Large cell neuroendocrine carcinoma of the tongue base: case report of an unusual location with immunohistochemical analysis.

A case of large cell neuroendocrine carcinoma (LCNEC) of the tongue base is described. It was characterized by solid tumor nests with central necrosis and rosette formation resembling basaloid squamous cell carcinoma. Immunohistochemical examination revealed that this tumor had neuroendocrine differentiation. It was diagnosed as LCNEC of the tongue base. Pulmonary LCNEC is a well-established entity, but LCNEC also occurs in other organs. This is the first report of mucosal LCNEC in the oral cavity. Basal cells in the normal squamous epithelium around the tumor indicated positivity for neural cell adhesion molecule and N-cadherin. These cells were considered neuroendocrine-related cells in the lingual squamous epithelium, which are related to the tumorigenesis of mucosal LCNEC in the tongue base.

Immunohistochemical localization of members of the transforming growth factor (TGF)-beta superfamily in normal human salivary glands and pleomorphic adenomas.

Although pleomorphic adenoma is the most common type of salivary gland epithelial tumor, it frequently contains "mesenchymal"-like components, including myxoid or chondroid tissues. We reported previously that chondroid tissue formation in pleomorphic adenoma was associated with overexpression of bone morphogenetic proteins (BMPs) by neoplastic myoepithelial cells. BMPs belong to the transforming growth factor (TGF)-beta superfamily, so we hypothesized that pleomorphic adenoma may express TGF-betas and that these molecules may regulate mesenchymal-like tissue formation. To evaluate this hypothesis, we immunohistochemically examined TGF-beta1, -beta2 and -beta3 expression and localization in normal salivary glands and in 43 cases of pleomorphic adenomas. There was no evidence of TGF-beta1 expression in normal salivary glands or pleomorphic adenomas. Signals for TGF-beta2 in the normal salivary glands were observed in the intercalated ducts, while in pleomorphic adenomas they were observed in the inner ductal cells of the tubulo-glandular structures. Signals for TGF-beta3 in the normal salivary glands were observed in mucous cells, whereas in pleomorphic adenomas they were observed in the solid nests of neoplastic myoepithelial cells, in the portion showing squamous metaplasia, and in the inner ductal cells of tubulo-glandular structures. TGF-betas induce ectopic cartilage formation in vivo, but chondroid tissues in pleomorphic adenomas showed only weak TGF-beta3 expression. TGF-beta may be related to differentiation of the inner ductal cells and the neoplastic myoepithelial cells. In conclusion, pleomorphic adenomas expressed TGF-beta2 and -beta3, which may be associated with differentiation of the inner ductal cells and neoplastic myoepithelial cells.

Ossification of tracheal cartilage in aged humans: a histological and immunohistochemical analysis.

Tracheal cartilage has been considered as permanent cartilage without endochondral ossification. We examined ossification of the tracheal cartilage in 25 adults (mean age 67.8 years; range 20-87 years; male:female = 17:8). Thirteen cases (52%) demonstrated ossification of the tracheal cartilage, accompanied by the formation of lamellar bones with fatty bone marrow. Ossification was observed at the lateral peripheral region of the tracheal cartilage, while vascular invasion into the cartilage was seen even where no ossification was present. Twenty-two cases (88%) showed marked hyalinization in the central region of the tracheal cartilage. Type II collagen was immunolocalized in the cartilage matrix, except for in the central hyalinized area, while type I collagen was immunolocalized around the perichondrium and ossified areas in the tracheal cartilage. Type X collagen immunolocalized on territorial matrices around the lacunae near the ossified regions. These results suggest that tracheal cartilage in aged humans frequently ossifies physiologically, and that aging promotes osteogenesis, even in permanent cartilage.

Cartilage-specific matrix protein chondromodulin-I is associated with chondroid formation in salivary pleomorphic adenomas: immunohistochemical analysis.

Chondromodulin-I (ChM-I) is a novel cartilage-specific matrix protein. In the growth plates of the long bones, ChM-I was shown to be expressed in mature to upper hypertrophic chondrocytes, and to be deposited in the cartilage matrix. As ChM-I strongly inhibits angiogenesis, cartilage is avascular. Also, ChM-I has bifunctional activity against chondrocyte proliferation. On the other hand, pleomorphic adenomas of the salivary glands frequently have chondroid elements. To elucidate the relationship between chondroid formation and hypovascularity in salivary pleomorphic adenomas, we immunohistochemically examined the expression and localization of ChM-I in 35 cases of this tumor. ChM-I was immunolocalized to the lacunae in the chondroid elements of pleomorphic adenomas (100%). Type II collagen and aggrecan were immunolocalized throughout the matrix around lacuna cells of the chondroid element (100%, 91.7%), and ChM-I was infrequently immunolocalized to the spindle-shaped myoepithelial cells in the myxoid element (37.5%). Fibroblast growth factor-2 was strongly immunolocalized to the lacuna cells in the chondroid element (100%), among the neoplastic myoepithelial cells in the myxoid elements (96.9%), and on the basement membranes around the solid nests of neoplastic myoepithelial cells (71.4%). Although CD34 is a marker of endothelial cells, CD34 was expressed in the endothelial cells in only a few areas around the epithelial elements and in the fibrous element of pleomorphic adenomas. No signals for CD34 were observed in chondroid elements in pleomorphic adenomas (P < 0.001), but a few signals were seen in the myxoid elements (P < 0.05). These findings suggested that lacuna cells and neoplastic myoepithelial cells expressed ChM-I, and that this molecule may play an important role in hypovascularity and chondroid differentiation in pleomorphic adenoma. In conclusion, pleomorphic adenoma expressed ChM-I, which is involved in hypovascularity and chondroid formation in this type of tumor.

An immunohistochemical study of the mesenchymal and epithelial components of pulmonary chondromatous hamartomas.

Twenty-five cases of solitary pulmonary chondromatous hamartomas (PCH) were examined by immunohistochemistry to evaluate the mesenchymal and epithelial components. PCH composed of predominantly mature cartilage were designated as C type, those predominantly composed of fibromyxoid tissue as FM type, and those predominantly composed of adipose tissue as A type. FM type PCH revealed various amounts of cartilage in various developmental stages, adipose tissue and fibromyxoid tissue, compared with a uniform pattern of cartilage tissue in C type. The cells of transitional form between spindle cells, stellate cells and chondrocytes were present in FM type. Epithelial components in PCH were bronchial, bronchiolar and cuboidal cells, mostly at the periphery of PCH. S-100 protein consistently stained chondrocytes, stellate and spindle cells in the fibromyxoid tissue of solitary PCH. Fibroblast growth factor was immunolocalized to chondrocytes, spindle and stellate cells in the fibromyxoid tissue. The collagen type was associated with differentiation from primitive mesenchymal cells to chondrocytes (i. e. type I and III collagen appeared in fibromyxoid matrix and type II collagen in the cartilaginous matrix). Fibronectin coordinately appeared with type I and III collagens. The proliferating cell nuclear antigen labeling index of epithelial cells was comparable to those of neoplastic mesenchymal cells, but it was not significantly different between C type and FM type PCH. The primitive mesenchymal cells in the bronchial walls of the control premature neonates were also observed. This immunohistochemical study showed that the progenitor mesenchymal cells in the bronchial and bronchiolar walls may differentiate along chondrocytes, lipocytes, and smooth muscle cells in PCH and that epithelial proliferation is reactive and closely associated with neoplastic proliferation of the mesenchymal component.

Expression of bone matrix proteins, osteonectin and osteopontin, in salivary pleomorphic adenomas.

Osteonectin (OSN) is a glycoprotein involved in the early steps of the mineralization of skeletal tissue, while osteopontin (OPN) is a protein involved in normal and pathological calcifications. OSN and OPN are non-collageneous bone matrix proteins expressed by some epithelial tumor cells in exceptional cases. We immunohistochemically investigated the presence and the distribution of OSN and OPN in 43 pleomorphic adenomas to elucidate the production of their molecules by modified myoepithelial cells. In normal salivary glands, OSN was immunolocalized in the striated ducts, while OPN was not expressed. In pleomorphic adenomas, the inner layer of tubulo-glandular structures and modified myoepithelial cells in the myxoid areas showed moderate positivity for OSN (83.7%). OSN was expressed in all of the lacuna cells in the chondroid areas. OPN was strongly expressed in the stroma of the myxoid and hyaline areas of the pleomorphic adenomas (65.1%), but there was no expression of OPN in the chondroid area. All cases of pleomorphic adenomas expressed type IV collagen. These findings suggested that OSN was related to the production of the type IV collagen by modified myoepithelial cells, whereas OPN was involved in the stromal formation of myxoid or hyaline tissues in pleomorphic adenomas. In summary, pleomorphic adenomas expressed the bone matrix proteins OSN and OPN.

Immunohistochemical localization of the bone morphogenetic protein-6 in salivary pleomorphic adenomas.

Salivary pleomorphic adenomas are often associated with chondroid tissue formation. We have found that bone morphogenetic proteins (BMP), especially BMP-2, may play an important role in ectopic chondrogenesis in this tumor. Bone morphogenetic protein-6 was reported to be related to the osteogenic metastasis of prostatic carcinomas. The relationship between BMP-6 expression and chondroid tissue formation is investigated. Twenty-three pleomorphic adenomas were examined immunohistochemically. The overexpression of BMP-6 was observed in 10 pleomorphic adenomas of the major salivary glands (43. 5%), and no evidence of BMP-6 expression in any of the nine pleomorphic adenomas of the palate. Bone morphogenetic protein-6 was immunolocalized in the lacuna cells of the chondroid tissue, in which type II collagen was localized. Bone morphogenetic protein-6 was expressed in inner ductal cells of the tubulo-glandular structures in the pleomorphic adenomas. This finding indicates that BMP-6 may be associated with the differentiation of inner ductal cells. Bone morphogenetic protein-6 was expressed weakly in neoplastic myoepithelial cells in the myxoid areas, which may be related to the production of extracellular matrices. Bone morphogenetic protein-6 has a role in chondroid formation, and also tubulo-glandular differentiation in pleomorphic adenomas. In conclusion, a large portion of pleomorphic adenomas of the salivary gland origin, but not of palate origin, was shown to overexpress BMP-6 protein.

Immunohistochemical localization of fibroblast growth factors (FGFs) and FGF receptor-1 in human normal salivary glands and pleomorphic adenomas.

Basic and acidic fibroblast growth factors (bFGF and aFGF) are heparin-binding growth factors, and promote fibrogenesis and angiogenesis. We investigated the immunohistochemical localization of bFGFE, aFGF, and FGF receptor-1 in pleomorphic adenomas. In the normal salivary glands, bFGF was localized in the basement membranes of intercalated ducts, acini and basal cells of the excretory ducts, while aFGF was localized focally in the intercalated ductal cells and basal cells of the excretory ducts. In pleomorphic adenomas, bFGF was immunolocalized in the basement membranes around the solid nests of myoepithelial cells, around the neoplastic myoepithelial cells in the myxoid areas, and in the lacuna cells in the chondroid areas. In contrast, chondroid areas exhibited no immunoreactivity with aFGE. Positive signals for aFGF were localized in luminal cells of the tubuloglandular structures in pleomorphic adenomas. FGF receptor-1 immunolocalized in the lacuna cells and myoepithelial cells in the solid and myxoid areas. These observations suggest that bFGF and FGF receptor-1 produced by myoepithelial cells inhibited terminal differentiation and enchondral ossification in pleomorphic adenomas. These results also suggest important roles for FGFs in the formation of various structures with mesenchymal-like histology.

Expression of bone morphogenetic proteins in salivary pleomorphic adenomas.

Salivary pleomorphic adenomas are often associated with chondroid tissue formation. We investigated the relationship between chondroid tissue formation and the expression of bone morphogenetic proteins (BMPs), which are strong inducers of ectopic bone and cartilage formation. Fifteen pleomorphic adenomas and seven normal salivary glands were examined genetically and immunohistochemically. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that BMP-1, BMP-2, BMP-3, BMP-4, and BMP-7 mRNAs were overexpressed in 10 (66.7%), 9 (60.0%), 1 (6.7%), 8 (53.3%), and 12 (80.0%), respectively, of the 15 pleomorphic adenomas. Overexpression of BMP-2 mRNA was observed in pleomorphic adenomas. Marked chondroid formation or expression of type II collagen was frequently observed in pleomorphic adenomas that overexpressed BMP-2 mRNA. Immunohistochemically, BMP-2 was detected in modified myoepithelial cells aroud chondroid tissue and basement membranes. These results suggest that BMPs, and expecially BMP-2, have a role in chondroid formation in pleomorphic adenomas.

Composite carcinoid-adenocarcinoma tumor of the stomach: report of a case.

We describe herein the case of an extremely unusual composite carcinoid-adenocarcinoma tumor of the stomach, most of which was found to be carcinoid. The carcinoid tumor component exhibited argyrophilic granules, immunohistochemical localization of chromogranin, and serotonin immunoreaction. Conversely, none of the adenocarcinoma component reacted with argyrophilia, chromogranin, or serotonin. DNA flow cytometric analysis revealed a near-diploid pattern in the carcinoid element and an aneuploid pattern in the adenocarcinoma element. The transitional zone and continuity between the two tumor components were observed. These findings suggest that the tumor originated from the endocrine system, although part of it showed nonendocrine differentiation. The patient died approximately 6 months after the onset of symptoms and an autopsy could not be performed.

[Expressions of oncogene products in adenoid cystic carcinomas of salivary glands: immunohistochemical study].

In 43 cases of adenoid cystic carcinomas of the salivary glands (ACC), expressions of the oncogene products such as epidermal growth factor receptor (EGF-R), erbB-2 product, c-myc product and N-myc product were investigated immunohistochemically. First, we confirmed the specificity of the antibodies used with the 13 cell lines. Of the anti-EGF-R antibodies, clone 29. 1. 1 reacted only with A431 but not with the other cell lines overexpressing EGF-R, so that it was most likely to cross-react with the blood type A antigen. Also, the anti-N-myc product antibody revealed the presence of a certain cross-reacting antigen in Lu65. Overexpression of EGF-R was observed in only one case. Nine cases (20.9%) showing tubular and cribriform patterns overexpressed the erbB-2 product, but the signals were mainly localized in the cytoplasm as a granular appearance. Eighteen cases (41.9%) with slight cellular atypia showed an overexpression of the c-myc product. The immunolocalization of the c-myc product was at the nuclei in most cases, or both the nuclei and the cytoplasm in some cases. None of the ACC expressed the N-myc product. It is speculated that the multiple oncogene expressions might be partly related to the acquirement of the differentiated or malignant phenotype in the ACC.

Hepatic involvement in graft-versus-host disease associated with blood transfusion.

A 73-year-old man developed graft-versus-host disease (GVHD) after blood transfusion; he developed hepatitis, fever, rash, and pancytopenia. Although similar cases have been previously reported, the spectra of their liver injury was not clarified. The clinical and pathological findings of this case and a review of earlier reports suggest a possible predominance of hepatocellular injury in cases of GVHD after blood transfusion, which is in contrast to the prevalence of cholestatic liver disease in GVHD following bone marrow transplantation.