EGFR-Expression in pulmonalen neuroendokrinen Zellhyperplasien

15 cases of pulmonary neuroendocrine cell hyperplasia (carcinoid-tumorlets, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia/DIPNECH) and 20 neuroendocrine pulmonary tumors (10 carcinoid tumors, 5 large cell neuroendocrine, and 5 small cell neuroendocrine lung carcinomas) were immunohistochemically analyzed for the expression of epidermal growth factor receptor (EGFR, = HER-1). All cases of neuroendocrine cell hyperplasia exhibited a maximum EGFR expression (score 3 in 100% of cells) showing predominantly membranous, partly cytoplasmic staining. 4 ot the 10 carcinoid tumors were strongly positive for EGFR, whereas the other 6 were EGFR-negative. A total of 90% of large cell neuroendocrine and small cell neuroendocrine carcinomas were negative for EGFR. Overexpression of EGFR in pulmonary neuroendocrine cell hyperplasia might be significant for the pathogenesis of these lesions. As DIPNECH is characterized by clinical signs and symptoms including mild cough and obstructive functional impairment, a specific antagonistic therapeutic trial could aim at blocking EGFR/HER-1 or its subsequent signal transduction pathway.     

Sox10-positive sustentacular cells in neuroendocrine carcinoma of the lung

Tsuta K, Raso M G, Kalhor N, Liu D C, Wistuba I I & Moran C A
(2011) Histopathology  58, 276–285
Sox10‐positive sustentacular cells in neuroendocrine carcinoma of the lung Aims: Sustentacular cells are found in approximately half of pulmonary carcinoid tumours. However, most studies of sustentacular cells have used the less‐specific antibody to the S100 protein, and any correlation between the presence of sustentacular cells and other clinicopathological factors is unclear. The aim of this study was to analyse the significance of sustentacular cells in pulmonary neuroendocrine carcinomas (NECs). Methods and results: A Sox10 antibody was used to investigate 113 pulmonary NECs. Sustentacular cells were observed in 66.7% of typical carcinoid (TC) and 58.3% of atypical carcinoid (AC) cases, but not in high‐grade NECs. Sustentacular‐rich tumours had a statistically significant correlation with peripheral locations. We found no statistical differences in age, gender, smoking history, overall survival, or the occurrence of lymph node metastasis. In all but one case, when sustentacular cells were present in the primary site, they were also present in the metastatic lymph nodes. The presence of sustentacular cells differed in morphological subtypes, with the spindle pattern being the most common subtype. Conclusions: Sox10‐positive sustentacular cells were observed in carcinoid tumours but not in high‐grade NECs. Sustentacular‐rich carcinoid tumours did not show a correlation with the occurrence of lymph node metastasis or survival. The sustentacular cells found differed in morphological subtypes.     

Pulmonary paraganglioid carcinoids and bcl-2 oncoprotein expression

Bcl-2 protein immunoreactivity was examined in 10 pulmonary carcinoid tumors with abundant S-100 protein-positive sustentacular cells (SCs) diagnosed as paraganglioid carcinoids. Its positivity in the mentioned tumors was compared with that of neoplasms formed of neuroendocrine cells only (30 pulmonary carcinoids), and with another group of 30 lesions consisting of neuroendocrine and sustentacular elements, i.e., paragangliomas (11 paragangliomas of the glomus caroticum and 9 jugulotympanic paragangliomas [JPTGs]), pheochromocytomas (5 cases), and a rare form of pulmonary tumorlets (PTUs) with a high frequency of SCs (5 cases). Bcl-2 protein was found in all 70 examined cases, and its expression showed no difference between the examined groups. On the basis of these results, bcl-2 protein expression was not found to be an indicator for either survival or useful for the differential diagnosis of pulmonary carcinoid tumors.     

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia with a Central and Peripheral Carcinoid and Multiple Tumorlets: A Case Report Emphasizing the Role of Neuropeptide Hormones and Human Gonadotropin-Alpha

We report a case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). We performed immunohistochemical analysis of 17 neuropeptides and human gonadotropin-alpha (hCGα), a trophoblastic peptide that promotes the proliferation of neuroendocrine cells. A 51-year-old woman with no history of smoking was found to have a nodule in the right middle lobe. Upon examination, the nodule was found to comprise diffuse linear and nodular neuroendocrine cell hyperplasia (NECH), numerous pulmonary tumorlets merging with one peripheral carcinoid, and an additional central carcinoid. Immunohistochemical analysis revealed diffuse but intense expression of the general neuroendocrine markers CD56, synaptophysin, and chromogranin A, together with gastrin-releasing peptide (GRP), calcitonin, and hCGα throughout the carcinoids, tumorlets, and NECH. Positive staining was also noted for adrenocorticotropic hormone, corticotropin-releasing hormone, met-enkephalin, vasoactive intestinal polypeptide, neurotensin, and growth hormone-releasing hormone in a few isolated cells of the carcinoids and the tumorlets, but staining for these proteins was entirely negative in the NECH lesions. The presence of these neuropeptides in neuroendocrine tumors might explain the presence of neuropeptide-producing tumors of the lungs, cases of which have been reported over the last 30 years. The preoperative serum proGRP level was high but returned to normal after surgical intervention, indicating that GRP was produced and secreted by carcinoids, tumorlets, and/or NECH lesions. It is also probable that neuroendocrine cells secreted GRP into the interstitium in a paracrine manner, leading to the development of dense fibrosis around the tumorlets. During the preoperative and postoperative periods, no evidence of bronchiolitis obliterans was noted, in contrast to some previously reported cases of DIPNECH.     

Cytological features of mixed adenoneuroendocrine carcinoma of the ampulla: Two case reports with review of literature

Mixed adenoneuroendocrine carcinoma (MANEC) of ampulla is rare, with only 13 cases reported, and the diagnoses were all based on histology mostly after surgery. We describe two new cases with cytological features of signet ring‐cell carcinoma mixed with small‐cell carcinoma, and intestinal adenocarcinoma mixed with large‐cell neuroendocrine carcinoma. Our cases and literature review demonstrate the higher frequency of periampullary‐duodenum subtype in MANEC compared with non‐MANEC ampullary carcinomas. In accordance, of the 14 MANEC cases with detailed morphology available, the most common glandular components are intestinal‐type carcinoma (6/14), followed by goblet carcinoid tumor (3/14), signet ring‐cell carcinoma (2/14), pancreatobiliary‐type carcinoma (2/14), and pancreatic acinar cell carcinoma (1/14). The intestinal‐type carcinoma and goblet carcinoid in MANEC are favorable histological types showing no distant metastasis or mortality (0/9) during 6–36 months follow‐up. In contrast, the signet ring cell, pancreatobiliary‐type carcinoma, and acinar cell carcinoma are unfavorable with distant metastatic rate and mortality rate of 80% (4/5) during 3–16 months follow‐up. The combination of favorable glandular histological types with high‐grade neuroendocrine tumors (neuroendocrine carcinoma) has a mortality rate of 0% (0/3), whereas the combination of unfavorable glandular types with low‐grade neuroendocrine tumors (e.g., carcinoid, atypical carcinoid) has a mortality rate of 100% (3/3). In addition, younger age (<40 years) seems to be associated with high mortality rate of 100% (2/2). Overall, cytology preparations are able to make the diagnosis of MANEC and distinguish the subcomponents. Disease progression is apparently driven by the carcinomatous component of the tumor. Diagn. Cytopathol. 2014;42:1075–1084. © 2014 Wiley Periodicals, Inc.     

Neuroendocrine tumors of the appendix

The vast majority of neuroendocrine neoplasms of the appendix are carcinoid tumors. Most are of enterochromaffin (EC) cell type, although rare examples are of L cell type. EC cell carcinoids of the appendix differ from those encountered elsewhere in the gastrointestinal system. For example, they are remarkably common given the small size of the appendix, are usually benign, occur in younger patients, and typically contain sustentacular cells that express S-100. Origin from subepithelial neuroendocrine cells could explain these characteristics. It has also been suggested that most appendiceal carcinoids are hyperplastic rather than neoplastic, although this hypothesis requires further study. Nevertheless, truly neoplastic EC cell carcinoids of the appendix undoubtedly occur, and those greater than 2 cm in diameter have a significant risk of producing distant metastases. Carcinoid syndrome is a very rare presentation. Tubular carcinoids are unusual benign neoplasms; it has been proposed that they represent L cell carcinoids with a predominant tubular pattern of growth. Goblet cell carcinoids tend not to produce a grossly visible tumor mass but diffusely infiltrate the wall. They typically exhibit tight clusters of goblet cells, usually with scattered neuroendocrine cells and sometimes with Paneth cells, sometimes surrounding a small lumen. They may behave as a low-grade malignancy. The distinction between goblet cell carcinoid and other types of tumor is of great importance because of the implications for treatment and prognosis. Frank adenocarcinoma can arise from goblet cell carcinoids, and tumors with both components are classified as mixed goblet cell carcinoid-adenocarcinoma. The carcinoma component of the latter determines their prognosis, which would be worse than for a goblet cell carcinoid alone.     

Multicentric metachronous pulmonary and intravagal paraganglioma: a case report with immunohistochemical findings

An unprecedented presentation of multicentric paraganglioma in a 48-year-old man is described. One of the paragangliomas, originally diagnosed as a carcinoid tumor, presented as a lung mass and was removed. Four years later, an intravagal paraganglioma was discovered. The lung and intravagal tumors had identical morphologic and immunoreactive characteristics. Both tumors consisted of chief cells (type 1) and sustentacular cells (type 2). The chief cells were immunoreactive with neuroendocrine markers (synaptophysin and chromogranin), but nonreactive with epithelial markers (CAM 5.2, high- and low-molecular-weight keratins, epithelial membrane antigen, and carcinoembryonic antigen). The sustentacular cells were positive for S100 protein. Although pulmonary carcinoids may mimic paragangliomas and occasionally contain sustentacular cells, the diagnosis was rejected because the tumor cells did not demonstrate reactivity with epithelial markers.     

Immunohistochemical and ultrastructural analysis of bronchopulmonary neuroendocrine neoplasms. II. Well-differentiated neuroendocrine carcinomas

We have attempted to characterize a group of bronchopulmonary neoplasms that share certain structural features with true carcinoids but appear distinctly more pleomorphic and behave far more aggressively. In reviewing our files from 1973 to 1982, 11 such neoplasms were identified; the original diagnoses were "atypical bronchial carcinoid" (3 cases), "malignant carcinoid" (1 case), "bronchial carcinoid" (3 cases), "peripheral carcinoid" (2 cases), and "peripheral oat cell carcinoma" (2 cases). Of the 11 neoplasms, 5 were central and 6 were peripherally located. At presentation, 7 patients had lymph node metastases and 1 had a distant metastasis. No patient had a conventionally defined hormonal syndrome; however, 2 patients had a history of episodic flushing, one of which was associated with diarrhea. All cases were studied by light microscopy and light microscopic immunohistochemistry for NSE (neuron-specific enolase), serotonin, and broad-spectrum neuropeptides. Five cases were studied by electron microscopy. By light microscopy, the tumors were composed of solid clusters of polygonal to fusiform cells in an evident organoid arrangement. Foci of glandular and/or squamous differentiation were seen in 7 cases. Pleomorphism was moderate and mitoses were readily found. Focal necrosis was seen. By immunohistochemistry, 10 cases expressed NSE immunoreactivity. All cases demonstrated hormonal immunoreactivity; in 9 cases, immunoreactivity for more than one hormone was observed. The hormones most frequently expressed were serotonin, bombesin, gastrin, leu-enkephalin, and ACTH. By electron microscopy, all cases studied contained heterogeneous populations of neurosecretory granules; the latter, however, were not abundant and tended to aggregate either in the basal pole of the cells or, more frequently, interlacing "dendritelike" cytoplasmic processes. Aggregates of intermediate filaments were frequently seen. Basal lamina deposition was seen but gaps and larger areas of discontinuity were frequent. We believe that these neoplasms constitute a distinct pathologic entity for which the term "well-differentiated neuroendocrine carcinoma" has been proposed. Clinically, these tumors merit special attention since they are demonstrably more aggressive than true carcinoids but are distinctly less malignant than the intermediate or small cell variants of neuroendocrine carcinoma.     

Lung carcinoid tumours: histology and Ki-67, the eternal rivalry

WHO classification of Thoracic Tumours defines lung carcinoid tumours (LCTs) as well-differentiated neuroendocrine neoplasms (NENs) classified in low grade typical (TC) and intermediate grade atypical carcinoids (AC). Limited data exist concerning protein expression and morphologic factors able to predict disease aggressiveness. Though Ki-67 has proved to be a powerful diagnostic and prognostic factor for Gastro-entero-pancreatic NENs, its role in lung NENs is still debated. A retrospective series of 370 LCT from two oncology centers was centrally reviewed. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR-2A, Ascl1, and p53) were studied and correlated with Overall Survival (OS), Cancer-specific survival (CSS) and Disease-free survival (DFS). Carcinoid histology was confirmed in 355 patients: 297 (83.7%) TC and 58 (16.3%) AC. Ki-67 at 3% was the best value in predicting DFS. Ki-67 ≥ 3% tumours were significantly associated with AC histology, stage III-IV, smoking, vascular invasion, tumour spread through air spaces OTP negativity, and TTF-1, Ascl1 and p53 positivity. After adjustment for center and period of diagnosis, both Ki-67 (≥3 versus <3) and histology (AC versus TC) alone significantly added prognostic information to OS and CSS multivariable model with age, stage and OTP; addition of both variables did not provide further prognostic information. Conversely, an improved significance of the DFS prediction model at multivariate analysis was seen by adding Ki-67 (≥3 versus <3, P adj = 0.01) to TC and AC histological distinction, age, lymph node involvement, residual tumour and OTP. Ki-67 ≥ 3% plays a potentially pivotal role in LCT prognosis, irrespective of histological grade.     

52例胃神经内分泌肿瘤临床病理分析

目的 对胃内分泌肿瘤进行分型,并探讨其临床病理意义。方法 收集５２例胃神经内分泌肿瘤,应用组织学及免疫组织化学学ＡＢＣ法及透射电镜技术对肿瘤及其瘤旁粘膜进行观察。参照Ｂｏｒｄｉ和Ｒｉｎｄｉ分类将肿瘤分成Ⅰ、Ⅱ、Ⅲ型,并设有阳性、阴性和替代对照组。结果 胃神经内分泌肿瘤可分为３个临床病理类型,其病理学特点、生物学行为及治疗方案均有不同。Ⅰ型伴有萎缩性胃炎型类癌（２６例）：分为单发及多发两型。单发型多     

Extrapulmonary small cell carcinomas express K homology domain containing protein overexpressed in cancer, but carcinoid tumors do not

A number of malignancies, including high-grade neuroendocrine carcinomas of the lung, have been reported to express K homology domain containing protein overexpressed in cancer (KOC), a member of the insulin-like growth factor messenger RNA-binding protein (IMP) family also known as L523S and IMP3. KOC acts to promote tumor cell proliferation by enhancing insulin-like growth factor-II protein expression. This study aimed to examine KOC expression pattern in extrapulmonary neuroendocrine tumors. Seventy-five extrapulmonary neuroendocrine tumors that were surgically resected or had undergone biopsy, including 53 small cell carcinomas (uterine cervix, 21; bladder, 10; colorectum, 13; prostate, 7; stomach, 1; and esophagus, 1) and 22 carcinoid tumors (colorectum, 10; appendix, 5; ileum, 4; duodenum, 2; and stomach, 1), were immunohistochemically studied using a monoclonal antibody against KOC. Our results demonstrated that 47 small cell carcinomas (89%) showed moderate to strong positive staining for KOC, with 25 cases (53%) showing positivity in more than 90% of tumor cells and 22 cases (47%) in 40% to 80% of tumor cells. Three cases showed weak staining in 5% to 10% of the tumor cells. The remaining 3 cases (uterine cervix, 2; bladder, 1) showed completely negative immunoreactivity. No KOC immunostaining was detected in 22 carcinoid tumors. These findings indicate that KOC may play an important role in the regulation of biologic behavior of extrapulmonary small cell carcinomas. In addition, immunohistochemical detection of KOC expression may serve as a useful diagnostic tool in the distinction between small cell carcinoma and carcinoid tumor, particularly when the diagnostic material is a small biopsy with crushing artifact.