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.

Gastrin releasing peptide is a selective mitogen for small cell lung carcinoma in vitro.

Human small cell lung carcinoma (SCLC) cells have been shown to contain significant levels of a bombesin-immunoreactive peptide. The 27-amino acid peptide, gastrin releasing peptide (GRP), has recently been shown to be responsible for the bombesin-like immunoreactivity found in SCLC cells. Among four lung cancer cell lines examined in vitro, GRP exhibited mitogenic activity for two SCLC subtypes, but not for a squamous carcinoma or adenocarcinoma lung cell line. The mitogenicity of the GRP molecule has been isolated to the carboxyterminal fragment, designated GRP 14-27, which is in part homologous to bombesin. The aminoterminal fragment, GRP 1-16, is no homologous to bombesin and exhibits no mitogenic activity. Thus, GRP may be an important growth regulating or autocrine factor in human SCLC.

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.

Immunocytochemical detection of human lung cancer heterogeneity using antibodies to epithelial, neuronal, and neuroendocrine antigens.

Lung cancers were investigated for their heterogeneity as expressed by their immunoreactivity for cytokeratins and neurofilament proteins, as well as for the neuroendocrine differentiation antigen MOC-1. Using broadly cross-reacting antibodies, cytokeratins were detected in nearly all cases of lung carcinomas. Keratinization could be detected only in cases of moderately to well-differentiated squamous cell carcinoma (SQC) using a monoclonal antibody to cytokeratin 10, while a monoclonal antibody reactive with cytokeratin 18, and specific for glandular epithelia, reacted with adenocarcinomas, small cell lung carcinomas (SCLC), and lung carcinoids. In SQC this antibody could detect non-squamous cell differentiation, showing increasing numbers of positive cells with decrease of histologically detectable SQC differentiation. Cells positive for neurofilaments were demonstrated in some of the poorly differentiated SQCs and in some of the cases of SCLC, possibly representing the variant type of SCLC. Also in some of the lung carcinoids neurofilament proteins were present, colocalizing with cytokeratins. MOC-1 was present in all SCLC and lung carcinoids. This antibody could also detect neuroendocrine differentiation in all combined small cell carcinomas, in one poorly differentiated adenocarcinoma, and in about 30% of the poorly differentiated SQCs. Therefore, lung cancer heterogeneity can be detected using a panel of well-defined antibodies to intermediate filaments in combination with the MOC-1 antibody. The use of these antibodies in diagnosis can have prognostic significance and can lead to a more selective therapeutic approach.

Lung cancer-associated monoclonal antibody 15 that recognizes cell growth-related membrane antigens gp85/45 and its growth-inhibitory effect on human lung cancer cells in vitro.

In order to find lung cancer-specific markers, monoclonal antibody 15 (MAb15) was produced against a variant-type cell of small cell lung carcinoma. Its gp85/45 antigens were demonstrated in 70% of lung cancers, and particularly in the proliferating zone of cancer cell nests, but they are scarcely detected in noncancerous tissues. Immunoelectron microscopy revealed that gp85/45 antigens were expressed alternatively on the cell membrane of living cancer cells according to their biological states. MAb15 added to the culture medium inhibited the proliferation of lung cancer cells, depending on its concentration, but cell death rate did not increase. The growth inhibition by MAb15 was reevaluated by a colonogenic assay. On DNA histogram, MAb15 decreased the number of DNA-synthesizing cells in the S phase with an elevation of the G1 peak, indicating a G1-S boundary block in the cell cycle. gp85/45 detected by this lung cancer-associated monoclonal antibody could be a functional membrane unit, such as a growth factor receptor, which is related to the cell proliferation of lung cancer. The growth inhibition by MAb15 may be caused by the blocking of a growth factor receptor which is specific to lung cancer.

Relationships between neuroendocrine differentiation and sensitivity to gamma-radiation in culture line OH-1 of human small cell lung carcinoma.

After 16 months, an established line of human small cell lung cancer (OH-1) underwent a subtle morphological change which was associated with a virtually complete loss of neuroendocrine differentiation as judged by electron microscopy studies and a 12-fold loss in L-dopa decarboxylase activity. In nude (athymic) mouse heterotransplants, the histology of the early-passage cells (oat or lymphocyte-like) differed only slightly from the late-passage cells (intermediate or polygonal type); cytology studies showed no diagnostic differences between the passages. However, the early-passage endocrine-like cells showed up to 100-fold less cell survival after irradiation than the late-passage cells. Thus, subtle changes in the morphology of OH-1 cells are accompanied by a profound loss of neuroendocrine differentiation and the emergence of radiation resistance. These changes could have important parallelisms for behavior of small-cell lung carcinoma in humans. The cell culture model described may be useful in investigating the interrelationships occurring between endocrine and nonendocrine cells in the spectrum of human lung cancer. The findings emphasize that neuroendocrine-related ultrastructure and biochemistry may help define important cell populations in lung cancer with respect to therapeutic sensitivity.

Isolation and characterization of plasma membranes from transplantable human astrocytoma, oat cell carcinoma, and melanomas.

Purified plasma membranes were obtained from five transplantable human tumors, a grade IV astrocytoma, an oat cell carcinoma, and three melanomas. Plasma membrane fractions were isolated from tumor homogenates by differential and discontinuous sucrose gradient centrifugation. Determination of enzyme activities indicated that the plasma membranes were enriched 10- to 20-fold with respect to 5'-nucleotidase, nicotinamide adenine dinucleotide glycohydrolase, Mg2+-activated nucleoside triphosphatase, and sialic acid. Specific activities of nearly all the enzymes varied with the individual tumors, even among tumors of the same type, i.e., the melanomas. Electron micrographs of the plasma membrane fractions showed smooth single-membrane vesicles with slight contamination by lysosomes. Therefore, these membranes are suitable for comparative biochemical studies and for the preparation of tumor-specific monoclonal antibodies. Plasma membranes from all five tumors contained very high Mg2+-adenosine triphosphatase (ATPase) activities. The Na+-K+-ATPase was a minor component of the total ATPase of these membranes (less than 30%). The major component was an ATPase exhibiting similar activity toward several nucleoside triphosphates. The activity of such a nucleoside triphosphatase has been correlated with tumorigenicity in cultured liver epithelial cells. The nucleoside triphosphatase of the plasma membranes of astrocytoma and oat cell carcinoma was stimulated from 50 to 1005 by concanavalin A, whereas ATPase of the melanoma plasma membranes was not or only slightly stimulated. The different response to concanavalin A could be due to differences in the ATPase molecules of the individual tumors or to the different environment of the ATPase.

Human small cell lung cancer cell lines express functional atrial natriuretic peptide receptors.

Small cell lung cancer cell (SCLC) lines, NCI-H82, NCI-H660, and NCI-H1284, and HeLa cells were analyzed for the presence of atrial natriuretic peptide (ANP) receptors. In these SCLC cell lines and HeLa cells, ANP A receptor mRNA was identified by Southern blot analyses of polymerase chain reaction products and RNase protection assays using poly(A)(+)-selected RNA. Saturable binding assays revealed that HeLa cells had 2000 to 5000 high affinity atrial natriuretic peptide receptors per cell with a dissociation constant of 140 pM. In the SCLC cell lines, the binding was saturable but too low to accurately estimate the number of binding sites. After addition of human ANP, radioimmunoassays revealed accumulation of cyclic GMP in SCLC cells as well as HeLa cells in a dose-dependent fashion. The half-maximal stimulation concentration of cyclic GMP accumulation in HeLa and these SCLC cell lines was approximately 2 nM. Tetrazolyl blue assays and tritiated thymidine incorporation did not show any remarkable growth inhibition or growth stimulation of SCLC cell lines after addition of human ANP up to 3.3 microM, more than 1000-fold greater than the half-maximal stimulation concentration of cyclic GMP accumulation. Our results indicate that human SCLC cells express functional ANP receptors but ANP addition produced no detectable change in their growth pattern.

Antitumor effects of an adenovirus expressing antisense insulin-like growth factor I receptor on human lung cancer cell lines.

Insulin-like growth factors (IGFs) are often essential for the maintenance of the malignant phenotype, and in lung cancer the IGF-I receptor (IGF-Ir) is often expressed at high levels. Stable transfection of antisense plasmids expressing the first 300 bp of the IGF-Ir reduces the tumorigenicity of a variety of tumor cell lines and has been reported to induce systemic antitumor effects on established, non-gene-modified tumors in animal model systems. We have constructed an adenovirus expressing an antisense IGF-Ir (Ad-IGF-Ir/as) in an attempt to develop these observations into a clinical therapeutic approach. A single transduction by Ad-IGF-Ir/as (at a multiplicity of infection of 10:1) decreased the IGF-Ir number by about 50% in human lung cancer cell lines NCI H460 and SCC5, as measured by an 125I-labeled IGF-I competitive binding assay. After the transduction of these human lung cancer cell lines by Ad-IGF-Ir/as, the soft agar clonogenicity was reduced by 84%. The i.p. treatment of nude mice bearing established i.p. NCI H460 cells resulted in prolonged survival compared to that of nude mice treated with a reporter virus. These results suggest that Ad-IGF-Ir/as has a therapeutic effect on established human lung cancer xenografts and may represent an effective and practical cancer gene therapy strategy.

Electron microscopy in small cell lung carcinomas: clinical correlation.

In order to investigate the relationship of subcellular differentiation of small cell lung carcinomas (SCLC) and clinical response, we reviewed the electron microscopic (EM) features of tumor biopsy specimens from 33 patients with SCLC diagnosed by light microscopy (LM). These tumors were divided by EM into four groups according to the ultrastructural features. Group I (13 patients) had tumors with only neurosecretory granules on EM. Group II (11 patients) had tumors with neurosecretory granules and other subcellular features of non-SCLC. Group III (five patients) had tumors that lacked neurosecretory granules but contained subcellular features of non-SCLC. Group IV (four patients) had tumors that lacked all of these features. The complete and partial response rate to systemic chemotherapy with or without radiation therapy was 88% in the total population studied. The response rates were not statistically different in any of the four groups based on EM findings. The results of this study suggest that the LM diagnosis of SCLC alone adequately identifies lung cancer patients with a high response rate to systemic therapy.

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.

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.

Changes in immunocytochemical detectability of proteasome epitopes depending on cell growth and fixation conditions of lung cancer cell lines.

The localization of proteasome epitopes in the lung cancer cell lines NCI-H82, derived from a small cell lung cancer, and MR65, derived from a squamous cell lung carcinoma, was studied in relation to cell growth conditions. For this purpose the proteasome monoclonal antibodies MCP34 and MCP20 were applied to the cells growing under different nutritional conditions, resulting in different proliferative states. Using indirect immunofluorescence microscopy with brief fixation in methanol (5 sec, -20 degrees C) followed by three dips in acetone (5 sec at room temperature), it became obvious that the intracellular detectability of the proteasomes changes depending on the nutritional and proliferative status of the tumor cells. Two types of experiments were carried out: (1) cells were grown for two days at different cell densities, with an excess of culture medium, and (2) cells were seeded in a low cell density and monitored for 6 days without change of medium. In cells grown at low density, the proteasomes can be detected mainly in the nuclei, while the nucleoli are almost devoid of staining, and the cytoplasm is only slightly stained. In cells grown at high density, the staining pattern changes with a much less pronounced nuclear staining than in the cells at low density, while the cytoplasm remains slightly stained. In the nutrient depletion experiment similar changes were seen. In cells growing under favorable conditions (1 or 2 days in fresh medium) proteasomes are detected mainly in the nuclei, whereas when the medium becomes depleted of nutrients (4 or 5-day-old medium) the staining pattern changes to one with a much less pronounced nuclear staining. However, in immunofluorescence studies on cells grown under similar conditions but fixed in ethanol (-20 degrees C) for 15 min, the changes in proteasome localization pattern were not detected during medium depletion. Using this fixation protocol the proteasomes are detected mainly in the nuclei at all stages of the medium exhaustion experiment. These apparently contrasting results suggest that upon nutrient depletion the proteasome epitopes become less accessible to the antibodies used. Apparently, the epitopes can regain accessibility if an extended ethanol fixation is used. This hypothesis was confirmed by flow cytometry and immunoblotting experiments. In flow cytometry of ethanol-fixed cells the fluorescence intensity of only a minor part of the cell population decreases to some extent with medium depletion, but in the majority of the cells fluorescence remains at its initial level. The immunoblotting experiments show no quantitative changes in proteasome content of the tumor cells at the different growth conditions.

Corticotropin-releasing factor receptors in human small cell lung carcinoma cells: radioligand binding, second messenger, and northern blot analysis data.

Numerous peptides, growth factors, and receptors have been identified in small cell lung carcinoma (SCLC) cells. The present study was designed to examine the radioligand binding, second messenger, and messenger RNA (mRNA) characteristics of CRF receptors in a variety of SCLC lines and to compare their characteristics to CRF receptors in the mouse pituitary tumor AtT-20 cells. The human SCLC cell lines NCI-H69, H82, H146, H209, H345, H446, and H510A and control AtT-20 cells all demonstrated specific [125I]Tyr(o)-ovine CRF ([125I]oCRF) binding, which was linear with increasing protein concentrations, saturable, reversible, and of high affinity. NCI-H82 cells showed the highest level of specific [125I]oCRF binding (approximately 60% of the total binding). Scatchard analysis revealed a single homogeneous class of binding sites in NCI-H82 and AtT-20 cells, with Kd values of 263 +/- 48 and 285 +/- 75 pM, respectively, and binding capacities of 74 +/- 7 and 70 +/- 13 fmol/mg protein, respectively. [125I]oCRF-binding sites on NCI-H82 and AtT-20 cells had comparable pharmacological characteristics with the following rank order of inhibitory potencies: rat/human CRF approximately ovine CRF approximately bovine CRF > alpha-helical oCRF-(9-41) > bovine CRF-(1-41)OH >> vasoactive intestinal peptide, secretin, GH-releasing hormone. [125I]oCRF binding in the cell lines was inhibited by guanine nucleotides, suggesting a coupling of receptors to guanine nucleotide-binding proteins. The functional nature of the CRF receptor was demonstrated in second messenger studies in which rat/human CRF stimulated cAMP production in NCI-H82 and AtT-20 cells with comparable EC50 values of about 3 nM; the percent stimulation over basal activity was significantly higher in NCI-H82 cells (approximately 30-fold increase) than in AtT-20 cells (approximately 12-fold increase). Northern blot analysis of total RNA revealed the presence of a 2.6-kilobase mRNA band in NCI-H82 cells corresponding to the recently cloned human CRF receptor. In summary, the data demonstrate the presence of CRF receptors in SCLC cell lines with kinetic, pharmacological, second messenger, and mRNA characteristics comparable to those in pituitary and brain and suggest a possible role for CRF as a regulatory peptide in human SCLC.

Characterization of two monoclonal antibodies directed against the 67 kDa high affinity laminin receptor and application for the study of breast carcinoma progression.

Two monoclonal antibodies (mAbs), designated MLuC5 and MLuC6, were produced against a human small cell lung carcinoma cell line. They were found to exhibit a superimposable reactivity on different cell lines and on platelets. Moreover, they both immunoprecipitated a 67 kDa molecule from the membrane of the reference target cells. Immunodepletion and cross-inhibition tests indicated that the two mAbs recognize two epitopes closely localized on the same molecule. The MLuC5 mAb was further characterized for its reactivity on platelets. Immunoprecipitation and ELISA assays demonstrate that this mAb recognizes the 67 kDa high affinity laminin receptor. MLuC5 reactivity was evaluated by immunohistochemistry on a variety of normal and tumor tissues, in particular breast specimens including normal epithelium, dysplastic lesions, in situ carcinomas, invasive primary carcinomas and distant metastases. The laminin receptor was found to be strongly expressed in 50% of the infiltrating carcinomas, whereas in situ carcinomas and benign lesions, as well as the normal mammary epithelium, were only weakly and focally positive. In metastatic lesions MLuC5 reactivity was only found in 11% of the samples tested, independently of the site of origin of the lesion.

Small cell sweat gland carcinoma in childhood.

Sweat gland carcinomas are rare skin tumors that typically occur in older patients. The spectrum of their clinical and pathologic features is broad, and many different types of sweat gland carcinomas have been described, ranging from fairly indolent to highly aggressive neoplasms. We present two cases of sweat gland carcinoma with a predominant small cell morphology. Both tumors occurred in children. One lesion developed in an 8-year-old girl as an asymptomatic papule on her left forearm, which ultimately was evaluated using biopsy because of rapid growth and change in color. The other lesion occurred on the hand of a 12-year-old boy. Both tumors were pandermal and extended into fat. They were composed of monotonous cuboidal cells with scant cytoplasm that formed tubules and grew in anastomosing cords and trabeculae. The tumor cells were immunoreactive for cytokeratins but not for cytokeratin 20. Ultrastructural analysis (available in one case only) showed that the tumor cells lacked neurosecretory granules. This variant of sweat gland carcinoma needs to be distinguished from other small cell neoplasms of the skin, especially Merkel cell carcinoma, its closest mimic.

Small-cell undifferentiated carcinoma of the colon. A clinicopathological study of five cases and their association with colonic adenomas.

Colonic small-cell undifferentiated carcinoma (SCUC) is an extremely aggressive neoplasm. We describe five patients with colonic SCUC and review five additional, well-documented cases. The longest known duration of survival is 14 months and all patients with follow-up of this duration have died of disease. Regional lymph nodes are invariably involved at the time of diagnosis and when distant metastases were present, the liver was always affected. Four of our cases of SCUC arose in association with colonic adenomas and in two of these the SCUC component was confined to the superficial submucosa. Yet, both produced regional metastases and one had massive hepatic involvement. Ultrastructurally, colonic SCUC exhibits divergent, predominantly neuroendocrine differentiation. The ultrastructural features and association with colonic adenomas suggest an endodermal rather than neuroectodermal derivation.