Non-small cell lung carcinomas with neuroendocrine features. A light microscopic, immunohistochemical and ultrastructural study of 11 cases

Eleven resected primary lung carcinomas classified as large cell carcinomas or squamous cell carcinomas, but showing some microscopic resemblances to bronchial carcinoid and small cell carcinoma, were studied. All cases were neurone-specific enolase and protein gene product 9.5 positive, indicating neuroendocrine differentiation. Staining for bombesin, C-terminal peptide of human pro-bombesin and chromogranin was positive in some cases. Electron microscopy showed dense-core granules in six of seven cases investigated, the remaining case showing small granules of uncertain nature. All but one patient died within 15 months after operation. These data indicate that neuroendocrine differentiation in non-small cell carcinomas of the lung may in some cases be suspected on routine histology. The follow-up data suggest that the identification of these cases might have implications for prognosis and therapy, and consequently for diagnostic lung tumour classification.     

Atypical carcinoid tumour of the thymus: a study of eight cases

Atypical carcinoids of the thymus are rare neoplasms of uncertain prognosis. We have studied eight cases (six male, two female; age range 48–60 years, mean 55 years), none with evidence of a paraneoplastic neuroendocrine syndrome. Tumour size was large and ranged from 7.5 to 10 cm. Microscopically, all had a nesting/insular or trabecular pattern, eosinophilic cytoplasm, round nuclei with fine chromatin and small nucleoli. No small cell features were evident. Mitotic activity ranged from 2 to 21 per 1.52 mm². Focal necrosis was seen in all cases. All were positive for cytokeratin (AE1/AE3, CAM 5.2) and the neuroendocrine markers NSE, synaptophysin and chromogranin; five cases were positive for calcitonin. On electronmicroscopy all contained dense core granules, often numerous. Three cases were stage I and five stage III (infiltrating lung or chest wall). Follow-up information was available in four cases (one stage I and three stage III): the stage I tumour had local recurrence and metastasis to the lung within a year whilst the three patients with stage III tumours died of liver, bone and brain metastases within 3 years.     

Comparison of benign and malignant insulinoma

BackgroundHow malignant insulinomas present relative to benign insulinomas is unknown.MethodsA single-institution retrospective study identified patients with insulinoma. Malignancy was defined by distant metastases, positive lymph node(s), T stage of 4, direct invasion into surrounding peripancreatic tissue, or presence of lymphovascular invasion. Wilcoxon Rank Sum tests and Kaplan-Meier analysis were used.ResultsA total of 311 patients were identified: 51 malignant and 260 benign. Patients with malignant insulinoma presented with higher levels of insulin, proinsulin, and c-peptide. Malignant lesions were larger: 4.2 ± 3.2 vs 1.8 ± 0.8 cm in benign lesions, p < 0.01. Overall survival at 5 years was 66.8% vs 95.4% for malignant and benign insulinoma respectively, p < 0.01.ConclusionsLarger size of insulinoma and increased serum β-cell polypeptide concentrations were associated with malignancy. Malignant insulinoma has poorer survival. Further work-up to rule out malignancy may be indicated for larger pancreatic lesions and for patients with higher pre-operative insulin and pro-insulin.     

Thymic neuroendocrine tumours

Thymic epithelial tumours include the subcategory of thymic neuroendocrine neoplasms, which comprise a spectrum of entities that mirrors their counterparts in the lung, i.e. typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma. These tumours are classified according to the current WHO classification for lung tumours, and their relevant histomorphological and immunohistochemical criteria will be discussed in this brief review. Thymic neuroendocrine neoplasms do, however, also have clinical and molecular characteristics which set them apart from their pulmonary relatives, and recent research has provided valuable insights into possible molecularly-informed classification systems, which broadly align with classical categories, but also show some discrepancies. The most salient recent studies in that respect will also be discussed, as will the avenues for locally ablative therapy and possibilities for systemic treatment.     

Adverse childhood experiences and the development of Down syndrome regression disorder

Down syndrome regression disorder (DSRD) is a clinical symptom cluster of acute or subacute neurocognitive regression in otherwise health persons with Down syndrome. The objective of this study was to evaluate if adverse childhood experiences (ACEs) were more prevalent in children with DSRD than those with DS alone. A survey-based, cohort-based study was performed. Caregivers of individuals with DSRD with onset of symptoms between age 10 and 30 years and DS alone were administered the ACEs questionnaire via an online REDCap survey. A total of 159 responses were collected after excluding incomplete surveys and those not meeting criteria for DSRD. Individuals with DSRD were not more likely to experience ACEs (p = 0.18, 95% confidence interval [CI]: 0.43–1.17). In those with ACEs prior to the onset of symptoms, the median time prior was 7 months (interquartile range: 5–10). Individuals with DSRD were more likely to report three or more ACEs (52, 33%) compared to those with DS alone (39, 22%) (p = 0.02, 95% CI: 1.08–2.87). Exposure to ACEs were not predictive of response to particular therapeutic interventions although those with multiple ACEs 3 months prior to the onset of symptoms was associated with lower response rates to benzodiazepines and immunotherapy (p = 0.02, 95% CI: −3.64–−1.13). This study provides preliminary data that individuals with DSRD experience ACEs at a similar rate to individuals with only DS alone, although three or more ACEs, often preceding the onset of symptoms, was more prevalent in individuals with DSRD.     

Neuroendocrine Tumors of the Head and Neck: A Selected Review with Emphasis on Terminology

Virtually every variant of neuroendocrine neoplasia can occur, at least rarely, in the head and neck region. This review focuses on the terminology surrounding neuroendocrine carcinomas of the larynx and their distinction from morphologically similar but biologically distinctive neoplasmas. It is suggested that rare typical laryngeal carcinoids be labeled as such. There is little evidence that these lesions are part of a morphologic continuum. In contrast, more common “carcinoid-like” carcinomas, previously referred to as “atypical carcinoids” are more appropriately labeled as “moderately differentiated neuroendocrine carcinomas”. These neoplasms should, in turn, be distinguished from “small cell neuroendocrine carcinomas,” although these latter two neoplasms do represent a morphologic and behavioral spectrum. Light microscopic and immunohistochemical features distinguishing neuroendocrine carcinomas of the larynx from paraganglioma, metastatic medullary carcinoma, malignant melanoma, and basaloid squamous cell carcinoma are presented. The second portion of this review outlines the clinicopathologic features of two head and neck neoplasms exhibiting varying degrees of neuroendocrine differentiation. Olfactory neuroblastomas have well-developed neuroendocrine differentiation, almost invariably arise from the olfactory mucosa, typically exhibit low-grade cytologic features, and may have protracted clinical course with an approximately 50% overall 5-yr survival. In contrast, sinonasal undifferentiated carcinoma is a microscopically high-grade neoplasm with minimal, abortive neuroendocrine features, a highly aggressive clinical course, and virtually 100% mortality. They can arise throughout the sinonasal region. Presented at the Endocrine Pathology Society—USCAP Meeting, Washington, DC, March 23, 1996.     

High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumors: Clinical and biological effects

Background: Neuroendocrine tumors usually present with inoperable metastatic disease and severe hormonal symtoms. Specific chemotherapy, alpha-interferon and the somatostatin analog octreotide are established therapies in these patients but all of them eventually fail. Other somatostatin analogs, e.g., RC-160 and lanreotide, are currently being studied in different doses and modes of administration.Patients and methods: Nineteen patients with advanced neuroendocrine gastrointestinal tumors [13 carcinoids and six endocrine pancreatic tumors (EPT)], liver metastases being present in 18, most of them heavily pretreated, were included. Seventeen out of 18 patients had somatostatin receptors demonstrated by octreotide scintigraphy. Lanreotide was given as four daily subcutaneous injections, starting with 750 µg/d, then increasing every week up to 12,000 µg/d after six weeks, a dose which was maintained, if tolerated, for 12 months, or until progression.Results: There was a significant tumor size response (>50%) in one patient (5%), whereas 12 patients (70%) had tumor stabilization for 12 months. Bichemical tumor markers were significantly reduced at six months (urinary 5-hydroxyindoleacetic acid and plasma chromogranin) and 12 months (chromogranin) and the overall biochemical response rate was 58% with this high dose of lanreotide. Adverse events were observed and four patients stopped the treatment due to adverse events. Studies of tumor biopsies before and during treatment indicated induction of apoptosis in patients with tumor stabilization and biochemical response.Conclusion: High-dose treatment with lanreotide (12,000 µg/d) produced tumor size response in 5%, stabilization in 70% and a biochemical response in 58% of patients. These results should be related to the advanced stage of the disease as indicated by the mean duration of disease of more than four years, but they do not appear to be better than those achieved with standard doses of somatostatin analogs. However, in responding patients we observed induction of apoptosis in the tumors, a phenomenon not seen with regular doses of somatostatin analogs, but often produced by chemotherapeutic agents.     

肺神经内分泌癌组织中c-myc和E2F1蛋白表达的临床病理意义

目的:探讨转录因子c-myc和E2F1蛋白在肺神经内分泌癌组织中的表达及其临床病理意义。方法:采用免疫组化SP法检测90例多种肺神经内分泌癌组织中c -myc及E2F1蛋白表达,并分析其与各临床病理指标的关系。结果:c- myc和E2F1蛋白表达定位于癌细胞核;c- myc蛋白表达与组织学类型、临床分期、淋巴结转移、肿瘤大体类型以及预后相关,P<0. 05(P值分别为0. 041、0 .003、0 .019、0. 033和0 .000),与患者性别、年龄无关,P>0 05(P值分别为0 069 和1 000);E2F1表达与组织学类型、临床分期、淋巴结转移、肿瘤大小、预后有关,P<0 .05(P值分别为0. 000、0. 001、0. 000、0 .011和0 .000),与患者性别、年龄无关,P>0. 05(P值分别为0. 105和0 .844)。结论:c- myc、E2F1 蛋白在肺神经内分泌癌的发生、演进过程中起着重要作用,并可作为分子指标检测患者预后。     

Immunobiologic, cytogenetic and drug response features of a newly established cell line (SCRC-1) from renal small cell carcinoma

PURPOSE: We describe the establishment and preliminary characterization of a cell line designated SCRC-1, which was derived from a primary renal small cell carcinoma. MATERIALS AND METHODS: Continuous cultures of a primary stage IVa renal small cell carcinoma and a xenograft in nude mice derived therefrom were characterized by immunohistology, electron microscopy, immunofluorescence/flow cytometry, cytogenetic analysis, and an in vitro drug resistance assay. RESULTS: SCRC-1 cells were reactive with antibodies to NSE, chromogranin-A, bombesin, Bcl-2, CD44s, CD44v6, CD44v7 to 8, vimentin and S100 protein (predominantly beta-subunit), and were unreactive with antibodies to EMA, CD54, EGFR(R1), URO-5, URO-7, URO-8 and URO-10. A similar immunoprofile was also found in both the primary tumor and the xenograft. Cytogenetic analysis revealed the following common clonal aberrations in all 50 metaphases analyzed: 45, XX, t (X;10;18) (p11;p11;q11), -der(18)t(X;10;18), indicating the clonal nature of this neoplasm. SCRC-1 cells showed low drug resistance to cyclophosphamide, doxorubicin, gemcitabine and fluorouracil, intermediate resistance to carmustine and mitomycin-C, and extreme resistance to cisplatin. CONCLUSION: We have documented the initial characterization of SCRC-1, which may be the first cell line reported to be derived from a primary small cell carcinoma of the kidney. This cell line can be used for further studies uncovering the biology and histogenesis of this rare cancer and delineating differences among small cell carcinomas of the kidney and other histological types.     

肺癌神经内分泌分化与术后生存关系探讨(英文)

目的探讨非小细胞肺癌神经内分泌(NSCLC-NE)分化与患者手术后生存关系。方法收集1997年4月～1999年4月98例肺癌手术切除病理标本,采用免疫组化标记特异性烯醇化酶(NSE)及突触素(SY),并按强弱区分为“+、++、+++”。对同一手术病例标本采用电镜观察特异性 NE 颗粒。术后病例随访36例,最长60月。采用Cox 多因素风险模型分析 NSCLC-NE 分化与患者术后生存的关系。结果 91例为非小细胞肺癌。非小细胞肺癌 NE 阳性表达率为63.7%(58/91),其中 NSE 阳性表达54例(59.3%),SY 阳性表达22例(24.1%),电镜观察 NE 特异性颗粒30例(33.0%)。结合免疫组化和电镜观察 NSCLC-NE 分化44例(48.4%)。Cox 模型多因素分析结果表明 NSCLC-NE 分化者术后生存时间明显缩短(P=0.048)。术后生存与肺癌细胞分化程度(P=0.006)、病理分期(P=0.001)、NE 表达强弱(P=0.054)有密切关系。结论 NSCLC-NE 分化与肿瘤细胞分化和患者术后生存有关。采用 NE 标志特标记肿瘤,并观察其强弱改变,对术后评估具有较重要的参考意义,可作为临床判断患者预后指标之一。