Clinicopathological Spectrum of Gastroenteropancreatic Neuroendocrine Tumours- A Series of Ten Cases

Poorly differentiated neuroendocrine carcinomas (NECs) of the pancreas are rare malignant neoplasms with a poor prognosis. The aim of this study was to determine the clinicopathologic and genetic features of poorly differentiated NECs and compare them with other types of pancreatic neoplasms. We investigated alterations of KRAS, CDKN2A/p16, TP53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, and RB1 by immunohistochemistry and/or targeted exomic sequencing in surgically resected specimens of 9 small cell NECs, 10 large cell NECs, and 11 well-differentiated neuroendocrine tumors (PanNETs) of the pancreas. Abnormal immunolabeling patterns of p53 and Rb were frequent (p53, 18 of 19, 95%; Rb, 14 of 19, 74%) in both small cell and large cell NECs, whereas Smad4/Dpc4, DAXX, and ATRX labeling was intact in virtually all of these same carcinomas. Abnormal immunolabeling of p53 and Rb proteins correlated with intragenic mutations in the TP53 and RB1 genes. In contrast, DAXX and ATRX labeling was lost in 45% of PanNETs, whereas p53 and Rb immunolabeling was intact in these same cases. Overexpression of Bcl-2 protein was observed in all 9 small cell NECs (100%) and in 5 of 10 (50%) large cell NECs compared with only 2 of 11 (18%) PanNETs. Bcl-2 overexpression was significantly correlated with higher mitotic rate and Ki67 labeling index in neoplasms in which it was present. Small cell NECs are genetically similar to large cell NECs, and these genetic changes are distinct from those reported in PanNETs. The finding of Bcl-2 overexpression in poorly differentiated NECs, particularly small cell NEC, suggests that Bcl-2 antagonists/inhibitors may be a viable treatment option for these patients.

BACKGROUNDGastric neuroendocrine carcinoma (GNEC) is a rare histological subtype of gastric cancer, which is categorized into small cell and large cell neuroendocrine carcinomas. It is characterized by strong invasiveness and poor prognosis. Mixed large and small cell neuroendocrine carcinoma (L/SCNEC) is an extremely rare pathological type of gastric cancer, and there have been no reports on this situation until now.CASE SUMMARYHerein, we first present a 57-year-old patient diagnosed with L/SCNEC of the stomach. A 57-year-old Chinese male presented with epigastric discomfort. Outpatient gastroscopic biopsy was performed, and pathological examination revealed that the cardia was invaded by adenocarcinoma. The patient underwent laparoscopic-assisted radical proximal subtotal gastrectomy and was diagnosed with L/SCNEC. He refused adjuvant treatment and was followed up every 3 mo. Eight months after the operation, the patient showed no evidence of local recurrence or distant metastasis.CONCLUSIONWe advocate conducting further genomic studies to explore the origin of gastric large cell and small cell neuroendocrine carcinoma and using different chemotherapy schemes according to large or small cell neuroendocrine carcinoma of the stomach for clinical research to clarify the heterogeneity of GNEC and improve the prognosis of patients with GNEC.

Trends in Prognostic Factors for Neuroendocrine Lung Tumors

Delta-like ligand 3 (DLL3) is frequently expressed in pulmonary small cell neuroendocrine carcinoma (SCNEC) and has emerged as a promising therapeutic target. However, limited data on DLL3 expression in other neuroendocrine neoplasms (NEN), such as extrapulmonary SCNEC, large cell neuroendocrine carcinomas (LCNEC), mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), gastroenteropancreatic neuroendocrine tumours (GEP-NET), and pulmonary carcinoids, impedes an estimation if other types of NEN might be suitable candidates for anti-DLL3 therapies. We evaluated DLL3 expression in 1294 NEN and 479 non-neuroendocrine carcinomas, correlating the findings with histological subtypes, tumour localisation, and overall survival (OS). Furthermore, we explored the concordance of DLL3 expression during metastatic progression in 67 paired primary NEN and metastases. DLL3 expression was significantly higher in NEC (64.0%) compared to GEP-NET and pulmonary carcinoids (10.1%, p < 0.001), particularly in SCNEC (80.4%), followed by LCNEC (62.6%) and MiNEN (28.6%). DLL3 was common in pulmonary carcinoids (41.5%), but rare in GEP-NET (5.1%) and non-neuroendocrine carcinomas (1.3%). Overall DLL3 expression was highly concordant between metastases and corresponding primary NEN (92.5%, p < 0.001). In univariable analyses, DLL3-expressing pulmonary carcinoids (p = 0.005) and GEP-NET (p = 0.018) were associated with decreased OS, but this was not retained in multivariable analyses adjusting for stage and grade (p = n. s.). No prognostic impact was observed in pulmonary (p = 0.708) or GEP-NEC (p = 0.87). Our study highlights significant differences in DLL3 expression across NEN subtypes and localisations, with largely concordant expression in metastases. DLL3-based therapies may be effective in many NEC and pulmonary carcinoids, while DLL3 appears to be a minor therapeutic target for GEP-NET and non-neuroendocrine carcinomas.

Rationale:Endometrial neuroendocrine carcinoma is a rare histological subtype of endometrial cancer, divided into low-grade neuroendocrine carcinoma (carcinoid) and high-grade neuroendocrine carcinoma (small cell and large cell neuroendocrine carcinoma). It is characterized by high invasiveness and poor prognosis. L/SCNEC is an extremely rare pathological type of endometrial carcinoma, and the number of reports on this condition is few globally.Patient concerns:A 54-year-old Chinese female presented with vaginal bleeding.Diagnoses:Outpatient hysteroscopy and endometrial biopsy were performed, and the pathological examination revealed that cervix was invaded by endometrial malignancy. The patient underwent a laparoscopic radical hysterectomy was diagnosed with the mixed large and small cell neuroendocrine carcinoma (L/SCNEC) of the endometrium combined with serous carcinoma III C2 (FIGO2009).Interventions:Chemotherapy-radiotherapy-chemotherapy “sandwich” treatment was performed as postoperative therapy.Outcomes:After three chemotherapy circles, the patient showed no evidence of further disease progression.Lessons:L/SCNEC is a rare and invasive disease. Once diagnosed, comprehensive treatments including surgery, radiotherapy, and chemotherapy can prolong the survival of patients and improve the prognosis.

This review aimed to critically analyse data pertaining to the clinical presentation and treatment of neuroendocrine carcinomas of the larynx. A PubMed search was performed using the term 'neuroendocrine carcinoma'. English-language articles on neuroendocrine carcinoma of the larynx were reviewed in detail.Results and conclusionWhile many historical classifications have been proposed, in contemporary practice these tumours are sub-classified into four subtypes: carcinoid, atypical carcinoid, small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma. These tumours exhibit a wide range of biological behaviour, ranging from the extremely aggressive nature of small and large cell neuroendocrine carcinomas, which usually have a fatal prognosis, to the less aggressive course of carcinoid tumours. In small and large cell neuroendocrine carcinomas, a combination of irradiation and chemotherapy is indicated, while carcinoid and atypical carcinoid tumour management entails conservation surgery.

Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Next-Generation Sequencing Identified a Novel Crizotinib-Sensitive PLB1-ALK Rearrangement in Lung Large-Cell Neuroendocrine Carcinoma

298 Background: The WHO classified pancreatic neuroendocrine Neoplasms (pNEN) in 2010 as G1, G2, and neuroendocrine carcinoma (NEC). However, pNEC is suspected to include heterogeneous disease entities, but is still not fully studied. We aimed to clarify the clinicopathological and molecular characteristics of NECs. Methods: A total of 100 cases clinical data and pathological slides originally diagnosed as NEC by the WHO in 2010(WHO-NEC) were retrospectively collected from 31 institutes. Expert pathologists were reassessed all cases slide using the designed protocol and reclassified as well differentiated NET (NET-G3), small cell NEC(SCNEC), and large cell NEC(LCNEC) by morphological features. Results: Thirty cases were eliminated mostly because acinar cell carcinoma, NET-G2 and malignant tumor not otherwise specified. Remaining 70 cases were subclassified into 21(30%) NET-G3, 31 (44.3%) SCNEC, 18(25.7%) LCNEC. Comparisons of NET-G3 vs. SCNEC vs. LCNEC revealed the following traits: ENETS stageⅣ: 76%, 81% and 78%; median Ki67 LI: 28.5% (15-53), 85 % (50-100) and 70.0 %(22-90); abnormal Rb expression: 0 %, 59% and 47%; KRAS mutations: 0 %, 48% and 50%; response rates to platinum-based chemotherapy: 0%, 60% and 44.4% ;and median survival(days): 1255, 340 and 196, respectively. When KRAS divided wild (n = 20) and KRAS mutation group (n = 42), response rate to platinum-based chemotherapy was 77% vs 23%.In the same manner, when Rb immune stain divided negative (n = 24) and positive (N = 41), response rate to platinum-based chemotherapy was 80% vs 23.8%. Besides response rate to platinum-based chemotherapy of KRAS mutation(+) and Rb immunopositivity(-) group (n = 7) were 100%, on the other hand, KRAS mutation(-) and Rb immunopositivity(+) group (n = 7) were 18.7%. Conclusions: In this retrospective study, WHO-NEC include 30% NET-G3. NET-G3 are genetically different from SCNEC and LCNEC. As for chemotherapy,Mutated KRAS and/or Rb immunonegativity in tumors with pNEC is associated with response to platinum-based chemotherapy.

neoplasms of the head and neck, thus accurate histologic classification is essential. lCNC is a high-grade malignant neuroendocrine tumor that was first defined in the lungs by travis et al. [1] in 1991. this tumor accounts for approximately 3 % of all lung cancers [2], and the prognosis is poor. the diagnosis of lCNC is based on high-grade features, and the presence of both neuroendocrine morphology as well as immunohistochemical evidence of neuroendocrine differentiation. lCNC is a poorly differentiated neuroendocrine neoplasm that has several morphological and biologic features in common with both moderately differentiated neuroendocrine carcinoma (atypical carcinoid) and SCNC. However, the prognosis of pulmonary lCNC and SCNC is significantly worse than for moderately differentiated neuroendocrine carcinoma. the 2005 World Health Organization Classification of Head and Neck tumours [3] was a significant step towards diagnostic standardization of head and neck neuroendocrine carcinomas. It did not specifically include lCNC as a distinct tumor type, however. In the last 10 years, though, there have been new data supporting the recognition of “large cell neuroendocrine carcinoma” as a distinctive high-grade carcinoma in the head and neck, an entity not included in the 2005 Classification [4]. By the 2005 WHO classification, laryngeal lCNCs would actually be classified as variants of moderately differentiated neuroendocrine carcinoma (atypical carcinoid), whereas the pulmonary WHO classification considers lCNCs as poorly differentiated neuroendocrine carcinomas essentially grouping them with SCNC. the proper distinction among these entities is of paramount importance as it has significant therapeutic and prognostic implications. the first report of lCNC in the head and neck was published by Hui et al. [5] in 1990 and at that time the authors Head and neck cancers account for approximately five percent of all cancers, and the majority are squamous cell carcinoma. Neuroendocrine carcinomas of the head and neck are uncommon and present unique challenges both in diagnosis and treatment. tumors with neuroendocrine morphology are a distinct subset of neoplasms that share specific morphologic, histochemical, immunohistochemical, ultrastructural, and molecular characteristics. these tumors include paraganglioma, well-differentiated neuroendocrine carcinoma (or typical carcinoid), moderately differentiated neuroendocrine carcinoma (or atypical carcinoid), small cell neuroendocrine carcinoma (SCNC), and large cell neuroendocrine carcinoma (lCNC). Staging, treatment, and prognosis vary widely among the five neuroendocrine

Cervical small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) are uncommon but highly aggressive neoplasms. From a diagnostic point of view, there may be problems both in distinguishing these from other neoplasms and in confirming a cervical origin. This is important as management is critically dependent on the correct histologic diagnosis. We undertook a detailed immunohistochemical analysis of a relatively large series of primary cervical SCNEC (n=13) and LCNEC (n=8). Cases were stained with AE1/3, chromogranin, CD56, synaptophysin, PGP9.5, TTF1, p16, p63, CK7, CK20, neurofilament, and CD99. CK20 and neurofilament staining was undertaken to investigate whether some of these neoplasms might exhibit a Merkel cell immunophenotype and CD99 staining to assess whether there is immunohistochemical overlap with neoplasms in the Ewing family of tumors (EFT). For all markers, staining was classified as negative, 1+ (<10% cells immunoreactive), 2+ (10 to 50% cells immunoreactive), or 3+ (>50% cells immunoreactive). Eleven and 6 SCNEC and LCNEC, respectively were positive with AE1/3. Chromogranin, CD56, synaptophysin, and PGP9.5 were positive in 11, 19, 19, and 9 cases, respectively. Altogether 15 cases (71%) (11 SCNEC, 4 LCNEC) exhibited nuclear positivity, often diffuse, with TTF1. All but 1 case was diffusely positive with p16. p63 was positive in 9 cases, including 5 with diffuse nuclear immunoreactivity. Ten and 4 neoplasms were positive with CK7 and CK20, respectively. Neurofilament was positive in 7 tumors. The 4 neoplasms that were CK20 positive were stained with the monoclonal antibody CM2B4, generated against an antigenic epitope on the Merkel cell polyomavirus T antigen; all were negative. CD99 was positive in 6 cases. In 2 cases, adjacent foci of adenocarcinoma in situ (AIS) contained scattered individual chromogranin positive cells, raising the possibility that some cervical neuroendocrine carcinomas arise from neuroendocrine cells in AIS. Four of 13 cases of pure AIS also contained scattered chromogranin positive cells. Our results illustrate that a proportion of cervical neuroendocrine carcinomas are negative with broad spectrum cytokeratins and some of the commonly used neuroendocrine markers. TTF1 positivity is extremely common and may be a useful marker of a neuroendocrine carcinoma. It is of no value in exclusion of a pulmonary primary. p16 is almost always positive in cervical neuroendocrine carcinomas, possibly owing to an association with oncogenic human papillomavirus, although other mechanisms of expression are also possible. Cervical neuroendocrine carcinomas may be p63 positive, illustrating that this marker is not specific for squamous differentiation. CK20 and neurofilament positivity in some cervical neuroendocrine carcinomas is in keeping with a Merkel cell immunophenotype, similar to that described in SCNECs in other organs. However, the absence of staining with CM2B4 argues against a true Merkel cell tumor. CD99 staining in a cervical neuroendocrine carcinoma should not result in misdiagnosis as a neoplasm in the Ewing family of tumors.

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. To provide clinicopathologic evidence to streamline and clarify the histomorphologic criteria for this group of tumors, emphasizing the prognostic implications. 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. 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. 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.

c 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. (Arch Pathol Lab Med. 2002;126:545‐553)

Neuroendocrine neoplasms include a heterogeneous group of malignant tumors. Primary neuroendocrine tumors in the genitourinary tract are rare, comprising approximately 1-2% of genitourinary malignancies. An extensive search was performed for publications between 2000 and 2018 regarding neuroendocrine tumors of the genitourinary tract. Epidemiological, clinical, histopathological, prognostic and therapeutic data were evaluated. Neuroendocrine tumors of the kidneys are exceedingly rare, mostly well-differentiated. 0.5-1% of all primary bladder malignancies are small cell neuroendocrine carcinomas. Characteristically, prostatic adenocarcinoma with neuroendocrine differentiation occurs in androgen receptor-independent/castrate-resistant cancer. Small cell and large cell neuroendocrine carcinomas are the most aggressive tumors in each location. Due to the rarity and poor prognosis of these tumors, proper pathological diagnosis and early therapy are important. Therapeutic guidelines are not available. Surgery, radiotherapy and/or chemotherapy are possible treatment options; somatostatin analogs are used as standard therapy in case of well-differentiated neuroendocrine tumors.

A century ago, it was a signiWcant accomplishment to distinguish between laryngeal epithelial malignancies (carcinomas), mesenchymal malignancies (sarcomas) and hematopoietic malignancies (lymphomas). A great deal has changed since that time; while the vast majority of laryngeal malignancies will prove to be carcinomas, the family of carcinomas has grown to encompass an impressively large array of diVerent pathologically deWned entities. One subset of epithelial malignancies of the larynx that can give rise to some confusion is one of the more uncommon subsets, the group of neuroendocrine carcinomas of the larynx. To be clear, this group—to be discussed here— comprises the epithelial-derived neuroendocrine tumors, and so excludes the neurally derived tumors (such as paraganglioma, neuroblastoma, Ewing’s sarcoma, and primitive neuroectodermal tumor). As such, this group of epithelial neuroendocrine carcinomas of the larynx encompasses four discrete pathologically deWned entities: carcinoid tumor, atypical carcinoid tumor, small cell neuroendocrine carcinoma, and large cell neuroendocrine carcinoma (as well, combined tumors—such as atypical carcinoid tumors, small cell and large cell neuroendocrine carcinomas—may be encountered, but are not further discussed here in light of their extreme rarity) [1–4]. While these four tumor types are marked by widely diVering light microscopic appearances, they are united by the presence of some combination of positivity by immunohistochemistry with antibodies including cytokeratin, chromogranin, synaptophysin, CD56, CD57, neuron-speciWc enolase, serotonin, somatostatin, bombesin, and protein gene product 9.5 [5].