Divergent differentiation in small round-cell tumours of the soft tissues with neural features—an analysis of 10 cases

A series of 10 small round-cell tumours, having in common evidence of neural differentiation, were investigated by immunohistochemistry and electronmicroscopy. In seven, evidence of divergent muscle and/or epithelial differentiation was found. This phenomenon thus appears more common than previously appreciated and suggests that there may be a continuous and overlapping phenotypic spectrum from Ewing's tumour of soft tissue to intra-abdominal desmoplastic small cell tumour.     

Intra-abdominal desmoplastic small cell tumour in a patient with Peutz-Jeghers syndrome

A surgical case of intra-abdominal desmoplastic small cell tumour with divergent differentiation (IDS-CT) in a patient with Peutz-Jeghers syndrome (PJS) is reported. The patient was a 23-year-old woman who underwent surgery for a tumour in the left paraovarian region. Widespread peritoneal metastases were noted. Histopathological examination revealed solid cell nests composed of medium-sized cells demarcated by desmoplastic stroma. Gland-like spaces were found within many cell nests. Tumour cells were positive for cytokeratin and smooth muscle actin, but negative for desmin. Both ovaries contained minute foci of a sex cord tumour with annular tubules. This is the first documentation of the association of IDSCT with PJS. Since patients with PJS have an increased risk of cancer in various organs, the occurrence of IDSCT in the present patient might not be fortuitous.     

Immunohistochemical detection of the Wilms' tumour gene WT1 in desmoplastic small round cell tumour

The desmoplastic small round cell tumour (DSRCT) is a rare, highly malignant neoplasm usually presenting in the abdomen of adolescent males. A characteristic translocation between the Ewing's sarcoma gene on chromosome 22 and the Wilms' tumour gene WT1 on chromosome 11 has been described, producing a fusion gene with expression of the DNA binding area of WT1. Some Wilms' tumour antibodies recognize epitopes of this part of the WT1 protein. All four cases of DSRCT examined showed strong staining of the tumours with an anti-WT1 antibody, suggesting this may be useful in the diagnosis of these tumours.     

Frequent presence of neuroendocrine small cells in thymic carcinoma: a light microscopic and immunohistochemical study

AIMS: Neuroendocrine differentiation has been described in conventional carcinomas of various organs. Small cells postulated to be neuroendocrine cells were observed previously in some thymic carcinomas. This study was conducted to confirm and characterize the presence of neuroendocrine small cells in thymic carcinomas by light microscopy and immunohistochemistry. METHODS AND RESULTS: Twenty-two thymic carcinomas were studied by light microscopy to detect the presence of small neuroendocrine-like cells. They were found in four of 10 squamous cell carcinomas (SCC) and seven of eight adenosquamous carcinomas (ASC). No small cells were observed in three lymphoepithelioma-like carcinomas (LELC) and one adenocarcinoma. The small cells were located within the tumour nests and constituted less than 1% of the entire tumour. In one case, small cells also extended outside the tumour nests. Rosette formation was seen in three cases. They were proved to be neuroendocrine cells by their immunoreactivity to neuron-specific enolase, chromogranin A, and/or synaptophysin. A few scattered neuroendocrine small cells were found only by immunohistochemistry in one case each of SCC, ASC, and LELC. The small cells were also strongly positive for cytokeratin (CK) 8 and CK18 but negative for CK19 and CK20. The predominant carcinoma cells other than the neuroendocrine small cells also displayed neuroendocrine markers in 68% of the cases studied. CONCLUSIONS: Neuroendocrine small cells can be recognized by light microscopic examination in approximately 61% of thymic SCC and ASC. Neuroendocrine markers, CK8 and CK18 can aid in confirming their presence. The neuroendocrine small cells present in thymic carcinomas are different from the main carcinoma cells displaying immunohistochemical neuroendocrine markers. The presence of neuroendocrine small cells could be an useful marker for the differentiation of thymic carcinomas from thymomas and carcinomas of other sites.     

Gangliosides inhibit the development from monocytes to dendritic cells

Dendritic cell (DC) development and function is critical in the initiation phase of any antigen-specific immune response against tumours. Impaired function of DC is one explanation as to how tumours escape immunosurveillance. In the presence of various soluble tumour-related factors DC precursors lose their ability to differentiate into mature DC and to activate T cells. Gangliosides are glycosphingolipids shed by tumours of neuroectodermal origin such as melanoma and neuroblastoma. In this investigation we address the question of whether gangliosides suppress the development and function of monocyte-derived DC in vitro. In the presence of gangliosides, the monocytic DC precursors showed increased adherence, cell spreading and a reduced number of dendrites. The expression of MHC class II molecules, co-stimulatory molecules and the GM-CSF receptor (CD116) on the ganglioside-treated DC was significantly reduced. Furthermore, the function of ganglioside-treated DC was impaired as observed in endocytosis, chemotactic and T cell proliferation assays. In contrast to monocytic DC precursors, mature DC were unaffected even when higher doses of gangliosides were added to the culture. With regard to their carbohydrate structure, five different gangliosides (GM2, GM3, GD2, GD3, GT1b), which are typically shed by melanoma and neuroblastoma, were tested for their ability to suppress DC development and function. Suppression was induced by GM2, but not by the other gangliosides. These data suggest that certain gangliosides impair DC precursors, implying a possible mechanism for tumour escape.     

Small cell carcinoma of the liver: a hitherto unreported variant of hepatocellular carcinoma

We report three cases of an unusual primary carcinoma of the liver composed of small cells. The patients were adult males (56 to 89 years) who presented with jaundice, weight loss and abdominal discomfort. Surgery was attempted in one case. Clinical evolution was rapid, with death ensuing between 1 and 5 months after diagnosis. Surgical (1 case) and autopsy (2) tissues were available for review. All three tumours arose in non-cirrhotic livers. They were composed of broad nests of small epithelial cells with little supporting tissue. They were positive for low-molecular weight keratins and alpha-fetoprotein. One case was immunoreactive for erythropoietin antigen. Expression of neuroendocrine markers was focal and erratic. No immunostaining was observed for carcinoembryonic antigen or S-100 protein. In one case ultrastructural investigation disclosed canaliculi surrounded by microvilli and junctional complexes. In the light of these features, it appears that small cell carcinoma represents a rare, but definite variant of hepatocellular carcinoma. Although it does not segregate in a peculiar clinical setting, it should be distinguished from metastatic pulmonary small cell carcinoma as well as from other malignancies featuring small cells.     

Prevalence of neuroendocrine granules in small cell lung carcinoma. Usefulness of electron microscopy in lung cancer classification

Fifty-four lung carcinomas submitted for routine electron microscopy under the light microscopical diagnosis of small cell carcinoma were investigated. In 42 or of 45 evaluable cases, neuroendocrine granules were considered definitely or probably present, the modification 'probably' being necessary in suboptimal material. In three cases, squamous cell differentiation was seen, but no neuroendocrine granules were found. On revision of these three cases, the light microscopical diagnosis was changed to squamous cell carcinoma in one instance, and neither of the other two cases was considered classical for small cell carcinoma. Patient follow-up of these three cases showed tumour behaviour indicative of non-small cell carcinoma in two evaluable cases, the third case yielding no significant data. These results indicate that neuroendocrine granules can generally be found in small cell lung carcinomas, provided the material is sufficient for evaluation. When these granules are absent, and other differentiation is found on electron microscopy, the final classification of the tumour should incorporate this finding, to warn the clinician that the tumour will not necessarily behave as a small cell carcinoma.     

The 'grey area' between small cell and non-small cell lung carcinomas. Light and electron microscopy versus clinical data in 14 cases

We studied 14 lung tumours which on light microscopy had posed difficulties on classification as either small cell or non-small cell carcinomas. The light and electron microscopical features were compared with patient follow-up data. Electron microscopy showed neuroendocrine granules in 12 cases, and adeno- and squamous cell differentiation but no neuroendocrine granules in the remaining two cases. The latter two cases showed prolonged patient survival (both patients alive after 2 1/2 and 2 years, respectively). Ten of the cases with neuroendocrine granules showed a rapid course of disease (death between 2 1/2 weeks and 15 months after diagnosis) and marked initial response to multiagent chemotherapy. Thus, the clinical impression of these cases was that of small cell carcinoma. The remaining two cases with neuroendocrine granules showed a more protracted course, with death after 1 1/2 and 2 1/2 years. These two tumours did not show the light microscopical features of atypical carcinoid. The results illustrate the value of electron microscopy in predicting clinical behaviour of carcinomas difficult to place into small cell or non-small cell carcinoma groups. They also point to the existence of neuroendocrine carcinomas other than carcinoids with a more protracted course than small cell carcinomas.     

Immunocytochemical characterization of neuroendocrine tumours of the larynx

Twenty-two neuroendocrine tumours of the larynx were investigated using a panel of immunocytochemical markers. Three were small cell carcinomas, eight were large cell neuroendocrine carcinomas and 11 were paragangliomas. Twenty were positive for protein gene product 9.5, 19 for neuron-specific enolase, 15 for chromogranin A, nine for bombesin, eight for substance P, eight for neuropeptide Y, eight for metenkephalin, seven for somatostatin, five for calcitonin, eight for calcitonin gene-related peptide and one for vasoactive intestinal polypeptide. Bombesin immunoreactivity was largely restricted to the small cell carcinomas and large cell neuroendocrine carcinomas and neuropeptide Y, metenkephalin and substance P to the parangangliomas. This comprehensive immunocytochemical analysis of neuroendocrine tumours of the larynx demonstrates that these tumours represent special entities but have similar patterns of immunostaining to those of neuroendocrine tumours in other sites.     

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。     

Morphometric grading of squamous cell carcinoma

Histological grading of squamous cell carcinoma is subjective and suffers from poor observer reproducibility. We investigated the feasibility of quantifying histological differentiation via point counting, using both the degree of keratinization and a novel definition of differentiation that was based on architectural features of the tumour. Multiple recounts of 20 cases of human oral squamous cell carcinoma were performed at several magnifications (X100, X160 and X250). Six lines of human squamous cell carcinoma tumour lines were examined for changes in differentiation following transplantation to athymic nude mice. Observer reproducibility was extremely high for all recounts except at the highest magnification, where the tumour architecture may have been obscured. Of the human squamous cell carcinomas transplanted to nude mice, five of six tumour lines showed significant histological changes, most commonly toward decreased differentiation. The changes were usually present in the initial transplant and were similar to those we have reported for transplants of adenocarcinomas. We conclude that histological differentiation can be quantified in squamous cell carcinomas with a high degree of observer reproducibility, even in the absence of keratinization; the method employed is sufficiently sensitive to be applied to practical problems of biological significance.     

Mitotic activity of Sertoli cells in adult human testis: an immunohistochemical study to characterize Sertoli cells in testicular cords from patients showing testicular dysgenesis syndrome

During puberty, normal somatic Sertoli cells undergo dramatic morphological changes due to the differentiation of immature pre-Sertoli cells in functionally active adult Sertoli cells. Sertoli cell maturation is accompanied with loss of their mitotic activity before onset of spermatogenesis and loss of pre-pubertal and occurrence of adult immunohistochemical Sertoli cell differentiation markers. Testes of infertile adult patients often exhibit numerous histological signs of testicular dysgenesis syndrome (TDS) such as microliths, Sertoli cell only (SCO) tubules, tubules containing carcinoma in situ and immature seminiferous tubules (Sertoli cell nodules). Sertoli cell tumours, however, are very rare neoplasms possibly due to the fact that the mechanism and temporal origin of neoplastic Sertoli cells underlying Sertoli cell tumourigenesis still remain unknown. To clarify the state of Sertoli cell differentiation in both immature seminiferous tubules of adult patients with TDS and Sertoli cell tumour, we compared the expression of the Sertoli cell differentiation markers vimentin, inhibin-α, anti-Muellerian-hormone, cytokeratin 18, M2A-antigen, androgen receptor and connexin43 with that of SCO tubules with hyperplasia. In addition, we demonstrated for the first time the existence of proliferating Sertoli cells by Ki67- and PCNA-immunostaining in Sertoli cell nodules of the adult human testis. Our data indicate that mitotically active Sertoli cells in Sertoli cell nodules will be arrested prior to puberty and, contrary to dogma, do not represent foetal or neonatal cells. Since all markers in Sertoli cell nodules revealed a staining pattern identical to that in neoplastic Sertoli cells, but different to that in Sertoli cells of SCO tubules with hyperplasia, it may be speculated that Sertoli cell tumours in adult men may originate from Sertoli cell nodules.     

Bipolar (neural and myoblastic) phenotype in cell lines derived from human germ cell tumours of testis

Non-seminomatous germ cell tumours of the testis (NSGCT) form a heterogeneous group of neoplasms. Cell lines derived from NSGCT may provide useful data concerning the biology of neoplasic precursor germ cells, differentiation of tumour stem cells and the relationship between various tissue components of these tumours. Four NSGCT were studied, two mixed tumours composed of teratocarcinoma, yolk sac and trophoblastic elements, and two malignant teratomas with a massive neuroectodermal component, equivalent to primary neuroectodermal tumours (PNET) of the testis. The explanted tumours gave rise to various cell populations, including epitheloid cells, flattened large cells, spindle cells and tear drop cells of neuroblastic type. Ultrastructurally, cultured cells expressed various degrees of neural and muscular differentiation: neurosecretory granules, intermediate filaments of glial nature, and filaments resembling Z-bands. Cultured cells showed the expression of several neural and muscular markers, including neurofilaments, cytokeratin, actin, desmin, neuron-specific enolase, glial fibrillary acidic protein and HNK-1. In addition, three cases expressed HBA-71 antigen and two expressed MyoDI protein. All cases were aneuploid, and an isochromosome 12p, i(12p), was detected in three cases. Myoblastic and neural cells are the predominant tumour cells that grow in vitro, independent of the nature and composition of the primary germ cell tumour. A histogenetic relationship between germ cell tumours and small round cell tumours of childhood is suggested.     

Ultrastructural and immunocytochemical definition of component neoplasms in an unusual gastrooesophageal collision tumour

An unusual collision tumour (concrescence of two neighbouring independent neoplasms) is reported. One tumour was a small cell undifferentiated (oat cell) carcinoma of the lower oesophagus and the other was a gastro-oesophageal adenocarcinoma. There was little intermingling of the two patterns. The adenocarcinoma stained strongly positive for mucin and carcinoembryonic antigen (CEA), but the small cell carcinoma was negative for both and also argyrophil-negative; both were negative for neurone-specific enolase and common leukocyte antigen. Ultrastructural study showed extra-cellular glandular lumina lined by cells with apical microvilli and junctional complexes in the adenocarcinoma; primitive cells without tonofilaments or dense-core granules, and joined by rudimentary desmosomes were seen in the small cell carcinoma. Collision carcinomas may result from a carcinogenic stimulus affecting two neighbouring regions of mucosa or may simply be the chance apposition of two unrelated tumours.     

Molecular classification of urothelial carcinoma: global mRNA classification versus tumour‐cell phenotype classification

Global mRNA expression analysis is efficient for phenotypic profiling of tumours, and has been used to define molecular subtypes for almost every major tumour type. A key limitation is that most tumours are communities of both tumour and non‐tumour cells. This problem is particularly pertinent for analysis of advanced invasive tumours, which are known to induce major changes and responses in both the tumour and the surrounding tissue. To identify bladder cancer tumour‐cell phenotypes and compare classification by tumour‐cell phenotype with classification by global gene expression analysis, we analysed 307 advanced bladder cancers (cystectomized) both by genome gene expression analysis and by immunohistochemistry with antibodies for 28 proteins. According to systematic analysis of gene and protein expression data, focusing on key molecular processes, we describe five tumour‐cell phenotypes of advanced urothelial carcinoma: urothelial‐like, genomically unstable, basal/SCC ‐like, mesenchymal‐like, and small‐cell/neuroendocrine‐like. We provide molecular pathological definitions for each subtype. Tumours expressing urothelial differentiation factors show inconsistent and abnormal protein expression of terminal differentiation markers, suggesting pseudo‐differentiation. Cancers with different tumour‐cell phenotypes may co‐cluster (converge), and cases with identical tumour‐cell phenotypes may cluster apart (diverge), in global mRNA analyses. This divergence/convergence suggests that broad global commonalities related to the invasive process may exist between muscle‐invasive tumours regardless of specific tumour‐cell phenotype. Hence, there is a systematic disagreement in subtype classification determined by global mRNA profiling and by immunohistochemical profiling at the tumour‐cell level. We suggest that a combination of molecular pathology (tumour‐cell phenotype) and global mRNA profiling (context) is required for adequate subtype classification of muscle‐invasive bladder cancer. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.