RESUMEN
PLAG1 gene fusions were recently identified in a subset of uterine myxoid leiomyosarcomas (M-LMS). However, we have encountered cases of PLAG1-rearranged uterine sarcomas lacking M-LMS-like morphology and/or any expression of smooth muscle markers. To better characterize their clinicopathologic features, we performed a multiinstitutional search that yielded 11 cases. The patients ranged in age from 34 to 72 years (mean, 57 years). All tumors arose in the uterine corpus, ranging in size from 6.5 to 32 cm (mean, 15 cm). The most common stage at presentation was pT1b (n = 6), and 3 cases had stage pT1 (unspecified), and 1 case each presented in stages pT2a and pT3b. Most were treated only with hysterectomy and adnexectomy. The follow-up (range, 7-71 months; median, 39 months) was available for 7 patients. Three cases (7-21 months of follow-up) had no evidence of disease. Three of the 4 remaining patients died of disease within 55 to 71 months, while peritoneal spread developed in the last patient, and the patient was transferred for palliative care at 39 months. Morphologically, the tumors showed a high intertumoral and intratumoral heterogeneity. M-LMS-like and epithelioid leiomyosarcoma-like morphology were present in 3 and 5 primary tumors, respectively, the remaining mostly presented as nondescript ovoid or spindle cell sarcomas. Unusual morphologic findings included prominently hyalinized stroma (n = 3), adipocytic differentiation with areas mimicking myxoid liposarcoma (n = 2), osteosarcomatous differentiation (n = 1), and undifferentiated pleomorphic sarcoma-like areas (n = 1). The mitotic activity ranged from 3 to 24 mitoses per 10 high-power fields (mean, 9); 3 of 10 cases showed necrosis. In 3 of 11 cases, no expression of smooth muscle actin, h-caldesmon, or desmin was noted, whereas 5 of 5 cases expressed PLAG1. By RNA sequencing, the following fusion partners were identified: PUM1, CHCHD7 (each n = 2), C15orf29, CD44, MYOCD, FRMD6, PTK2, and TRPS1 (each n = 1). One case only showed PLAG1 gene break by fluorescence in situ hybridization. Our study documents a much broader morphologic spectrum of PLAG1-rearranged uterine sarcomas than previously reported, encompassing but not limited to M-LMS-like morphology with occasional heterologous (particularly adipocytic) differentiation. As it is currently difficult to precisely define their line of differentiation, for the time being, we suggest using a descriptive name "PLAG1-rearranged uterine sarcoma."
RESUMEN
Lipoblastoma-like tumor (LLT) is a benign soft tissue tumor demonstrating mixed morphologic features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma but lacking genetic alterations associated with those tumors. LLT was originally thought to be specific to the vulva but has since been reported in the paratesticular region. The morphologic features of LLT overlap with those of "fibrosarcoma-like lipomatous neoplasm" (FLLN), a rare, indolent adipocytic neoplasm considered by some to form part of the spectrum of atypical spindle cell and pleomorphic lipomatous tumor. We compared the morphologic, immunohistochemical, and genetic features of 23 tumors previously classified as LLT (n = 17) and FLLN (n = 6). The 23 tumors occurred in 13 women and 10 men (mean age, 42 years; range, 17 to 80 years). Eighteen (78%) cases arose in the inguinogenital region, whereas 5 tumors (22%) involved noninguinogenital soft tissue, including the flank (n = 1), shoulder (n = 1), foot (n = 1), forearm (n = 1), and chest wall (n = 1). Microscopically, the tumors were lobulated and septated, with variably collagenized fibromyxoid stroma, prominent thin-walled vessels, scattered univacuolated or bivacuolated lipoblasts, and a minor component of mature adipose tissue. Using immunohistochemistry, 5 tumors (42%) showed complete RB1 loss, with partial loss in 7 cases (58%). RNA sequencing, chromosomal microarray, and DNA next-generation sequencing study results were negative for significant alterations. There were no clinical, morphologic, immunohistochemical, or molecular genetic differences between cases previously classified as LLT or FLLN. Clinical follow-up (11 patients [48%]; range, 2-276 months; mean, 48.2 months) showed all patients were alive without disease, and only one patient had experienced a single local recurrence. We conclude that LLT and FLLN represent the same entity, for which "LLT" seems most appropriate. LLT may occur in either sex and any superficial soft tissue location. Careful morphologic study and appropriate ancillary testing should allow for the distinction of LLT from its potential mimics.
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Fibrosarcoma , Lipoblastoma , Lipoma , Liposarcoma Mixoide , Liposarcoma , Masculino , Adulto , Humanos , Femenino , Lipoblastoma/genética , Biomarcadores de Tumor/genética , Lipoma/genética , Lipoma/patología , Liposarcoma/genética , Biología MolecularRESUMEN
OBJECTIVE: Alterations in DNA methylation are early events in endometrial cancer (EC) development and may have utility in EC detection via tampon-collected vaginal fluid. METHODS: For discovery, DNA from frozen EC, benign endometrium (BE), and benign cervicovaginal (BCV) tissues underwent reduced representation bisulfite sequencing (RRBS) to identify differentially methylated regions (DMRs). Candidate DMRs were selected based on receiver operating characteristic (ROC) discrimination, methylation level fold-change between cancers and controls, and absence of background CpG methylation. Methylated DNA marker (MDM) validation was performed using qMSP on DNA from independent EC and BE FFPE tissue sets. Women ≥45 years of age with abnormal uterine bleeding (AUB) or postmenopausal bleeding (PMB) or any age with biopsy-proven EC self-collected vaginal fluid using a tampon prior to clinically indicated endometrial sampling or hysterectomy. Vaginal fluid DNA was assayed by qMSP for EC-associated MDMs. Random forest modeling analysis was performed to generate predictive probability of underlying disease; results were 500-fold in-silico cross-validated. RESULTS: Thirty-three candidate MDMs met performance criteria in tissue. For the tampon pilot, 100 EC cases were frequency matched by menopausal status and tampon collection date to 92 BE controls. A 28-MDM panel highly discriminated between EC and BE (96% (95%CI 89-99%) specificity; 76% (66-84%) sensitivity (AUC 0.88). In PBS/EDTA tampon buffer, the panel yielded 96% (95% CI 87-99%) specificity and 82% (70-91%) sensitivity (AUC 0.91). CONCLUSION: Next generation methylome sequencing, stringent filtering criteria, and independent validation yielded excellent candidate MDMs for EC. EC-associated MDMs performed with promisingly high sensitivity and specificity in tampon-collected vaginal fluid; PBS-based tampon buffer with added EDTA improved sensitivity. Larger tampon-based EC MDM testing studies are warranted.
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Neoplasias Endometriales , Humanos , Femenino , Marcadores Genéticos , Ácido Edético/metabolismo , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Endometrio/metabolismo , ADN , Metilación de ADNRESUMEN
Inflammatory myofibroblastic tumors (IMT) are rare neoplasms of intermediate malignant potential which have been described in the gynecologic tract, predominantly in the myometrial wall, but also in association with the placenta. Like those in other organs, IMT of the placenta are characterized by molecular abnormalities, most commonly anaplastic lymphoma kinase gene rearrangements, and are often positive for anaplastic lymphoma kinase immunohistochemically. Although the clinical behavior of placental IMTs has so far proven benign, a successful intrauterine pregnancy with subsequent negative hysterectomy following a placental IMT has not been documented. Herein is presented a case of a 27-yr-old noted to have a 2 cm IMT of the extraplacental membranes at delivery, after which the patient received no further treatment. After 56 mo, the patient experienced a subsequent normal delivery in a pregnancy complicated by gestational diabetes. No longer desiring fertility, the patient elected to have a hysterectomy to confirm the absence of IMT at 59 mo and the uterus was unremarkable. This case provides insight into possible outcomes for patients with a rare tumor who may desire future fertility and may otherwise be advised to undergo hysterectomy in the setting of an unclear clinical course.
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Granuloma de Células Plasmáticas , Neoplasias Uterinas , Humanos , Femenino , Embarazo , Quinasa de Linfoma Anaplásico/genética , Placenta/patología , Estudios de Seguimiento , Neoplasias Uterinas/patología , Granuloma de Células Plasmáticas/patología , HisterectomíaRESUMEN
Application of molecular testing in clinical practice has led to significant advances in the classification of soft tissue sarcomas. Despite remarkable progress, there are still challenging cases that remain unclassified. In this study, we present an unusual spindle cell sarcoma arising in the abdominal cavity of a 37-year-old female. An extensive panel of immunostains was nonspecific for a line of differentiation and the tumor was subjected to targeted RNA sequencing for further classification. The findings showed a novel WWTR1::AFF2 fusion, which was further confirmed by break-apart FISH analysis for WWTR1 gene rearrangement. The tumor was attached to the wall of sigmoid colon and showed a highly cellular proliferation of plump spindle to epithelioid cells arranged in intersecting fascicles. Areas of extensive endometriosis were identified adjacent to the tumor. The immunoprofile was significant for reactivity with desmin, calponin, WT-1, ER, and PR, while negative for CD10, SMA, caldesmon, pan-keratin, ALK, CD117, and S100. The patient is alive and well after 11 months of follow-up. The exact histogenesis of this sarcoma remains unclear, however, the presence of adjacent endometriosis and coexpression of WT1/ER/PR raises the possibility of an unusual endometrioid stromal sarcoma, occurring outside the GYN tract. Additional cases are needed to establish the recurrent potential of this fusion event and to better define its pathogenesis and clinical behavior.
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Cavidad Abdominal , Neoplasias Endometriales , Endometriosis , Sarcoma , Neoplasias de los Tejidos Blandos , Cavidad Abdominal/patología , Adulto , Biomarcadores de Tumor/genética , Neoplasias Endometriales/genética , Endometriosis/genética , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Proteínas Nucleares , Sarcoma/patología , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZRESUMEN
OBJECTIVE: Aberrant DNA methylation is an early event in carcinogenesis which could be leveraged to detect ovarian cancer (OC) in plasma. METHODS: DNA from frozen OC tissues, benign fallopian tube epithelium (FTE), and buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify OC MDMs. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent OC and FTE FFPE tissues. MDMs were tested using Target Enrichment Long-probe Quantitative Amplified Signal (TELQAS) assays in pre-treatment plasma from women newly diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated. RESULTS: Thirty-three MDMs showed marked methylation fold changes (10 to >1000) across all OC subtypes vs FTE. Eleven MDMs (GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, RIPPLY3, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (73 (80%) high-grade serous (HGS)) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95% CI, 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86-0.96)). Among the 5 stage I/II HGS OCs included, all were correctly identified. CONCLUSIONS: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded candidate MDMs for OC that performed with high sensitivity and specificity in plasma. Larger plasma-based OC MDM studies, including testing of pre-diagnostic specimens, are warranted.
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Metilación de ADN , Neoplasias Ováricas , Biomarcadores de Tumor/genética , Proteínas CELF/genética , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/genética , Estudios de Factibilidad , Femenino , Marcadores Genéticos , Humanos , Proteínas del Tejido Nervioso/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Transaminasas/genéticaRESUMEN
STUDY OBJECTIVE: To assess the association between laparoscopic appearance of superficial endometriosis lesions, histopathology, and systemic hormone use. DESIGN: Retrospective study. SETTING: Tertiary care academic medical center. PATIENTS: We identified 266 women who underwent laparoscopic surgery at an endometriosis center with excision of lesions consistent with possible superficial endometriosis between September 2015 and November 2018. INTERVENTIONS: Appearance of the peritoneal lesions was confirmed with review of surgical videos and correlated with each pathology specimen. Lesions were dichotomized on positive or negative pathology assessment. All pathology-positive lesions were further dichotomized by hormone use within 1 month of surgery. MEASUREMENTS AND MAIN RESULTS: A total of 841 lesions were biopsied from included subjects during the study period. Of those, 251 biopsies were negative, and 590 were positive for endometriosis on pathology assessment. Lesions had significantly higher odds of positive histology when they were red (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.17-2.48), white (OR, 1.99; 95% CI, 1.47-2.70), blue/black (OR, 2.98; 95% CI, 2.00-4.44), or puckering (OR, 9.78; 95% CI, 2.46-38.91) in appearance. The following combined characteristics had significantly higher odds of positive histology: white and blue (OR, 5.98; 95% CI, 2.97-12.02), red and white (OR, 2.22; 95% CI, 1.38-3.56), red and blue (OR, 4.11; 95% CI, 1.83-9.24), and clear and white (OR, 8.77; 95% CI, 1.17-66.02). Among positive biopsies, those with hormone exposure were more likely to have clear lesions than those without hormone use (OR, 3.36; 95% CI, 1.54-7.34) and were 2.89 times more likely to have clear and white lesions (95% CI, 1.07-7.85). CONCLUSION: Although lesions suspicious for endometriosis may have differing rates of positive pathology based on appearance, no lesion characteristic was able to exclude the possibility of endometriosis. In addition, hormone use may influence lesion appearance at the time of surgery, with clear lesions more prevalent. These data have implications for appropriate identification of endometriosis at the time of laparoscopy to ensure accurate diagnosis and complete treatment of disease.
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Endometriosis , Laparoscopía , Enfermedades Peritoneales , Humanos , Femenino , Estudios Retrospectivos , Endometriosis/patología , Enfermedades Peritoneales/cirugía , HormonasRESUMEN
Desmoplastic small round cell tumor (DSRCT) is a high-grade round cell sarcoma that typically arises in the abdominopelvic cavity of young males, co-expresses keratins and desmin, and carries a pathognomonic EWSR1-WT1 gene fusion. The EWSR1-WT1 gene fusion is generally considered specific for DSRCT, although there are two reports of this fusion in tumors otherwise lacking features of DSRCT. We report three female genital tract tumors with EWSR1-WT1 fusions but showing morphologic and immunohistochemical features incompatible with DSRCT. The tumors occurred in the uterine cervix, uterine corpus/ovaries, and vagina, respectively, of 46, 30, and 20-year-old women. Two tumors consisted of a sheet-like to fascicular proliferation of relatively uniform spindled to occasionally more epithelioid cells arrayed about thick-walled, hyalinized, and capillary-sized vessels, with distinctive areas of pseudovascular change, and absence of desmoplastic stroma. The third tumor resembled a monomorphic spindle cell sarcoma with necrosis. All had diffuse desmin and variable but more limited keratin expression, two of three expressed smooth muscle actin, and all were negative for h-caldesmon, CD10, estrogen receptor, myogenin, N-terminus WT-1, and S100 protein. One patient received neoadjuvant chemotherapy and radiation therapy followed by resection and is disease-free 42 months after diagnosis. Another patient was managed by resection only and is disease-free 9 months after initial diagnosis. The remaining patient recently underwent resection of multifocal pelvic disease. Comprehensive differential gene expression analysis on two tumors compared to two classic DSRCTs with known EWSR1-WT1 fusions resulted in 1726 genes that were differentially expressed (log2 fold change >2 or < -2) and statistically significant (FDR < 5%). In combination with previous reports, our findings suggest pleiotropy of the EWSR1-WT1 fusion is possible and not limited to DSRCT. Subsets of non-DSRCT EWSR1-WT1 positive tumors may represent discrete entities, but further study is necessary.
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Neoplasias de los Genitales Femeninos/patología , Fusión de Oncogenes/genética , Proteína EWS de Unión a ARN/genética , Proteínas WT1/genética , Adulto , Femenino , Neoplasias de los Genitales Femeninos/genética , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
Primary lung tumors are very rare in children and constitute only 0.2 percent of all pediatric malignancies. Carcinoids are the most common primary pediatric lung tumor and account for 80 percent of all primary malignant bronchial tumors. Carcinoid tumors can be histologically categorized as typical or atypical. They are derived from neuroendocrine cells in the bronchial epithelium and are locally infiltrative. Surgical resection of endobronchial carcinoid tumors is the mainstay of treatment with a five-year survival of 95 percent. Endoscopic resection has been reported in adult patients with typical carcinoid tumors (less than 20 mm) with no extrabronchial disease. We present the first pediatric bronchial carcinoid tumor treated with endoscopic resection.
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Tumor Carcinoide , Neoplasias Pulmonares , Neumonía , Adulto , Tumor Carcinoide/complicaciones , Tumor Carcinoide/diagnóstico , Niño , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/diagnóstico , Neumonía/etiología , SíndromeRESUMEN
Lipoblastoma-like tumor of the vulva was first described as a benign mesenchymal neoplasm of adipocytic differentiation having features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma. Prior studies of lipoblastoma-like tumor have evaluated PLAG1, HMGA2, and RB1 immunohistochemistry and DDIT3 rearrangement status, with results supporting its distinction from lipoblastoma and myxoid liposarcoma. However, absent RB1 expression was reported in a majority of tested cases, suggesting that lipoblastoma-like tumor may have underlying 13q alterations and be related to RB1-deleted soft tissue tumors. To further understand the molecular genetics of lipoblastoma-like tumor, we examined 7 cases by RB1 immunohistochemistry, DDIT3 and PLAG1 break apart FISH probes, RB1 enumeration FISH probe, and genomic copy number analysis by microarray. Patient age ranged from 21 to 56 years (median 35 years). Clinical follow up was available for 5 patients (71%) ranging 3-264 months (median 74 months). Microscopically, lipoblastoma-like tumor formed large lobules separated by thin and/or thick bands of fibrous tissue and had a prominent network of thin-walled vessels. Each tumor was predominantly composed of spindle cells and lipoblasts with variable quantities of mature adipocytes. RB1 immunohistochemistry exhibited a heterogeneous or "mosaic" pattern of weak and negative nuclear expression in all seven cases. DDIT3 and PLAG1 FISH were negative in each case. No evidence of RB1 regional gain or loss was identified by FISH. Genomic copy number analysis by chromosomal microarray showed a normal diploid profile in six tumors (86%). One tumor had copy number abnormalities consisting of an 11.9 megabase deletion from 1p13.3 to 1p11.2 and monosomy 14. Although lipoblastoma-like tumor has features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma, it is genetically different from these tumors. Furthermore, lipoblastoma-like tumor does not appear to have structural abnormalities of 13q resulting in deletion of RB1.
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Neoplasias de los Tejidos Conjuntivo y Blando/genética , Neoplasias de los Tejidos Conjuntivo y Blando/patología , Neoplasias de la Vulva/genética , Neoplasias de la Vulva/patología , Adulto , Femenino , Dosificación de Gen , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Persona de Mediana Edad , Adulto JovenRESUMEN
Of the subtypes of extracardiac rhabdomyoma, genital rhabdomyoma is most uncommon and is occasionally classified as fetal rhabdomyoma due to morphologic similarities. In contrast to other forms of rhabdomyoma, the genetic alterations of genital rhabdomyoma are unknown. The clinical and pathologic findings in 12 cases were reviewed and 2 cases were processed for whole genome copy number analysis by single nucleotide polymorphism microarray. Twelve patients ranged in age from 43 to 65 yr (mean: 50.2 yr). Nine tumors arose in the vagina and 3 in the cervix, with their greatest dimension spanning 0.9 to 1.7 cm (mean: 1.4 cm). Follow-up was available for 7 patients and none had evidence of recurrence (67-263 mo, mean: 153.7 mo). No somatic copy number alterations, particularly involving genes in Hedgehog signaling, were identified by microarray. Although genital rhabdomyoma has sufficiently unique clinicopathologic characteristics including age of onset and organs of involvement to distinguish it from fetal rhabdomyoma, the genetic mechanisms underlying its development are unclear given the lack of copy number variation and loss of heterozygosity by single nucleotide polymorphism microarray.
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Neoplasias de los Genitales Femeninos/genética , Rabdomioma/genética , Adulto , Anciano , Variaciones en el Número de Copia de ADN , Femenino , Neoplasias de los Genitales Femeninos/patología , Genitales Femeninos/patología , Humanos , Pérdida de Heterocigocidad , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Rabdomioma/patologíaRESUMEN
Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a recently described, clinically aggressive variant of inflammatory myofibroblastic tumor with a predilection for intraabdominal sites, tendency to arise in male patients and resistance to conventional chemotherapy and radiotherapy. We present a case of a 15-year-old girl with EIMS of the ovary with a RANBP2-ALK fusion. During 2 years of follow up, she experienced multiple recurrences. Following classification of the tumor as EIMS, the patient began treatment with an ALK inhibitor (crizotinib), which led to disease improvement within weeks of administration. To the best of our knowledge, this represents the first reported case of EIMS arising in the female genital tract.
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Proteínas de Fusión Oncogénica/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Sarcoma/genética , Sarcoma/patología , Adolescente , Femenino , HumanosRESUMEN
Dermatofibrosarcoma protuberans (DFSP) is a low-grade fibroblastic sarcoma that tends to arise in young to middle age adults and involve the trunk and proximal extremities. Rare examples of vulvar DFSP have been reported, including myxoid, myoid, and fibrosarcomatous variants, but detection of the characteristic t(17;22)(q22;q13) that produces COL1A1-PDGFB gene fusion has not been evaluated in a large series of primary vulvar tumors. The clinical, morphologic, immunohistochemical, and molecular cytogenetic features of 11 cases were examined. Patient age ranged from 29 to 75 yr (mean, 46 yr; median, 43 yr). Seven tumors were purely classic DFSP, 1 was purely myxoid DFSP and the remaining 3 had varying quantities of fibrosarcomatous DFSP. All cases of classic DFSP had diffuse expression of CD34 and low-level p53 immunoreactivity. Myxoid variants had strong, but reduced expression of CD34. Fibrosarcomatous DFSP showed focal CD34 expression and increased p53 reactivity. Nine of 11 tumors (82%) had rearrangement of PDGFB by fluorescence in situ hybridization. The 2 nonrearranged tumors were a classic DFSP and a myxoid DFSP with fibrosarcomatous transformation. Follow-up was available for 9 patients (82%) and ranged from 1 to 108 mo (mean, 30 mo; median, 21 mo). Eight patients had tumors with positive margins, one of which developed local recurrence after no further therapy. No patient developed metastasis. The high frequency of PDGFB rearrangement in vulvar DFSP provides a useful exploit in diagnostically challenging cases and genetic evidence of probable clinical response to targeted therapeutics in cases of locally advanced or metastatic tumors.
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Dermatofibrosarcoma/genética , Reordenamiento Génico , Proteínas Proto-Oncogénicas c-sis/genética , Neoplasias Cutáneas/genética , Vulva/patología , Neoplasias de la Vulva/genética , Adulto , Anciano , Biomarcadores de Tumor , Dermatofibrosarcoma/patología , Femenino , Humanos , Hibridación Fluorescente in Situ , Persona de Mediana Edad , Neoplasias Cutáneas/patología , Neoplasias de la Vulva/patologíaRESUMEN
To date, the vast majority of collision tumors in the ovary include either a teratoma, sex cord-stromal tumor, or both. Here we report the first case of a collision tumor consisting of a steroid cell tumor and a signet-ring stromal tumor.
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Carcinoma de Células en Anillo de Sello/diagnóstico , Neoplasias Ováricas/diagnóstico , Tumores de los Cordones Sexuales y Estroma de las Gónadas/diagnóstico , Carcinoma de Células en Anillo de Sello/patología , Carcinoma de Células en Anillo de Sello/cirugía , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Ovario/patología , Ovario/cirugía , Salpingooforectomía , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/cirugíaAsunto(s)
Neoplasias Endometriales , Tumores Estromáticos Endometriales , Leiomioma , Sarcoma Estromático Endometrial , Tumor de Músculo Liso , Neoplasias Uterinas , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Neoplasias Endometriales/cirugía , Tumores Estromáticos Endometriales/diagnóstico , Tumores Estromáticos Endometriales/patología , Femenino , Humanos , Leiomioma/patología , Leiomioma/cirugía , Músculo Liso/patología , Sarcoma Estromático Endometrial/diagnóstico , Sarcoma Estromático Endometrial/genética , Sarcoma Estromático Endometrial/cirugía , Tumor de Músculo Liso/diagnóstico , Tumor de Músculo Liso/genética , Tumor de Músculo Liso/patología , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Neoplasias Uterinas/cirugíaRESUMEN
Uterine tumors with adipocytic differentiation are very uncommon. Mature adipocytes are sometimes seen as an element of smooth muscle neoplasms, more often as lipoleiomyoma, but also in the rare lipoleiomyosarcoma. Exceptional cases have been reported of various subtypes of liposarcoma associated with uterine smooth muscle tumors with or without adipocytic differentiation. We present a case of pleomorphic liposarcoma arising in a lipoleiomyosarcoma of the uterus. Genomic profiling was performed using a validated next generation sequencing panel covering 410 common cancer genes. Alterations were identified in TP53, PTEN, RB1, FAT1 and TERT. The patient's presentation and clinical course as well as the tumor's morphologic, immunohistochemical and molecular genetic findings are reviewed.
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Biomarcadores de Tumor/genética , Leiomiosarcoma/patología , Liposarcoma/patología , Tumor de Músculo Liso/patología , Neoplasias Uterinas/patología , Anciano , Diferenciación Celular , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leiomiosarcoma/diagnóstico , Leiomiosarcoma/genética , Liposarcoma/diagnóstico , Liposarcoma/genética , Recurrencia Local de Neoplasia , Tumor de Músculo Liso/diagnóstico , Tumor de Músculo Liso/genética , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Útero/patologíaRESUMEN
The Cancer Genome Atlas described four major genomic groups of endometrial carcinomas, including a POLE ultramutated subtype comprising â¼10% of endometrioid adenocarcinoma, characterized by POLE exonuclease domain mutations, ultrahigh somatic mutation rates, and favorable outcome. Our aim was to examine the morphological and clinicopathological features of ultramutated endometrial carcinomas harboring somatic POLE exonuclease domain mutations. Hematoxylin and eosin slides and pathology reports for 8/17 POLE-mutated endometrial carcinomas described in the Cancer Genome Atlas study were studied; for the remaining cases, virtual whole slide images publicly available at cBioPortal (www.cbioportal.org) were examined. A second cohort of eight POLE mutated endometrial carcinomas from University of Calgary was also studied. Median age was 55 years (range 33-87 years). Nineteen patients presented as stage I, 1 stage II, and 5 stage III. The majority of cases (24 of the 25) demonstrated defining morphological features of endometrioid differentiation. The studied cases were frequently high grade (60%) and rich in tumor-infiltrating lymphocytes and/or peri-tumoral lymphocytes (84%); many tumors showed morphological heterogeneity (52%) and ambiguity (16%). Foci demonstrating severe nuclear atypia led to concern for serous carcinoma in 28% of cases. At the molecular level, the majority of the Cancer Genome Atlas POLE-mutated tumors were microsatellite stable (65%), and TP53 mutations were present in 35% of cases. They also harbored mutations in PTEN (94%), FBXW7 (82%), ARID1A (76%), and PIK3CA (71%). All patients from both cohorts were alive without disease, and none of the patients developed recurrence at the time of follow-up (median 33 months; range 2-102 months). In conclusion, the recognition of ultramutated endometrial carcinomas with POLE exonuclease domain mutation is important given their favorable outcome. Our histopathological review revealed that these tumors are commonly high grade, have obvious lymphocytic infiltrates, and can show ambiguous morphology. As they frequently harbor TP53 mutations, it is important not to misclassify them as serous carcinoma.
Asunto(s)
Carcinoma Endometrioide/genética , Cistadenocarcinoma Seroso/genética , ADN Polimerasa II/genética , Neoplasias Endometriales/genética , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Endometrioide/patología , Proteínas de Ciclo Celular/genética , Fosfatidilinositol 3-Quinasa Clase I , Cistadenocarcinoma Seroso/patología , Proteínas de Unión al ADN , Neoplasias Endometriales/patología , Proteínas F-Box/genética , Proteína 7 que Contiene Repeticiones F-Box-WD , Femenino , Humanos , Inestabilidad de Microsatélites , Persona de Mediana Edad , Proteínas Nucleares/genética , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas de Unión a Poli-ADP-Ribosa , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
MDM2 amplification is known to occur in a variety of neoplasms and its detection by fluorescence in situ hybridization is helpful in distinguishing well-differentiated and dedifferentated liposarcoma from classic lipoma. We recently evaluated a mesenteric mass initially diagnosed as dedifferentiated liposarcoma, largely due to the neoplasm's myxoid morphology and MDM2 expression by immunohistochemistry, from a 46-yr-old woman with a history of uterine low-grade endometrial stromal sarcoma (LG-ESS) with a JAZF1 rearrangement. Our workup of the mesenteric mass revealed a JAZF1 rearrangement and a revised diagnosis of metastatic LG-ESS with myxoid change was rendered. Retrospective testing of the mesenteric mass was negative for MDM2 amplification, an uncommon, but known diagnostic pitfall in MDM2 expression by immunohistochemistry. As MDM2 amplification is not specific for the diagnosis of liposarcoma, we investigated its occurrence in 43 cases of endometrial stromal tumors: 14 uterine LG-ESS, 11 metastatic or recurrent uterine LG-ESS, 8 undifferentiated uterine sarcomas, 5 endometrial stromal nodules, and 4 high-grade ESS with YHWAE rearrangement. In addition, 40 of the 43 cases had previously undergone fluorescence in situ hybridization analysis of JAZF1, PHF1, and YHWAE. Two of the 43 cases (5%) had MDM2 amplification: one was a uterine LG-ESS (JAZF1 rearrangement) and the other was a undifferentiated uterine sarcoma (polysomy intact JAZF1, PHF1, and YHWAE), both metastatic to the lung. Both cases positive for MDM2 amplification showed MDM2 expression by immunohistochemistry. At last follow-up, both patients had died of disease (19 and 60 mo). Our study is the first to demonstrate MDM2 amplification in endometrial stromal tumor. Awareness of MDM2 amplification in endometrial stromal tumor is critical; particularly in locations more common to liposarcoma, to avoid diagnostic errors.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias Endometriales/diagnóstico , Tumores Estromáticos Endometriales/diagnóstico , Proteínas Proto-Oncogénicas c-mdm2/biosíntesis , Anciano , Neoplasias Endometriales/genética , Tumores Estromáticos Endometriales/genética , Femenino , Amplificación de Genes , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Liposarcoma/diagnóstico , Liposarcoma/genética , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-mdm2/análisis , Proteínas Proto-Oncogénicas c-mdm2/genéticaRESUMEN
Ovarian carcinoid tumors are very rare entities that often mimic other ovarian neoplasms. A case of primary ovarian carcinoid in a 44-year-old woman is presented with emphasis on the magnetic resonance imaging (MRI) features of the tumor and pathologic correlation. Ovarian carcinoid tumors can be variable in their MRI appearance, presumably due to different tumor subtypes and tumor components, thus requiring pathologic diagnosis. It is imperative to accurately diagnose primary ovarian carcinoid tumors, as their prognosis is usually more favorable compared to other malignant ovarian neoplasms.
RESUMEN
Tumors with pathogenic DICER1 mutation are rare and encompass sporadic or hereditary benign, intermediate and malignant tumors. DICER1-associated sarcomas are heterogeneous; however, the prototypical ones in the GYN-tract include embryonal rhabdomyosarcoma, adenosarcoma and moderately to poorly differentiated Sertoli-Leydig tumor. In this report, we present three unique uterine sarcomas with DICER1 mutation and remarkable diffuse round/spindle cell morphology. The tumors occurred in cervix (n = 1), and uterine corpus (n = 2). The patient ages were 30, 37 and 59 years with tumor size of 8.8, 10 and 8.6 cm, respectively. Morphologically all three tumors were characterized by distinct spindle/round cell morphology and various amounts of neuroectodermal differentiation (yolk sac-like tubules, blastomatous areas and rosette formation). Other morphologic features of DICER1-sarcoma reported in the literature including cambium layer, focal or diffuse anaplasia, solid and cystic architecture, and chondroid/osteoid areas were absent. All three sarcomas were positive for SALL4 and had variable neuroendocrine marker expression. Whole genome methylation analysis was performed on one of the uterine sarcomas, which clustered the tumor with embryonal tumor with multilayered rosettes. Follow up information was available on all three cases. Two patients were alive with no evidence of disease 13 and 14 months post operation, while one patient had imaging evidence of local recurrence 4 months post operation. In summary, we describe three unique DICER1-sarcomas and expand the phenotypic spectrum of this emerging entity, particularly with GYN-tract origin.