Diagnostic histopathologic criteria in pediatric tumors: an eclectic review

Malignant tumors of infants and children, unlike their adult counterparts, are commonly undifferentiated or show minimal evidence of differentiation. Because of this, many of these tumors pose a formidable dilemma to the general pathologist in distinguishing one from another. A broad sampling of the more common malignant neoplasms and of newly recognized histologic subtypes which are restricted more or less to the pediatric age group is presented. The minimal microscopic criteria required to establish a diagnosis are given using widely accepted pathologic classifications and seminal journal references as a guide. Ancillary microscopic features, helpful histochemical stains, immunohistochemistry, and ultrastructural morphology are described for most tumors. Histologic distinction from diagnostic mimickers is discussed. Where appropriate, histologic grading and tumor subclassification are presented and their prognostic relevance is reviewed.     

Carcinomas of the colon with multidirectional differentiation

Summary Two cases of colonic carcinomas with multidirectional differentiation are presented. Both tumors showed light microscopic and immunohistochemical evidence of areas of adenocarcinomatous, squamous cell carcinomatous, and neuroendocrine differentiation. Only six similar cases have been previously reported. These highly malignant tumors support the recent concept of a multipotential stem cell within the mucosa of the gastrointestinal tract capable of differentiation in several directions.     

Clear cell thyroid cancer--undifferentiated type--an immunohistochemical and electron microscopical study

Two cases of clear cell thyroid cancer are described. In both tumors immunohistochemical methods detected the presence of intracytoplasmic thyroglobulin that confirmed the follicular origin. Simultaneously performed electron microscopic studies visualized the accumulation of smooth surfaced, membrane coated vesicles of varying size in the cytoplasm. Bad prognosis predicted on the base of undifferentiated histological structure was confirmed by extended hematogenic metastases.     

Morphology of adenohypophysial tumors in mice transgenic for vasopressin-SV40 hybrid oncogene.

Transgenic mice for the promoter sequence of bovine arginine vasopressin (AVP) gene fused to large SV40 T-antigen coding sequence develop pituitary tumors and insulin-producing pancreatic tumors. In order to establish the cellular composition of the pituitary tumors, histological, immunocytochemical, in situ hybridization, and electron microscopic technics were applied. Pituitary anterior lobe tumors were identified in 10 out of 14 glands examined. In 2 of these cases, intermediate lobe tumors were also found. The anterior lobe tumors contained a variable number of GH immunoreactive cells. In situ hybridization performed in 7 cases revealed a diffuse distribution of GH messenger RNA over all tumor cells. Ultrastructurally, the tumors contained undifferentiated cells with very small secretory granules and rare cells showing some resemblance to somatotrophs. The results indicate that these pituitary tumors are composed of undifferentiated somatotrophs. The presence of a few PRL immunoreactive cells in four tumors and scattered TSH immunoreactive cells in two tumors supports the view that somatotrophs have the potential to produce PRL and TSH. The intermediate lobe tumors were immunoreactive for ACTH and intensely positive for POMC mRNA. In the nontumorous adenohypophyses, no hyperplasia of any cell type was noted. Several GH immunoreactive cells exhibited pleomorphic, giant nuclei and mitoses. In conclusion, the majority of transgenic mice for AVP/large T-antigen develop pituitary tumors originating in and composed of somatotrophs. Less frequently, intermediary lobe tumors were present as well. AVP/SV40 transgenic mice provide a unique experimental model for somatotroph tumors that are neither preceded by, nor associated with somatotroph hyperplasia.     

Basaloid squamous carcinoma of esophagus:a clinicopathological, immunohistochemical and electron microscopic study of sixteen cases

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Tumor differentiation and immunocompetence in cervical cancer patients

The authors investigated cell-mediated and humoral immunity parameters of 161 and 131 cervical cancer patients in connection with the histological differentiation of the tumor. As regards the carcinoembryonic antigen and acute phase proteins no difference was found between differentiated and undifferentiated types of tumors. Significantly higher levels of IgA, IgM, 3rd component of the complement and of skin reactivity to phytohemagglutinin were observed in patients with differentiated tumors.     

MR imaging of malignant mesenchymal tumors of the liver.

Magnetic resonance (MR) features of five primary malignant mesenchymal neoplasms (plasmocytoma, leiomyosarcoma, undifferentiated sarcoma, epithelioid hemangioendothelioma, and angiosarcoma) of the liver were reported. All tumors were hypointense on T1-weighted images and hyperintense on T2-weighted images. No halo and intravenous extension were noted. A target appearance was revealed in epithelioid hemangioendothelioma. MR findings of angiosarcoma were essentially the same as those of cavernous hemangiomas (markedly hyperintense with hypointense linear septa on T2-weighted images). MR findings of these rare hepatic malignancies were nonspecific, although they were quite different from those of typical hepatocellular carcinomas. This study suggested that MR differentiation of primary hepatic mesenchymal tumors from other common benign and malignant neoplasms was difficult; however, the number of studied cases was limited.     

Plasticity of the neoplastic phenotype in vivo is regulated by epigenetic factors

Age of host and transplantation-site microenvironment influence the tumorigenic potential of neoplastically transformed liver epithelial cells. Tumorigenic BAG2-GN6TF rat liver epithelial cells consistently form tumors at ectopic sites, but differentially express tumorigenicity or hepatocytic differentiation in the liver depending on host age and route of cell transplantation into the liver. Direct inoculation into host livers concentrates tumor cells locally, resulting in undifferentiated tumors near the transplantation site in both young (3-month-old) and old (18-month-old) rats. Transplantation-site tumors regress within 1 month in the livers of young rats, but grow progressively in old rats. However, inoculation of cells into the spleen distributes transplanted cells individually throughout the liver, resulting in hepatocytic differentiation by tumor cells with concomitant suppression of their tumorigenicity in young rats. When transplanted into livers of old rats by splenic inoculation, or when young hepatic-transplant recipients are allowed to age, hepatocytic progeny of BAG2-GN6TF cells proliferate to form foci, suggesting that the liver microenvironment of old rats incompletely regulates the proliferation and differentiation of tumor cell-derived hepatocytes. Upon removal from the liver, BAG2-GN6TF-derived hepatocytes revert to an undifferentiated, aggressively tumorigenic phenotype. We posit that the spectrum between normal differentiation and malignant potential of these cells reflects the dynamic interaction of the specific transformation-related genotype of the cells and the characteristics of the tissue microenvironment at the transplantation site. Changes in the tissue milieu, such as those that accompany normal aging, may determine the ability of a genetically aberrant cell to produce a tumor.     

Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor

Hepatic tumors, exhibiting mature hepatocytes and undifferentiated cells merging with cholangiocyte and hepatocyte phenotypes, are frequently described. The mechanisms by which they occur remain unclear. We report differentiation and transdifferentiation behaviors of human HepaRG cells isolated from a differentiated tumor developed consecutively to chronic HCV infection. We demonstrate that, in vitro, proliferating HepaRG cells differentiate toward hepatocyte-like and biliary-like cells at confluence. If hepatocyte-like cells are selectively isolated and cultured at high cell density, they proliferate and preserve their differentiation status. However, when plated at low density, they transdifferentiate into hepatocytic and biliary lineages through a bipotent progenitor. In accordance, transplantation of either undifferentiated or differentiated HepaRG cells in uPA/SCID mouse damaged liver gives rise mainly to functional human hepatocytes infiltrating mouse parenchyma. Analysis of the differentiation/transdifferentiation process reveals that: (1) the reversible differentiation fate of HepaRG cells is related to the absence of p21(CIP1) and p53 accumulation in differentiated cells; (2) HepaRG bipotent progenitors express the main markers of in vivo hepatic progenitors, and that cell differentiation process is linked to loss of their expression; (3) early and transient changes of beta-catenin localization and HNF3beta expression are correlated to Notch3 upregulation during hepatobiliary commitment of HepaRG cells. CONCLUSION: Our results demonstrate the great plasticity of transformed hepatic progenitor cells and suggest that the transdifferentiation process could supply the pool of hepatic progenitor cells. Moreover, they highlight possible mechanisms by which transdifferentiation and proliferation of unipotent hepatocytes might cooperate in the development of mixed and differentiated tumors.     

Predicting histologic findings from endoscopic appearance of early gastric cancer.

In 156 cases of depressed early gastric cancer in the antrum or corpus, the differences between differentiated and undifferentiated carcinoma were studied by comparing the histological diagnosis of the resected specimens and their endoscopic appearance. We reached the following conclusions: (a) Younger patients more often had undifferentiated carcinoma (mean age: 59.8 years) than differentiated carcinoma (mean age: 77.2 years). (b) One hundred and twenty-five of 156 cases were limited to the mucosa and 29 cases were limited to the submucosa. (c) Undifferentiated gastric cancers more often invaded beyond the mucosa even when the tumor was small than did differentiated tumors. (d) Many differentiated tumors showed a smooth depressed surface, erythema at the edge of the cancer, and tapering of the gastric rugae. (e) In undifferentiated lesions the depressed tumor surface had a varied appearance, with various sized granules and nodules, as well as fading of the mucosal color and fusion of the rugae. It is important at endoscopy to consider not only whether a lesion is benign or a malignant, but also to consider its histological type. In particular, it is vital to detect small, undifferentiated gastric cancers as early as possible.     

Development of tumors in the glandular stomach of rats after oral administration of carcinogens. II. Different cell types in antral carcinoma as revealed by electron microscopy.

In the present study electron microscopic investigations of tumors of the glandular stomach of rats induced by oral administration of MNNG or ENNG are dealt with. The aim of the study was to describe the different cell types found in the carcinoma and to elucidate the possible relationship between the undifferentiated carcinoma cells and the more differentiated cell types found in the tumor. The results show that besides undifferentiaded carcinoma cells, several differentiated cell types such as goblet cells, endocrine cells, cells with lamellated inclusions in their cytoplasm, and squamous carcinoma cells can be observed. The most conspicuous findings were carcinomatous gland cells with well differentiated microvilli on their luminal surface and typical tonofilamentous structures in their cytoplasm. These cells exhibited signs of the squamous epithelium and of gland cells. Therefore they may be considered as intermediate variants between adenocarcinoma cells and squamous carcinoma cells. The occurrence of such intermediate steps points to the possibility of differentiation by cell division of adenocarcinoma cells into several metaplastic cell types in the experimental stomach carcinoma induced by MNNG or ENNG.     

Pattern of recurrence after extended esophagectomy for squamous cell carcinoma of the esophagus

BACKGROUND/AIMS: To further investigate the underlying mechanism of the systemic spread of esophageal squamous cell carcinoma. METHODOLOGY: Out of 151 patients who underwent a curative esophageal resection, 41 (27.1%) developed recurrent esophageal cancer. Nine recurrences (22%) were distant-hematogenous, 17 (41.5%) non-hematogenous, and 15 (36.5%) mixed. Hematogenous deposits accompanied 58.5% of the recurrences. The relation between several clinicopathological factors and the pattern of recurrence was evaluated. RESULTS: Univariate analysis recognized the lack of adjuvant chemoradiation, the tumor location in the lower esophagus and the tumor dedifferentiation as promoting factors for hematogenous recurrence. Poorly differentiated or undifferentiated tumors presented a significantly higher microvessel density than moderately or well differentiated tumors. Tumor differentiation and tumor lower localization were independent predictors of hematogenous recurrence. CONCLUSIONS: Patients with poorly differentiated or undifferentiated tumors, which are located at the lower esophagus and present high microvessel density, should be considered at high risk for hematogenous recurrences after extended esophagectomy.     

Mutation in the type IB bone morphogenetic protein receptor Alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish

Germ-cell tumors (GCTs), which arise from pluripotent embryonic germ cells, exhibit a wide range of histologic differentiation states with varying clinical behaviors. Although testicular GCT is the most common cancer of young men, the genes controlling the development and differentiation of GCTs remain largely unknown. Through a forward genetic screen, we previously identified a zebrafish mutant line, tgct, which develops spontaneous GCTs consisting of undifferentiated germ cells [Neumann JC, et al. (2009) Zebrafish 6:319-327]. Using positional cloning we have identified an inactivating mutation in alk6b, a type IB bone morphogenetic protein (BMP) receptor, as the cause of the zebrafish GCT phenotype. Alk6b is expressed in spermatogonia and early oocytes, and alk6b mutant gonads display impaired BMP signal transduction, altered expression of BMP target genes, and abnormal germ-cell differentiation. We find a similar absence of BMP signaling in undifferentiated human GCTs, such as seminomas and embryonal carcinoma, but not in normal testis or in differentiated GCTs. These results indicate a germ-cell-autonomous role for BMP signal transduction in germ-cell differentiation, and highlight the importance of the BMP pathway in human GCTs.     

Proliferation and differentiation of human myeloid leukemic cells in immunodeficient mice: electron microscopy and cytochemistry

To study the influence of a biologic environment on cultured human leukemia cells, KG-1, KG-1a, and HL-60 cells were inoculated subcutaneously into newborn nude mice. The cells developed myelosarcomas at the site of inoculation and in lungs and kidneys. KG-1 and HL-60 myelosarcomas were successfully passaged through adult nude mice, whereas KG-1a tumors proliferated only after transplantation into newborn hosts. The human nature of the cells forming myelosarcomas in mice was assessed by chromosomal analyses and detection of cross- reactivity with an antibody to the human leukemia cell line K562. We undertook electron microscopic and cytochemical examinations of the cells proliferating in vitro and in the mice. The granules of KG-1 cells in vivo did not react for acid phosphatase, as observed in vitro, and the HL-60 cells proliferating in mice lost the perinuclear myeloperoxidase (MPO) demonstrated in cultured cells. Although the influence of an in vivo selection of cell subpopulations cannot be ruled out, the enzymatic changes are compatible with induced cell differentiation. Conclusive evidence of differentiation in vivo was observed in the KG-1a cell subline. The undifferentiated KG-1a blasts developed cytoplasmic granules and synthesized MPO during proliferation in vivo. These observations indicate that human leukemia cells from established cell lines proliferate in nude mice and may acquire new differentiated properties in response to the in vivo environment.     

Factors associated with pN3 stage tumors according to the TNM classification in advanced gastric cancer

BACKGROUND/AIMS: The aim of the present study was to analyze factors associated with pN3-stage tumors, as classified according to the TNM Classification of Malignant Tumors, in patients who undergo curative resection for advanced gastric cancer. METHODOLOGY: A total of 391 patients with advanced gastric cancer (247 males and 144 females; average age, 59.2 years) were enrolled in the present study. The numbers of dissected regional lymph nodes and positive nodes were assessed, and node stage was determined according to TNM. Patient survival and factors associated with pN3-stage tumors were then analyzed. RESULTS: The 5-year survival rate was 82.9% for the 132 N0 patients, 66.4% for the 154 N1 patients, 41.1% for the 64 N2 patients and 21.1% for the 41 N3 patients. A significant difference was found between some of the curves (N0 and N1, p = 0.0012; N1 and N2, p = 0.0007; N2 and N3, p = 0.0055). In logistic regression analysis, independent factors associated with advanced gastric cancers with a pN3-stage tumor were tumor diameter (> 6 cm vs. < or = 6 cm, p = 0.0037), number of dissected nodes (> 30 vs. < or = 30, p = 0.0143), depth of invasion (T3 or T4 vs. T2, p = 0.0028) and microscopic type (undifferentiated vs. differentiated, p = 0.0147). CONCLUSIONS: The results of the present study suggest that tumor diameter (> 6 cm), depth of invasion (T3 or T4) and microscopic type (undifferentiated type) are the most reliable indicators of pN3-stage tumors in patients who undergo curative resection for advanced gastric cancer.     

Effects of relaxin on the mouse mammary gland. I. The myoepithelial cells

Myoepithelial cells (MEC) were studied in the mammary gland of ovariectomized virgin mice without any hormonal treatment and following the administration of either estrogen or estrogen plus relaxin (either purified porcine relaxin standard or partially purified human relaxin extracted from decidua). Changes in MEC lineage were observed at both the light and electron microscopic levels in the hormonally treated animals as compared with the untreated controls. After 7 days of estrogen administration, there was a moderate elongation and branching of ducts. At the growing tips and buds undifferentiated precursors and promyoepithelial cells at various stages of their differentiation were seen with some frequency. After relaxin administration (18-20 hrs) to mice pre-treated with estrogen, branching and elongation of ducts were greatly increased as compared to mice treated with estrogen alone. At the growing points the ducts showed multi-layered walls and undifferentiated precursors were quite frequently found with some mitotic figures. Moreover several promyoepithelial cells at various stages of differentiation were observed. These findings, which were similar after administration of the two different relaxin preparations, indicate a high rate of proliferation and differentiation of MEC in these experimental conditions and hence suggest that relaxin greatly enhances the de novo formation of MEC. A stimulatory effect of relaxin on MEC growth is discussed in terms of a possible role of this hormone in the genesis of benign and malignant neoplasms of the mammary gland, in which MEC proliferation can be recognized.     

Solid pseudopapillary tumor of the pancreas: emphasis on differential diagnosis from aggressive tumors of the pancreas.

Solid pseudopapillary tumor is an unusual primary tumor of the pancreas with a low potential for malignancy and unknown cell origin, seen mostly in young women. Although it is discussed among pancreatic epithelial tumors, many cases do not express cytokeratin but show neuroendocrine differentiation. Three cases (2 female, 1 male, aged 24, 45 and 50 years, respectively) of solid pseudopapillary tumor localized in the pancreas are presented. All cases displayed a well-circumscribed tumor, with an average diameter of 6 cm and a red-brown colored, hemorrhagic, cystic cut surface. Microscopically they were encapsulated with large areas composed of thin papillary formations and solid areas focally. Tumor cells were dyscohesive with small, round- to-oval, central nuclei, and vacuolated, clear or eosinophilic cytoplasm without mitotic activity. NSE, vimentin, synaptophysin, ER, PR, Ki-67, S-100, Pan CK, a1-antitrypsin, a2-antichymotrypsin, and antibodies were used in the immunohistochemical study. Vimentin, synaptophysin, NSE, PR, and a1-antitrypsin showed expression in all cases, while Pan-CK was expressed in two cases. Ki-67 expression was below 1% in all cases. Morphologic features of solid pseudopapillary tumor may be confused with pancreatic endocrine neoplasm and ductal adenocarcinoma. All cases showed features of histiocytic and neuroendocrine differentiation. Epithelial differentiation was identified in two cases. We conclude that immunohistochemistry is incapable of giving additional information for the diagnosis of solid pseudopapillary tumor due to different lines of differentiation of tumor cells. We believe that macroscopic and microscopic features (using hematoxylin and eosin stain) are more important for the diagnosis and differential diagnosis of this tumor.