Male infertility: assessment of juvenile testicular dysfunction and risk for malignancy in cryptorchid boys based on resin section evaluation.

Infertility is sometimes more a man's problem than a woman's, failure of one or both of the testes to descend (cryptorchidism) being the most frequent genital malformation in boys. Untreated, the undescended testis impairs germ cell development and significantly reduces adult fertility. A-dark spermatogonia are the stem cells for all future spermatozoa, and their depletion can be reliably estimated in resin semithin sections. Additionally, there is an increased risk of testicular preneoplasia in the form of carcinoma in situ (CIS) cells. The authors report how the pathologic biopsy examination of juvenile cryptorchid testes can assess infertility and malignancy risk.

Embryonal tumor with abundant neuropil and true rosettes: an autopsy case-based update and review of the literature.

INTRODUCTION: Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a rare subtype of primitive neuroectodermal tumors first reported in 2000. It is rare among the group of embryonal central nervous system tumors with approximately 50 reported cases. ETANTR has been suggested to be a separate entity among this group of tumors. CASE REPORT: Herein, we present only the second autopsy case of ETANTR, which occurred in a 17-month-old boy, and was located in the brainstem. The tumor was inoperable, and despite chemotherapy, the child died 3 months after initial hospitalization. A brain only autopsy was performed. DISCUSSION: Neuropathological and neuroimaging examinations suggest ETANTR grew by expansion rather than invasion distorting anatomical structures of the posterior fossa. We suggest that the characteristic histopathological picture of the tumor is the result of multifocal and dispersed germinative activity surrounded by mature neuropil-like areas. CONCLUSION: ETANTR is a pediatric tumor occurring in children under 4 with a significantly poor prognosis with more cases and research required to characterize this rare embryonal tumor.

Papel de los nuevos marcadores inmunohistoquímicos en los tumores de células germinales malignos gonadales / The role of new immunohistochemical markers in malignant germ cell tumours of the gonads

Los tumores de células germinales malignos (TCGM), debido a su tratamiento individualizado, se presentan como un reto diagnóstico y terapéutico donde el estudio inmunohistoquímico reproducible es de suma importancia. Revisamos el valor diagnóstico de nuevos anticuerpos provenientes de investigaciones de células madre tales como OCT3/4, SOX2 y SALL4. Su expresión en los TCGM confirma una vez más el carácter pluripotencial de estas neoplasias. El SALL4 puede ser considerado un marcador general de los TCGM. La expresión de OCT3/4 en disgerminoma/seminoma lo confirma como precursor de otros TCGM. La expresión simultánea de SALL4, SOX2 y OCT3/4 confirman al carcinoma embrionario como el tumor de células madre pluripotenciales, con SOX2 y CD30 como marcadores altamente característicos. El D2-40 es útil para diferenciar el disgerminoma/seminoma del carcinoma embrionario. La alfa-fetoproteína es diagnóstica de tumores vitelinos, pero en casos de escasa expresión, la reevaluación positiva con GLP3 y SALL4 y la negatividad frente al OCT3/4 confirman el diagnóstico. Un panel mínimo de anticuerpos con cobertura de los tipos más frecuentes de los tumores de células germinales debería incluir alfa-fetoproteína, CD30, D2-40, OCT3/4, GLP3 y SALL4(AU)

Malignant germ cell tumours (MGCT) of the ovary and testis often represent a diagnostic challenge due to their frequent overlap and primitive histology. New antibodies, mostly originating from the stem cell research field, provide accurate tools for the identification of different tumour types. The expression of antibodies such as OCT3/4, SOX2 and SALL4 indicates the pluripotent character of these neoplasms. SALL4 represents a good screening antibody for the diagnosis of MGCT while OCT3/4 indicates a totipotential role for dysgerminoma/seminoma. OCT3/4, SOX2 and SALL4 are coexpressed in embryonal carcinoma, where SOX2 and CD30 represent highly specific markers. D2-40 podoplanin is useful to differentiate dysgerminoma/seminoma from embryonal carcinoma. AFP is highly diagnostic of yolk sac (endodermal primitive) tumours but in cases with low expression, diagnosis is facilitated by a concurrent positivity of Glypican3 and SALL4 and OCT3/4 negativity. An antibody panel that includes alpha-foetoprotein, CD30, D2-40, OCT3/4, Glypican3 and SALL4 is useful in the identification and taxonomy of MGCT(AU)

Embryonal carcinoma in the abdominal cavity of a male calf.

An embryonal carcinoma was diagnosed in the abdominal cavity of a 55-day-old male calf. Macroscopically, a large volume of ascitic fluid was observed along with white to yellowish-white masses of various sizes densely located on the abdominal wall and the surface of abdominal organs. There was an absence of testes in the scrotum. Histologically, the tumor cells were polygonal, and the tumor was mostly composed of sheets of densely packed solid patterns with occasional papillary and tubular structures. Cell nuclei were variable in size, and cellular mitotic rate was high. Immunohistochemically, tumor cells were positive for alpha-fetoprotein, placental alkaline phosphatase, cytokeratin, and carcinoembryonic antigen. Ultrastructurally, the tumor cells had large nuclei, extensive rough endoplasmic reticulum, and small numbers of mitochondria. Microvillus-like structures and desmosomes were occasionally observed. From lectin histochemical examination, the tumor cells were positive for concanavalin A, wheat germ agglutinin, peanut agglutinin, Dolichos biflorus agglutinin, soybean agglutinin, Griffonia simplicifolia I, and Bauhinia purpurea, and negative for Ulex europaeus agglutinin I. Results of histopathological, immunohistochemical, and ultrastructural examinations of the tumor were similar to those obtained for human embryonal carcinoma.

The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors.

The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort 7to better understand its preclinical properties in models of embryonal tumors (ET), a family of childhood malignancies sharing relevant biological and genetic features such as deregulated expression of MYC oncogenes. In our study, NBT-272 displayed a strong antiproliferative activity in vitro that resulted from the combination of diverse biological effects, ranging from G(1)/S arrest of the cell cycle to apoptosis and autophagy. The compound prevented the full activation of both eukaryotic translation initiation factor 4E (eIF4E) and its binding protein 4EBP-1, regulating cap-dependent protein translation. Interestingly, all responses induced by NBT-272 in ET could be attributed to interference with 2 main proproliferative signaling pathways, that is, the AKT and the MEK/extracellular signal-regulated kinase pathways. These findings also suggested that the depleting effect of NBT-272 on MYC protein expression occurred via indirect mechanisms, rather than selective inhibition. Finally, the ability of NBT-272 to arrest tumor growth in a xenograft model of neuroblastoma plays a role in the strong antitumor activity of this compound, both in vitro and in vivo, with its potential to target cell-survival pathways that are relevant for the development and progression of ET.

Fine-needle aspiration cytology of pancreatoblastoma in a young woman: report of a case and review of the literature.

Pancreatoblastoma is a rare tumor and has been reported only four times in the cytologic literature, three times in fine-needle aspiration (FNA) biopsy and once in an imprint of resected tumor. We are reporting the fourth case of FNA cytology with immunohistochemical and electron microscopic studies. The patient is a 24-yr-old African American woman, who presented with a pancreatic mass, hepatic masses, and abdominal lymphadenopathy. The aspiration smears of the liver mass showed a biphasic tumor composed of bland-appearing primitive spindled stromal fragments with "spider-web"-like long fibrils interconnecting with sharply angulated islands of cohesive epithelium. At high power, the epithelium is composed of medium-sized cells with round-to-oval vesicular nuclei with fine chromatin and one-to-two small nucleoli. The neuroendocrine component was demonstrated immunohistochemically with synaptophysin and chromogranin expressions. The acinar component and squamoid component were demonstrated ultrastructurally by the presence of 400-600 nm zymogen granules and tonofilaments. The literature was reviewed and the cytological features of all the four cases of pancreatoblastoma are summarized.

Light and electron microscopy of the pagetoid spread of germ cell carcinoma in the rete testis: morphologic evidence suggestive of field effect as a mechanism of tumor spread.

The purpose of this study is to investigate the mechanism of tumor spread in the pagetoid spread of germ cell tumors in the rete testis (PSRT). Twenty consecutive cases of germ cell tumor of the testis (9 seminomas, 3 embryonal carcinomas, and 8 teratocarcinomas) were retrieved to identify the cases with PSRT. The areas of pagetoid spread were examined by the serial sectioning of the entire thickness of the tissue block. Available fresh tissue was submitted for electron microscopic study. Ten cases were associated with PSRT and had focal or extensive areas of intratubular germ cell neoplasia (IGCN) in the proximity of the tumor and the rete testis (RT). In the remaining 10 cases, 6 were associated with IGCN distant from the RT and the last 4 were not associated with IGCN. Seminiferous tubules with IGCN were seen connecting with the RT with pagetoid spread. Isolated single intraepithelial tumor cells also were identified at the periphery of the areas with PSRT. Electron microscopic study of the RT of 4 cases with PSRT (2 seminomas, 1 embryonal carcinoma, and 1 teratocarcinoma) revealed desmosome-type junctions between tumor cells with RT epithelial cells. Direct tumor expansion and cell motility as mechanisms of tumor spread in PSRT does not explain the presence of isolated cells and desmosome-type junctions of the tumor cells as demonstrated in this study. The authors believe that the field effect plays an important part in the pathogenesis of this pagetoid spread in the RT. It is likely that this field effect is induced by the germ cell tumor and is operated through the immature germ cells or undifferentiated epithelial cells in the RT adjacent to the tumor cells.

Cystic embryonal sarcoma of kidney: a case report.

BACKGROUND: Morphologic analysis of malignant renal tumors of childhood and adolescence has resulted in the identification of a variety of tumor types with characteristic histology and clinical behavior. The authors report a case of renal sarcoma in a 19-year-old male that differs in morphology from the various established categories of primitive renal tumors. METHODS: Sections taken from the nephrectomy specimen were stained by routine methods and by immunohistochemistry for stromal and epithelial markers, and for proliferation markers. In addition, ultrastructural studies were undertaken. RESULTS: The tumor, which the authors termed cystic embryonal sarcoma, was comprised of poorly differentiated malignant mesenchyme in a myxoid stroma. Numerous epithelial-lined cysts were present. The distribution of the cysts and proliferation kinetics of cyst-lining epithelial cells suggested that they were derived from entrapped renal tubules. The tumor showed early recurrence postoperatively and after aggressive chemotherapy. The pathologic features and clinical behavior of the tumor resemble those of 2 previously reported cases and an additional 25 cases from the files of the National Wilms' Tumor Study Pathology Center. CONCLUSIONS: The clinical and histologic features of cystic embryonal sarcoma differ from those of other renal tumors of childhood and adolescence, and the tumor appears to be a novel form of renal malignancy.

[Embryonal neuroepithelial tumors of the cerebral hemispheres]. / Embrional'nye neiroépitelial'nye opukholi bol'shikh polusharii golovnogo mozga.

33 embryonal neuroepithelial tumours of the cerebral hemispheres were examined light- and electron-microscopically, immunohistochemically. 4 types of tumours were distinguished: neuroblastoma, neuroepithelioma, ependymoblastoma and choroid carcinoma. Each type was characterised by its own pathohistological, immunohistochemical and ultrastructural features. Our results and literature data prove immunophenotypic and ultrastructural heterogeneity of embryonal neuroepithelial tumors of the cerebral hemispheres, in spite of some similarities in their pathohistological features.

Pleuropulmonary blastoma (pulmonary blastoma of childhood): genetic link with other embryonal malignancies?

A case of pleuropulmonary blastoma (childhood variant of pulmonary blastoma) was examined using histological, immunohistochemical, ultrastructural and cytogenetic methods. The tumour consisted of undifferentiated 'blastematous' areas admixed with zones of rhabdomyoblastic and chondroid differentiation and fascicular areas. Desmin and S-100 protein immunoreactivity confirmed the myogenic and cartilaginous differentiation. Ultrastructurally only undifferentiated mesenchymal cells were present. The cytogenetic analysis revealed abnormalities of 2q. Involvement of 2q has also been described in hepatoblastoma and embryonal rhabdomyosarcoma. Although further confirmation is needed, our cytogenetic findings in pleuropulmonary blastoma suggest common genetic mechanisms in some paediatric embryonal malignancies.

Intermediate filaments in ovarian tumors.

The availability in recent years of an ever increasing number of monoclonal antibodies to intermediate filaments which react with formalin-fixed, paraffin-embedded sections by the immunoperoxidase method, makes it possible to apply this technique in most surgical pathology laboratories. In addition to representing a major diagnostic tool that is often indispensable in the differential diagnosis, intermediate filaments typing of complex ovarian neoplasms has also shed some light on the histogenesis and differentiation potential of ovarian tumors.

Primitive neuroectodermal tumor and Ewing's sarcoma.

Many of the major solid, malignant tumors of childhood have histologic similarities that reflect their dysembryonic and primitive features. One subset of these neoplasms, Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET), presents primarily in the bone and soft tissues. Both tumor types were reported at a time and date well before the advent of electron microscopy and immunohistochemistry. Opposition to ES and PNET as distinctive entities developed and persisted because these tumors were considered incompletely documented examples of metastatic neuroblastoma or malignant lymphoma. General acceptance of ES as a unique tumor type occurred well before the PNET had been fully defined and characterized. Once these neoplasms had joined the other round cell neoplasms, the quest for the histogenesis was pursued, but the results were frustratingly inconclusive, especially for ES. Because of the resemblance of the PNET to classic neuroblastoma, the neural crest was regarded as the most likely progenitor. With the recognition of osseous PNET, extraosseous ES, and a shared cytogenetic abnormality between ES and PNET, more recent speculation has focused on the possibility that these presumably separate neoplasms are closely related histogenetically without directly answering the question of histogenesis. Despite the likely common progenitorship of ES and PNET, the latter neoplasm is seemingly the more aggressive. Although melanotic neuroectodermal tumor of infancy, intra-abdominal desmoplastic small cell tumor, and polyphenotypic small cell tumors have some overlapping microscopic and immunohistochemical features with PNET, their relationship to ES-PNET has otherwise not been resolved.

Ultrastructure of developing and malignant germ cells.

Ultrastructural studies have provided special insights on the growth and differentiation of normal and neoplastic germ cells. Prespermatogenic germ cells in the fetal and postnatal testis are large spherical to ovoid cells characterized by a central symmetrical nucleus, prominent reticular nucleoli and abundant cytoplasm with accumulation of glycogen and paucity of other organelles. Similar findings have been observed in seminoma and intratubular neoplasia. These observations support origin of the tumours from germ cells at early stages of differentiation. Evidence is presented to suggest that the pathogenesis of germ cell neoplasia involves excessive proliferation of precursor germ cells associated with loss of intercellular communication.

Peripheral primitive neuroectodermal tumors. A flow cytometric analysis with immunohistochemical and ultrastructural observations.

Flow cytometry of classical neuroblastoma has provided provocative evidence that cell cycle and ploidy analysis generate prognostically useful information. To determine whether such analyses of peripheral primitive neuroectodermal tumors might yield similar results, formalin-fixed, paraffin-embedded tissue specimens from 19 peripheral primitive neuroectodermal tumors, each previously characterized by immunohistochemical or ultrastructural study, were assessed. An acceptable histogram was obtained in 16 cases. Of these, nine neoplasms were diploid and seven contained aneuploid DNA. Among patients with diploid lesions, four were free of disease, whereas three had persistent or recurrent disease, and two had died of tumor. Among patients with aneuploid neoplasms, four were free of disease, one had recurrence, and two had died. There was no apparent correlation between immunophenotype and proliferative activity with the clinical outcome. Among aneuploid peripheral primitive neuroectodermal tumors, DNA index did not predict survival. Hence, cell cycle and DNA ploidy analyses do not appear to contribute to the prognostic assessment of peripheral primitive neuroectodermal tumors, as they do to presumably related neoplasms of the central and peripheral nervous system.

Müllerian adenosarcomalike tumor of the seminal vesicle. A case report with immunohistochemical and ultrastructural observations.

A müllerian adenosarcomalike tumor of the seminal vesicle is described in a 49-year-old man. The tumor occupied the entire right seminal vesicle and adhered to the right lobe of the prostate, in the area adjacent to the seminal vesicle. The tumor was also adherent to the rectum. Microscopically, the cells were seen to invade the prostatic tissue. The tumor consisted of a highly cellular stroma with spindle-shaped pleomorphic cells, suggesting the diagnosis of a low-grade sarcoma. In addition, dilated cystic spaces lined by columnar epithelium were seen. Immunohistochemically, most tumor cells showed positivity for vimentin, desmin, and muscle-specific actin, suggesting smooth-muscle cell differentiation. Furthermore, electron microscopy also demonstrated smooth-muscle differentiation of the tumor cells. The patient has been disease-free for 48 months since undergoing a cystoprostatetectomy.

Chondrocytic differentiation of peripheral neuroectodermal tumor cell line in nude mouse xenograft.

We have established a cell line (KU-SN) from a peripheral neuroectodermal tumor originating in the left scapula of a 4-year-old girl. The original tumor was immunoreactive with antibodies for neurofilament proteins, neuron-specific enolase, vimentin, S100 protein, and beta 2-microglobulin. Dense core granules, 50-150 nm in diameter, were identified by electron microscopy. The cell line was established from tumor cells in metastatic lung fluid. KU-SN cells were immunoreactive with the antibodies for neurofilament proteins, vimentin, neuron-specific enolase, S100 protein, glial fibrillary acidic protein, cytokeratin, and carcinoembryonic antigen. Besides these neuronal features, KU-SN cells express type 2 collagen and insulin-like growth factor 1 receptor. The addition of insulin-like growth factor 1 (100 ng/ml) increased the growth rate of KU-SN cells 2.1-fold over control. Some cells were positive for Alcian blue and alkaline phosphatase staining. Cytogenetic analysis of KU-SN cells disclosed a reciprocal chromosomal translocation [t(11,22)]. Northern blot analysis of KU-SN cells demonstrated amplified expression of the c-myc gene but not the N-myc gene. When tumor cells were transplanted into nude mice, cartilage was formed. The cartilage was immunoreactive with the antibody for HLA-ABC, indicating that it was derived from the tumor cells, not from mouse tissue. Chondrocytic differentiation was not observed in xenografts of Ewing's sarcoma cell lines SK-ES or RD-ES or the peripheral neuroectodermal tumor cell line SK-N-MC. These results indicate that KU-SN cells represent primitive neural crest cells having the potential for chondrocytic differentiation.

Sinonasal primitive neuroectodermal tumor arising in a long-term survivor of heritable unilateral retinoblastoma.

BACKGROUND: Patients who survive retinoblastoma (RB) are at risk for having second nonocular tumors, usually osteosarcomas, which often are fatal. Such patients almost always have bilateral RB. METHODS: This article reports a woman who, at the age of 1 year had been cured of a unilateral RB by radiation therapy and enucleation. Eighteen years later, she had a sinonasal small cell tumor that rapidly recurred and proved fatal 2 months after surgical debulking. The tumor was studied by immunohistochemistry and electron microscopic (EM) examination. RESULTS: It showed diffuse neuron-specific enolase staining, focal weak staining for chromogranin, synaptophysin, and Leu-7 monoclonal antibodies in paraffin-embedded, B5-fixed tissue (Great Lakes Diagnostics, Troy, MI). EM study showed an undifferentiated primitive neuroectodermal tumor with many polyribosomes, simple cell junctions, few microtubules, and rare dense core granules. CONCLUSIONS: The combined immunohistochemical, ultrastructural, and clinical features of the tumor were interpreted as a sinonasal primitive neuroectodermal tumor with early neuronal differentiation. The tumor was pathologically indistinguishable from poorly differentiated olfactory neuroblastoma (ONB) and Ewing sarcoma.

Two cell lines established from mixed müllerian tumors of the uterus. Morphologic, immunocytochemical, and cytogenetic analyses.

To clarify the cellular origin and characteristics of malignant mixed müllerian tumor (MMMT), the authors investigated two cell lines (designated as FU-MMT-1 and FU-MMT-2) established from two patients with heterologous MMMT of the uterus. Both cell lines propagated continuously for 83 and 55 serial passages over 1.5 years, respectively. Morphologically, FU-MMT-2 was a mixture of carcinoma cells and sarcoma cells with predominance of carcinoma cells; FU-MMT-1 only had a sarcomatous element with distinct rhabdomyoblastic differentiation. Immunocytochemically, the sarcoma cells of each cell line expressed, not only myogenic and mesenchymal antigens (desmin, myoglobin, and vimentin), but also epithelial antigens, including epithelial membrane antigen and keratin. The carcinoma cells in FU-MMT-2 were positive for the epithelial antigens and vimentin and negative for desmin and myoglobin. Both lines had abnormal karyotypes; the modal chromosome numbers of FU-MMT-1 and FU-MMT-2 were 47 and 80, respectively. In addition, FU-MMT-1 had trisomy 8, and FU-MMT-2 had complex structural abnormalities. When transplanted into nude mice, FU-MMT-1 reproduced and maintained the characteristics of the original tumor. These cell lines and xenografts appear to provide a useful system for studying the biologic behavior, cytogenetic features, and histogenesis of MMMT. In conclusion, the presence of epithelial antigens in the sarcomatous and carcinomatous elements seemed to support the hypothesis that both elements are derived from a common stem cell.