Immunoreactive secretory component of IgA in human tissues and tumors

Secretory component (SC) of IgA is known to be produced by many glandular epithelial cells. To assess the usefulness of this antigen as a glandular tumor differentiation marker, the authors evaluated its normal body distribution and tested a variety of glandular neoplasms. The known normal distribution of SC was confirmed and extended to include the prostate. Immunoreactive SC was detected only in epithelial and glandular tumors. Many types of well-differentiated adenocarcinomas, (ovary, prostate, small bowel, pancreas, stomach, biliary) however, contained little or no immunoreactive SC. Therefore, the authors conclude that immunoreactive SC cannot be used as a general differentiation marker in tumors of glandular derivation. A high frequency of antigenic expression was found in adenocarcinomas of the lung (4/10), breast (5/10), and colon (24/27). No correlation between expression and tumor differentiation was observed in pulmonary or mammary tumors. Only in colonic neoplasia was such a relationship detected. SC expression in colonic tumors was not related to mucin content but was associated with the presence of a visible brush border.     

Pulmonary blastoma. Comparison between its epithelial components and fetal bronchial epithelium.

Three cases of pulmonary blastoma exhibiting biphasic epithelial and stromal patterns, and a case of fetal lung-type adenocarcinoma, were examined by immunohistochemistry and electron microscopy (EM) and compared with fetal bronchial epithelium in order to explore the multidirectional differentiation of their epithelial components. The glandular cells of all four tumors resembled fetal bronchial epithelial cells in the pseudoglandular stage. Neuroendocrine (NE) cells were also present; they were argyrophilic and expressed pan-NE markers, neurosecretory granules and peptide hormones. The neural cell adhesion molecule (NCAM) was strongly expressed on the cell membranes of glandular cells, as in the case of proximal bronchial epithelial cells at the pseudoglandular stage in fetal lung. Sialosylated Lewis X was also expressed, indicating that the epithelial cells were possibly of endodermal origin. Two of the four cases showed considerable immunoreactivity for alpha-fetoprotein (AFP). The epithelial cells of pulmonary blastomas may occasionally de-differentiate into cells functionally resembling fetal hepatic, foregut and yolk sac cells expressing AFP. Tumor examination by immunohistochemistry and EM suggested that the glandular cells of the tumors may differentiate to some extent like those of fetal large bronchi at the pseudoglandular stage, but there was concordance and discordance in the expression of neuroendocrine and oncofetal markers between blastomatous tumors and fetal bronchial epithelium.     

Pulmonary Blastoma

Three cases of pulmonary blastoma exhibiting biphasic epithelial and stromal patterns, and a case of fetal lung type adenocarcinoma, were examined by immunohisto-chemistry and electron microscopy (EM) and compared with fetal bronchial epithelium in order to explore the multidirectional differentiation of their epithelial components. The glandular cells of all four tumors resembled fetal bronchial epithelial cells in the pseudoglandular stage. Neuroendocrine (NE) cells were also present: they were argyrophilic and expressed pan NE markers, neurose-cretory granules and peptide hormones. The neural cell adhesion molecule (NCAM) was strongly expressed on the cell membranes of glandular cells, as in the case of proximal bronchial epithelial cells at the pseudoglandular stage in fetal lung. Sialosylated Lewis^X was also expressed, indicating that the epithelial cells were possibly of endodermal origin. Two of the four cases showed considerable immunoreactivity for alpha fetoprotein (AFP). The epithelial cells of pulmonary blastomas may occasionally de-differentiate into cells functionally resembling fetal hepatic, foregut and yolk sac cells expressing AFP. Tumor examination by immunohistochemistry and EM suggested that the glandular cells of the tumors may differentiate to some extent like those of fetal large bronchi at the pseudoglandular stage, but there was concordance and discordance in the expression of neuroendocrine and oncofetal markers between blastomatous tumors and fetal bronchial epithelium. Acta Pathol Jpn 42: 884–892, 1992.     

Gastroenteropancreatic neuroendocrine tumors. A histochemical and immunohistochemical study of epithelial (keratin proteins, carcinoembryonic antigen) and neuroendocrine (neuron-specific enolase, bombesin and chromogranin) markers in foregut, midgut, and hindgut tumors

Thirty-four gastroenteropancreatic (GEP) neuroendocrine tumors were evaluated for expression of epithelial (keratin, carcinoembryonic antigen [CEA] and neuroendocrine (neuron-specific enolase, chromogranin, bombesin) markers, and results were correlated with histologic patterns and histochemical staining. Tumors of mixed pattern (insular or trabecular with glandular areas) predominated. CEA localization corresponded to staining for mucin, with polarized apical or lumenal staining in glandular areas. Four trabecular midgut carcinoids, however, revealed diffuse cytoplasmic staining for CEA. Staining for keratin proteins was present in 68% of tumors. Bombesin immunoreactivity was demonstrated in 60% of GEP neuroendocrine tumors, indicating that bombesin positive metastatic tumors may not be predominantly of pulmonary origin, as previously suggested. Chromogranin was a sensitive marker for identifying normal gastrointestinal neuroendocrine cells that were not demonstrated by staining for neuron-specific enolase. Chromogranin was present in most neuroendocrine tumors, but was absent from three of five rectal carcinoids in keeping with the distinctive profile of hormonal and silver staining in these tumors. All GEP neuroendocrine neoplasms expressed both neuroendocrine and epithelial markers, supporting their derivation from endodermal epithelium.     

Gastrointestinal cancer - only a deregulation of stem cell differentiation? (Review)

Recent research on embryonic and adult stem cells questions the currently accepted models of multi-step carcinogenesis in solid cancer. Accordingly, differentiated epithelial cells are considered to be the main target for mutational steps, leading to a growth and survival advantage of malignantly transformed cells. In contrast, the stem cell model of carcinogenesis emphasizes the role of stem cells as the initiating structure for tumor development. Yet, it is unclear if tumors contain dysregulated (embryonic) stem cells or if tumors consist of differentiated adult cells that obtained a de-differentiated stem cell-like phenotype. Here, we review the current knowledge on the roles of stem cells in gastrointestinal cancer formation and the implication on future diagnostic and therapeutic strategies.     

MMC-E cells--origin and changes in karyotype accompanying malignant transformation

Karyotype analysis of an established nontumorigenic cell line (MMC-E) indicated that the cells are of rat origin instead of mouse, as interpreted earlier. This cell line, now termed RE (rat epithelial) had a karyotype of 39,X,-5,-15,-?16,+t(3q11q) in the stem line. There was also one subline that had a karyotype of 40,X,-5,-15,-?16,+t(3q11q), +?t(5;?). Chromosome changes and frequency of sister chromatid exchanges (SCEs) were studied from seven malignantly transformed RE cell lines. These included cells transformed by Moloney murine sarcoma virus, the acute transforming retrovirus 3611-MSV, murine leukemia virus, or ethylnitrosourea. Changes in chromosomes #3 and #5 seemed to be associated with malignant transformation of RE cells. In addition to the t(3q11q) and monosomy for chromosome #5 seen in the parent cell line, monosomy for chromosome #3 and the t(5;?) were observed in all malignant cell lines. The latter changes either were absent (monosomy for chromosome #3) or present only occasionally [t(5;?)] in the parental cells. The results of SCEs showed that the malignantly transformed cell lines do not have increased frequency of SCEs as compared with that of the parental cell line.     

Cardiac Myxoma with Glandular Differentiation: An Immunohistochemical and Ultrastructural Study

A case of cardiac myxoma with glandular differentiation is reported. The patient did not have elements of the Carney triad or syndrome. The tumor was mainly composed of characteristic stellate cells in a focally collagenized, myxoid stroma, along with aggregates of glandular-forming epithelial cells, with mucin-containing intra- and intercellular lumina. Ultrastructurally, these gland spaces displayed short, straight microvilli and junctional complexes. The epithelial cells were positive for cytokeratin 7 and negative for cytokeratin 20. Calretinin was positive in the stellate cells and negative in the epithelial component. The potential origin from pluripotent mesenchymal cells or from seeded stem cells is hypothesized for glandular differentiation in myxomas. Further studies are required to unravel the relationship between stellate cells and the diverse heterologous components reported in these tumors.     

Melanosis of the prostate: an immunohistochemical study

We report here a case of prostatic melanosis examined immunohistochemically. The patient was a 70-year-old man with prostatic hyperplasia. Six foci with brown pigmentation were found, not only in stromal cells but also in glandular epithelial cells among many pieces of prostatic tissue. Immunohistochemically, only pigment-laden stromal cells were obviously positive with antibodies to S-100 protein and melanoma (HMB45), but not for CD57, while epithelial cells were only positive for CD57 after depigmentation with bleaching. This is the first report demonstrating immunopositivity of stromal cells for antimelanoma antibody (HMB45), which can label reactive or dysplastic but not normal melanocytes. These results clearly demonstrated that pigment-laden stromal cells are neuroectodermal in origin, and probably reactive or dysplastic but not normal melanocytes.     

Histochemical and Immunohistochemical Evidence of Glandular Differentiation in Thymic Carcinoma

Eighteen cases of primary thymic carcinoma were reviewed from the viewpoint of glandular differentiation. Squamous differentiation was evident in 14 cases (83%). Immunohistochemical study revealed secretory component (SC) positive carcinoma cells in 12 cases (67%), most of which were also associated with squamous differentiation. Three of these 12 cases contained areas with a definite glandular or microcystic structure with occasional epithelial mucin, and were diagnosed as adenosquamous carcinoma. Review of patients'medical records revealed that thymic carcinomas with a glandular element were more often resectable at surgery, and had a much better prognosis than those without a glandular element. However, further study on larger number of cases is necessary to confirm this relationship. Because SC positive epithelial cells do exist in the nonneoplastic thymus, the presence of a glandular component suggests another direction of morphological and/or functional differentiation of thymic carcinoma cells in addition to the well-known squamous differentiation. Acta Pathol Jpn 39: 433 438, 1989.     

Keratin 17 expression as a marker for epithelial transformation in viral warts.

The profile of keratin expression in benign warts from various cutaneous and mucosal sites along with dysplastic warts and squamous cell carcinomas has been examined using a panel of monospecific antibodies to epithelial keratins. Viral warts and verrucous keratoses from immunosuppressed renal transplant recipients show a spectrum of squamous atypia from benign lesions, from minimal changes to full thickness dysplasia. Changes associated with malignancy include loss of differentiation-specific keratins 1 and 10 together with expansion of basal cell epitopes and inappropriate expression of simple epithelial keratins 8, 18, and 19 in advanced squamous cell carcinoma. This late expression of keratins 8 and 18 contrasts with early expression of keratin 17 in all dysplastic lesions examined. Keratin 17 is found suprabasally in hyperproliferative lesions, including benign warts, but marked basal plus suprabasal expression is seen increasingly in malignantly transformed epidermis. These findings were not specific to immunosuppression, as shown by identical findings in control squamous cell carcinoma from nonimmunosuppressed individuals. Keratin 17 expression may prove prognostically helpful when assessing dysplasia in epidermal tumors.     

Epithelial Localization of Antiendometrial Antibodies Associated With Endometriosis

ABSTRACT: Antiendometrial antibodies have been demonstrated in patients with endometriosis. As a further step in understanding the immunological alterations against the endometrium, isolated glandular and stromal monolayer endometrial cell preparations and endometrial, breast, and ovarian carcinoma cell lines were tested by indirect immunofluorescence assay utilizing sera of patients with endometriosis previously shown to have antibodies against endometrium. In dilutions of serum of 1:1 to 1:16, significant fluorescence staining was noted only in the glandular (epithelial) component and not in the stromal component of normal endometrium without regard to phase of the menstrual cycle. The significance of this finding as it relates to the pathophysiology of endometriosis awaits further study.     

Binding of estrogen and progesterone to human endometrium in the different phases of the menstrual cycle. A histochemical study

Specific estrogen and progesterone binding in human endometrium was studied histochemically using fluorochrome-labeled steroids (estradiol-17 beta-BSA-FITC and progesterone-BSA-TMRITC), endometrial samples from 36 women being investigated. The binding pattern was similar with both reagents. The relationship between the bindings to glands and to stroma, however, varied with the menstrual phase of the tissue. The specific fluorescence was more intense in the epithelial structures in the proliferative phase. In the secretory phase, the fluorescence from stromal cells was as intense as, or more intense than, that from the glands. The localization of the fluorophores in the glandular epithelial cells also varied by menstrual phase. In the proliferative phase, the fluorescence was most intense in the basal part or the whole cytoplasm of the glandular epithelial cells, while in the secretory phase the fluorescence was most intense in the apical and sometimes also in the basal part of the epithelial cells.     

Polypoid squamous cell carcinoma of the larynx. An immunohistochemical study for ras p21 and cytokeratin

Polypoid squamous cell carcinoma of the larynx consists of two components, namely, squamous cell carcinoma and sarcomatoid spindle cells. To further investigate the histogenesis of the spindle cell component, we studied two cases of polypoid squamous cell carcinoma of the larynx by immunohistochemistry and ultrastructural analysis. Positive staining for ras oncogene p21 and cytokeratin was demonstrated in both squamous cell carcinoma and spindle cell component. Only the latter component was positive for vimentin. Electron microscopic examination showed well-developed desmosomes in spindle cells. These results suggest that the spindle cell component is epithelial in origin and malignantly neoplastic; it originates from mesenchymal metaplasia or squamous cell carcinoma.     

Angiogenic histogenesis of stromal cells in hemangioblastoma: ultrastructural and immunohistochemical study

Controversy regarding the origin of characteristic stromal cells (SC) is responsible for the placement of hemangioblastoma as a single entity in the category of "tumors of uncertain histogenesis" in the current WHO classification of brain tumors. This subclassification of hemangioblastoma is, to a large extent, a consequence of a remarkable antigenic heterogeneity of SC demonstrated in many, often contradictory immunohistochemical studies. In contrast, most of the electron microscopic studies demonstrated a number of features indicating angiogenic nature of SC and, therefore, hemangioblastoma. This study reevaluated the histogenesis of SC, applying immunohistochemistry as well as electron microscopy and immunoelectron microscopy. Immunohistochemical studies confirmed most of the previous results indicating a very frequent expression of vimentin, S-100 protein, neuron-specific enolase, and cytokeratins. SC were less commonly immunoreactive for desmin, factor XIIIa, and Ricinus communis lectin receptors, and only occasionally for factor VIII and Ulex europeus lectin. They were negative for other markers of endothelial, neuronal, glial, neuroendocrine, and smooth muscle differentiation. Approximately 1% of SC showed Ki67 immunoreactivity, indicating their slight proliferative activity, consistent with the benign nature of the tumor. In contrast to the inconclusive results of the immunohistochemistry, electron microscopy demonstrated a clear relationship of SC to endothelial cells, smooth muscle cells, and pericytes. Occasional SC were found within the vascular lumina. SC often showed intracellular caveolae consistent with the formation of early capillary lumina. Moreover, occasional SC contained small Weibel-Palade bodies positive for factor VIII in immunoelectron microscopy. SC represent a heterogenous population of abnormally differentiating mesenchymal cells of angiogenic lineage, with some morphological features of endothelium, pericytes, and smooth muscle cells. Occurrence of SC in hemangioblastoma could be related to a limited ability of angioformative stromal cells to develop an architecture of capillary lumina integrated with the vascular network of the tumor. Hemangioblastoma should be reclassified and included together with other vascular tumors of the central nervous system.     

Autofluorescence characterisation of isolated whole crypts and primary cultured human epithelial cells from normal, hyperplastic, and adenomatous colonic mucosa

BACKGROUND/AIMS: In vivo autofluorescence endoscopic imaging and spectroscopy have been used to detect and differentiate benign (hyperplastic) and preneoplastic (adenomatous) colonic lesions. This fluorescence is composed of contributions from the epithelium, lamina propria, and submucosa. Because epithelial autofluorescence in normal and diseased tissues is poorly understood, this was the focus of the present study. METHODS: Whole colonic crypts were isolated, and short term primary cultures of epithelial cells were established from biopsies of normal, hyperplastic, and adenomatous colon. Autofluorescence (488 nm excitation) was examined by confocal fluorescence microscopy. Fluorescently labelled organelle probes and transmission electron microscopy were used to identify subcellular sources of fluorescence. RESULTS: Mitochondria and lysosomes were identified as the main intracellular fluorescent components in all cell types. Normal and hyperplastic epithelial cells were weakly autofluorescent and had similar numbers of mitochondria and lysosomes, whereas adenomatous (dysplastic) epithelial cells showed much higher autofluorescence, and numerous highly autofluorescent lysosomal (lipofuscin) granules. CONCLUSIONS: Short term primary cell cultures from endoscopic biopsies provide a novel model to understand differences in colonic tissue autofluorescence at the glandular (crypt) and cellular levels. The differences between normal, hyperplastic, and adenomatous epithelial cells are attributed in part to differences in the intrinsic numbers of mitochondria and lysosomes. This suggests that the detection of colonic epithelial fluorescence alone, if possible, may be sufficient to differentiate benign (hyperplastic) from preneoplastic and neoplastic (adenomatous) colonic intramucosal lesions during in vivo fluorescence endoscopy. Furthermore, highly orange/red autofluorescent intracellular granules found only in dysplastic epithelial cells may serve as a potential biomarker.     

Mitochondrial expression of the two-pore domain TASK-3 channels in malignantly transformed and non-malignant human cells

The presence of TASK-3 channels has been described in a number of healthy and malignantly transformed cells, showing mainly intracellular distribution with relatively insignificant labelling of the cell surface membrane. In this work, immunochemical and molecular biology methods were utilised to establish the intracellular organelle whose TASK-3 expression accounts for this strong intracellular labelling using cultured melanoma and HaCaT cells. Before the immunocytochemical experiments, the presence of TASK-3 mRNA was also confirmed in melanoma cells. Comparison of the results of the TASK-3- and mitochondrion-specific labelling indicated that the TASK-3 channel subunits were strongly expressed by mitochondria in both investigated cell types. Moreover, prominent TASK-3 expression of keratinocytes could also be demonstrated in histological sections excised from the human skin. These results indicate that TASK-3 channels are present in the mitochondria in both malignantly transformed and healthy cells, suggesting that they might have roles in ensuring mitochondrial functions.     

Histochemical and immunohistochemical evidence of glandular differentiation in thymic carcinoma

Eighteen cases of primary thymic carcinoma were reviewed from the viewpoint of glandular differentiation. Squamous differentiation was evident in 14 cases (83%). Immunohistochemical study revealed secretory component (SC)-positive carcinoma cells in 12 cases (67%), most of which were also associated with squamous differentiation. Three of these 12 cases contained areas with a definite glandular or microcystic structure with occasional epithelial mucin, and were diagnosed as adenosquamous carcinoma. Review of patients' medical records revealed that thymic carcinomas with a glandular element were more often resectable at surgery, and had a much better prognosis than those without a glandular element. However, further study on larger number of cases is necessary to confirm this relationship. Because SC-positive epithelial cells do exist in the non-neoplastic thymus, the presence of a glandular component suggests another direction of morphological and/or functional differentiation of thymic carcinoma cells in addition to the well-known squamous differentiation.     

Surface expression of secretory component and HLA class II DR antigen on glandular epithelial cells from human endometrium and two endometrial adenocarcinoma cell lines

The expression of secretory component (SC) by human glandular endometrial cells cultured invitro was significantly increased by estradiol in the medium. Interferon-gamma and interleukin-4 stimulated the expression of SC only in the presence of estrogen. Tumor necrosis factor-alpha plus estrogen also caused a significant increase in the number of cells expressing SC. HLA class II antigen DR was detected on few glandular epithelial cells of human endometrium cultured in control medium, whereas interferon-gamma and interleukin-4, but not tumor necrosis factor-alpha, caused significant increases in the expression of DR. Estrogen in the culture medium did not significantly affect DR expression. The human endometrial adenocarcinoma cell lines, HEC and RL-95, expressed SC in approximately 50 and 20% of the cells. Also, approximately 20% of the RL-95 cells stained for DR antigen. Interferon-gamma did not influence the degree of expression of either surface marker of the two cell lines. Cells of both lines bound polymeric IgA and IgM but showed little to no binding of monomeric IgA, IgG, or an IgM previously shown not to bind SC.     

Surfactant protein A detection in large cell carcinoma of the lung.

Large cell carcinomas of the lung are undifferentiated malignant epithelial tumors that lack cytologic features of small cell carcinoma, glandular cell carcinoma, or squamous cell differentiation. Lung surfactant protein A (SP-A) is produced by alveolar type II cells and Clara cells. Most bronchioloalveolar carcinomas of the lung react positively for SP-A. Positive SP-A staining of large cell carcinoma of the lung could indicate that at least part of these tumors have the same cellular origin or differentiation as bronchioloalveolar carcinoma. The authors determined the SP-A staining of 63 large cell carcinomas of the lung by IHC. In 20 of the 63 (32%), the tumors stained positive for SP-A. This may imply that about one third of large cell carcinomas of the lung have a similar cellular origin or differentiation as bronchioloalveolar carcinoma. The significance of this finding for prognosis and new forms of treatment remains to be determined.     

Expression of Telomerase Activity in Human Endometrium Is Localized to Epithelial Glandular Cells and Regulated in a Menstrual Phase-Dependent Manner Correlated with Cell Proliferation

Telomerase activity is observed in most malignant tumors and germ cells, whereas normal somatic cells usually do not express it. Human endometrium is composed of glandular and stromal components and exhibits dramatic changes in proliferative activity during the menstrual cycle, which is exquisitely regulated by estrogen function. We previously reported that normal human endometrium expresses telomerase activity. However, it remains unclear which of the above components are the major sources of telomerase activity and how levels of telomerase activity are regulated over the menstrual cycle. Quantitative analysis of telomerase activity revealed that it changes dramatically over the course of the menstrual cycle and is strictly regulated in a menstrual-phase-dependent manner. Maximal activity equivalent to that in endometrial cancer was present in late proliferative phase, and minimal activity in late secretory phase. Postmenopausal endometrium and endometrium treated with anti-estrogen drugs exhibited decreased telomerase activity. Testing isolated epithelial glandular cells and stromal cells, we found that telomerase activity was localized to epithelial glandular cells. In situ RNA hybridization analysis also revealed epithelial-specific expression of human telomerase RNA. In vitro analysis of cultured epithelial cells demonstrated that telomerase activity is correlated with epithelial proliferation but not affected by estrogen treatment. These findings suggest that expression of telomerase activity is specific to epithelial cells and linked to cell proliferative status. The involvement of estrogen in telomerase regulation remains to be elucidated.