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Ovarian serous borderline tumors (SBTs) have a generally favorable prognosis. Although the risk of progression to low-grade serous carcinoma is well documented, progression to high-grade carcinoma is rare. We report the clinicopathologic features of seven SBTs, each associated with the presence of a morphologically unique high-grade component with an extremely dismal prognosis. All of the SBTs exhibited typical hierarchical branching and scattered eosinophilic cells, whereas the high-grade component consisted of a profuse proliferation of epithelioid cells with abundant dense, eosinophilic cytoplasm, variable nuclear pleomorphism, and evident loss of WT1, estrogen receptor, and p16 positivity. In most cases, the SBT demonstrated an abrupt transition to the high-grade component, but one patient initially presented with the usual SBT and developed a recurrent disease that was composed entirely of the high-grade component. Targeted next-generation sequencing revealed identical driver mutations in both the SBT and high-grade components (BRAF in 3, KRAS in 1), confirming clonality. Three cases, in addition, harbored telomerase reverse transcriptase promoter mutations in both components. One case, despite insufficient material for sequencing, was BRAF V600E-positive by immunohistochemistry. Most patients with available follow-up data died within 9 months of diagnosis. This study confirms prior reports of ovarian SBT transformation to high-grade carcinoma and further characterizes a distinct subset with abundant dense eosinophilic cytoplasm and an extremely dismal prognosis. The presence of BRAF mutations in a major subset of these tumors questions the notion that BRAF is associated with senescent eosinophilic cells and improved outcomes in SBT. The role of the additional telomerase reverse transcriptase promoter mutations merits further investigation.
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AIMS: Molecular classification according to The Cancer Genome Atlas (TCGA) improves endometrial endometrioid carcinoma (EEC) prognostication and has specific treatment implications; however, original data were skewed towards low-grade and low-stage tumours. Herein, we molecularly classify EECs metastatic at the time of diagnosis or with subsequently documented recurrent/metastatic disease to examine correlation with clinical outcomes. METHODS: TCGA categories include POLE-mutated, microsatellite instability (MSI), p53 abnormal (p53 abnl) and no specific molecular profile (NSMP). POLE targeted sequencing at exons 9, 11, 13 and 14 and immunohistochemistry (IHC) for PMS2, MSH6 and p53 were performed to establish molecular classification. RESULTS: The distribution in our cohort of 141 EECs was similar to that generally reported in EEC, with nine POLE-mutated (6%), 45 MSI (32%), 16 p53 abnl (11%) and 71 NSMP (50%), with similar distributions between low- and high-stage cohorts. We demonstrate that when stratified by molecular subtype, disease-specific survival from the time of high-stage (stages III-IV) presentation or time of recurrence in low-stage (stages I-II) disease among metastatic and/or recurrent EEC is strongly associated with TCGA classification (high-stage P = 0.02, low-stage P = 0.017). Discordant molecular classification between primary and metastatic/recurrent tumours occurred in four of 105 (3.8%) patients, two related to PMS2/MSH6 IHC and two related to p53 IHC. CONCLUSIONS: We demonstrate that molecular classification is prognostically relevant not only at the time of diagnosis, but also at the time of recurrence and in the metastatic setting. Rare subclonal alterations occur and suggest a role for confirming TCGA classification in recurrent/metastatic tumours.
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Carcinoma Endometrioide , Neoplasias Endometriales , Inestabilidad de Microsatélites , Recurrencia Local de Neoplasia , Humanos , Femenino , Neoplasias Endometriales/patología , Neoplasias Endometriales/genética , Neoplasias Endometriales/clasificación , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/genética , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Adulto , Anciano de 80 o más Años , Proteínas de Unión a Poli-ADP-Ribosa/genética , Mutación , Inmunohistoquímica , Estadificación de NeoplasiasRESUMEN
We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of ß-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.
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Neoplasias Endometriales , Metformina , Proteogenómica , Femenino , Humanos , Proteínas Proto-Oncogénicas c-akt/genética , Estudios Prospectivos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Metformina/farmacologíaRESUMEN
OBJECTIVES: Emerging data suggests that abnormal (nuclear) ß-catenin expression in some settings is associated with poorer outcomes. Our study aimed to verify the significance of abnormal ß-catenin expression in early-stage endometrial cancer patients and determine if adjuvant radiation therapy (RT) improves local control. METHODS: We identified 213 patients with FIGO 2018 stage I-II endometrioid endometrial cancer who underwent surgery from 2009 to 2021 with ß-catenin expression assessed. Vaginal, regional, and distant recurrences were analyzed using competing risk methods, and overall survival was analyzed using Kaplan-Meier. RESULTS: Median follow up was 53.2 months; 6.9% experienced vaginal, 8.2% regional, and 7.4% distant recurrence. For the entire cohort, abnormal ß-catenin expression was significantly associated with vaginal recurrence and remained significant on multivariate analysis (p = 0.03). There were 114 patients in the no specific molecular profile (NSMP) subgroup, and abnormal ß-catenin expression was present in 46.5%. In the NSMP subgroup, abnormal ß-catenin expression was associated with increased rates of vaginal recurrence (p = 0.06). Abnormal ß-catenin expression in the NSMP subgroup was significant on multivariate analysis for vaginal recurrence (p = 0.04). RT significantly decreased vaginal recurrences in the entire cohort in patients with abnormal ß-catenin expression (0%) versus wild type expression (17.5%; p = 0.03). In the NSMP subgroup 0% of patients who received RT versus 20.9% of patients who did not receive RT experienced a vaginal recurrence (p = 0.03). CONCLUSION: Use of adjuvant RT for stage I-II NSMP endometrial cancer with abnormal ß-catenin expression improved local control. RT should be considered in these patients to decrease risk of vaginal recurrences.
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Neoplasias Endometriales , beta Catenina , Femenino , Humanos , Radioterapia Adyuvante/métodos , Estadificación de Neoplasias , Histerectomía , Neoplasias Endometriales/radioterapia , Neoplasias Endometriales/cirugía , Recurrencia , Recurrencia Local de Neoplasia/patología , Estudios RetrospectivosRESUMEN
CONTEXT.: Clinical testing for tumor cell-free DNA (cfDNA) has evolved rapidly, but no practice guidelines exist. OBJECTIVE.: To summarize cfDNA laboratory practices based on self-reporting and assess preanalytical, analytical, and postanalytical trends that may influence the quality, accuracy, and consistency of cfDNA testing. DESIGN.: Data were derived from the College of American Pathologists cfDNA proficiency testing program submitted by 101 participating laboratories from 2018 to 2019. RESULTS.: Most laboratories performing clinical circulating tumor DNA testing are commercial/nonhospital (71.2%; 72 of 101) and international (77.2%; 78 of 101) laboratories. Commercial laboratories had higher monthly test volumes than hospital-based laboratories (median, 36 versus 7-8) and tended to have larger gene panels (median, 50 versus 11 genes) when panel-based testing was offered. The main clinical indications include therapy selection and treatment/disease monitoring. Plasma is the most commonly accepted specimen, which is predominantly collected in cell-stabilizing tubes. Equal proportions of laboratories use next-generation sequencing (NGS) and non-NGS methods to assess key genes, including EGFR, BRAF, KRAS, NRAS, and IDH1. Most laboratories reported a lower limit of detection (LLOD) of 0.5%, variant allele frequency or less, which did not differ by method, NGS or non-NGS, except for EGFR. Sixty-five percent (17 of 26) of laboratories using the US Food and Drug Administration (FDA)-approved non-NGS EGFR assay report analytical sensitivities higher than 0.5%, as compared to 15% (16 of 104) of laboratories using an alternative NGS or non-NGS method. There is also a wider range in LLODs obtained for the FDA-approved EGFR assay than nonapproved assays. CONCLUSIONS.: These results highlight emerging practice trends and serve as a foundation to initiate future practice recommendations.
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Ácidos Nucleicos Libres de Células , Neoplasias , Humanos , Estados Unidos , Ácidos Nucleicos Libres de Células/genética , Patólogos , Mutación , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patología , Receptores ErbB/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Ensayos de Aptitud de Laboratorios/métodosRESUMEN
Amplicon-based next-generation sequencing (NGS) assays employ highly sensitive, rapid, and cost-effective methods to detect clinically actionable mutations for the diagnosis, prognosis, and treatment of patients with cancer. However, recognition of certain limitations inherent to amplicon-based NGS assays is crucial for the correct interpretation and reporting of variants in the clinical setting. In this report, we illustrate three different potential pitfalls related to amplicon-based NGS assays based on our institutional experience and highlight how the risk of such events can be minimised.
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Reacción en Cadena de la Polimerasa Multiplex , Neoplasias , Humanos , Neoplasias/genética , Mutación , Pronóstico , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
PURPOSE: Microsatellite instability-high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). EXPERIMENTAL DESIGN: Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan-Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses. RESULTS: Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively). CONCLUSIONS: MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.
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Neoplasias Endometriales , Inestabilidad de Microsatélites , Neoplasias Encefálicas , Neoplasias Colorrectales , ADN , Reparación de la Incompatibilidad de ADN/genética , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Mutación de Línea Germinal , Humanos , Homólogo 1 de la Proteína MutL/genética , Síndromes Neoplásicos HereditariosRESUMEN
HER2 is an established therapeutic biomarker in advanced or recurrent endometrial serous carcinoma. Current clinical guidelines recommend HER2 testing exclusively in this endometrial carcinoma (EC) subtype; however, the full spectrum of ECs harboring HER2 amplification remains ill-defined. The present study characterizes the clinicopathologic and molecular features of HER2-amplified ECs across all histologic subtypes. Retrospective analysis of our institutional cohort of 2,042 ECs subjected to targeted clinical massively parallel sequencing identified 77 (3.8%) cases with HER2 amplification, a group comprised of serous (n = 29), endometrioid (low-grade, n = 2, high-grade, n = 1) and clear cell (n = 4) carcinomas, carcinosarcomas (n = 18) and high-grade ECs with ambiguous features (HGEC, n = 23). A co-existing TP53 mutation was identified in 94% (72/77) of HER2-amplified ECs. Other recurrent genetic alterations included amplification of CCNE1 (22%) and ERBB3 (10%), FBXW7 mutations or deletions (13%), and mutations in PIK3CA (40%) and PPP2R1A (13%). The HER2 immunohistochemistry score was 2+ or 3+ for all evaluable cases (n = 61). Apart from carcinosarcomas, which often showed lower HER2 expression, particularly in the sarcomatous component, HER2 immunohistochemical staining pattern and intensity were similar across EC subtypes. Intratumor heterogeneity in HER2 expression was common and correlated with genetic heterogeneity as detected by fluorescence in-situ hybridization. These results demonstrate the frequent co-occurrence of HER2 amplification with TP53 mutation and high-grade histology, rather than being specific to serous carcinoma, per se. Overall, these findings suggest that HER2 targeted therapy may be more broadly applicable to all high-grade EC histotypes and consideration should be given to expanding therapeutic eligibility.
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Carcinosarcoma , Cistadenocarcinoma Seroso , Neoplasias Endometriales , Carcinosarcoma/genética , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Humanos , Biología Molecular , Mutación , Recurrencia Local de Neoplasia , Estudios RetrospectivosRESUMEN
CONTEXT.: Neoplastic cellularity assessment has become an essential component of molecular oncology testing; however, there are currently no best practice recommendations or guidelines for this potentially variable step in the testing process. OBJECTIVE.: To describe the domestic and international practices of neoplastic cellularity assessment and to determine how variations in laboratory practices affect neoplastic cellularity assessment accuracy. DESIGN.: Data were derived from 57 US and international laboratories that participated in the 2019 College of American Pathologists Neoplastic Cellularity Proficiency Testing Survey (NEO-B 2019). NEO-B 2019 included 29 laboratory practice questions and 5 images exhibiting challenging histologic features. Participants assessed the neoplastic cellularity of hematoxylin-eosin-stained digital images, and results were compared to a criterion standard derived from a manual cell count. RESULTS.: The survey responses showed variations in the laboratory practices for the assessment of neoplastic cellularity, including the definition of neoplastic cellularity, assessment methodology, counting practices, and quality assurance practices. In some instances, variation in laboratory practice affected neoplastic cellularity assessment performance. CONCLUSIONS.: The results highlight the need for a consensus definition and improved standardization of the assessment of neoplastic cellularity. We put forth an initial set of best practice recommendations to begin the process of standardizing neoplastic cellularity assessment.
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Laboratorios , Ensayos de Aptitud de Laboratorios , Recolección de Datos , Hematoxilina , Humanos , Oncología Médica , Técnicas de Diagnóstico MolecularRESUMEN
Fumarate hydratase-deficient leiomyomas (dFH leiomyomas) often display atypical pathologic features yet exhibit a benign clinical course. Recent data suggest that dFH leiomyomas may be misclassified as smooth muscle tumors of uncertain malignant potential, a category that encompasses a heterogenous subgroup of uterine neoplasms with smooth muscle differentiation and atypical features that impart ambiguity regarding their expected clinical behavior. dFH leiomyomas can be seen in the context of hereditary leiomyomatosis and renal cell carcinoma syndrome or in the sporadic setting. In this retrospective study, we sought to examine the prevalence and clinicopathologic characteristics of dFH leiomyomas in 48 tumors previously diagnosed as smooth muscle tumors of uncertain malignant potential from 38 patients. Of these 48 tumors, 3 (6.3%) occurring in 2 patients were found to be deficient for FH by immunohistochemistry, including 1 uterine and 2 extrauterine (abdominopelvic) tumors. The 3 tumors showed histologic features typical of dFH leiomyomas, including hemangiopericytoma-like vessels, edema, macronucleoli, and atypia. Neither patient developed recurrent leiomyomas or renal cell carcinoma, and both were alive without disease at last follow-up. Our data suggest that dFH leiomyomas should be considered in the differential diagnosis of smooth muscle tumors of uncertain malignant potential, even in the context of extrauterine disease. Identification of FH deficiency in these tumors supports their classification as dFH leiomyomas despite their atypical morphologic features and/or clinical presentation. Importantly, detection of dFH in these cases may identify women at increased risk for hereditary leiomyomatosis and renal cell carcinoma who would benefit from genetic counseling and consideration for FH germline testing.
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Carcinoma de Células Renales , Neoplasias Renales , Leiomiomatosis , Neoplasias Cutáneas , Tumor de Músculo Liso , Neoplasias Uterinas , Carcinoma de Células Renales/diagnóstico , Diagnóstico Diferencial , Femenino , Fumarato Hidratasa/deficiencia , Fumarato Hidratasa/genética , Humanos , Neoplasias Renales/diagnóstico , Leiomiomatosis/diagnóstico , Leiomiomatosis/genética , Leiomiomatosis/patología , Masculino , Errores Innatos del Metabolismo , Hipotonía Muscular , Trastornos Psicomotores , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Tumor de Músculo Liso/diagnóstico , Neoplasias Uterinas/patologíaRESUMEN
The comprehensive genomic analysis of endometrial carcinoma (EC) by The Cancer Genome Atlas (TCGA) led to the discovery of four distinct and prognostically significant molecular subgroups. Molecular classification has the potential to improve risk-stratification when integrated with clinicopathologic features and has recently been included in national and international patient management EC guidelines. Thus, the adoption of molecular classification into routine pathologic and clinical practice is likely to grow significantly in the upcoming years. Establishing an efficient and standardized workflow for performing molecular classification on ECs, and reporting both the molecular and histologic findings in an integrative manner, is imperative. Here we describe our effort to implement rapid and routine molecular classification on all ECs diagnosed at our institution. To this effect, we performed immunohistochemistry as a surrogate marker for identifying genetic and/or epigenetic alterations in DNA mismatch repair (e.g., MLH1, PMS2, MSH6, MSH2), and TP53 genes. In addition, we have developed and employed a single-gene POLE SNaPshot assay, which is a rapid and analytically sensitive method for detecting select POLE exonuclease domain mutations (EDMs). We report our molecular testing workflow and integrative reporting system as well as the clinicopathologic and molecular features of 310 ECs that underwent routine molecular classification at our institution. The 310 ECs were molecularly classified as follows: 15 (5%) POLE mutant (POLEmut), 79 (25%) mismatch repair-deficient (MMRd), 135 (44%) no specific molecular profile (NSMP), and 81 (26%) p53 abnormal (p53abnl). This work provides an initial framework for implementing routine molecular classification of ECs.
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Neoplasias Endometriales , Biomarcadores de Tumor/genética , Reparación de la Incompatibilidad de ADN , Neoplasias Endometriales/patología , Femenino , Genes p53 , Humanos , Inmunohistoquímica , Mutación , Estudios ProspectivosRESUMEN
Determining the replicative DNA polymerase epsilon ( POLE) mutation status in endometrial carcinomas (ECs) has important clinical implications given that the majority of "ultramutated" tumors harboring pathogenic exonuclease domain mutations in POLE ( POLE mut) have a favorable prognosis, even among high-grade histotypes. Currently, there are no specific morphologic or immunophenotypic features that allow accurate detection of POLE mut tumors without molecular testing. Consequently, identifying POLE mut tumors has been challenging without employing costly and/or time-consuming DNA sequencing approaches. Here we developed a novel SNaPshot assay to facilitate routine and efficient POLE mutation testing in EC. The SNaPshot assay interrogates 15 nucleotide sites within exons 9, 11, 13, and 14 encoding the POLE exonuclease domain. The variant sites were selected based on recurrence, evidence of functional impact, association with high tumor mutation burden and/or detection in EC clinical outcome studies. Based on the pathogenic somatic variants reported in the literature, the assay is predicted to have a clinical sensitivity of 90% to 95% for ECs. Validation studies showed 100% specificity and sensitivity for the variants covered, with expected genotypic results for both the positive (n=11) and negative (n=20) patient controls on multiple repeat tests and dilution series. Analytic sensitivity was conservatively approximated at a 10% variant allele fraction (VAF), with documented detection as low as 5% VAF. As expected, the SNaPshot assay demonstrated greater sensitivity than Sanger sequencing for VAFs below 20%, an important characteristic for somatic mutation detection. Here we have developed and validated the first SNaPshot assay to detect hotspot POLE mutations. While next-generation sequencing and Sanger sequencing-based approaches have also been used to detect POLE mutations, a SNaPshot approach provides useful balance of analytical sensitivity, cost-effectiveness, and efficiency in a high-volume case load setting.
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Carcinoma Endometrioide , Neoplasias Endometriales , Femenino , Humanos , Carcinoma Endometrioide/patología , Análisis Costo-Beneficio , Exonucleasas/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , MutaciónAsunto(s)
Biomarcadores de Tumor/genética , Fusión Génica , Coactivador 2 del Receptor Nuclear/genética , Neoplasias Ováricas/genética , Tumor Rabdoide/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Neoplasias Uterinas/genética , Adulto , Biomarcadores de Tumor/análisis , Femenino , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Ováricas/química , Neoplasias Ováricas/patología , Fenotipo , Tumor Rabdoide/química , Tumor Rabdoide/patología , Tumor Rabdoide/cirugía , Tumores de los Cordones Sexuales y Estroma de las Gónadas/química , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Resultado del Tratamiento , Neoplasias Uterinas/química , Neoplasias Uterinas/patología , Neoplasias Uterinas/cirugíaRESUMEN
Uterine sarcomas with variable CD34 and S100 expression represent an emerging class of tumor in the female genital tract which commonly presents in the endocervix of premenopausal women. Initial molecular characterization identified NTRK1 and NTRK3 gene fusions as oncogenic drivers in these tumors; however, the repertoire of genetic alterations is likely more diverse given the recent discovery of PDGFB and RET gene fusions in similarly described tumors. Importantly, these fusion events lead to the aberrant activation of kinases that are potentially therapeutically targetable; therefore, recognizing this class of tumor becomes critical for initiating the molecular testing required for an accurate diagnosis and identification of clinically actionable fusions. Here, we report our institutional experience with 12 cases of uterine spindle cell sarcomas harboring kinase-related fusions. Patients ranged from 21 to 80 years old (median, 38 y) and presented either asymptomatically or with pelvic pain and/or uterine bleeding. Eleven (92%; 11/12) tumors were localized to the cervix and 1 (8%; 1/12) tumor was localized in the anterior fundus of the uterine corpus. Tumors ranged in size from 1.5 to 15.0 cm (median, 6.0 cm) and were histologically characterized by a moderately cellular, infiltrative proliferation of spindle cells with features of benign gland entrapment, stromal collagen deposition, perivascular hyalinization, occasionally myxoid stroma, a lymphocytic infiltrate, occasional nuclear pseudoinclusions, and a pseudophyllodes architecture. RNA-sequencing identified NTRK1 (8/12), NTRK3 (1/12), and PDGFB (2/12) gene fusions, which have been previously implicated in this tumor class, as well as a novel FGFR1-TACC1 (1/12) fusion. All tumors in this cohort showed coexpression of CD34 and S100 by immunohistochemistry except for those tumors with PDGFB fusions which showed solely CD34 expression. Of the 10 surgically resected tumors with follow-up, outcomes best correlated with the stage of disease. One of 4 patients with stage IA tumors (1/4) had recurrences, half of the stage IB (2/4) tumors had recurrences and all of the stage IIB tumors (2/2) had recurrences and died of disease. Future studies are still required to better understand the spectrum of genetic alterations as well as evaluate the efficacy of targeted kinase inhibitors in this class of tumor.
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Biomarcadores de Tumor/genética , Proteínas Fetales/genética , Fusión Génica , Proteínas Asociadas a Microtúbulos/genética , Neurofibrosarcoma/genética , Proteínas Nucleares/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Sarcoma/genética , Neoplasias Uterinas/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Bases de Datos Factuales , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Estadificación de Neoplasias , Neurofibrosarcoma/enzimología , Neurofibrosarcoma/patología , Neurofibrosarcoma/cirugía , RNA-Seq , Sarcoma/enzimología , Sarcoma/patología , Sarcoma/cirugía , Resultado del Tratamiento , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/patología , Neoplasias Uterinas/cirugía , Adulto JovenRESUMEN
Inflammatory myofibroblastic tumors (IMTs) of the uterus are often associated with pregnancy and are delivered with the placenta. We describe the clinical, pathologic, and molecular findings in nine cases of placenta-associated IMT (PaIMT). All the lesions were incidentally discovered at delivery or on placental pathological examination. The maternal age ranged from 21 to 41 (mean = 30.6) years. Eight patients had high-risk pregnancies, and when known, all patients were multigravida. Macroscopically, eight tumors were well defined, ranging in size from 2 to 6 cm present at the maternal surface of the placenta (n = 3) and membranes (n = 4) or separately delivered with the placenta (n = 2). All nine lesions revealed classical IMT morphology with spindle cells associated with a lymphoplasmacytic infiltrate and thin elongated vessels. Five showed decidualization, and five showed coagulative necrosis. All tumors expressed CD10. Of the seven tumors that were anaplastic lymphoma kinase (ALK) positive, six were confirmed to have an ALK rearrangement by fluorescence in situ hybridization (FISH), whereas one failed FISH testing. Fusions included TIMP3-ALK (n = 3), THBS1-ALK (n = 2), and a novel SYN3-ALK fusion (n = 1). Clinical follow-up was available in three patients, with no recurrence reported. There appears to be an increased frequency of uterine IMTs in pregnancy and associated with the placenta. No PaIMT has behaved aggressively, although follow-up has been quite limited. This may speak to a specific behavior of these tumors when associated with pregnancy.
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Miofibroblastos/patología , Placenta/patología , Complicaciones Neoplásicas del Embarazo/patología , Neoplasias Uterinas/patología , Adulto , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Bases de Datos Factuales , Femenino , Fusión Génica , Humanos , Histerectomía , Hallazgos Incidentales , Miofibroblastos/química , Placenta/química , Embarazo , Complicaciones Neoplásicas del Embarazo/genética , Complicaciones Neoplásicas del Embarazo/metabolismo , Complicaciones Neoplásicas del Embarazo/cirugía , Resultado del Tratamiento , Carga Tumoral , Neoplasias Uterinas/química , Neoplasias Uterinas/genética , Neoplasias Uterinas/cirugía , Adulto JovenRESUMEN
As inflammatory myofibroblastic tumors (IMTs) have become more widely recognized in the female genital tract, an intriguing subset of uterine tumors associated with pregnancy has emerged. Whether uterine IMTs occurring in the setting of pregnancy are clinically or biologically distinct from other uterine IMTs is unknown. Furthermore, little is known about the perinatal factors that may influence the development of these tumors. Here, we report the largest case series of 8 pregnancy-associated IMTs. All pregnancy-associated IMTs in this series occurred in association with pregnancy complications, including abnormal implantation (n=1), gestational diabetes (n=2), preeclampsia and/or HELLP syndrome (n=2), antiphospholipid syndrome (n=1), premature rupture of membranes (n=1), and hepatitis B (n=1). Notably, all IMTs were expelled at the time of delivery or immediately postpartum and were either adherent to the placenta or presented as separate, detached tissue. Tumors ranged from 2.0 to 6.0 cm (median, 3.9 cm), were well-circumscribed and showed classic histologic features of IMTs, including myxoid stroma and a lymphoplasmacytic infiltrate. Seven of 8 cases were positive by ALK immunohistochemistry and confirmed to have an ALK gene rearrangement by fluorescent in situ hybridization and RNA sequencing. The ALK-rearranged IMTs were found to be particularly enriched for TIMP3-ALK (n=5) and THBS1-ALK (n=2) fusions. The single case that was negative for an ALK rearrangement exhibited the classic morphology of an IMT. None of the 4 cases with available clinical follow-up recurred. The clinicopathologic features of pregnancy-associated IMTs in this series in conjunction with those reported in the literature suggests that these may be transient tumors that develop during pregnancy and shed at parturition; they appear to have a relatively indolent clinical course and favorable outcome, although studies with a longer duration of follow-up are still required.
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Quinasa de Linfoma Anaplásico/genética , Neoplasias de Tejido Muscular/diagnóstico , Proteínas de Fusión Oncogénica/genética , Complicaciones Neoplásicas del Embarazo/diagnóstico , Trombospondina 1/genética , Inhibidor Tisular de Metaloproteinasa-3/genética , Neoplasias Uterinas/diagnóstico , Adulto , Quinasa de Linfoma Anaplásico/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias de Tejido Muscular/genética , Neoplasias de Tejido Muscular/patología , Fusión de Oncogenes , Proteínas de Fusión Oncogénica/metabolismo , Embarazo , Complicaciones Neoplásicas del Embarazo/genética , Complicaciones Neoplásicas del Embarazo/patología , Análisis de Secuencia de ARN , Trombospondina 1/metabolismo , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologíaRESUMEN
Smooth muscle tumors are the most common mesenchymal tumors of the female genital tract. However, awareness of tumor variants and unconventional growth patterns is critical for appropriate classification and patient management. For example, recognition of fumarate hydratase-deficient leiomyomas allows pathologists to alert providers to the potential for hereditary leiomyomatosis and renal cell carcinoma. Furthermore, myxoid and epithelioid smooth muscle tumors have different thresholds for malignancy than spindled tumors and should be classified by criteria specific to these variants. This article provides an overview of smooth muscle tumors of each major organ of the gynecologic tract and discusses diagnostic challenges.
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Neoplasias de los Genitales Femeninos/patología , Tumor de Músculo Liso/patología , Diagnóstico Diferencial , Femenino , Neoplasias de los Genitales Femeninos/diagnóstico , Humanos , Leiomioma/diagnóstico , Leiomioma/patología , Leiomiosarcoma/diagnóstico , Leiomiosarcoma/patología , Pronóstico , Tumor de Músculo Liso/diagnóstico , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologíaRESUMEN
CONTEXT.: Next-generation sequencing-based assays are being increasingly used in the clinical setting for the detection of somatic variants in solid tumors, but limited data are available regarding the interlaboratory performance of these assays. OBJECTIVE.: To examine proficiency testing data from the initial College of American Pathologists (CAP) Next-Generation Sequencing Solid Tumor survey to report on laboratory performance. DESIGN.: CAP proficiency testing results from 111 laboratories were analyzed for accuracy and associated assay performance characteristics. RESULTS.: The overall accuracy observed for all variants was 98.3%. Rare false-negative results could not be attributed to sequencing platform, selection method, or other assay characteristics. The median and average of the variant allele fractions reported by the laboratories were within 10% of those orthogonally determined by digital polymerase chain reaction for each variant. The median coverage reported at the variant sites ranged from 1922 to 3297. CONCLUSIONS.: Laboratories demonstrated an overall accuracy of greater than 98% with high specificity when examining 10 clinically relevant somatic single-nucleotide variants with a variant allele fraction of 15% or greater. These initial data suggest excellent performance, but further ongoing studies are needed to evaluate the performance of lower variant allele fractions and additional variant types.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/normas , Ensayos de Aptitud de Laboratorios , Oncología Médica/normas , Patología Clínica/normas , Humanos , Reproducibilidad de los ResultadosRESUMEN
Smooth muscle tumor of uncertain malignant potential (STUMP) is a rare diagnosis rendered when there is uncertainty concerning the biological potential of a smooth muscle tumor. The initial differential diagnosis is often broad, as tumors in this subgroup are morphologically heterogenous. Recent data suggest uterine inflammatory myofibroblastic tumors (IMTs) with anaplastic lymphoma kinase (ALK) rearrangement may be misclassified as STUMPs, but the extent to which this occurs has not been examined. We identified 60 female patients with tumors previously diagnosed as STUMP (48 cases) or prospectively considered for the diagnosis of STUMP (12 cases). Each case underwent histologic review, ALK immunohistochemistry (IHC) and confirmatory break-apart fluorescence in situ hybridization (FISH) for ALK if immunoreactive. Six of the 43 (14%) uterine and cervical tumors were ALK IHC positive, whereas tumors at all other sites were ALK IHC negative. Myxoid features, although limited in some cases, were present in all 6 ALK IHC positive tumors, representing 35% (6/17) of tumors displaying myxoid features at uterine and cervical sites. All ALK immunoreactive tumors were confirmed to have ALK rearrangements by FISH with 1 tumor showing numerous (3 to 8) 3' ALK signals, an unusual FISH pattern not previously described in uterine IMTs. Two patients developed recurrent disease and were treated with ALK-targeted therapy with initial response. Our data demonstrate that a significant proportion of uterine and cervical tumors considered to be STUMPs are ALK-positive by IHC and FISH. Future screening of all uterine and cervical mesenchymal tumors under consideration for the diagnosis of STUMP, particularly those with myxoid features, is recommended to identify ALK-rearranged IMTs that could potentially be treated with targeted therapy using tyrosine kinase inhibitors.