The Evolving Spectrum of Endometrial Glandular Proliferations With Corded and Hyalinized Features.

We present the clinicopathologic and immunohistochemical features of 14 endometrial glandular proliferations with conspicuous corded and hyalinized (CH) features comprised entirely or predominantly of endometrial hyperplasia. Endometrial glandular lesions ranged in severity from endometrial hyperplasia with and without cytologic atypia (5/14 [36%]) to hyperplasia with architectural complexity bordering on well-differentiated endometrioid adenocarcinoma (3/14 [21%]) to frank corded and hyalinized endometrial carcinoma ("CHEC") (6/14 [43%]). In addition to sex cord-like growth and hyalinized stroma, other common histologic features included prominent spindle cells (11/14 [79%]), keratinizing and/or morular squamous differentiation (10/14 [71%]), and osseous metaplasia (6/14 [43%]). Immunohistochemical characterization revealed aberrant nuclear beta-catenin in all cases (14/14 [100%]); additionally, all cases demonstrated positive estrogen receptors, intact PTEN, PMS2 and MSH6, and wild-type p53 expression. Patients ranged in age from 24 to 58 (mean 38) years. Of 5 patients with hyperplasia with CH features, 2 experienced complete resolution after progestin therapy and none progressed to adenocarcinoma (mean follow-up 15.6 mo, range 2 to 64). By contrast, of 2 patients with hyperplasia bordering on CHEC and with available follow-up, both subsequently developed adenocarcinoma, suggesting that even focal increased architectural complexity may predict an elevated risk of malignancy. We conclude that CH morphology is not limited to endometrioid carcinoma and may occur across a spectrum of neoplastic proliferations, including those without sufficient architectural complexity or cytologic atypia to warrant classification as adenocarcinoma. We propose the term "corded and hyalinized endometrial hyperplasia" to describe this precursor lesion and report favorable outcomes with conservative treatment.

The Use of Fluorescence in situ Hybridization to Confirm PRKACA Gene Rearrangement in Fibrolamellar Hepatocellular Carcinoma: A Validation Study.

OBJECTIVE: The objectives of this study are to define the specificity of the DNAJB1-PRKACA fusion transcript for the fibrolamellar subtype of hepatocellular carcinoma (FL-HCC) by testing a targeted sampling of other hepatic neoplasms/proliferations and extrahepatic neoplasms seen in children and young adults and to develop a FISH assay using a commercially available PRKACA break apart probe for use in a CLIA-certified clinical laboratory. METHODS: Formalin 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 the PRKACA gene locus on chromosome 19 using standard techniques. RESULTS: The PRKACA gene rearrangement was detected in 11/12 (92%) FL-HCC cases and 1/94 (1%) of conventional HCC cases. All other cases and background control tissues were negative for the PRKACA gene rearrangement. These findings establish a test sensitivity of 91.7% and specificity of 99.5%. CONCLUSION: This study shows that, using standard techniques, FISH testing with a commercially available break apart probe targeting the PRKACA gene can be used as a surrogate for the DNAJB1-PRKACA fusion commonly found in FL-HCC. Also, the PRKACA gene rearrangement is not expressed in other hepatic neo-plasms/proliferations or extrahepatic neoplasms seen in children and young adults. Finally, FISH testing can be used as a diagnostic tool to confirm the diagnosis of FL-HCC, in the appropriate clinical setting.

DICER1-associated Tumors in the Female Genital Tract: Molecular Basis, Clinicopathologic Features, and Differential Diagnosis.

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.

PAX7 Is a Sensitive Marker of Skeletal Muscle Differentiation in Rhabdomyosarcoma and Tumors With Rhabdomyosarcomatous Differentiation in the Female Genital Tract.

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.

Fumarate Hydratase Deficiency Should be Considered in the Differential Diagnosis of Uterine and Extrauterine Smooth Muscle Tumors of Uncertain Malignant Potential (STUMP).

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.

Prospective molecular classification of endometrial carcinomas: institutional implementation, practice, and clinical experience.

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.

Neurofibrosarcoma Revisited: An Institutional Case Series of Uterine Sarcomas Harboring Kinase-related Fusions With Report of a Novel FGFR1-TACC1 Fusion.

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: surgical approach and perioperative management.

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.

Clusters of ligands on dendrimer surfaces.

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.