Small Cell Neuroendocrine Carcinoma of the Urinary Bladder: Report of Three Cases with Ultrastructural Analysis

Three cases of small cell neuroendocrine carcinoma of the urinary bladder were studied by light and electron microscopic techniques. Dense-core, membrane-bound granules were identified in the cytoplasm of all 3 cases, substantiating the light microscopic impression of a morphologic similarity to other neuroendocrine carcinomas, such as small cell (oat cell) carcinoma of the lung. Two of the three cases showed clinical evidence of distant metastases, suggesting an aggressive biologic potential of this tumor similar to oat cell carcinoma of the lung. A partial remission was induced in these 2 cases using chemotherapy protocols similar to the drug regimens for small cell (oat cell) carcinomas of the lung. Recognition of this distinct entity has important clinical implications regarding therapeutic approach.     

Exocytosis of Neurosecretory Granules in Small Cell Undifferentiated Carcinoma

The tumor cells in the pleural effusions of a case of small cell undifferentiated carcinoma have been studied by light microscopy and by thin section and freeze-fracture electron microscopy. Evidence of exocytosis of neurosecretory granules from the tumor cells is presented. The tumor cells form clumps, with the cells joined by focal tight junctions and small desmosomes. These findings are discussed with reference to the neuroendocrine origin of these tumors and the role of the junctional complexes in the formation of tumor cell aggregates.     

Exocytosis of Neurosecretory Granules in Small Cell Undifferentiated Carcinoma

The tumor cells in the pleural effusions of a case of small cell undifferentiated carcinoma have been studied by light microscopy and by thin section and freeze-fracture electron microscopy. Evidence of exocytosis of neurosecretory granules from the tumor cells is presented. The tumor cells form clumps, with the cells joined by focal tight junctions and small desmosomes. These findings are discussed with reference to the neuroendocrine origin of these tumors and the role of the junctional complexes in the formation of tumor cell aggregates.     

Small Cell Neuroendocrine Carcinoma of the Urinary Bladder: Report of Three Cases with Ultrastructural Analysis

Three cases of small cell neuroendocrine carcinoma of the urinary bladder were studied by light and electron microscopic techniques. Dense-core, membrane-bound granules were identified in the cytoplasm of all 3 cases, substantiating the light microscopic impression of a morphologic similarity to other neuroendocrine carcinomas, such as small cell (oat cell) carcinoma of the lung. Two of the three cases showed clinical evidence of distant metastases, suggesting an aggressive biologic potential of this tumor similar to oat cell carcinoma of the lung. A partial remission was induced in these 2 cases using chemotherapy protocols similar to the drug regimens for small cell (oat cell) carcinomas of the lung. Recognition of this distinct entity has important clinical implications regarding therapeutic approach.     

Primary Neuroendocrine Carcinoma of the Liver

A case of primary neuroendocrine carcinoma in an unusual location, the liver, is reported. The neoplasm was composed of small, uniform cells that had distinct borders and grew in strands, ribbons and nests; its appearance resembled that of a carcinoid. Electron microscopy and special staining of the neoplastic cells confirmed the neuroendocrine nature of the tumor, and the cells showed immunoreactivity for gastrin and pancreatic polypeptide by the PAP. The recent literature is reviewed, and the possible histogenesis of hepatic neuroendocrine carcinoma is discussed.     

Dual Differentiation in Small Cell Carcinoma (Oat Cell Carcinoma) of the Lung

Two cases of small cell “undifferentiated” carcinoma (oat cell carcinoma) of the lung with dual neurosecretory and squamous differentiation are reported. One was treated with various regimens of chemotherapy and radiotherapy; the other was untreated at the time of biopsy. By electron microscopy, the same tumor cells showed membrane-bound, dense-core, neurosecretory-type granules and bundles of tonofibrils denoting squamous differentiation. This dual differentiation underlies the difficulty of ascribing an exclusively neural histogenesis to small cell carcinomas with neurosecretory-type granules. It is possible that entoderm-associated neuroectodermal tumors develop features of autochthonous entodermal tumors as a result of microenvironmental influences. An alternative hypothesis would be that small cell tumors are derived from basal reserve bronchoepithelial cells with pluripotentialities.     

Immunogold Detection of Chromogranin a in the Neuroendocrine Tumor

Immunogold ultrastructural localization of chromogranin A in secretory granules within tumor cells provides convincing evidence of endocrine or neuroendocrine differentiation. A modified immunogold method (designed for use on osmicated tissue) produced positive labeling of small granules not only in well-differentiated tumors but also in poorly differentiated small cell tumors primary in lung, cervix, and skin; only a proportion of granules in some of the tumor cells were positively labeled. Many non-small cell lung tumors often stain focally positive for chromogranin A at the light microscopy level, and such tumors may also contain sparse, small, dense granules. Because positive labeling could not be demonstrated over small granules in non-small cell lung tumors, the theory that such tumors are neuroendocrine in type may be erroneous.     

Primary Small Cell Neuroendocrine Carcinoma of the Kidney

The histological, immunohistochemical, and ultrastructural features of a primary small cell neuroendocrine carcinoma of the renal parenchyma are described. Tumor cells were positive for cytokeratin, neuron-specific enolase, and Leu 7, but Grimelius- and chromogranin-negative. They also exhibited positivity with anti-MIC2 antibody. By electron microscopy, tonofibrils, primitive desmosomes, and dense-core granules with a neuroendocrine appearance were present. This is only the 7th recorded example of such a tumor at this site, which showed an aggressive course characterized by widespread bony metastases.     

Electron Microscopy of Small Cell Carcinoma of the Lung with Special Reference to the Crush Phenomenon

Four cases of small cell carcinoma of the lung were studied ultrastructurally. The tumor cells contained scattered neurosecretory granules. Areas of the tumor that showed the characteristic crush phenomenon were found to be surrounded by myofibroblasts. It is proposed that the crush phenomenon is caused by contraction of the encircling myofibroblasts. The myofibroblasts and collagen may also cause degeneration and necrosis of the tumor cells. Myofibroblasts have not been observed in other histologic types of carcinoma of the lung.     

Electron Microscopy of Small Cell Carcinoma of the Lung with Special Reference to the Crush Phenomenon

Four cases of small cell carcinoma of the lung were studied ultrastructurally. The tumor cells contained scattered neurosecretory granules. Areas of the tumor that showed the characteristic crush phenomenon were found to be surrounded by myofibroblasts. It is proposed that the crush phenomenon is caused by contraction of the encircling myofibroblasts. The myofibroblasts and collagen may also cause degeneration and necrosis of the tumor cells. Myofibroblasts have not been observed in other histologic types of carcinoma of the lung.     

Undifferentiated Retroperitoneal Small Cell Carcinoma

Ultrastructural immunolabeling techniques can be reproducibly applied to resolve diagnostic dilemmas in surgical pathology. The technique utilized for processing and labeling the cases presented in this article is simple and reproducible. The specimens were fixed in Carson-Millonig phosphate-buffered 4% formaldehyde fixative and embedded in LR White resin following a well-described protocol. Immunogold labeling allows precise localization of antigenic sites without compromise of the underlying ultrastructural morphologic findings; thus detailed immunomorphologic assessment is achieved. Immunoelectron microscopy techniques permit clarification of doubtful immunocytochemistry results by labeling antigenic epitopes in cases in which light microscopy immunocytochemistry techniques fail to show unequivocal positive results (probably as a consequence of small amounts of detectable antigen present in the tissues). Not only does ultra-structural labeling permit identification of focally positive reactions essential for accurate diagnosis in a given case, but it also localizes the antigenic determinants to specific cellular sites, providing immunomorphologic correlation. The specificity of the interpreted results can then be judged accordingly. Overall, ultrastructural immunolabeling is more sensitive than light microscopic immunocytochemistry. Ultrastructural immunolabeling can play a crucial role in the characterization of some tumors that cannot be accurately classified with other diagnostic techniques, even when combined.     

Nondifferentiated-Type Small Cell Sarcoma of Kidney in a Young Woman

A case of rapidly fatal small cell sarcoma of kidney in a young woman is described. Histologic, immunohistochemical, and ultrastructural studies demonstrated some features not reported previously in the literature, such as the arrangement of vimentin intermediate filaments in small irregular masses and the presence of various types of cytoplasmic projections. These findings, together with the observation of rare neoplastic elements with immunophenotypic and subcellular aspects of histiocytic and myofibroblastic differentiation, suggest that this tumor should be included in a group of small cell sarcomas of kidney lacking features of differentiation and should be considered a new variant occurring in adulthood.     

上皮性标记物在人肺小细胞癌免疫组化研究中的应用

为证实肺小细胞癌的上皮特性,以上皮性标记物角蛋白(KT,细胞角蛋白(CKT),上皮性膜抗原(EMA),分泌成份(SC),糖脂类抗原(SLX)、糖脂类抗原(SLEA)、癌胚抗原(CEA)等用于本实验中。人肺两型小细胞癌(燕麦细胞癌和中间细胞型小细胞癌)均不同程度地表达了这些抗原,显示其上皮性分化的特性。根据抗原的阳性率和在细胞内存在形式不同,提示中间细胞型小细胞癌在生物学和组织学上更类似于腺癌和鳞癌的特征。上皮性膜抗原是小细胞癌较理想的标记物,而联合应用这些标记物能够增强诊断的准确性及评价标本的质量。     

Small cell carcinoma arising from the outer urethral orifice: A case report examined by histologic, ultrastructural and immunohistochemical methods

A case of small cell carcinoma arising In the outer urethral orifice is presented. The resected tumor showed a proliferation of small round or fusiform neoplastic cells in the submucosa. Tumor cells were arranged in sheets or a trabecular manner and possessed markedly hyper-chromatic nuclei with a high N: C ratlo, closely resembling small cell carcinoma of the lung. Characteristically, pagetoid lntraepithellal spreading could be identified. However, there was no evidence of in sku transitional cell carcinoma and adene or squamous cell carcinoma components anywhere. Ultrastructurally, each tumor cell contained only a few membrane-bound cored granules measuring 60–100 nm, which were compatible with neurosecretory granules, and desmosomellke Intercellular attachments, but lacked aggregated microfilaments. By immunohistochemical examination, tumor cells were positive for eplthelial markers, such as cytokeratln and epithellal membrane antlgen, and neuron specific enolase, but negative for any other neuro-endocrine markers. Extensive systemic examinatlon falled to show the primary site to be other than the outer urethral oritlce. These findings lndicate that the current tumor is a small cell carclnoma with neume-ndocrine differentiation arising from the outer urethral orifice.     

Small Cell Undifferentiated Carcinoma of the Pancreas

Small cell undifferentiated carcinoma of the pancreas is a rare neoplasm: Only 12 cases have previously been documented. This paper describes the clinical evolution, immunohistochemical profile, and ultrastructural features of a case occurring in a 37-year-old woman.     

Neuroendocrine Carcinomas of the Esophagus

Special thanks for invaluable technical and secretarial assistance to Mary Baerwaldt and Sandy Velasco, respectively.

Of a total of 928 primary esophageal cancers, 16 cases of “undifferentiated” esophageal carcinoma were isolated. The topographic and age distributions as well as the clinical presentation and evolution of these tumors were basically similar to those of the usual esophageal squamous carcinoma. By light microscopy, the tumors were comprised exclusively or predominantly of small, round-to-fusiform cells. The cytoplasm appeared scanty and the nuclei were comparatively large and hyperchromatic. Mitotic activity was prominent. Four of the sixteen neoplasms showed occasional foci of squamous differentiation. Argyrophilic cells were seen in all cases, although their number and distribution were variable. Occasional mucosubstance droplets were present in 2 cases. Argentaffin and amyloid stains were negative in all tumors.

Ultrastructural studies revealed variable numbers of granules consisting of a dense core, a pale halo, and a single, delimiting membrane; these measured between 80 and 220 nm in diameter. Four of the sixteen cases displayed conspicuous tonofilament bundles and rare keratohyalin granules.

The predominant ultrastructural common denominator of these tumors was the presence of characteristic neurosecretory-type granules; thus, their classification as neuroendocrine carcinomas would appear justified. Nevertheless, the abundant tonofilaments and the rare keratohyalin granules and mucosubstance droplets seen in several cases indicate that some of these epithelial cancers possess and express variable capabilities toward multidirectional differentiation.     

Acinar Cell Carcinoma of the Pancreas

A case of acinar cell carcinoma of the pancreas is presented. The differential diagnosis is discussed and includes endocrine neoplasm of the pancreas (islet cell and carcinoid tumor) and a poorly differentiated adenocarcinoma. The separation of the various entities by light microscopic, histochemical, immunocytochemical, and ultrastructural methods is described. The acinar cell carcinoma characteristically is positive for pancreatic digestive enzymes by immunocytochemistry, and at the ultrastructural level zymogen-type granules can be demonstrated; these have a tendency to aggregate in the apical region of acinar structures. Clinically the acinar cell carcinoma is an aggressive malignant neoplasm that may present with a characteristic syndrome of disseminated fat necrosis. Survival is generally less than 1 year.     

Large Cell Variant Ovarian Small Cell Carcinoma: Case Report

Ultrastructural data about large cell variant ovarian small cell carcinoma (LCV-SCC) are scarce and contradictory and the role of transmission electronmicroscopy (TEM) is not clear in the assessment of such tumors. The authors present a case of LCV-SCC without hypercalcemia in a 30-year-old woman. The diagnosis was confirmed by histopathological and immunohistochemical studies. Cytopathological examination of peritoneal washing showed a population of large neoplastic cells. TEM demonstrated that the neoplasia comprised two types of cells: one type showed many coarse secretory granules without dense core, and the other type was without granules and showed dilated endoplasmic reticulum and sometimes indented nuclei. The present case indicates that different underlying ultrastructural patterns, not yet well known, exist in connection with the pathological and clinical behaviour of LCV-SCC. TEM might play a role in the identification of subtypes of LCV-SCC with different prognostic and therapeutic impact.     

BK Polyomavirus Interstitial Nephritis in a Renal Allograft Recipient

Human polyomavirus (PV) interstitial nephritis has recently been recognized as a cause of severe renal allograft dysfunction. It occurs in immunosuppressed patients after reactivation of the latent virus PV type BK (BK virus) in the renal epithelium. BK disease is defined as a morphologically manifest renal infection with cytopathic signs accompanied by varying degrees of interstitial inflammatory cell infiltrates and functional impairment. It is also identified by the presence of cells containing viral inclusion bodies (decoy cells) in the urine. The authors report a case of BK PV interstitial nephritis in a 36-year-old renal allograft recipient. Under light microscopy the chief diagnostic indicator was detection of intranuclear viral inclusions, which were found exclusively in tubular epithelial cells. Cells with viral changes were often enlarged with nuclear atypia and chromatin basophilia. Widespread interstitial plasma cell infiltrates associated with tubulitis were present. Intranuclear paracrystalline arrays of virus particles 35-38 nm in diameter were present as characteristic ultrastructural indicators. Urine samples revealed decoy cells with ground-glass-type intranuclear inclusions positive for BK virus by electron microcopy.