scholarly journals SMARCA4/BRG1-Deficient Sinonasal Carcinoma: Morphologic Spectrum of an Evolving Entity

2021 ◽  
Author(s):  
Aanchal Kakkar ◽  
Subiyathul Farah Ashraf ◽  
Amber Rathor ◽  
Amit Kumar Adhya ◽  
Suresh Mani ◽  
...  
Keyword(s):  
Early Recognition ◽  
Multimodality Treatment ◽  
Large Cell ◽  
Undifferentiated Carcinoma ◽  
Small Cell ◽  
Biological Behavior ◽  
Clinicopathologic Features ◽  
Sinonasal Carcinoma ◽  
Poorly Differentiated Carcinoma ◽  
Poorly Differentiated

Context.— Molecular analysis of poorly differentiated/undifferentiated sinonasal neoplasms has resulted in identification of a growing number of genetically defined tumors. SMARCA4-deficient sinonasal carcinoma is one such recently described entity that emerged from within sinonasal undifferentiated carcinoma (SNUC), neuroendocrine carcinoma (NEC), and teratocarcinosarcoma (TCS). Objective.— To identify SMARCA4-deficient sinonasal carcinomas from a large institutional cohort of poorly differentiated/undifferentiated carcinomas and evaluate their clinicopathologic features. Design.— SMARCA4/BRG1 immunohistochemistry was performed on all tumors diagnosed as SNUC, poorly differentiated carcinoma, NEC, and TCS during a 12-year period. SMARCA2/BRM and INSM1 immunostaining was performed in SMARCA4-deficient cases. Results.— Twelve SMARCA4-deficient sinonasal carcinomas were identified among 299 cases. Morphologically, 5 cases were large cell NEC, 2 cases were small cell NEC, and 5 were TCS. SMARCA4 loss was diffuse and complete in 10 cases, while 2 cases showed focal retention. Most cases showed diffuse cytokeratin staining accompanied by weak, usually focal staining for chromogranin and synaptophysin. INSM-1 showed negativity in most cases. All cases showed retained SMARCA2 expression. IDH1/2 mutation was absent in all cases analyzed. Four of 7 patients died of disease, and aggressive multimodality treatment had better outcome. Conclusions.— SMARCA4-deficient sinonasal carcinomas are morphologically akin to sinonasal poorly differentiated NECs and TCS, display cytokeratin positivity and only focal staining for neuroendocrine markers, and have aggressive biological behavior. Inclusion of SMARCA4 in the immunohistochemical panel for diagnostic workup of all sinonasal NEC and TCS phenotypes will facilitate their early recognition. Comprehensive germline and somatic mutational analyses of these tumors are necessary for further insights into their molecular pathogenesis.

scholarly journals Challenging Diagnosis in NUT Carcinoma

2021 ◽  
pp. 106689692110195
Author(s):  
Grosse Claudia ◽  
Grosse Alexandra
Keyword(s):  
Nuclear Protein ◽  
Hematological Malignancy ◽  
Undifferentiated Carcinoma ◽  
Squamous Differentiation ◽  
Poorly Differentiated Carcinoma ◽  
Poorly Differentiated ◽  
Nut Carcinoma ◽  
Disseminated Disease ◽  
Generation Sequencing

Nuclear protein in testis (NUT) carcinoma represents a highly aggressive, poorly differentiated carcinoma that is genetically defined by rearrangement of NUT gene. The histomorphological appearance ranges from entirely undifferentiated carcinoma to carcinoma with prominent squamous differentiation. NUT carcinoma can display neuroendocrine features. Although it is typically distributed along the midline axis, it may manifest in nonmidline locations. The majority of patients develop rapidly disseminated disease. We illustrate 2 cases of NUT carcinoma, one located in the lung, which closely resembled a neuroendocrine carcinoma, and the other one with assumed lung origin demonstrating metastatic dissemination with diffuse bone involvement, which was clinically first suspected to be a hematological malignancy. Due to its undifferentiated nature, NUT carcinoma may be confused with many entities. NUT immunohistochemistry is considered to be sufficient for the diagnosis. Fluorescence in-situ hybridization analysis and next-generation sequencing are currently used to confirm the diagnosis.

Phase II study of pembrolizumab-based therapy in previously treated extrapulmonary poorly differentiated neuroendocrine carcinomas: Results of Part B (pembrolizumab + chemotherapy).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4148-4148
Author(s):  
Jennifer A. Chan ◽  
Nitya Prabhakar Raj ◽  
Rahul Raj Aggarwal ◽  
Susan Calabrese ◽  
April DeMore ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Large Cell ◽  
Small Cell ◽  
Type I ◽  
First Line ◽  
Open Label ◽  
Total N ◽  
Poorly Differentiated ◽  
Neuroendocrine Carcinomas

4148 Background: The efficacy of immune checkpoint inhibitor (CPI) therapy has not been established in extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). In small cell lung cancer, CPI therapy is approved for use in the first-line and salvage settings. We investigated the efficacy and safety of pembrolizumab (PEM)-based therapy in biomarker-unselected patients (pts) with EP-PDNECs. PEM alone (Part A, N=14) was inactive (ASCO GI 2019; Abstr#363). We now report the results of Part B (PEM plus chemotherapy). Methods: We conducted an open label, multicenter, phase 2 study of PEM-based therapy in pts with EP-PDNECs, excluding Merkel cell carcinoma and well differentiated grade 3 neuroendocrine tumors (NET), with disease progression on first-line systemic therapy. In Part B of this trial, patients were treated with PEM 200 mg IV every 3 week cycle plus dealers’ choice chemotherapy (chemo): weekly irinotecan (IRI, 125 mg/m2 day 1,8 of every 21 day cycle) or weekly paclitaxel (PAC, 80 mg/m2). After PEM/IRI safety lead-in (N=6), 16 additional pts (total N=22) were enrolled. This was based on a primary endpoint of objective response rate (ORR) by RECIST 1.1 and a plan to test Ha ORR 31% vs H0 ORR 10% with 80% power at a type I error rate of 0.05. Secondary endpoints include safety, overall survival (OS), and progression-free survival (PFS). Serial blood samples and baseline tumor biopsies were required in all pts. Results: Preliminary data from Part B are available. Of 22 pts enrolled, male/female 15/7; median age 57 years (range 34-75); ECOG PS 0/1: 10/12; 6 large cell, 8 small cell, 8 NOS. Primary sites of disease: GI 73%, GYN 5%, unknown 23%. Ki67 index (available for 18 pts) median 68% (range 30 to >95%). Chemo choice: 17 IRI (77%) and 5 PAC (23%). PEM/IRI was safe based on lead-in. Median number of cycles of therapy administered was 3 (range 0-13). Treatment-related Gr 3 or 4 AE occurred in 7 (32%) of 22 pts overall: 4 (18%) had at least one Gr 3 AE attributed to PEM (1 pt each with pain, ALT increase, or nausea; 2 with fatigue); 7 (32%) had at least one Gr 3/4 AE attributed to chemo (2 with fatigue, 2 with neutropenia; 1 each with pain, ALT increase, hyponatremia, diarrhea, nausea, and/or acute kidney injury). No grade 5 AE. ORR was 9%: PR in 2 pts (9%), SD 3 pts (14%), PD 13 pts (60%); 4 pts (18%) unevaluable (off study before first scheduled scan). Median PFS 2 mo. At last follow-up, 5 pts (23%) were alive with 1 pt still on treatment. Median OS 4 mo. Of 21 pts off treatment, 76% off for PD, 10% off for AE, 14% off for withdrawal of consent/other therapy. Conclusions: PEM + chemotherapy was not effective in this pretreated, biomarker-unselected population of EP-PDNECs arising in different organs. Biomarker studies are planned (Parts A/B). Clinical trial information: NCT03136055.

scholarly journals Rare Occurrence of a Poorly Differentiated Neuroendocrine Tumor of the Bladder

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Katherine Dowd ◽  
Charles Rotenberry ◽  
Douglas Russell ◽  
Mitchell Wachtel ◽  
Werner de Riese
Keyword(s):  
Cell Carcinoma ◽  
Neuroendocrine Tumor ◽  
Survival Data ◽  
Large Cell Carcinoma ◽  
Large Cell ◽  
Disease Recurrence ◽  
Small Cell ◽  
Treatment Regimens ◽  
Poorly Differentiated ◽  
Carcinoma Of The Bladder

Neuroendocrine tumors rarely occur in the urinary bladder. They can be carcinomatous, subdivided into small cell and large cell pathology. Small cell carcinoma of the bladder is a rarity that may present at an advanced pathologic stage. No treatment regimens have been standardized for local or metastatic disease. Review of the recent literature shows equivalent survival data for localized disease treated with chemoradiotherapy combined with either bladder sparing surgery or radical cystectomy. Patients with significant comorbidities are an additional challenge. We report a case of poorly differentiated neuroendocrine tumor of the bladder, which could not be classified as small or large cell carcinoma, complicated by significant comorbidities. After management with transurethral resection of the tumor, adjuvant chemotherapy, and radiation, the patient is alive and asymptomatic nearly 1 year after initial TURBT with no evidence of disease recurrence.

scholarly journals Are G3 ENETS neuroendocrine neoplasms heterogeneous?

2013 ◽  
Vol 20 (5) ◽  
pp. 649-657 ◽  
Author(s):  
Fritz-Line Vélayoudom-Céphise ◽  
Pierre Duvillard ◽  
Lydia Foucan ◽  
Julien Hadoux ◽  
Cecile N Chougnet ◽  
...  
Keyword(s):  
Mitotic Index ◽  
Somatostatin Receptor ◽  
Neuron Specific Enolase ◽  
Morphological Differentiation ◽  
Large Cell ◽  
Cell Types ◽  
Small Cell ◽  
Neuroendocrine Neoplasms ◽  
Cell Type ◽  
Poorly Differentiated

The new WHO classification of gastroenteropancreatic (GEP) neuroendocrine tumors (NET) implies that G3 neoplasms with mitotic index >20 and/or Ki67 index >20% are neuroendocrine carcinomas (NEC), described as poorly differentiated, small or large cell types, by analogy with lung NEC. To characterize the subgroup of non-small-cell-type GEP and thoracic NET with mitotic index >20 and/or Ki67 >20% according to their pathological features, response to cisplatin and overall survival (OS). We reviewed pathological and clinical presentation of G3 non-small-cell-type NET referred to our institution for 5 years. Data from 166 patients with metastatic thoracic and GEP-NET were collected. Twenty-eight patients (17%) fulfill the inclusion criteria. Tumors were classified as well-differentiated NET (G3-WDNET) in 42.8% of cases and poorly differentiated, large-cell NEC (G3-LCNEC) in 57.2% of cases. Plasma chromogranin A or neuron-specific enolase were elevated in 42 and 25% respectively of G3-WDNET and 31 and 50% of G3-LCNEC. Somatostatin receptor scintigraphy was positive in 88 and 50% of G3-WDNET or G3-LCNEC respectively. Complete or partial response to cisplatin was observed in 31% of cases, all classified as G3-LCNEC. The median OS was 41 months for G3-WDNET but 17 months for G3-LCNEC (P=0.34). Short survival was observed in 25% of G3-WDNET but 62.5% of G3-LCNEC patients (P=0.049). G3 ENETS GEP and thoracic neuroendocrine neoplasms (NEN) could constitute a heterogeneous subgroup of NEN as regards diagnosis, prognosis, and treatment. If confirmed, future classifications may consider splitting them into two groups according to their morphological differentiation.

Pulmonary Neuroendocrine Carcinomas

2002 ◽  
Vol 126 (5) ◽  
pp. 545-553 ◽  
Author(s):  
Qin Huang ◽  
Alona Muzitansky ◽  
Eugene J. Mark
Keyword(s):  
Neuroendocrine Tumors ◽  
Neuroendocrine Carcinoma ◽  
Large Cell ◽  
Small Cell ◽  
The Body ◽  
Low Grade ◽  
Typical Carcinoid ◽  
Poorly Differentiated Neuroendocrine Carcinoma ◽  
Poorly Differentiated ◽  
Neuroendocrine Carcinomas

Abstract Context.—Primary pulmonary neuroendocrine tumors are traditionally classified into 3 major types: typical carcinoid (TC), atypical carcinoid (AC), and large cell neuroendocrine carcinoma (LC) or small cell neuroendocrine carcinoma (SC). Confusion arises frequently regarding the malignant nature of TC and the morphologic differentiation between AC and LC or SC. Objective.—To provide clinicopathologic evidence to streamline and clarify the histomorphologic criteria for this group of tumors, emphasizing the prognostic implications. Patients.—To minimize variability in diagnostic criteria and treatment plans, we analyzed a group of patients whose diagnosis and treatment occurred at a single institution. We reviewed 234 cases of primary pulmonary neuroendocrine tumors and thoroughly studied 50 cases of resected tumors from 1986 to 1995. Results.—On the basis of morphologic characteristics and biologic behaviors of the tumors, we agree with many previous investigators that these tumors are all malignant and potentially aggressive. Based on our accumulated data, we have modified Gould criteria and reclassified these tumors into 5 types: (1) well-differentiated neuroendocrine carcinoma (otherwise called TC) (14 cases, with less than 1 mitosis per 10 high-power fields [HPF] with or without minimal necrosis); (2) moderately differentiated neuroendocrine carcinoma (otherwise called low-grade AC) (6 cases, with less than 10 mitoses per 10 HPF and necrosis evident at high magnification); (3) poorly differentiated neuroendocrine carcinoma (otherwise called high-grade AC) (10 cases, with more than 10 mitoses per 10 HPF and necrosis evident at low-power magnification); (4) undifferentiated LC (5 cases, with more than 30 mitoses per 10 HPF and marked necrosis); and (5) undifferentiated SC (15 cases, with more than 30 mitoses per 10 HPF and marked necrosis). The 5-year survival rates were 93%, 83%, 70%, 60%, and 40% for well, moderately, and poorly differentiated, and undifferentiated large cell and small cell neuroendocrine carcinomas, respectively. We found nodal metastasis in 28% of TC in this retrospective review, a figure higher than previously recorded. Conclusion.—Using a grading system and terms comparable to those used for many years and used for neuroendocrine tumors elsewhere in the body, we found that classification of pulmonary neuroendocrine carcinomas as well, moderately, poorly differentiated, or undifferentiated provides prognostic information and avoids misleading terms and concepts. This facilitates communication between pathologists and clinicians and thereby improves diagnosis and management of the patient.

scholarly journals SMARCA4/BRG1–Deficient Non–Small Cell Lung Carcinomas: A Case Series and Review of the Literature

2020 ◽  
Vol 145 (1) ◽  
pp. 90-98 ◽  
Author(s):  
Aruna Nambirajan ◽  
Varsha Singh ◽  
Nishu Bhardwaj ◽  
Saurabh Mittal ◽  
Sunil Kumar ◽  
...  
Keyword(s):  
Case Series ◽  
Growth Factor Receptor ◽  
Large Cell ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Lung Carcinomas ◽  
Anaplastic Lymphoma ◽  
Thyroid Transcription Factor 1 ◽  
Poorly Differentiated

Context.— Somatic mutations in SMARCA4 (SWI/SNF–related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene and/or BRG1 (Brahma-related gene 1) loss identifies a subset of non–small cell lung carcinomas (NSCLCs) lacking alterations in EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), and ROS1 (ROS proto-oncogene 1) genes. Preliminary observations suggest responsiveness to immunotherapy and targeted therapies. Objective.— To study BRG1 loss in NSCLCs and elucidate the clinicopathologic profile of such SMARCA4-deficient NSCLCs. Design.— Non–small cell lung carcinomas diagnosed during 6 years were subject to immunohistochemistry for BRG1 and BRM (Brahma). Tumors with BRG1 loss were stained with antibodies against thyroid transcription factor 1 (TTF-1), p40, cytokeratins, hepatocyte paraffin 1 (Hep Par 1), Sal-like protein 4 (SALL4), CD34, SRY-box 2 (SOX2), chromogranin, synaptophysin, p53, integrase interactor 1, ALK, and ROS1. EGFR mutation testing was performed by polymerase chain reaction–based method. Results.— Among 100 NSCLCs tested, 4 cases (4%) showed BRG1 loss. The histology ranged from solid adenocarcinomas (n = 1) to large cell/poorly differentiated carcinomas (n = 3) with clear cell cytology in 2 cases. All showed loss/reduction of BRM with variable cytokeratin and SALL4 expression, and were negative for TTF-1, p40, Hep Par 1, ALK, ROS1, and EGFR mutations. CD34 and SOX2 were negative in all 4 cases. Isolated BRM loss was common (21%), distributed across all NSCLC subtypes including squamous cell carcinomas and a hepatoid adenocarcinoma. Conclusions.— BRG1 loss occurs in a subset of TTF-1/p40–negative poorly differentiated NSCLCs. Identification and follow-up will clarify the prognosis, diagnostic criteria, and potential for therapeutic personalization.

scholarly journals Undifferentiated large cell/rhabdoid carcinoma presenting in the intestines of patients with concurrent or recent non-small cell lung cancer (NSCLC): clinicopathologic and molecular analysis of 14 cases indicates an unusual pattern of dedifferentiated metastases

2021 ◽  
Author(s):  
Abbas Agaimy ◽  
Ondrej Daum ◽  
Michal Michal ◽  
Mona W. Schmidt ◽  
Robert Stoehr ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Large Cell ◽  
Undifferentiated Carcinoma ◽  
Small Cell ◽  
Molecular Testing ◽  
Small Cell Lung ◽  
Gastrointestinal Carcinoma ◽  
Undifferentiated Histology

AbstractUndifferentiated carcinoma metastatic to the bowel is uncommon in surgical pathology practice and might be confused with primary gastrointestinal carcinoma, melanoma, lymphoma, and others. We present 14 cases of uni- (n = 9) or multifocal (n = 5) undifferentiated large cell/rhabdoid carcinoma presenting in the bowel of patients with concurrent (n = 9) or recent (diagnosed 1 to 25 months earlier; median, 4) non-small cell lung cancer (NSCLC). Patients were 6 females and 8 males, aged 52 to 85 years. Primary NSCLC was verified histologically in 10 cases and by imaging in 4. The undifferentiated histology was present in the lung biopsy in 4/10 patients (as sole pattern in 3 and combined with adenocarcinoma in 1) and was limited to the intestinal metastases in the remainder. PDL1 was strongly expressed in 7/9 cases (CPS: 41 to 100). Loss of at least one SWI/SNF subunit was detected in 7/13 cases (54%). SMARCA2 loss (n = 6) was most frequent and was combined with SMARCA4 loss in one case. PBRM1 loss was observed in one tumor. Successful molecular testing of 11 cases revealed BRAF mutations in 4 (3 were non-V600E variants), KRAS mutations in 3, and wildtype in 4. None had EGFR mutations. Analysis of 4 paired samples revealed concordant KRAS (2) and BRAF (1) mutations or wildtype (1). Our study indicates that undifferentiated carcinoma within the intestines of patients with concurrent/recent NSCLC represents dedifferentiated metastasis from the NSCLC. Recognition of this unusual presentation is cardinal to avoid misdiagnosis with inappropriate therapeutic and prognostic implications.

scholarly journals Managing Severe Dysgeusia and Dysosmia in Lung Cancer Patients: A Systematic Scoping Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Ana Sofia Spencer ◽  
David da Silva Dias ◽  
Manuel Luís Capelas ◽  
Francisco Pimentel ◽  
Teresa Santos ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Carcinoma ◽  
English Language ◽  
Early Recognition ◽  
Pilot Trial ◽  
Large Cell ◽  
Small Cell ◽  
Lung Cancer Patients ◽  
Mesh Terms ◽  
Taste And Smell

IntroductionLung cancer (LC) is highly prevalent worldwide, with elevated mortality. In this population, taste and smell alterations (TSAs) are frequent but overlooked symptoms. The absence of effective therapeutic strategies and evidence-based guidelines constrain TSAs’ early recognition, prevention and treatment (Tx), promoting cancer-related malnutrition and jeopardizing survival outcomes and quality of life.ObjectivesTo systematically review the literature on TSAs in LC patients, understand the physiopathology, identify potential preventive and Tx strategies and to further encourage research in this area.MethodsLiterature search on English language articles indexed to PubMed, CINALH, SCOPUS and Web of Science using MeSH terms “Lung neoplasms”,”Dysgeusia”, “Olfaction Disorders”, “Carcinoma, Small Cell”,”Carcinoma, Non- Small-Cell Lung “Adenocarcinoma of Lung”,”Carcinoma, Large Cell”, and non-MeSH terms “Parageusia”, “Altered Taste”, “Smell Disorder”, “Paraosmia”, “Dysosmia”,”Lung Cancer” and “Oat Cell Carcinoma”.ResultsThirty-four articles were reviewed. TSAs may follow the diagnosis of LC or develop during cancer Tx. The estimated prevalence of self-reported dysgeusia is 35-38% in treatment-naïve LC patients, and 35-69% in those undergoing Tx, based on studies involving LC patients only.One prospective pilot trial and 1 RCT demonstrated a clinically significant benefit in combining flavor enhancement, smell and taste training and individualized nutritional counselling; a systematic review, 1 RCT and 1 retrospective study favored using intravenous or oral zinc-based solutions (150mg 2-3 times a day) for the prevention and Tx of chemotherapy (CT) and radiotherapy (RT) -induced mucositis and subsequent dysgeusia.ConclusionsThis is the first review on dysgeusia and dysosmia in LC patients to our knowledge. We propose combining taste and smell training, personalized dietary counselling and flavor enhancement with oral zinc-based solutions (150mg, 2-3 times a day) during CT and/or RT in this population, in order to prevent and help ameliorate Tx-induced dysgeusia and mucositis. However due to study heterogeneity, the results should be interpreted with caution. Developing standardized TSA measurement tools and performing prospective randomized controlled trials to evaluate their effect are warranted.

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