Primary small cell neuroendocrine carcinoma of the kidney: morphological, immunohistochemical, ultrastructural, and cytogenetic study of a case and review of the literature.

Poorly differentiated neuroendocrine carcinomas (PDNECs) of the kidney are extremely rare high-grade cancers accounting for only 42 cases reported in the literature. In this paper, we describe the morphological, immunohistochemical, ultrastructural, and for the first time, cytogenetic features of a renal PDNEC. In addition, we have reviewed the literature and compared the published clinicopathological data with our morphological and genetic results. The tumor arose within the kidney parenchyma and showed the typical histological features of a pure small cell PDNEC. Fluorescence in situ hybridization study demonstrated a complex chromosomal assessment indicative of a high degree of chromosome instability with gain of multiple chromosomes, loss of p53, and amplification of myc gene. These results suggest that renal PDNEC has a different genetic background to renal clear cell carcinoma, mainly characterized by the loss of the short arm of chromosome 3. Conversely, genetic alterations seem to resemble those of type 2 papillary renal cell carcinoma. The review of the literature demonstrated that PDNECs are associated with poor prognosis and that parenchymal tumors show some differences from those arising in the pelvis, in that parenchymal tumors are purely neuroendocrine while pelvic tumors are mostly mixed neuroendocrine-exocrine neoplasms.

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.

Desmoplastic small round cell tumor of the kidney in childhood.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare malignant tumor that generally manifests as abdominal paraserosal masses and affects mainly male adolescents and young adults. When presenting within visceral organs, the diagnosis of DSRCT poses significant difficulties. METHODOLOGY: Four primary renal DSRCT in children diagnosed during a 3-year period are the basis of this report. The medical records and pathologic material were reviewed, including immunohistochemical, ultrastructural, and cytogenetic/molecular studies. RESULTS: The age at presentation was 6 to 8 years, and all children presented with a left renal mass. The tumors measured 3.7 to 13.4 cm and consisted of nests, cords, or sheets of small undifferentiated cells with foci of necrosis and calcification. Desmoplasia was not seen. Tumor cells were immunopositive for vimentin, WT-1 (monoclonal and polyclonal), desmin, cytokeratin, and epithelial membrane antigen. A distinct paranuclear dotlike pattern was observed with vimentin and desmin. Tumor cells possessed rare or focal immunoreactivity for platelet derived growth factor-A and transforming growth factor-beta3, which have been implicated in the pathogenesis of desmoplasia in DSRCT. The EWS-WT1 t(11;22)(p13;q12) translocation was demonstrated in all 4 tumors by fluorescence in situ hybridization and/or reverse transcription-polymerase chain reaction. CONCLUSIONS: DSRCT should be considered in the differential diagnosis of renal tumors composed of small round cells. Undifferentiated morphology and lack of desmoplasia contribute to the difficulty in its recognition. Ancillary studies such as immunohistochemistry may suggest the diagnosis, but cytogenetic and molecular genetic studies are required for confirmation.

Primary gastric small cell carcinoma: report of a case and review of the literature.

A 52-year-old man suffering from a pure-type primary gastric small cell carcinoma was treated with surgery and combination chemotherapy. The small cell carcinoma, approximately 6.5 cm in diameter, was situated in the posterior wall of the antrum and there were no distant metastases. Total gastrectomy and regional lymph node dissection was carried out. Histological examination revealed a solid pattern of proliferation of small cells with hyperchromatic, round nuclei and scant cytoplasm. Neoplastic cells infiltrated into the subserosal layer with severe lymphatic and vascular invasion. Regional lymph node cells were mostly replaced by tumor cells that stained positive for Grimelius, neuron-specific enolase (NSE), and synaptophysin. Accumulations of electron-dense core granules in the small neoplastic cells were seen by electron microscopy. Following surgery, the patient was treated with adjuvant chemotherapy consisting of cisplatin and etoposide. The patient is alive and recurrence free 3 years after surgical operation. We review 107 published cases of primary gastric small cell carcinoma, an extremely rare disease first reported in 1976. Small cell carcinoma is an aggressive, malignant tumor. Intensive chemotherapy is essential for patient survival even when curative surgical resection is carried out.

Imaging of P-glycoprotein of H69/VP small-cell lung cancer lines by scanning near-field optical microscopy and confocal laser microspectrofluorometer.

Chemoresistance remains the major obstacle to successful therapy of the lung cancer. The multi-drug resistance (MDR) is generally associated with altered expression of drug transporter proteins, such as P-glycoprotein (P-gp). So the distribution of P-gp on the membrane is of great importance to further study the interaction between drug and P-gp. In the present work, the P-gp of the H69/VP small-lung cancer cells was detected using monoclonal antibody UIC2. A secondary goat-anti mouse antibody coupled with biotin was used. The fluorescence emission was detected from a streptavidin-Texas Red. Results were investigated by a homemade scanning near-field optical microscope (SNOM) coupled to a confocal laser microspectrofluorometer (CLMF). Topographical images and localized spectra were obtained at the level of one cell membrane. It was found that the distribution of P-gp is not homogeneous and this observation is basically in accord with the fluorescent images obtained by classical microscopy. The distribution of P-gp would be localized in a higher region on a cell surface. This methodology would also enhance our understanding of MDR under physiological conditions.

Development of a shear force scanning near-field fluorescence microscope for biological applications.

In this paper, a shear force scanning near-field fluorescence microscope combined with a confocal laser microspectrofluorometer is described. The shear force detection is realized based on a bimorph cantilever, which provides a very sensitive, reliable, and easy to use method to control the probe-sample distance during scanning. With the system, high-quality shear force imaging of various samples has been carried out. Furthermore, simultaneous shear force and near-field fluorescence imaging of biological cells has also been realized. As an example, we especially present the result on the distribution of P-glycoprotein in the plasma membrane of human small cell lung cancer cells, suggesting that the system would be a promising tool for biological applications.

[Thoracic neuroendocrine tumors]. / Tumeurs neuroendocrines thoraciques.

Neuroendocrine pulmonary and thymic tumors constitute a distinct category of tumors collectively disclosing morphologic and biologic neuroendocrine features. They are classified in 4 histopathological types and 3 malignancy grades. The typical carcinoids are of low grade, the atypical carcinoids of intermediate grade and the large cell neuroendocrine carcinoma with the small cell carcinoma are high grade neuroendocrine tumors. Their distinction relies on objective morphologic and phenotypic criteria of strong clinical significance and predictive prognostic value.

Large cell variant of small cell carcinoma, hypercalcemic type, of primary peritoneal origin.

BACKGROUND: Large cell variant of small cell carcinoma hypercalcemic type (SCC-HT) is extremely rare. All reported cases involved an ovary, and one with primary peritoneal origin has not been described. Also, convincing neuroendocrine granules have not been illustrated. CASE: A 35-year-old woman underwent an exploratory laparotomy for leiomyomas. Intraoperative impression of peritoneal carcinomatosis was confirmed on frozen section. TAH/BSO, debulking/omentectomy followed. The tumor was present on the pelvic/abdominal peritoneum. The normal-sized ovaries were free of tumor grossly. The tumor had features of large cell variant of SCC-HT, described in the ovary. Furthermore, unequivocal neuroendocrine granules were present. The patient received standard chemotherapy for SCC. At 22 months she is NED. CONCLUSION: SCC-HT should be considered in the differential diagnosis of primary neoplasms of the peritoneum.

Fine-needle aspiration of adult small-round-cell tumors studied with flow cytometry.

Immunophenotypic study is critical for the diagnosis of adult small-round-cell tumors (SRCTs). We describe three patients with Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) and one patient with neuroblastoma in which flow cytometry immunophenotyping (FCI) on the fine-needle aspirate (FNA) and bone marrow aspirate (BMA) demonstrated an abnormal population of cells that were CD45(-) and CD16/CD56(+). Four patients with mean age of 30 years, three male and one female, clinically suspicious for a lymphoma or SRCT are described. FNA, BMA, and biopsy specimens were obtained for routine cytologic and histologic evaluation. Fresh tissue was studied by FCI. In all cases, the cytology smears showed small cells with round nuclei, slightly irregular nuclear membranes, fine chromatin, and scant cytoplasm. FCI showed CD16/56(+) and CD45(-) neoplastic cells in all cases. In one case, 76% of these cells were CD99(+). The diagnoses of ES/PNET were confirmed by immunohistochemical, ultrastructural, and cytogenetic studies. ES/PNET in FNA and BMA can be efficiently and rapidly diagnosed by combining cytologic examination with FCI using a panel including CD45, CD16/56, and CD99.

Mice expressing SV40 T antigen directed by the intestinal trefoil factor promoter develop tumors resembling human small cell carcinoma of the colon.

The colonic epithelium contains three major types of mature cells, namely, absorptive, goblet, and enteroendocrine cells. These cells are maintained by a complex process of cell renewal involving progenitor and stem cells, and colon cancers develop when this process goes awry. Much is known about the genetic and epigenetic changes that occur in cancer; however, little is known as to the specific cell types involved in carcinogenesis. In this study, we expressed the SV40 Tag oncogene in the intestinal epithelium under the control of an intestinal trefoil factor (ITF) promoter. This caused tumor formation in the proximal colon with remarkable efficiency. ITFTag tumors were rapidly growing, multifocal, and invasive. ITFTag tumor cells express synaptophysin and contain dense core secretory granules, markers of neuroendocrine differentiation. The cell type involved in the early steps of ITFTag tumorigenesis was studied by examining partially transformed crypts that contained populations of both normal and dysplastic cells. The dysplastic cell population always expressed both Tag and synaptophysin. Cells expressing Tag alone were never observed; however, normal enteroendocrine cells expressing synaptophysin but not Tag were readily visualized. This suggests that ITFTag tumor cells originate from the enteroendocrine cell lineage following a transforming event that results in Tag expression. ITFTag tumors closely resemble human small cell carcinomas of the colon, suggesting the possibility that these tumors might be derived from the enteroendocrine cell lineage as well.

Unusual aspects of desmoplastic small round cell tumor.

Desmoplastic small round cell tumor (DSRCT) is a neoplasia that occurs mainly in childhood and involves abdominal or peritoneal sites, coexpressing ectodermal and mesenchimal immunophenotypic markers, and is endowed with an impressive stromal desmoplasia that tends to decrease on tumor relapse. To date, over 150 cases have been collected in the literature. Its presumed neuroectodermal histogenesis has been challenged by cytogenetic findings different from those usually associated with neoplasms of neuroectodermal origin. The authors report a case bearing clinical and histologic aspects of typical desmoplastic retroperitoneal small cell tumor, with intense and diffuse nuclear immunopositivity for WT1, but lacking divergent immunophenotype. Ultrastructural investigation revealed that desmoplasia could result from fibrillary synthesis by neoplastic cells.

Juvenile granulosa cell tumor of the testis: a case presenting as a small round cell tumor of childhood.

We describe the case of a testicular juvenile granulosa cell tumor (JGCT) in a 4-year-old boy. The highly undifferentiated appearance and robust mitotic activity of the neoplasm led to an initial impression of an aggressive, small round cell tumor of childhood. Immunocytochemical and ultrastructural studies excluded the usual members of that group, and led to the correct diagnosis. To our knowledge, this is the oldest reported patient to present with this tumor in the testis, and the first with clinical evidence of hormonal activity. The benign behavior of testicular JGCT mandates that it be distinguished from other, much more aggressive, neoplasms which it may resemble.

Case report: esophageal collision tumor (oat cell carcinoma and adenocarcinoma) in Barrett's esophagus: immunohistochemical, electron microscopy and LOH analysis.

We report a case of an esophageal collision tumor composed of adenocarcinoma and oat cell carcinoma. Both tumors appeared to arise from dysplastic Barrett's mucosae in a 75-year-old man. Immunohistochemical stains and electron microscopy demonstrated a separate identity for each of the tumors in collision. Molecular analysis of microsatellite regions was performed in different microdissected areas. Identical loss of heterozygosity (LOH) at 9p21 and 17p13 was determined in the three different microdissected areas of the adenocarcinoma component. LOH was not determined in any area of the oat cell carcinoma. This is the first study that analyzes the allele status of an esophageal collision tumor. Our findings suggest a biclonal origin for both components of the collision tumor.

Cell adhesion-mediated transformation of a human SCLC cell line is associated with the development of a normal phenotype.

Small cell lung carcinoma (SCLC) is a highly metastatic disease with a poor prognosis due to its resistance to current modes of therapy. SCLC cells appear to arise by oncogenic transformation of self-renewing pulmonary neuroendocrine cells, which have the potential to differentiate into a variety of lung epithelial cell lineages. Epithelial-mesenchymal conversion involved in such cell type transitions leads to the acquisition of an invasive and metastatic phenotype and may be critical for neoplastic progression and its eventual resistance to therapy. In order to investigate mechanisms involved in such transitions, a SCLC cell line was exposed to 5-bromodeoxyuridine. This treatment induced a dramatic conversion from non-substrate-adherent aggregates to monolayers of cells exhibiting an epithelioid phenotype. The phenotypic transition was concomitant with downregulation of vimentin, upregulation of cytokeratins, and cell-cell and cell-matrix adhesion molecules as well as redistribution of the actin cytoskeleton. The changes in the levels and organization of cell-cell and cell-matrix adhesion molecules were correlated with an in vivo loss of tumorigenicity.

Morphometry confirms the presence of considerable nuclear size overlap between "small cells" and "large cells" in high-grade pulmonary neuroendocrine neoplasms.

We morphometrically evaluated 5-micron H&E-stained sections from 28 surgically resected high-grade pulmonary neuroendocrine neoplasms, including 16 small cell lung carcinomas (SCLCs) and 12 large cell neuroendocrine carcinomas (LCNECs). For each case, 200 tumor nuclei and 20 to 100 normal lymphocytes were measured. The frequency distributions of tumor cell/lymphocyte (TC/L) size ratios were plotted in bins ranging from 1 to 6, classified into 6 histogram types with TC/L size ratio peaks ranging from 2 to 6 (A-E) and a histogram with a wide distribution (F). SCLCs fit histograms A through E; LCNECs, A through F. Morphometry demonstrated considerable nuclear size overlap in high-grade neoplasms. Approximately one third of SCLCs exhibited considerable numbers of neoplastic cells that were larger than 3 normal lymphocytes, while 4 of 12 LCNECs had a predominant number of small cells. Ten tumors exhibited a B histogram with a "borderline" peak TC/L of 3. The rule that a TC/L size ratio larger than 3 helps distinguish "large" from "small" neoplastic cells was confirmed in only 9 of 28 cases. The use of more generic terminology such as "high-grade neuroendocrine carcinoma" or "grade III neuroendocrine carcinoma" for SCLC and LCNEC is discussed.

Ultrastructural morphology and localisation of cisplatin-induced platinum-DNA adducts in a cisplatin-sensitive and -resistant human small cell lung cancer cell line using electron microscopy.

Ultrastructural morphology (transmission electron microscopy) and localisation of cisplatin-induced platinum (Pt)-DNA adducts (immunoelectron microscopy) were analysed in the human small cell lung cancer cell line GLC(4) and its 40-fold in vitro acquired cisplatin-resistant subline GLC(4)-CDDP, which is characterised by, among other things, a decreased DNA platination. Immunolabelling of Pt-DNA adducts was performed with the polyclonal antibody GPt, known to detect the main Pt-containing intrastrand and interstrand DNA adducts. Morphological analysis of GLC(4) and GLC(4)-CDDP at the ultrastructural level showed cells with a high nucleus/cytoplasm ratio with the majority of nuclei containing one or more nucleoli. GLC(4)-CDDP showed, in contrast to GLC(4), an extensive Golgi apparatus and an increased number of mitochondria. DNA platination was detectable in both GLC(4) and GLC(4)-CDDP. Immunoelectron microscopy showed Pt-DNA adducts primarily in the nucleus, preferentially at loci with high-density chromatin (e.g. heterochromatin, pars granulosa around nucleoli, condensed DNA in proliferating and apoptotic cells), and in mitochondria. The level of detectable Pt-DNA adducts was cell cycle status-dependent. In both cell lines, Pt-DNA adduct levels increased from non-dividing interphase cells to dividing cells and were highest in cells undergoing apoptosis. Overall localisation of Pt-DNA adducts was comparable in GLC(4) and GLC(4)-CDDP cells.

Desmoplastic small round-cell tumor: a case report on the large cell variant with immunohistochemical, ultrastructural, and molecular genetic analysis.

examination. The patient died 10 months after surgery. Histologically, the tumor was composed of predominantly large epithelioid cells with foci of anaplasia mimicking metastatic carcinoma. Immunohistochemically, the tumor cells stained with anti-cytokeratin, EMA, desmin, and NSE antisera. Electron microscopy showed secretory lumina, desmosomes, cell processes with microtubules and electron-dense granules, and focal whorls of intermediate filaments. Reverse transcriptase-polymerase chain reaction performed on paraffin block-retrieved tissue demonstrated the EWS/WT-1 fusion transcript characteristic of the t(11;22)(p13;q12). This case illustrates a less common histological pattern of DSRCT, i.e., diffuse large cells, thus supporting the view that this tumor presents a wider morphological spectrum than that previously recognized.

Small cell undifferentiated carcinoma of the submandibular gland: immunohistochemical evidence of myoepithelial, basal and luminal cell features.

A primary small cell undifferentiated carcinoma of the submandibular gland is reported. Histological studies revealed that the major part of this tumor was composed of cells slightly larger (10-14 microm) than lymphocytes. These tumor cells showed myoepithelial-cell differentiation, which was confirmed by the immunohistochemical and ultrastructural findings. Furthermore, some of them showed luminal-cell and basal-cell differentiation immunohistochemically. However, there was no evidence of neuroendocrine differentiation. These findings demonstrated that the tumor had the features of all the salivary ductal components (myoepithelial, basal, and luminal cells) and supported that the tumor might arise from the salivary duct. Furthermore, it supports the hypothesis of multipotential stem cells as the origin for small cell undifferentiated carcinomas in salivary glands.

Desmoplastic small round cell tumour of the pleura: a case report with further cytogenetic and ultrastructural evidence of 'mesothelioblastemic' origin.

A typical case of desmoplastic small round cell tumour of the pleura in a 25-year-old man is described. In addition to the typical histological and immunohistological findings, the EWS-WT1 fusion product was also observed. Ultrastructurally, some tumour cells displayed intracytoplasmic neolumina, with short microvilli characteristic of submesothelial cells. These findings support the theory of a splanchnopleuric intraembryonic mesodermal, 'mesothelioblastemic' origin, both morphologically and cytogenetically.