NUT Carcinoma Research Articles

Diagnosis, Treatment and Prognosis of Primary Pulmonary NUT Carcinoma: A Literature Review.

NUT carcinoma is a rare, highly lethal cancer characterized with the rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14, which primarily occurs in the midline organs. Primary pulmonary NUT carcinoma (NC) lacks characteristic clinical manifestations, which leads to the high rate of misdiagnose and nonstandard treatment. To date, fewer than one hundred cases have been reported worldwide. Here, a comprehensive literature search involving a total of 35 articles with 55 patients was conducted in this paper. We reviewed and analyzed the associated clinical and pathological characteristics, the efficacy of various treatment options and the prognosis. Pulmonary NC mainly occurred in middle young-aged men (median age, 36) with no smoking history (2:1) and would present with symptoms of cough (63.6%), dyspnea (29.5%), chest pain (18.2%) and hemoptysis (18.2%). The initial imaging frequently revealed large and irregular lesions in the lower lobe (46.5%) of the left or right lungs; lymph node metastasis was also prevalent (91.9%). A focal squamous differentiation with abrupt keratinization often occurred in the undifferentiated or poorly differentiated (93.75%) tumor cells, with abundant necrosis and numerous neutrophils infiltrated. The mean overall survival (OS) in patients of this malignant disease was 6.21 months, and the median OS was 4.4 months. According to our results, this disease is sensitive to radiotherapy, and chemoradiotherapy (either concurrent chemoradiotherapy or sequential chemoradiotherapy) was the most efficient therapeutic regimen to prolong the OS of patients with pulmonary NC.

EP07.01-006 Clinicopathologic Determinants of Survival in Thoracic NUT Carcinoma (TNUT): Analysis of a Pooled Database

NUT carcinoma is a poorly differentiated squamous cancer characterized by the translocation of nuclear protein in testis gene that is mostly fused with bromodomain and extra-terminal family proteins. NUT carcinoma is a rare and aggressive cancer that tends to involve midline structures, frequently the head and neck (H&N) areas and thoracic (T) cavity. Several studies reported on a small mixed NUT samples from different sites. The characteristics and optimal management of thoracic NUT carcinoma (TNUT) are unclear.

NUTM1 -rearranged Carcinoma of the Thyroid : A Distinct Subset of NUT Carcinoma Characterized by Frequent NSD3 - NUTM1 Fusions.

NUT carcinoma (NC) is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT fusion oncoproteins (the most frequent fusion partner being BRD4 ) that carries a very poor prognosis, with most patients dying in under 1 year. Only rare primary thyroid NCs have been reported. Here, we evaluated a series of 14 cases. The median patient age at diagnosis was 38 years (range: 17 to 72y). Eight of 13 cases with slides available for review (62%) showed a morphology typical of NC, whereas 5 (38%) had a non-NC-like morphology, some of which had areas of cribriform or fused follicular architecture resembling a follicular cell-derived thyroid carcinoma. For cases with immunohistochemistry results, 85% (11/13) were positive for NUT on biopsy or resection, though staining was significantly decreased on resection specimens due to fixation; 55% (6/11) were positive for PAX8, and 54% (7/13) for TTF-1. Tumors with a non-NC-like morphology were all positive for PAX8 and TTF-1. The fusion partner was known in 12 cases: 9 (75%) cases had a NSD3-NUTM1 fusion, and 3 (25%) had a BRD4-NUTM1 fusion. For our cohort, the 2-year overall survival (OS) was 69%, and the 5-year OS was 58%. Patients with NC-like tumors had a significantly worse OS compared with that of patients with tumors with a non-NC-like morphology ( P =0.0462). Our study shows that NC of the thyroid can mimic other thyroid primaries, has a high rate of NSD3 - NUTM1 fusions, and an overall more protracted clinical course compared with nonthyroid primary NC.

The contemporary management of cancers of the sinonasal tract in adults.

Sinonasal malignancies make up <5% of all head and neck neoplasms, with an incidence of 0.5-1.0 per 100,000. The outcome of these rare malignancies has been poor, whereas significant progress has been made in the management of other cancers. The objective of the current review was to describe the incidence, causes, presentation, diagnosis, treatment, and recent developments of malignancies of the sinonasal tract. The diagnoses covered in this review included sinonasal undifferentiated carcinoma, sinonasal adenocarcinoma, sinonasal squamous cell carcinoma, and esthesioneuroblastoma, which are exclusive to the sinonasal tract. In addition, the authors covered malignances that are likely to be encountered in the sinonasal tract-primary mucosal melanoma, NUT (nuclear protein of the testis) carcinoma, and extranodal natural killer cell/T-cell lymphoma. For the purpose of keeping this review as concise and focused as possible, sarcomas and malignancies that can be classified as salivary gland neoplasms were excluded.

NUT Carcinoma-An Underdiagnosed Malignancy.

NUT carcinoma (NC) is a rare and highly aggressive malignancy with a dismal prognosis and a median survival of 6–9 months only. Although very few cases of NC are reported each year, the true prevalence is estimated to be much higher, with NC potentially widely underdiagnosed due to the lack of awareness. NC primarily occurs in midline structures including thorax, head, and neck; however, other sites such as pancreas and kidney are also affected, albeit at lower frequencies. NC is characterized by a single translocation involving the NUTM1 (NUT midline carcinoma family member 1) gene and different partner genes. The resulting fusion proteins initiate tumorigenesis through a mechanism involving BET (bromo-domain and extra-terminal motif) proteins such as Bromodomain-containing protein 4 (BRD4) and inordinate acetylation of chromatin, leading to the dysregulation of growth and differentiation genes. While no clinical characteristics are specific for NC, some histologic features can be indicative; therefore, patients with these tumor characteristics should be routinely tested for NUTM1. The diagnosis of NC using immunohistochemistry with a highly specific antibody is straightforward. There are currently no standard-of-care treatment options for patients with NC. However, novel therapies specifically addressing the unique tumorigenic mechanism are under investigation, including BET inhibitors. This review aims to raise awareness of this underdiagnosed cancer entity and provide all patients the opportunity to be properly diagnosed and referred to a clinical study.

A Young Male Patient with Nuclear Protein in Testis Carcinoma of the Thorax

A Young Male Patient with Nuclear Protein in Testis Carcinoma of the Thorax

Efficacy of Oncolytic Herpes Simplex Virus T-VEC Combined with BET Inhibitors as an Innovative Therapy Approach for NUT Carcinoma.

Simple SummarySince T-VEC is already approved for treatment of melanoma, its promising efficacy shown here also for NUT carcinoma (NC) cell lines may create a rapid transition to individual treatments as well as clinical trials in NC patients. The idea of combining T-VEC immunotherapy with BET inhibitors is strengthened by the assumption that the initial rapid response of NC to BET inhibitor therapy and the additional direct tumor cell lysis triggered by virotherapeutics may be able to effectively stabilize or even shrink the tumor cell mass to bridge the time gap until the durable immune response, induced by immunovirotherapy, can lead to complete tumor remission. This would signify a real breakthrough for patients suffering from this extremely aggressive tumor, whose average survival time is currently in the range of only six months.NUT carcinoma (NC) is an extremely aggressive tumor and current treatment regimens offer patients a median survival of six months only. This article reports on the first in vitro studies using immunovirotherapy as a promising therapy option for NC and its feasible combination with BET inhibitors (iBET). Using NC cell lines harboring the BRD4-NUT fusion protein, the cytotoxicity of oncolytic virus talimogene laherparepvec (T-VEC) and the iBET compounds BI894999 and GSK525762 were assessed in vitro in monotherapeutic and combinatorial approaches. Viral replication, marker gene expression, cell proliferation, and IFN-β dependence of T-VEC efficiency were monitored. T-VEC efficiently infected and replicated in NC cell lines and showed strong cytotoxic effects. This implication could be enhanced by iBET treatment following viral infection. Viral replication was not impaired by iBET treatment. In addition, it was shown that pretreatment of NC cells with IFN-β does impede the replication as well as the cytotoxicity of T-VEC. T-VEC was found to show great potential for patients suffering from NC. Of note, when applied in combination with iBETs, a reinforcing influence was observed, leading to an even stronger anti-tumor effect. These findings suggest combining virotherapy with diverse molecular therapeutics for the treatment of NC.

NUT carcinoma, an under-recognized malignancy: a clinicopathologic and molecular series of 6 cases showing a subset of patients with better prognosis and a rare ZNF532::NUTM1 fusion

NUT carcinoma (NC) is a rare malignancy with aggressive clinical behavior, defined by rearrangements involving the NUTM1 gene locus. This entity is often under-recognized and its diagnosis may be challenging. In this study, we describe a subset of patients that, despite the molecularly proven diagnosis of NC, show improved outcomes. In addition, we describe one case with the novel ZNF532::NUTM1 fusion. All cases of NC diagnosed from 2013 to 2022 in our department were retrieved. FISH using dual color bring-together probes and next-generation sequencing assay were performed to characterize the fusions involving NUTM1. Among6 patients identified, 5 were men with a median age of 35.6 years. Four patients had primary tumors in the head and neck region (2 ethmoid sinus, 1 parotid gland, and 1 lacrimal gland); 1 in the mediastinum, and another presented with a femoral bone tumor. In all cases, the initial diagnoses were not NC. The cases showed different morphological patterns, including monomorphic, rhabdoid, and pleomorphic appearances. One case showed a pseudopapillary pattern. By immunohistochemistry, all tumors showed squamous differentiation and ≥50% of neoplastic cells with nuclear positivity for NUT antibody. One case expressed WT1 (C-terminus) and other showed chromogranin positivity. Genetic study revealed a BRD4::NUTM1 fusion in all head and neck cases, BRD3::NUTM1 in mediastinum case, and ZNF532::NUTM1 fusion in the femur bone case. They were treated with surgical resection plus chemotherapy and radiotherapy. The median overall survival was 23.11 months (1.6-83.3months) and the median disease-free survival was 14.86 months (0-54.4months). The patients with longer overall survival were one with a lacrimal gland primary (83.3 months) and other with a parotid lesion (31.9 months). Both patients were primarily treated with complete surgical resection. Anatomic location may be directly related to the overall survival in NC cases. Resectability of the lesion is also an important factor related to survival. Pathologists should include NC in the differential diagnosis of any poorly differentiated and undifferentiated monomorphic malignancy, regardless of its anatomic location.

A Case of NUT Carcinoma with Favorable Result from VDC-IE Therapy for Systemic Recurrence

A Case of NUT Carcinoma with Favorable Result from VDC-IE Therapy for Systemic Recurrence

NUT Carcinoma: Investigating Drug Synergy and the Production of Drug Resistance

NUT Carcinoma (NC) is a rare cancer that results from the formation of an oncogenic fusion protein between a general bromodomain gene on chromosome 19 with NUT, which typically is only involved in genes for testes, on chromosome 15, causing high levels of undifferentiated cells to develop into malignant tumors. The average patient prognosis is between 6‐7 months with a 0% survival rate. In clinical applications, NC has a high chance of becoming resistant to treatments. Current clinical studies focus on the effects of single drugs on NC, yet there is more to be investigated for synergistic drug treatments. The purpose of this study is to investigate different drug combinations that could be of use clinically, as well as to create cell resistance in NC cell lines which will then be used to determine if resistant cells obtain collateral sensitivity or resistance to other chemotherapy drugs. Three separate cell lines (NC‐14, NC‐1015, and NC‐690) directly derived from NC patients (gifted from Dr. Christopher French, Brigham and Women’s Hospital, Boston) were evaluated for initial sensitivity to different chemotherapeutic drugs via GI50assays. Seven drugs were selected based on either clinical application in NC patients or use in cancers sharing similar mechanisms to NC including Mirdametinib, Molibresib, Venetoclax, Birabresib, ARV‐771, (+)‐JQ1, and Trametinib. Consistent results indicate that Mirdametinib, Trametinib, and Venetoclax do not appear to have an impact on any of the three NC cell lines. However, promising results for ARV‐771, (+)‐JQ1, and Birabresib for 1015 and 690 cell lines were obtained, with GI50values for both cells lines in the low nM range for all three drugs. Current, ongoing experiments include growing resistant 1015 and 690 cell lines to ARV‐771 and (+)‐JQ1, respectively, by initially dosing cells with GI10values from the collected data, as well as evaluating their sensitivity to combination treatments.

NUT Is a Driver of p300-Mediated Histone Hyperacetylation: From Spermatogenesis to Cancer

Simple SummaryThe functional characterization of the BRD4-NUT fusion protein as the driver of the highly aggressive NUT Carcinoma is fundamental to the understanding of the mechanisms responsible for the genome-wide hyperacetylation of histones prior to their eviction during the final stages of sperm cells maturation.In maturing sperm cells, a major genome re-organization takes place, which includes a global increase in the acetylation of histones prior to their replacement by protamines, the latter being responsible for the tight packaging of the male genome. Understanding the function of the oncogenic BRD4-NUT fusion protein in NUT carcinoma (NC) cells has proven to be essential in uncovering the mechanisms underlying histone hyperacetylation in spermatogenic cells. Indeed, these studies have revealed the mechanism by which a cooperation between BRD4, a bromodomain factor of the BET family, NUT, a normally testis-specific factor, and the histone acetyltransferase p300, induces the generation of hyperacetylated chromatin domains which are present in NC cells. The generation of Nut ko mice enabled us to demonstrate a genetic interaction between Nut and Brdt, encoding BRDT, a testis-specific BRD4-like factor. Indeed, in spermatogenic cells, NUT and p300 interact, which results in an increased acetylation of histone H4 at both positions K5 and K8. These two positions, when both acetylated, are specifically recognized by the first bromodomain of BRDT, which then mediates the removal of histone and their replacement by protamines. Taken together, these investigations show that the fusion of NUT to BRD4 in NUT Carcinoma cells reconstitutes, in somatic cells, a functional loop, which normally drives histone hyperacetylation and chromatin binding by a BET factor in spermatogenic cells.

Therapeutic impact of BET inhibitor BI 894999 treatment: backtranslation from the clinic

BackgroundBET inhibitors have been tested in several clinical trials where, despite encouraging preclinical results, substantial clinical benefit in monotherapy remains limited. This work illustrates the translational challenges and reports new data around the novel BET inhibitor, BI 894999. At clinically achievable concentrations, mechanistic studies were carried out to study pathway modulation and rational drug combinations.MethodsBRD-NUT fusions are oncogenic drivers in NUT carcinoma (NC). The effects of BI 894999 on proliferation, chromatin binding and pathway modulation were studied in NC in vitro. These studies were complemented by efficacy studies either as a single agent or in combination with the clinical p300/CBP inhibitor CCS1477.ResultsBased on the modelling of preclinical and clinical data, we proposed and implemented a new clinical scheduling regimen. This led to plasma levels sufficient to fully dislodge BRD-NUT from chromatin and to sustained and pronounced pharmacodynamic (PD) modulation of HEXIM1 and HIST2H2BF. Platelet counts in patient blood samples were improved compared to previous schedules. Rational combination studies of BI 894999 performed at clinically meaningful concentrations led to tumour regressions in all NC xenograft models tested.ConclusionsBI 894999 holds significant potential as a combination drug and CCS1477 p300/CBP inhibitor is a promising partner for future clinical trials.

Report of the First International Symposium on NUT Carcinoma.

NUT carcinoma is a rare, aggressive cancer defined by rearrangements of the NUTM1 gene. No routinely effective treatments of NUT carcinoma exist, despite harboring a targetable oncoprotein, most commonly BRD4-NUT. The vast majority of cases are fatal. Poor awareness of the disease is a major obstacle to progress in the treatment of NUT carcinoma. While the incidence likely exceeds that of Ewing sarcoma, and BRD4-NUT heralded the bromodomain and extra-terminal domain (BET) inhibitor class of selective epigenetic modulators, NUT carcinoma is incorrectly perceived as "impossibly rare," and therefore receives comparatively little private or governmental funding or prioritization by pharma. To raise awareness, propagate scientific knowledge, and initiate a consensus on standard and targeted treatment of NUT carcinoma, we held the First International Symposium on NUT Carcinoma on March 3, 2021. This virtual event had more than eighty attendees from the Americas, Europe, Asia, and Australia. Patients with NUT carcinoma and family members were represented and shared perspectives. Broadly, the four areas discussed by experts in the field included (1) the biology of NUT carcinoma; (2) standard approaches to the treatment of NUT carcinoma; (3) results of clinical trials using BET inhibitors; and (4) future directions, including novel BET bromodomain inhibitors, combinatorial approaches, and immunotherapy. It was concluded that standard chemotherapeutic approaches and first-generation BET bromodomain inhibitors, the latter complicated by a narrow therapeutic window, are only modestly effective in a minority of cases. Nonetheless, emerging second-generation targeted inhibitors, novel rational synergistic combinations, and the incorporation of immuno-oncology approaches hold promise to improve the prognosis of this disease.

NUT carcinoma in children, adolescents and young adults

NUT carcinoma (NC), defined by the presence of the NUTM1 rearrangement, is an aggressive tumour associated with poor prognosis. This rare cancer is underdiagnosed and difficult to treat. The primary objective of this review is to describe the clinical, radiological and laboratory features of NC in young patients. The secondary objective is to propose a consensual strategy for the French very Rare Tumour group (FRACTURE group). NUT-specific antibody immunostaining in cases of undifferentiated or poorly differentiated carcinoma may demonstrate the specific NUT gene rearrangement. NCs are frequently advanced stage at diagnosis and the outcome remains poor despite a global strategy that generally includes conventional combination chemotherapy with wide local therapy (surgery, radiotherapy). Chemosensitivity is frequently only transient. Recent data have shown that new targeted drugs (histone deacetylase and bromodomain and extra-terminal protein inhibitors) are promising, but their role has yet to be evaluated in NC. Centralized data review is necessary to improve our knowledge of paediatric NC. We propose a multimodal strategy based on published data and their personal experience.

Measuring the Patient Experience in Rare Disorders: Benefit of Pragmatic Mixed-Methods Research in NUT Carcinoma.

IntroductionPatient-centered outcome measurement (PCOM) is essential to capture the outcomes important to patients. However, it presents unique challenges in rare diseases, particularly those that are “young” (not diagnosed before the twenty-first century), with limited literature, lack of disease-specific patient-reported outcome (PRO) measures, and difficult sampling and data collection. One example of this is NUT (nuclear protein in testis) carcinoma (NUTca), a rare and rapidly progressing cancer, with tumors preliminary in the head, neck, and lungs. The published literature on NUTca is scarce. The limited number of case reports focus primarily on the clinical development and presentation of tumors. Currently, there are no publications describing the patient experience of NUTca and no specific PRO measures to assess the patient experience. We conducted mixed-methods research, including concept elicitation interviews, cognitive debriefing, and quantitative data analyses, to fill this evidence gap and describe challenges and solutions in the context of NUTca.MethodsAs published previously, our conceptualization of NUTca was based on elicitation interviews with 27 participants (n = 10 patients; n = 17 caregivers) using a semi-structured format; this framework formed the basis for a bolt-on strategy to develop a bespoke PRO measure based on the EORTC QLQ-C30, supplemented by targeted items from the EORTC Item Library and new items. In this publication, 20 participants were interviewed (n = 10 patients; n = 10 caregivers) to debrief items. Given the variety of tumor locations and related symptoms, and the small sample of patients providing responses to location-specific symptom items, we used response option endorsement frequencies to illuminate the variability of response for the concepts measured.ResultsThis study highlights the challenges in implementing patient-centric research to inform and develop PRO measures in rare diseases.ConclusionsOur mixed-methods research used pragmatic solutions to collect patient experience data and provides an evidence base to inform PCOM in clinical programs in this rapidly progressing rare cancer with high unmet need.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40487-022-00192-6.

NUT Carcinoma: Clinicopathologic Features, Molecular Genetics and Epigenetics.

Nuclear protein in testis (NUT) carcinoma is a rare, highly aggressive, poorly differentiated carcinoma occurring mostly in adolescents and young adults. This tumor usually arises from the midline structures of the thorax, head, and neck, and exhibits variable degrees of squamous differentiation. NUT carcinoma is defined by the presence of a NUTM1 (15q14) rearrangement with multiple other genes. In about 70-80% of the cases, NUTM1 is involved in a balanced translocation with the BRD4 gene (19p13.12), leading to a BRD4-NUTM1 fusion oncogene. Other variant rearrangements include BRD3-NUTM1 fusion (~15-20%) and NSD3-NUTM1 fusion (~6%), among others. The diagnosis of NUT carcinoma requires the detection of nuclear expression of the NUT protein by immunohistochemistry. Additional methods for diagnosis include the detection of a NUTM1 rearrangement by fluorescence in situ hybridization or by reverse transcriptase PCR. NUT carcinoma is usually underrecognized due to its rarity and lack of characteristic histological features. Therefore, the goal of this review is to provide relevant recent information regarding the clinicopathologic features of NUT carcinoma, the role of the multiple NUTM1 gene rearrangements in carcinogenesis, and the impact of understanding these underlying molecular mechanisms that may result in the development of possible novel targeted therapies.

Towards a Molecular Classification of Sinonasal Carcinomas: Clinical Implications and Opportunities.

Simple SummaryIn recent years, there have been several molecular and immunohistochemical additions to the pathologic diagnosis of sinonasal malignancies that could facilitate the identification of clinically relevant groups of sinonasal malignancies. Molecular profiling is progressively integrated in the histopathologic classification of sinonasal carcinomas, and it is likely to influence the management of these tumors in the near future. In this article we review the recent literature on molecular analysis and/or subtyping of sinonasal carcinomas and we discuss the possible clinical implications of a classification of sinonasal tumors based on their molecular features.Sinonasal carcinomas are a heterogeneous group of rare tumors, often with high-grade and/or undifferentiated morphology and aggressive clinical course. In recent years, with increasing molecular testing, unique sinonasal tumor subsets have been identified based on specific genetic alterations, including protein expression, chromosomal translocations, specific gene mutations, or infection by oncogenic viruses. These include, among others, the identification of a subset of sinonasal carcinomas associated with HPV infection, the identification of a subset of squamous cell carcinomas with EGFR alterations, and of rare variants with chromosomal translocations (DEK::AFF2, ETV6::NTRK and others). The group of sinonasal adenocarcinomas remains very heterogeneous at the molecular level, but some recurrent and potentially targetable genetic alterations have been identified. Finally, poorly differentiated and undifferentiated sinonasal carcinomas have undergone a significant refinement of their subtyping, with the identification of several new novel molecular subgroups, such as NUT carcinoma, IDH mutated sinonasal undifferentiated carcinoma and SWI/SNF deficient sinonasal malignancies. Thus, molecular profiling is progressively integrated in the histopathologic classification of sinonasal carcinomas, and it is likely to influence the management of these tumors in the near future. In this review, we summarize the recent developments in the molecular characterization of sinonasal carcinomas and we discuss how these findings are likely to contribute to the classification of this group of rare tumors, with a focus on the potential new opportunities for treatment.

Proceedings of the North American Society of Head and Neck Pathology, Los Angeles, CA, March 20, 2022: SWI/SNF-deficient Sinonasal Neoplasms: An Overview

The pathology of poorly differentiated sinonasal malignancies has been the subject of extensive studies during the last decade, which resulted into significant developments in the definitions and histo-/pathogenetic classification of several entities included in the historical spectrum of “sinonasal undifferentiated carcinomas (SNUC)” and poorly differentiated unclassified carcinomas. In particular, genetic defects leading to inactivation of different protein subunits in the SWI/SNF chromatin remodeling complex have continuously emerged as the major (frequently the only) genetic player driving different types of sinonasal carcinomas. The latter display distinctive demographic, phenotypic and genotypic characteristics. To date, four different SWI/SNF-driven sinonasal tumor types have been recognized: SMARCB1(INI1)-deficient carcinoma (showing frequently non-descript basaloid, and less frequently eosinophilic, oncocytoid or rhabdoid undifferentiated morphology), SMARCB1-deficient adenocarcinomas (showing variable gland formation or yolk sac-like morphology), SMARCA4-deficient carcinoma (lacking any differentiation markers and variably overlapping with large cell neuroendocrine carcinoma and SNUC), and lastly, SMARCA4-deficient sinonasal teratocarcinosarcoma. These different tumor types display highly variable immunophenotypes with SMARCB1-deficient carcinomas showing variable squamous immunophenotype, while their SMARCA4-related counterparts lack such features altogether. While sharing same genetic defect, convincing evidence is still lacking that SMARCA4-deficient carcinoma and SMARCA4-deficient teratocracinosarcoma might belong to the spectrum of same entity. Available molecular studies revealed no additional drivers in these entities, confirming the central role of SWI/SNF deficiency as the sole driver genetic event in these aggressive malignancies. Notably, all studied cases lacked oncogenic IDH2 mutations characteristic of genuine SNUC. Identification and precise classification of these entities and separating them from SNUC, NUT carcinoma and other poorly differentiated neoplasms of epithelial melanocytic, hematolymphoid or mesenchymal origin is mandatory for appropriate prognostication and tailored therapies. Moreover, drugs targeting the SWI/SNF vulnerabilities are emerging in clinical trials.

Comparison of gene fusion detection methods in salivary gland tumors

Salivary gland neoplasms may pose diagnostic difficulties due to overlapping morphologic features. Recently, specific gene fusions have been discovered that correspond to particular tumor types, and can aid in accurate diagnosis. Gene rearrangements are commonly assessed by fluorescence in situ hybridization (FISH), although use of next-generation sequencing is increasing. However, there is no “gold standard” for fusion detection. We determined the concordance between FISH and a targeted RNA sequencing panel in gene fusion detection across twenty-two salivary gland tumors, including five mucoepidermoid carcinomas, four acinic cell carcinomas, four pleomorphic adenomas, two adenoid cystic carcinomas, two NUT carcinomas, and one each of basal cell adenoma, salivary duct carcinoma ex-pleomorphic adenoma, salivary duct carcinoma, clear cell carcinoma, and secretory carcinoma. Directed FISH testing based on the diagnosis was performed on cases that did not already have FISH conducted during clinical workup. Targeted RNA sequencing of 507 genes and their partners (using the Illumina TruSight Fusion Panel) was completed. Six of twenty-two (27.3%) cases had discordant results. In three cases, FISH results were negative while RNA sequencing results found fusion transcripts, which were all confirmed with RT-PCR and Sanger sequencing. In three cases, RNA sequencing results were negative while FISH results were positive for a gene rearrangement. Thus, if fusion analysis results are conflicting with the morphologic impression, a second mode of fusion detection may be warranted. Although both methods have advantages and drawbacks, RNA sequencing provides additional information about novel fusion partners and fusions that may not have been originally considered.

163 - A rare case of primary pulmonary NUT carcinoma with vertebral metastasis

163 - A rare case of primary pulmonary NUT carcinoma with vertebral metastasis