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DICER1 syndrome is a tumor predisposition syndrome in which patients are at an increased risk of developing a wide variety of benign and malignant neoplasms with a hallmark constellation of pediatric pleuropulmonary blastoma, cystic nephroma, and thyroid lesions. DICER1 encodes an RNA endoribonuclease that is crucial to the processing of microRNA and may play a role in the maturation of Müllerian tissue. Within the gynecologic tract, germline mutations in DICER1 are associated with an array of rare tumors, including Sertoli-Leydig cell tumor, embryonal rhabdomyosarcoma of the cervix, gynandroblastoma, and juvenile granulosa cell tumor, which typically present in childhood, adolescence, or early adulthood. In addition, somatic DICER1 mutations have been described in rare gynecologic tumors such as adenosarcoma, Sertoli cell tumor, ovarian fibrosarcoma, cervical primitive neuroectodermal tumor, carcinosarcoma, and germ cell tumors. In light of the significant association with multiple neoplasms, genetic counseling should be considered for patients who present with a personal or family history of these rare DICER1-associated gynecologic tumors. This review highlights the most current understanding of DICER1 genetic alterations and describes the clinical, histopathologic, and immunohistochemical features and differential diagnoses for gynecologic tumors associated with DICER1 mutation.

In the female genital tract, rhabdomyosarcoma may occur in "pure" form or as a heterologous constituent of a biphasic neoplasm such as carcinosarcoma or adenosarcoma. Discriminating rhabdomyosarcoma from its histologic mimics relies on confirmation of skeletal muscle differentiation by morphology or immunohistochemistry (IHC), which can be challenging to interpret in some cases owing to limited expression. PAX7, a transcription factor expressed in mammalian muscle progenitor cells, has been reported in up to 86% of soft tissue rhabdomyosarcomas by IHC. To determine whether PAX7 IHC could augment current approaches to identify rhabdomyosarcoma in gynecologic malignancies, we assessed PAX7, myogenin, and MyoD1 IHC on whole tissue sections from 100 gynecologic tumors: 50 with rhabdomyosarcomatous differentiation and 50 with features mimicking rhabdomyosarcoma. PAX7 expression was present in 96% (48/50) of gynecologic tumors with rhabdomyosarcomatous differentiation and was absent in all rhabdomyosarcoma mimics; it was more diffusely expressed than myogenin in 16 cases and was positive in a greater percentage of tumor cells in 28 cases. PAX7 and myogenin were typically coexpressed, and no rhabdomyosarcoma exhibited complete absence of both markers; however, 2 myogenin-negative tumors were PAX7-postive. Morphologically, PAX7 localized to the nuclei of primitive-appearing cells, whereas myogenin was observed in maturing rhabdomyoblasts including strap cells. Our findings highlight the utility of PAX7 as a complementary diagnostic marker of rhabdomyosarcomatous differentiation in gynecologic tumors. PAX7 should be used in combination with other markers of skeletal muscle differentiation, namely myogenin, and may be particularly helpful in cases where myogenin and/or MyoD1 expression is limited.

The objectives of this study are to define the specificity of theFormalin fixed paraffin embedded tissue sections from 12 FL-HCC cases, 142 cases of other hepatic neoplasms/proliferations (conventional HCC, focal nodular hyperplasia (FNH), hepatocellular adenoma (HA) and hepatoblastoma (HB)) and extrahepatic neoplasms (neuroblastoma (NB), Wilms tumor (WT) and Gastrointestinal neuroendocrine tumor (GNET)) and 60 matched background normal control tissues underwent fluorescence in situ hybridization (FISH) testing using a break apart probe targeting theTheThis study shows that, using standard techniques, FISH testing with a commercially available break apart probe targeting the

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.

Intracardiac paragangliomas most commonly arise from the left atrium and are often infiltrative and densely adherent to surrounding structures. Given their rarity, only scattered reports exist in the literature and standardized perioperative and surgical management is not well established. We describe a case of a 60-year-old woman with a mildly functioning intracardiac paraganglioma in which division of the superior vena cava improved exposure and enabled a complex limited resection. Further, we provide an overview of the diagnostic workup, perioperative medical management, surgical approach, and surveillance strategy in patients with these challenging tumors.

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.

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.

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.

Background: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune disorder that can lead to psychosis and severe neurological symptoms and is extremely rare in pregnancy. It is often associated with an ovarian teratoma, with many having symptomatic improvement after its removal. Many patients have a prolonged recovery time to their baseline neurological status. Case: This is a 33 year old G4P2012 who presented at 14 weeks gestation in status epilepticus after a 1 week history of acute behavioral changes, who was found to have an ovarian teratoma with anti-NMDA receptor encephalitis. She remained hospitalized throughout the duration of her pregnancy, which was complicated by drug induced hepatotoxicity, severe short term memory loss, tracheostomy and percutaneous gastric tube placement. The fetus was in breech presentation at 39 weeks, at which time an external cephalic version (ECV) was attempted and was unsuccessful, leading to an emergent primary cesarean delivery without complications. Conclusion: Anti-NDMA receptor encephalitis is a rare event that can occur in pregnancy that can lead to debilitating neurological symptoms. Due to the complexity of these patients, optimal care should be focused around a multidisciplinary team in order to optimize maternal care. We did not find a need to deliver the patient preterm and followed standard obstetric management in guiding decision-making around her pregnancy.

The development of methodology that is designed to allow a significant increase in the patterning and in the functionalization of the dendrimer is the ultimate goal of the research described here. Glycoside clusters based on TRIS were formed using click chemistry and were attached to PAMAM dendrimers. A series of dendrimers bearing tris-mannoside and an ethoxyethanol group was synthesized, and the binding interactions of these dendrimers with Concanavalin A were evaluated using inhibition ELISAs. The results of the inhibition ELISAs suggest that tris-mannoside clusters can replace individual sugars on the dendrimer without loss of function. Since tris-mannoside clustering allows for a redistribution of the dendrimers' surface functionalities, from this chemistry one can envision patterned dendrimers that incorporate multiple groups to increase the function and utility of the dendrimer.