Shingo Wakatsuki

Spectrum of different types of hypophysitis: a clinicopathologic study of hypophysitis in 31 cases.

Hypophysitis has been histologically classified into five types: lymphocytic hypophysitis (LYH), granulomatous hypophysitis (GRH), xanthogranulomatous hypophysitis (XGH), xanthomatous hypophysitis (XH), and necrotizing hypophysitis. The present study evaluated 31 cases of hypophysitis to clarify their characteristic clinicopathologic features. The lesions were histologically classified into four groups: LYH (22 cases) including lymphocytic adenohypophysitis (LAH) (19 cases) and lymphocytic infundibuloneurohypophysitis (LINH) (3 cases), GRH (5 cases), XGH (2 cases), and XH (2 cases). In each group, the pituitary gland showed lymphocytic infiltration associated with focal or diffuse hypophysial destruction of variable severity and fibrosis. Histologic and clinical overlap among different types of hypophysitis, especially between LAH and LINH, suggest that these entities may have similar etiologic background and/or represent different stages of the same lesion. Considering the sampling sites and clinical manifestations, LAH may not usually involve the neurohypophysis, but LINH may often extend to the adenohypophysitis. A selective loss of adrenocorticotropic hormone-positive cells was seen in two patients with LAH despite only very slight lymphoplasmacytic infiltration. This suggests that there may be at least two causative mechanisms for hypopituitarism in hypophysitis: nonspecific destruction of all types of adenohypophysical cells by severe inflammation and selective destruction of specific adenohypophysial cells.

Role of E-Cadherin, α-, β-, and γ-Catenins, and p120 (Cell Adhesion Molecules) in Prolactinoma Behavior

E-cadherin/catenin complex regulates cellular adhesion and motility and is believed to function as an invasion suppressor system. In a number of cancers, abnormal and reduced expression of E-cadherin/catenin complex is associated with tumor invasion and metastasis. Prolactinomas show frequent invasion on the surrounding structures, despite their histologically benign nature. Furthermore, gender-based differences in endocrine and surgical findings are found in patients with prolactinoma. To understand biological factors governing prolactinoma behavior, this study analyzed the expression of E-cadherin; α-, β-, and γ-catenins; p120; and cell proliferation marker MIB-1 labeling index in 13 invasive tumors (9 in men, 4 in women), 26 noninvasive tumors (4 in men, 22 in women), and 8 normal anterior pituitaries by immunohistochemistry. Immunostaining of E-cadherin; α-, β-, and γ-catenins; and p120 showed a membranous pattern of reactivity and generally stronger in normal pituitaries than in prolactinomas. Expression of E-cadherin and β-catenin was significantly lower in invasive than in noninvasive prolactinomas (P <.002 and P <.005, respectively), and reduced expression of E-cadherin and β-catenin was more frequent in invasive than in noninvasive prolactinomas (P <.001 and P <.05, respectively); in contrast, γ-catenin expression showed higher in invasive than in noninvasive prolactinomas (P <.05). Expression of E-cadherin was significantly lower in macroprolactinomas than in microprolactinomas (P <.01), and decreased expression of E-cadherin and β-catenin predicted high MIB-1 expression (P <.05). Moreover, the expression of E-cadherin and β-catenin was significantly lower in macroprolactinomas in men than in those in women (P <.01 and P <.02, respectively). No statistical correlations were observed between expression of α-catenin, p120, and clinicopathologic features. In conclusion, the reduction of E-cadherin and β-catenin expression was related to invasiveness and proliferative status of prolactinomas and correlated with the more aggressive behavior of prolactinomas in men compared with in women.

Malignant B-Lymphoid Cells with Bone Lesions Express Receptor Activator of Nuclear Factor-κB Ligand and Vascular Endothelial Growth Factor to Enhance Osteoclastogenesis

Purpose: Receptor activator of nuclear factor-κB ligand (RANKL) is a key mediator of osteoclastogenesis. Because certain types of tumor cells aberrantly express RANKL, and because bone destruction also develops in B-cell lymphomas of bone origin, we investigated RANKL expression and the mechanisms of osteoclastogenesis in B-lymphoid neoplasms. Experimental Design and Results: Immunohistochemistry of bone specimens resected from patients with primary B-cell lymphoma of bone with bone destruction revealed that lymphoma cells express RANKL as well as vascular endothelial cell growth factor (VEGF). The tumor cells isolated from the bone specimens enhanced osteoclastogenesis in vitro. In contrast, B-cell lymphoma infiltrating to the bone marrow without bone destruction did not express RANKL. Both RANKL and VEGF were expressed by a portion of B-lymphoid cell lines, including Daudi and IM-9. These RANKL-expressing tumor cells enhanced osteoclastogenesis from RAW264.7 cells and human monocyte-derived preosteoclasts in the absence of stromal cells/osteoblasts in a RANKL-dependent manner. Furthermore, conditioned media from Daudi cells enhanced transmigration of preosteoclasts that was inhibited by anti-VEGF antibody, suggesting that tumor cell–derived VEGF mediates recruitment of osteoclast precursors. Moreover, cocultures of B-lymphoid cell lines with osteoclasts enhanced the growth of B-lymphoid cells. Conclusions: Some malignant B cells aberrantly express functional RANKL as well as VEGF to enhance osteoclastogenesis. The coexpression of RANKL and VEGF may also contribute to the close cellular interactions with osteoclastic cells, thereby forming a vicious cycle between osteoclastic bone destruction and tumor expansion in bone.

Esophageal xanthoma: report of two cases and a review of the literature.

Abstract  So far, three cases of esophageal xanthoma have been reported. We describe here endoscopic, microscopic and immunohistochemical findings of two new cases of this rare condition, and a review of five cases of esophageal xanthoma, including our cases. Esophageal xanthomas endoscopically show yellow granular spots or a slightly elevated lesion, and are similar to an ectopic sebaceous gland. Microscopically, an aggregate of foamy histiocytes (lipid islands) is seen immediately beneath the squamous epithelium, particularly between the rete ridges. Immunohistochemically, xanthoma cells are positive for CD68, which indicate a histiocytic origin. The etiology of esophageal xanthoma remains unclear. We emphasize that esophageal xanthomas may have been erroneously diagnosed as an ectopic sebaceous gland on endoscopic examination.

Gallbladder Adenocarcinoma with Florid Neuroendocrine Cell Nests and Extensive Paneth Cell Metaplasia

We report a unique case of gallbladder adenocarcinoma associated with florid neuroendocrine cell nests and extensive Paneth cell metaplasia that has not been described previously. The patient was a 79-yr-old woman with a pedunculated, polypoid mass in the gallbladder. Microscopically, the mass was composed of tumor cells showing tubular and papillary growth patterns, consistent with well-differentiated adenocarcinoma. One-third or more of the tumor cells showed Paneth cell appearance. Goblet cell-type tumor cells were also intermingled. In addition, neuroendocrine cell nests, that were connected to the neoplastic glands, were scattered throughout the stroma. Immunohistochemically, the labeling index of MIB-1 in adenocarcinoma cells including Paneth cell-type carcinoma cells was approx 40%. Neuron-specific enolase, chromogranin A, and synaptophysin were positive in the neuroendocrine cells forming solid nests and intermingled within neoplastic glands. They were immunopositive for serotonin but negative for insulin, glucagon, somatostatin, and pancreatic polypeptide (PP). Although MIB-1-positive neuroendocrine cell nests were very few with weak staining, we think that the neuroendocrine cell nests were neoplastic in nature. The formation of the multifocal neuroendocrine nests may be a consequence of the trophic effects of unknown substance(s), which can promote serotonin-producing neuroendocrine cells to proliferate. We postulate that Paneth cell-type carcinoma cells may be intimately related to such substance(s) in our case.

Primary adult T-Cell leukemia/lymphoma of bone

A 77-year-old man developed primary adult T-cell leukemia/lymphoma (ATL) of the bone with osteolytic lesions. A biopsy of the lesion revealed proliferation of atypical, large lymphoid cells with a local increase of ostcoclasts. The clonal integration of human T-lymphotropic virus type I proviral DNA revealed the tumor cells to be ATL. They produced macrophage inflammatory protein 1 a (MIP-1 α) but not parathyroid hormone-related protein or other osteoclast-activating factors. Because MTP-1 produced by tumor cells enhances the expression of receptor activator of nuclear factor κB ligand (RANKL) of local osteoblasts and stromal cells, even of tumor cells, the increase of osteoclasts in the close vicinity of ATL cells was considered to result in local bone destruction.

Thrombopoietin-responsive essential thrombocythaemia with myelofibrosis

Platelet‐derived growth factor (PDGF) and other cytokines released from megakaryocytes are thought to play a crucial role in the pathogenesis of myelofibrosis. We describe a patient with essential thrombocythaemia (ET) who developed myelofibrosis with an increased level of serum thrombopoietin (TPO). Recombinant human (rh) TPO stimulated the proliferation and spontaneous megakaryocyte colony formation of the neoplastic cells in the peripheral blood. Moreover, serum concentrations of PDGF, platelet factor 4, and β‐thromboglobulin were elevated and the production of these growth factors from the megakaryocyte progenitors was augmented with the addition of rhTPO in vitro. These results indicate that TPO may contribute to the development of myelofibrosis in ET.

Fas ligand-induced apoptosis of hepatocytes in natural killer cell leukaemia.

Neoplastic natural killer (NK) cells overexpress Fas ligand (FasL), which may cause damage of Fas‐bearing tissues. We report a patient with NK cell leukaemia who developed liver injury after pharyngitis. The NK leukaemic cells expressed functional FasL. In addition to soluble FasL, serum levels of interleukin‐6 and interferon‐γ were increased dramatically when liver injury was aggravated. Moreover, hepatocytes expressed Fas and apoptotic hepatocytes were detected in the portal areas. These findings are consistent with the notion that inflammatory cytokines enhance the sensitivity to FasL and trigger apoptosis of hepatocytes in NK cell malignancies.

Vasitis nodosa: immunohistochemical findings--case report.

We report the immunohistochemical features of vasitis nodosa and discuss the differential diagnosis. The patient was a 42‐year‐old Japanese man with bilateral small indurations of the vas deferens at the site of a previous vasectomy. Microscopically, small‐sized ducts proliferated within the muscular wall of the vas deferens, and focally in the surrounding connective tissue. Immunohistochemically, most proliferating glandular cells were strongly positive for cytokeratins 7, 19, and 34βE12, and vimentin. Epithelial membrane antigen and Leu‐M1 reacted against the luminal surface of the cells. Focally, glandular cells were also positive for CA125. Cytokeratin 20, carcinoembryonic antigen, and prostate‐specific antigen were negative. We discuss the immunohistochemical differentiation of vasitis nodosa from prostatic adenocarcinoma, adenocarcinoma of the rete testis, and adenomatoid tumor.

Abnormal venous structures in salivary gland tumors: vasculature characteristics of pleomorphic adenoma.

To clarify the diagnostic significance of abnormal venous structures present in salivary gland tumors, we examined 21 pleomorphic adenomas, 14 Warthin tumors, 1 oncocytic adenoma, 3 myoepitheliomas, 7 basal cell adenomas, 5 mucoepidermoid carcinomas, and 6 adenoid cystic carcinomas. Verhoeff‐van Gieson staining was carried out and the morphology of the veins within the tumors was observed microscopically. Branching veins, thickened intima of the veins, discontinuous elastic membrane and multilayered elastic membrane were seen in 71.4%, 76.2%, 47.6% and 85.7% of pleomorphic adenomas, respectively, and were abundant and easily found in most cases. The abnormal venous structures were also found in other salivary gland tumors examined, but they were few in number and lacked variety. Elastic fibers extending radially into the surrounding stroma were seen in 66.7% of pleomorphic adenomas, and were not seen in other salivary gland tumors. Our results showed that a variety of abnormal venous structures are more abundant and more easily found in pleomorphic adenoma compared with other salivary gland tumors, and, in particular, that perivascular radiating elastic fibers are characteristic of pleomorphic adenoma. We emphasize that the presence of perivascular radiating elastic fibers may be helpful in diagnosing pleomorphic adenoma in small biopsy specimens.