Kenji Sano

Protocadherins: a large family of cadherin-related molecules in central nervous system.

Using the polymerase chain reaction, we have isolated numerous rat and human cDNAs of which the deduced amino acid sequences are highly homologous to the sequences of the extracellular domain of cadherins. The entire putative coding sequences for two human proteins defined by two of these cDNAs have been determined. The overall structure of these molecules is very similar to that of classic cadherins, but they have some unique features. The extracellular domains are composed of six or seven subdomains that are very similar to those of cadherins, but have characteristic properties. The cytoplasmic domains, on the other hand, have no significant homology with those of classic cadherins. Since various cDNAs with almost identical features were obtained also from Xenopus, Drosophila and Caenorhabditis elegans, it appears that similar molecules are expressed in a variety of organisms. We have tentatively named these proteins protocadherins. They are highly expressed in brain and their expression appears to be developmentally regulated. The proteins expressed from the two full‐length cDNAs in L cells were approximately 170 or 150 kDa in size, and were localized mainly at cell‐cell contact sites. Moreover, the transfectants showed cell adhesion activity.

Cloning of five human cadherins clarifies characteristic features of cadherin extracellular domain and provides further evidence for two structurally different types of cadherin

The entire coding sequences for five possible human cadherins, named cadherin-4, -8, -11, -12 and -13, were determined. The deduced amino acid sequences of cadherin-4 and cadherin-13 showed high homology with those of chicken R-cadherin or chicken T-cadherin, suggesting that cadherin-4 and cadherin-13 are mammalian homologues of the chicken R-cadherin or T-cadherin. Comparison of the extracellular domain of these proteins with those of other cadherins and cadherin-related proteins clarifies characteristic structural features of this domain. The domain is subdivided into five subdomains, each of which contains a cadherin-specific motif characterized by well-conserved amino acid residues and short amino acid sequences. Moreover, each subdomain has unique features of its own. The comparison also provides additional evidence for two structurally different types of cadherins: the first type includes B-, E-, EP-, M, N-, P- and R-cadherins and cadherin-4; the second type includes cadherin-5 through cadherin-12. Cadherin-13 lacks the sequence corresponding to the cytoplasmic domain of typical cadherins, but the extracellular domain shares most of the features common to the extracellular domain of cadherins, especially those of the first type of cadherins, suggesting that cadherin-13 is a special type of cadherin. These results, and those of other recent cloning studies, indicate that many cadherins with different properties are expressed in various tissues of different organisms.

A case of von Recklinghausen's disease with bilateral pheochromocytoma-malignant peripheral nerve sheath tumors of the adrenal and gastrointestinal autonomic nerve tumors.

A 48-year-old man with neurofibromatosis type 1 presented with chest pain, paroxysmal hypertension, tachycardia, and progressive respiratory insufficiency. Clinical investigation displayed calcified tumors in the anterior mediastinum and pararenal region. Histological examination at autopsy revealed composite tumors consisting of pheochromocytoma and malignant peripheral nerve sheath tumor (MPNST) at two sites: the left adrenal gland and the region surrounding the inferior vena cava, probably corresponding to the right adrenal gland. The MPNST component showed a varied histological appearance, including hyalinized bands with polygonal cells, a cartilaginous and myxoid stroma, a hemangiopericytomatous architecture, and a fibrosarcomatous structure, which suggested osteosarcoma, chondrosarcoma, angiosarcoma, and fibrosarcoma, respectively. In addition, based on the ultrastructural findings, the gastrointestinal tract was involved with mesenchymal tumors showing neurogenic differentiation. These lesions suggest the divergent cellular differentiation of neural crest-derived cells to mesenchymal elements as well as neuroectodermal neoplasms.

Sebaceous Epithelial-myoepithelial Carcinoma of the Salivary Gland: Clinicopathologic and Immunohistochemical Analysis of 6 Cases of a New Histologic Variant

Epithelial-myoepithelial carcinoma (EMC) of the salivary glands is an uncommon, low-grade malignant tumor. A recent report demonstrates sebaceous differentiation in this tumor even though its significance has never been documented as a precise histologic variant. Six cases of EMC exhibiting sebaceous differentiation (sebaceous EMC) of the parotid gland were analyzed for their clinicopathologic features and immunohistochemical characteristics. In addition, primary salivary sebaceous carcinomas were also examined for comparison. In our series, the incidence of sebaceous EMC was 0.2% among 3012 cases of parotid gland tumors and 14.3% of all EMC cases. The 6 patients comprised 2 men and 4 women, age ranging from 77 to 93 years (mean, 83.7u2009y). Neither cervical lymph node nor distant organ metastases were found in any cases of sebaceous EMC and no patients died of disease, though local recurrences developed in 1 patient. Conversely, cervical lymph node metastasis was detected in 2 of 3 patients with sebaceous carcinoma, 1 of whom died of disease at 12 months. Histologically, all 6 tumors had an area of sebaceous differentiation admixed with features of bilayered ductal structures typical of EMC. A component of sebaceous differentiation was distributed diffusely in 4 tumors and focally in 2. Cytologic atypia of sebaceous EMCs was lesser than that of sebaceous carcinomas. Immunohistochemically, putative myoepithelial markers such as α-smooth muscle actin, calponin, p63, cytokeratin 14, S-100 protein, and vimentin were highly expressed in sebaceous EMC. However, the expression of the latter 4 markers was also observed in primary sebaceous carcinomas, whereas these tumors were all negative for α-smooth muscle actin and calponin. Positive immunoreactivity for epithelial membrane antigen, adipophilin, and perilipin confirmed sebaceous differentiation in EMC. These results indicate that sebaceous EMC is a low-grade malignancy, similar to conventional EMC. Our data also suggest that immunohistochemical examination of specific myoepithelial markers is helpful in distinguishing sebaceous EMC from sebaceous carcinoma, which may occasionally be associated with an aggressive clinical course.

Improved detection of medically important fungi by immunoperoxidase staining with polyclonal antibodies

This study was performed to identify pathological fungi of eight species [Aspergillus fumigatus, Candida albicans, Torulopsis (Candida) glabrata, Cryptococcus neoformans, Fusarium anthophilum, Rhizopus oryzae, Sporothrix schenckii and Trichosporon beigelii] in formalin-fixed, paraffin-embedded tissue sections by indirect immunoperoxidase staining. Mature albino rabbits were immunized with formalin-killed organisms. Antibodies were prepared by precipitation. Immunoperoxidase staining was applied to the paraffin-embedded tissue sections of experimentally infected mice and human autopsy and surgical specimens. Although the cell walls of each fungus stained clearly, many cross-reactivities appeared. However, it was possible to obtain specificity for the eight species by absorption and dilution of the antisera.

Intussusception of the appendix: A report of three cases with different clinical and pathologic features

Three cases of intussusception of the appendix (IA) with distinctive pathologic changes were reported. All patients were women with different clinical presentations. Grossly, a complete intussusception was found in one case (case 1), while the others (cases 2 and 3) showed a partial intussusception. In case 1, almost the total segment of the appendix bearing the villous adenoma with focal malignant transformation became completely telescoped into the cecum. In case 2, no underlying appendiceal lesion was disclosed. In case 3, appendiceal endometriosis was found as the point of traction. Awareness of such a rare complication associated with various appendiceal lesions provides a clue for making an accurate diagnosis and selecting appropriate surgical management.

Intravascular granuloma induced by intravenous inoculation of Cryptococcus neoformans

In rodents an intravenous administration of viableCryptococcus (C.) neoformans cells frequently resulted in attachment of intravascular cryptococcal granulomas to inner walls of the large to medium-sized veins of various organs, including the lungs, liver and spleen. In order to elucidate the pathogenesis of granulomatous changes, the cells composing the intravascular granulomas were observed by electron microscopic peroxidase (PO) cytochemistry. The granuloma composing cells could be divided into the following four types according to the pattern of endogenous peroxidase activity: exudate macrophage (Mφ, type I), PO-negative Mφ (type II), resident Mφ (type III) and other inflammatory cells (type IV). In the intravenous granulomas of the lung, the percentages of composed cells were 39.0% for type I, 57.9% for type II, 0% for type III and 3.1% for type IV. By contrast, in the interstitial granulomas in the lung, type III Mφs, possibly derived from alveolar Mφs, played a significant role in granuloma formation. This may indicate that the intravascular granuloma is almost composed of macrophages derived from monocytes rather than alveolar macrophages. The expression of ICAM-1 on endothelia of the pulmonary veins was examined by immunoelectron microscopy. An immunogold labeling index was significantly augmented on the surface of endothelia in response to intravenous challenge ofC. neoformans. The intravascular granuloma demonstrates that the monocytes develop into the granuloma-composing macrophages and suppress the cryptococcal activities even hi the peripheral blood resulting in an assistance of endothelial functions.

Macrofollicular variant of papillary thyroid carcinoma

A rare case of a macrofollicular variant of papillary thyroid carcinoma occurring in an 18‐years‐old male is described. The extirpated tumor, 5.5 × 5.5 × 3.5 cm In size, was well demarcated and multinodular, and histopathologically showed a predominantly macrofolllcular structure reminiscent of adenomatous goiter or macrofollicular adenoma. In the tumor tissue, however, there were several small foci of microfollicular or paplllary structure with the nuclei charae teristic of papillary carcinoma. Parts of the macrofollicular areas also showed similar nuclear characteristics with a transition to microfollicular or papillary areas. Incomplete capsular invasion and minimal vascular invasion were also present. Additional resected specimens contained small metastatic nodules in the residual left lobe and lymph nodes. Immunohistochemistry showed a small number of p53‐positive tumor cells in the microfollicular or papillary areas. It is suggested that this tumor is a well‐differentiated variant which should be distinguished from benign thyroid lesions, although there have been some cases of metastases which appear related to capsular and/or vascular invasion.

Immunohistochemical, Electron Microscopic, and Immunoelectron Microscopic Features of Plasmacytoma of the Thyroid with Amyloid Deposition

A rare case of primary plasmacytoma of the thyroid with amyloid deposition is reported. The tumor consisted of diffuse proliferation of atypical plasma cells showing IgG lambda-type monoclonal growth. Amyloid deposition with focal giant cell reaction was also observed. Bone marrow aspiration and systemic skeletal radiographic surveys revealed no evidence of multiple myeloma and myelomatosis. Radial arrangement of amyloid bundles was observed ultrastructurally. By immunoelectron microscopic examination, lambda chain was detected in the amyloid fibrils and rough endoplasmic reticulum of the tumor cells. Our findings suggest the following: amyloid fibrils originate from monoclonal light chains produced by tumor cells, and histiocytes contribute to amyloid deposition as well as to giant cell reaction in extramedullary plasmacytoma.