Small Cell and Large Cell Neuroendocrine Carcinomas of the Pancreas are Genetically Similar and Distinct From Well-differentiated Pancreatic Neuroendocrine Tumors

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.

Download Full-text

Updates and management algorithm for neuroendocrine tumors of the uterine cervix

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2019-000504 ◽

2019 ◽

Vol 29 (6) ◽

pp. 986-995 ◽

Cited By ~ 9

Author(s):

Gloria Salvo ◽

Antonio Gonzalez Martin ◽

Naomi R Gonzales ◽

Michael Frumovitz

Keyword(s):

Neuroendocrine Tumors ◽

Treatment Options ◽

Distant Metastases ◽

Large Cell ◽

Initial Therapy ◽

Small Cell ◽

Oncologic Outcomes ◽

Low Grade ◽

High Tendency ◽

Neuroendocrine Carcinomas

Neuroendocrine carcinomas of the cervix account for less than 2% of all invasive cervical cancers and are classified as low-grade (carcinoid, atypical carcinoid tumor) or high-grade (known as small- and large-cell) neuroendocrine carcinomas. There are increasing data showing that cervical neuroendocrine carcinomas may be associated with the human papillomavirus (HPV), especially HPV18, and most will stain positive for p16. Immunohistochemistry markers such as synaptophysin and CD56 are the most sensitive markers. Although there are no commonly associated mutations,PIK3CA,KRAS, andTP53are the most frequently found mutations in neuroendocrine tumors. Neuroendocrine cervical carcinomas are exceedingly aggressive tumors with a high tendency for nodal involvement and distant metastases. Age, lymph node metastases, smoking, pure small-cell histology, and tumor size are independent prognostic factors. Overall, the 5-year survival rate is 36% and the median overall survival ranges between 22 and 25 months. Treatment options are often extrapolated from small-cell lung cancer and limited retrospective studies. The preferred treatment is a multimodal approach of surgery, chemoradiation, and systemic chemotherapy. The most common chemotherapy regimen used as initial therapy is a combination of cisplatin and etoposide. In the setting of recurrent disease, a combination of topotecan, paclitaxel, and bevacizumab has demonstrated favorable outcomes. Multicenter tumor registries, such as the Neuroendocrine Cervical Tumor Registry (NeCTuR), are an opportunity to evaluate patterns of disease treatment and oncologic outcomes.

Download Full-text

Multimodal Management of Grade 1 and 2 Pancreatic Neuroendocrine Tumors

Cancers ◽

10.3390/cancers14020433 ◽

2022 ◽

Vol 14 (2) ◽

pp. 433

Author(s):

Ugo Marchese ◽

Martin Gaillard ◽

Anna Pellat ◽

Stylianos Tzedakis ◽

Einas Abou Ali ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Postoperative Morbidity ◽

Current Data ◽

Pancreatic Neuroendocrine Tumors ◽

Tips And Tricks ◽

Poorly Differentiated ◽

Well Differentiated ◽

Multimodal Management ◽

Neuroendocrine Carcinomas

Pancreatic neuroendocrine tumors (p-NETs) are rare tumors with a recent growing incidence. In the 2017 WHO classification, p-NETs are classified into well-differentiated (i.e., p-NETs grade 1 to 3) and poorly differentiated neuroendocrine carcinomas (i.e., p-NECs). P-NETs G1 and G2 are often non-functioning tumors, of which the prognosis depends on the metastatic status. In the localized setting, p-NETs should be surgically managed, as no benefit for adjuvant chemotherapy has been demonstrated. Parenchymal sparing resection, including both duodenum and pancreas, are safe procedures in selected patients with reduced endocrine and exocrine long-term dysfunction. When the p-NET is benign or borderline malignant, this surgical option is associated with low rates of severe postoperative morbidity and in-hospital mortality. This narrative review offers comments, tips, and tricks from reviewing the available literature on these different options in order to clarify their indications. We also sum up the overall current data on p-NETs G1 and G2 management.

Download Full-text

A Subset of Large Cell Neuroendocrine Carcinomas in the Gastroenteropancreatic Tract May Evolve from Pre-existing Well-Differentiated Neuroendocrine Tumors

Endocrine Pathology ◽

10.1007/s12022-020-09659-6 ◽

2021 ◽

Author(s):

Giuseppe Pelosi ◽

Fabrizio Bianchi ◽

Elisa Dama ◽

Jasna Metovic ◽

Marco Barella ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Large Cell ◽

Well Differentiated ◽

Neuroendocrine Carcinomas

Download Full-text

Well-Differentiated Neuroendocrine Carcinoma of the Lung: A Clinicopathologic and Ultrastructural Study of 10 Cases

Tumori Journal ◽

10.1177/030089169207800212 ◽

1992 ◽

Vol 78 (2) ◽

pp. 121-129 ◽

Cited By ~ 6

Author(s):

Silvana Pilotti ◽

Carlo Patriarca ◽

Luciano Lombardi ◽

Lucio Scopsi ◽

Franco Rilke

Keyword(s):

Wide Spectrum ◽

Large Cell ◽

Small Cell ◽

Tumor Dissemination ◽

Poor Differentiation ◽

Well Differentiated ◽

Pulmonary Tumors ◽

Disease Free ◽

Neuroendocrine Carcinomas

The clinico-pathologic characteristics of 10 resected pulmonary tumors, which proved to be well-differentiated neuroendocrine carcinomas (WDNC) on the basis of light microscopic, immunocytochemical, ultrastructural and immunoelectron microscopic investigations, were evaluated. The tumors showed a wide spectrum of histologic features that could be referred to three basic patterns: 1) a carcinoid-like pattern; 2) an organoid pattern characterized by palisading cells at the edge of cellular areas, and 3) a prevalent adenocarcinoma-like pattern. The second pattern was the most distinct even though it often mimicked the small cell/large cell subtype of small cell carcinoma (SCC) owing to its association with marked atypia and poor differentiation. All but one of the patients were males and smokers. The mean age was 58 years. Half of the tumors were centrally located including those showing the adenocarcinoma-like pattern. Disease-free and overall survival and type of tumor dissemination in four patients were similar to those of SCC. Five evaluable patients were alive and disease-free after a mean follow-up of 74 months. Two of these were initially diagnosed as SCC. We conclude that, because of its impact on prognosis, the diagnosis of WDNC appears to be relevant although other factors able to adversely affect the clinical course remain undefined.

Download Full-text

CD117 immunoreactivity in high-grade neuroendocrine tumors of the lung: a comparative study of 39 large-cell neuroendocrine carcinomas and 27 surgically resected small-cell carcinomas

Virchows Archiv ◽

10.1007/s00428-004-1106-1 ◽

2004 ◽

Vol 445 (5) ◽

pp. 449-455 ◽

Cited By ~ 38

Author(s):

Giuseppe Pelosi ◽

Michele Masullo ◽

Maria Elena Leon ◽

Giulia Veronesi ◽

Lorenzo Spaggiari ◽

...

Keyword(s):

Comparative Study ◽

Neuroendocrine Tumors ◽

Large Cell ◽

Small Cell ◽

High Grade ◽

Neuroendocrine Carcinomas

Download Full-text

FAS and Subsequent Therapies in Pancreatic Neuroendocrine Tumors

Neuroendocrinology ◽

10.1159/000514339 ◽

2021 ◽

Author(s):

Jane E. Rogers ◽

Michael Lam ◽

Daniel M. Halperin ◽

Cecile G. Dagohoy ◽

James C. Yao ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Cox Regression ◽

Progression Free Survival ◽

Pancreatic Neuroendocrine Tumors ◽

Free Survival ◽

Prior Therapy ◽

Well Differentiated ◽

Grade 3 ◽

Line Of Therapy

We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5) and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line vs subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n=108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n=60; 53% > fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.

Download Full-text

Molecular Pathology of Well-Differentiated Pulmonary and Thymic Neuroendocrine Tumors: What Do Pathologists Need to Know?

Endocrine Pathology ◽

10.1007/s12022-021-09668-z ◽

2021 ◽

Vol 32 (1) ◽

pp. 154-168 ◽

Cited By ~ 1

Author(s):

Marco Volante ◽

Ozgur Mete ◽

Giuseppe Pelosi ◽

Anja C. Roden ◽

Ernst Jan M. Speel ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Young Patients ◽

Carcinoid Tumors ◽

Neuroendocrine Neoplasms ◽

Grey Zone ◽

Cell Hyperplasia ◽

Ki 67 ◽

Familial Form ◽

Well Differentiated ◽

Neuroendocrine Carcinomas

AbstractThoracic (pulmonary and thymic) neuroendocrine tumors are well-differentiated epithelial neuroendocrine neoplasms that are classified into typical and atypical carcinoid tumors based on mitotic index cut offs and presence or absence of necrosis. This classification scheme is of great prognostic value but designed for surgical specimens, only. Deep molecular characterization of thoracic neuroendocrine tumors highlighted their difference with neuroendocrine carcinomas. Neuroendocrine tumors of the lung are characterized by a low mutational burden, and a high prevalence of mutations in chromatin remodeling and histone modification-related genes, whereas mutations in genes frequently altered in neuroendocrine carcinomas are rare. Molecular profiling divided thymic neuroendocrine tumors into three clusters with distinct clinical outcomes and characterized by a different average of copy number instability. Moreover, integrated histopathological, molecular and clinical evidence supports the existence of a grey zone category between neuroendocrine tumors (carcinoid tumors) and neuroendocrine carcinomas. Indeed, cases with well differentiated morphology but mitotic/Ki-67 indexes close to neuroendocrine carcinomas have been increasingly recognized. These are characterized by specific molecular profiles and have an aggressive clinical behavior. Finally, thoracic neuroendocrine tumors may arise in the background of genetic susceptibility, being MEN1 syndrome the well-defined familial form. However, pathologists should be aware of rarer germline variants that are associated with the concurrence of neuroendocrine tumors of the lung or their precursors (such as DIPNECH) with other neoplasms, including but not limited to breast carcinomas. Therefore, genetic counseling for all young patients with thoracic neuroendocrine neoplasia and/or any patient with pathological evidence of neuroendocrine cell hyperplasia-to-neoplasia progression sequence or multifocal disease should be considered.

Download Full-text