Oat cell carcinoma of the bronchus and the carcinoid syndrome.

A man with high urinary levels of 5-hydroxyindole acetic acid had an oat cell carcinoma of the bronchus. The patient had symptoms of the carcinoid syndrome and at autopsy was found to have evidence of carcinoid heart disease. This report supports the hypothesis that bronchial carcinoids and oat cell carcinomas are derived from argentaffin (Kulchitsky)-type cells of the lung.     

肺类癌型微小瘤的临床病理及其形态发生分析

目的 描述肺类癌型微小瘤的病理特征和免疫表型,探讨其发生的形态学基础。方法 对3例支气管扩张症(支扩)伴发微小瘤进行临床病理学观察,另11例支扩和2例正常肺作对照;应用免疫组织化学En Vision法检测其特异性标志物和标记气道上皮内神经内分泌细胞(NECs)。结果肺类癌型微小瘤多为散发多灶性镜下结节,呈簇状、巢状或索团状,分布于支扩受损的支气管壁旁、细小支气管周围和瘢痕化的组织中;由短梭形或小圆形细胞构成,核呈圆形、椭圆或长椭圆形,染色深;胞质弱嗜酸性;细胞嗜银性强;强表达神经元特异性烯醇化酶(NSE)、嗜铬素、降钙素、胃泌素等神经内分泌性标志物,小灶性表达绒毛膜促性腺激素(HCG)、促肾上腺皮质激素(ACTH)、5-羟色胺(5-HT),弱表达细胞角蛋白(CK)、上皮膜抗原(EMA)、S-100。微小瘤旁气道黏膜上皮NECs明显增生,比不伴微小瘤的支扩肺和正常肺气道黏膜上皮内NECs计数的差异均具有统计学意义(P值均＜0．001)。结论肺微小瘤具有周围型典型性类癌的病理特征和免疫表型,可能是典型性类癌发生的早期阶段。它的发生可能与肺慢性损伤导致慢性缺氧刺激NECs增生有关。     

Carcinoid tumor of the uterine cervix

Summary A case of carcinoid tumor of the uterine cervix is reported. The patient was a 76-year-old Japanese woman with a complaint of vaginal bleeding. She was clinically diagnosed as stage IVb carcinoma of the uterine cervix. Light microscopically, the tumor was characterized by formation of solid cell nests and, in limited areas, glandular structures. The tumor cells in solid cells nests showed positive argyrophil reaction but were negative for argentaffin reaction. At the ultrastructural level, the cytoplasm of the tumor cells contain numerous neurosecretory granules, microfilaments and well-developed Golgi complexes. On the bases of histochemical and electron microscopic features of tumor cells, the tumor was diagnosed as carcinoid tumor of the uterine cervix.     

Solitary breast metastasis: First manifestation of an occult carcinoid of the ileum

Summary A metastasis to the breast was the first manifestation of a clinically occult ileal carcinoid in a 53 year old woman. Modified radical mastectomy was performed after the breast neoplasm had been interpreted clinically and pathologically as a primary carcinoma. Permanent sections demonstrated the tumor to be composed of sheets of small uniform cells subdivided into lobules by delicate vascular septa. Silver impregnation revealed the presence of argentaffin cytoplasmic granules. This feature, with the added ultrastructural findings which showed pleomorphic neurosecretory-type granules within the cytoplasm of the tumor cells strongly suggested a metastasis to the breast from a midgut carcinoid. The subsequently performed barium study of the small bowel showed an infiltrating neoplastic lesion in the terminal ileum, which after surgical excision and histologic examination proved to be two typical argentaffin carcinoids with pleomorphic cytoplasmic granules. This report thus clearly demonstrates the importance of a combined light microscopic, histochemical and ultrastructural analysis of this breast neoplasm in order to establish its metastatic origin and to separate it from a primary carcinoma or a primary carcinoid of the breast.     

Argentaffin endocrine carcinoma (carcinoid) of the pancreas with concomitant breast metastasis: an immunohistochemical and electron microscopic study

A pancreatic carcinoid tumor that metastasized to the breast is reported. The breast tumor was originally diagnosed as adenocarcinoma of the breast. Silver impregnation revealed the presence of argentaffin cytoplasmic granules. Immunocytochemical studies demonstrated immunoreactivity for serotonin but not for lactalbumin, a marker for breast epithelial cells. These features, together with the electron microscopic observation of pleomorphic secretory granules, permitted recognition of the tumor as metastatic carcinoid. This report illustrates the importance of the combined histochemical, immunocytochemical, and electron microscopic studies of breast tumors with a carcinoid pattern.     

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.     

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.     

An unusual bronchial carcinoid tumor analyzed by conjunctive staining

Two staining methods selective for pulmonary APUD endocrine cells-PAS-lead hematoxylin and a more elaborate procedure termed conjunctive staining-were applied to 2 μm. glycol methacrylate sections of a human bronchial carcinoid tumor, in order to display the advantage they hold over routine pathologic methods in revealing the presence as well as cytochemical characteristics of endocrine cell granules in the tumor cells. PAS-lead hematoxylin alone showed the tumor population to be mixed, with a wide range of staining in the granules, extending between the extremes of PAS only and lead hematoxylin only. The conjunctive staining protocol is described in detail. In tissue previously reacted for argyrophilia, it demonstrates, sequentially, fluorescence for serotonin, PAS alone, and PAS-lead hematoxylin, all in a single section. By comparing photomicrographs of a given field recorded during the process, exact point by point correlations of staining behavior can be made, limited only by the resolving power of the microscope. Conjunctive staining of the tumor revealed 10 distinct cytochemical cell signatures, far exceeding the number of types of endocrine cells known to exist in normal human lung. Preliminary results indicate that three types with PAS and lead hematoxylin positive granules may occur in adult human bronchi, although previous studies have reported but a single type of endocrine cell. Numerous tumorlets in the bronchial epithelium overlying the tumor were an unusual feature of the case. These were composed of cells staining similarly to cells in the tumor mass. Some were connected to it by cords of cells, whereas other tumorlets were interconnected in the epithelium, but a number of smaller ones were clearly isolated from other tumor cells, as shown by serial sections. A few tumorlets contained cells with both mucous and lead hematoxylin positive granules. With a population density that exceeded the expected distribution of normal small granule endocrine cells in the bronchial epithelium and including cells with mixed endocrine and nonendocrine characteristics, the tumorlets provided testimony favorable to the view that carcinoid tumors like this one arise from indifferent cells of the bronchial epithelium that have been driven by oncogenic forces toward expressing an APUD cell phenotype.     

Expression of vascular endothelial growth factor (VEGF) and its receptors (VEGF-R1 [Flt-1] and VEGF-R2 [KDR/Flk-1]) in tumorlets and in neuroendocrine cell hyperplasia of the lung

Pulmonary tumorlets and neuroendocrine (NE) cell hyperplasia are part of a continuous spectrum of NE-cell hyperplasia, going from NE hyperplasia to carcinoid. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen that has been shown to be increased in hypoxic lung. We hypothesized that tumorlets and NE-cell hyperplasia, which occur frequently in this context, were partly responsible for VEGF secretion. Immunohistochemical analysis of VEGF and both VEGF-R1 and VEGF-R2 was performed on paraffin sections of 12 lung tissues containing tumorlets and NE-cell hyperplasia in parallel with a control group of 11 lung specimens. VEGF and its receptor expressions were compared in bronchial epithelial cells and endothelial cells in both groups. VEGF and its receptors were consistently expressed in tumorlets and in NE-cell hyperplasia. When compared with control group lungs, the staining score for VEGF in lung bearing tumorlets was significantly higher in endothelial cells, but was not different in bronchial epithelial cells. VEGF-R1 expression was significantly increased both on bronchial epithelial cells (P = 0.001) and endothelial cells (P = 0.006), and VEGF-R2 expression was significantly increased on endothelial cell (P = 0.044). There was a significant positive correlation between the level of expression of VEGF and VEGF-R1 (P = 0.04) in both control groups and lung bearing tumorlets, but there was no significant correlation between VEGF and VEGF-R2 expression (P = 0.1). We concluded that VEGF is highly expressed in localized NE cell proliferations without potential of malignancy and might participate in local development of fibrosis.     

Synchronous triple malignant tumors of the lung. A case report of bronchial carcinoid, small cell carcinoma, and adenocarcinoma of the right lung

The authors report a case in which a highly unusual, simultaneous occurrence of a peripheral small cell carcinoma and a central bronchial carcinoid in the right upper lobe and a peripheral adenocarcinoma in the right middle lobe was observed. This is the fourth case of triple lung cancer reported in the literature. The role of computerized tomography in disclosing multiple lung carcinomas and the significance of the concurrence of pulmonary small cell carcinoma and bronchial carcinoid are discussed.     

Pulmonary oat cell carcinomas. Expression of plasma membrane antigen correlated with presence of cytoplasmic neurosecretory granules.

A plasma membrane antigen highly associated with pulmonary oat cell carcinoma has recently been identified. Expression of this surface antigen was now examined in routine surgical pathology material from 32 primary lung tumors by immunostaining. The staining patterns of 17 tumors diagnosed as oat cell carcinoma by light microscopy were compared to those of 10 epidermoid carcinomas, four carcinoid tumors, and one lymphocytic lymphoma. In addition, when available, the oat cell carcinoma group was also studied by electron microscopy for demonstration of cytoplasmic neurosecretory granules. Twelve of the 17 oat cell carcinomas and one of the epidermoid carcinomas expressed the antigen. In this group of small cell tumors of the lung, aggrement was found between the expression of this immunochemical marker and the presence of neurosecretory granules in the cytoplasm of the tumors. Demonstration of this surface antigen in routine surgical pathologic material may be a useful aid in the diagnosis of these tumors. The failure of a group of tumors, which satisfied the light microscopic criteria for oat cell carcinoma to stain for the antigen, demonstrates heterogeneity within the oat cell carcinoma group.     

Malignant fibrillocaveolated cell carcinoma of the human intestinal tract

The ultrastructural features of a peculiar midgut carcinoid, containing cytoplasmic filaments, fibrils, and caveolae, are presented. Because of the morphologic similarities between the tumor cells and the recently described intestinal caveolated cell, it is proposed that the cells of the reported carcinoid represent the malignant counterpart of this new type of cell. The name suggested for this variant of a tumor of the enterochromaffin group of intestinal endocrine cells is malignant fibrillocaveolated cell carcinoma.     

Observations on small granule cells in adult human bronchial epithelium and in carcinoid and oat cell tumors.

Small granule cells are described in the segmental bronchi of adult humans. Rarely, these cells were seen abutting the lumen of the airway. A luminal location has been described for these cells in the bronchial epithelium of human fetuses and neonates and it is suggested that luminal small granule cells may be a rare, although normal component of the adult human bronchial epithelium. The dense core granules of the small granule cells stained intensely with phosphotungstic and at low pH suggesting that they contain glycoprotein. Granules present in a carcinoid and an oat cell tumor stained similarly. The role of the small granule cell in the genesis of bronchial carcinoid and oat cell tumors is recognized.     

Adrenocorticotropin-producing pulmonary tumorlets with lymph node metastasis

A case of pulmonary tumorlets with ectopic adrenocorticotropin (ACTH) production and lymph node metastasis in a bronchiectatic patient is reported. A 65-year-old man underwent right lower lobe lobectomy because of a sudden attack of cough and hemoptysis. Histological study revealed multiple discrete uniform small nests of tumor cells surrounding dilated bronchioles. Tumor nests were also found in the hilar lymph node. Immunohistochemically, the proliferating cells were confirmed to be neuroendocrine in origin with ectopic ACTH production, despite being clinically silent. The findings in the present case suggest that the clinical behavior of pulmonary tumorlets may be like a carcinoid, and need to be treated as tumor-like lesions. Ectopic hormonal production in the present case suggests pulmonary tumorlets should be considered in the differential diagnosis of Cushing's syndrome.     

Sclerosing haemangiomas of the lung

A series of 29 pulmonary sclerosing haemangiomas is analysed. Included is one case with multiple tumours and another with metastatic growth in a hilar lymph node. Histochemical and electron microscopic studies show that type 2 pneumocytes are an important constituent cell type though bronchial structures, tumorlets and angiomas also occur within these tumours. They are considered to be pulmonary hamartomas formed from distal lung structures. They are of slow growth and have been confused in the past with pulmonary histiocytomas and plasma cell granulomas.     

PRIMARY MIXED CARCINOMAS OF THE BRONCHUS

Primary mixed carcinomas of the bronchus are found to occur more frequently than previously reported. Forty-two cases of primary mixed carcinomas of the bronchus were seen at the London Chest Hospital from 1966 to 1969. During this time, 3853 patients were admitted to the hospital and among them 733 had bronchial carcinomas. In 27 instances, the tumour histologically was squamous and adenocarcinomatous in type. Of the other 15; squamous and oat cell characters, and undifferentiated carcinoma of large polygonal cell and adenocarcinomatous characters were present in five instances; adenocarcinoma and oat cell, and undifferentiated carcinoma of large polygonal cell and oat cell characters were present in two instances; and only one had mixed alveolar and oat cell carcinomatous pattern. A study of the pathological changes in these mixed bronchial carcinomas revealed little differences, if any, from a primary bronchial carcinoma.
The histogenesis of these mixed carcinomas remains uncertain. The most plausible view is that they arise by divergent differentiation from the descendants of the original multipotent cancer cells. ACTA PATH. JAP. 22:555–564, 1972.     

Electrical excitability of oat cell carcinoma.

Cultured tumour cells from two oat cell carcinomas of the lung were demonstrated to generate all-or-nothing, short-duration action potentials similar to those previously reported in neurones, in bronchial carcinoid cells, and in a number of endocrine cells of proven or proposed neural ancestry. This observation provides new evidence to establish oat cell carcinomas and carcinoids as closely related tumours distinct from other pulmonary neoplasms, and raises the possibility of treating these tumours by manipulation of hormonal agents.     

Large spindle cell variant of peripheral bronchial carcinoid tumor

I report a case of peripheral bronchial carcinoid tumor composed of bundles of large spindle cells, very much resembling cells of smooth muscle or neural tumors. Despite the unusual appearance, argyrophil staining and electron microscopic examination demonstrated small secretory granules of the type found in other peripheral carcinoid tumors. The histologic heterogeneity of peripheral bronchial carcinoid tumors is emphasized.     

Carcinoid tumour of the thymus

Summary This report concerns a 49 year old asymptomatic male who had a mediastinal mass demonstrated on routine radiography. A large encapsulated tumour composed of small regular cells arranged in clumps and acini with fine vascular stroma was removed. The differential diagnosis on routine H&E section included parathyroid tumor, medullary carcinoma arising in ectopic thyroid tissue, epithelial thymoma or carcinoid tumor of the thymus. The presence of compressed thymic tissue around the tumor, and of argentaffin granules together with the electron microscopic appearance characteristic of the enterochromaffin or APUD group of cells allowed the diagnosis of carcinoid tumor of the thymus to be made. Electron microscopy showed that the cell cytoplasm contained electron dense membrane bound granules, together with bundles of microfilaments. Vesicles of smooth surfaced reticulum were present but rough surfaced reticulum was inconspicuous. No desmosomes were demonstrated. Special stains for amyloid and glycogen were negative.