an emphasis on defining molecular alterations and their morphologic and clinical correlates. The remaining entities comprise a miscellaneous group in which cell derivation does not have a normal counterpart in the uterus (eg, rhabdomyosarcoma) or is obscure (eg, undifferentiated uterine sarcoma). This article discusses their clinical relevance, recent insights into their molecular biology, and the most important differential diagnoses. Regarding the latter, immunohistochemistry and (increasingly) molecular diagnostics play a role in the diagnostic workup. We conclude with a few considerations on intraoperative consultation and macroscopic examination, as well as pathologic staging and grading of uterine sarcomas as per the most recent American Joint Cancer Commission and the Fédération Internationale de Gynécologie et d'Obstétrique staging systems.


Assuntos
Neoplasias Uterinas/diagnóstico , Adenossarcoma/diagnóstico , Adenossarcoma/genética , Adenossarcoma/patologia , Biomarcadores Tumorais/metabolismo , Diagnóstico Diferencial , Feminino , Predisposição Genética para Doença , Humanos , Mutação , Estadiamento de Neoplasias , Sarcoma do Estroma Endometrial/diagnóstico , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
18.
Surg Pathol Clin ; 12(2): xi-xii, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31097118
19.
J Clin Pathol ; 72(5): 347-353, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30679193

RESUMO

AIMS: The International Endocervical Adenocarcinoma Criteria and Classification (IECC) was recently proposed as an improved method for categorising endocervical adenocarcinoma (EA) into human papillomavirus (HPV)-associated adenocarcinomas (HPVAs) and non-HPV-associated adenocarcinomas (NHPVAs). Such categorisation correlates with patient age and tumour size; however, its association with patient outcome remains to be established. METHODS: Institutional cases of EA with histological material available were selected. Three gynaecological pathologists independently classified all tumours according to the IECC with consensus review used when necessary. Clinicopathologic variables were recorded for each case. RESULTS: Of a total of 87 EAs, 71 (82%) were classified as HPVA and 16 (18%) as NHPVA. Among HPVA, most were usual type (51/71, 72%) followed by mucinous not otherwise specified (10/71, 14%) and invasive stratified mucin-producing carcinoma (ISMC, 8/71, 11%). Most NHPVAs were of gastric type (12/16, 71%) followed by clear cell and mesonephric (two each, 12%). Compared with HPVAs, NHPVAs were significantly associated with older age (p<0.001), larger horizontal extent (p=0.013), greater depth of invasion (p=0.003), lymphovascular space invasion (p<0.001), advanced stage (p<0.001) and invasive pattern C (p<0.001). On univariate analysis, worse disease-free survival (DFS) and disease-specific survival (DSS) correlated with NHPVA group. Among the HPVA subtypes, ISMC showed worse DFS and DSS compared with other HPVA types. CONCLUSIONS: The simple morphological approach of the IECC appears to be prognostically valuable. NHPVA (in particular gastric type) and ISMC (a recently recognised subset of HPVA) have an adverse outcome and their recognition following the IECC is important. We provide further evidence to replace the current WHO classification with the IECC.


Assuntos
Adenocarcinoma/classificação , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/classificação , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/patologia , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Adulto Jovem
20.
Int J Gynecol Pathol ; 38(6): 543-551, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30134342

RESUMO

Female adnexal tumor of probable Wolffian origin (FATWO) is a rare gynecologic neoplasm of low-malignant potential presumed to be derived from mesonephric remnants in the upper female genital tract. Similarly, mesonephric remnants in the lower female genital tract are thought to be the origin for mesonephric carcinoma. Although the molecular alterations in mesonephric carcinoma have been recently reported, the pathogenesis of and molecular alterations in FATWO are not well understood. The aims of this study were to examine the molecular alterations in FATWO and to establish whether these neoplasms are molecularly similar to mesonephric carcinoma. Eight FATWOs underwent massively parallel sequencing to detect single nucleotide variations, copy number variations, and structural variants by surveying exonic DNA sequences of 300 cancer genes and 113 introns across 35 genes. Good quality DNA was isolated from 7 of 8 cases. Novel KMT2D variants (1 frameshift, 3 missense) were identified in 4 of 7 cases (57%), but were variants of uncertain biologic significance. STK11 mutations (both frameshift) were identified in 2 of 7 cases (29%); one of these was in a patient with a known history of Peutz-Jeghers syndrome. A mutation in the chromatin remodeling gene ARID1B was identified in 1 of 7 cases (14%). No cases harbored KRAS, NRAS, TP53, PIK3CA, PTEN, or DICER1 mutations. There were relatively low numbers of copy number variations, and no recurrent copy number variations were identified. One case demonstrated moderate copy gain of CCND1. No structural variants were identified. In summary, FATWO is characterized molecularly by the absence of KRAS/NRAS mutations (characteristic of mesonephric carcinoma), absence of DICER1 mutations (characteristic of Sertoli-Leydig cell tumor) and frequent KMT2D mutations of unknown biologic significance. FATWOs exhibit a limited number of molecular aberrations that are significantly different from those reported in tumors in the differential diagnosis, and our results question the relationship of mesonephric carcinoma with FATWO. Disease-defining molecular alterations for FATWO have yet to be discovered.


Assuntos
Adenoma/genética , Doenças dos Anexos/genética , Carcinoma/genética , Neoplasias dos Genitais Femininos/genética , Adenoma/patologia , Doenças dos Anexos/patologia , Adulto , Idoso , Carcinoma/patologia , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Diagnóstico Diferencial , Éxons/genética , Feminino , Neoplasias dos Genitais Femininos/patologia , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons/genética , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Ductos Mesonéfricos/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...