Pathology International

Fukuda, Toshio; Ichimura, Eiji; Shinozaki, Tetsuya; Sano, Takaaki; Kashiwabara, Kenji; Oyama, Tetsunari; Nakajima, Takashi; Nakamura, Toshikazu

doi: 10.1111/j.1440-1827.1998.tb03834.xpmid: 9788258

To understand the interaction between hepatocyte growth factor (HGF) and its receptor c‐Met on various bone and soft tissue tumors, their expressions were investigated by western blot analysts, immunohistochemistry and enzyme immunoassay. Western blot analysis revealed that c‐Met protein was expressed in 21 (38.8%) of 54 tumors, which detailed to seven (25.9%) of 27 bone tumors and 14 (51.8%) of 27 soft tissue tumors. Most malignant fibrous histiocy‐tomas (MFH) and all neurofibromas expressed c‐Met protein. The highest expression of c‐Met protein was seen in a case of biphasic synovial sarcoma, where its immunoreac‐tivity was localized only on the epithelial component and not on the sarcomatous component. By enzyme immunoassay for HGF, all but one MFH showed HGF production and the mean level of HGF was the highest among the tumors investigated. Neurofibmmas and osteosarcomas had the next highest mean levels of HGF production, respectively. Coexpression of HGF and c‐Met was obsewed in 19 (35.2%) of 54 tumors and was frequently observed in neurofibroma, followed by MFH and synovial sarcoma. Although the mode of interaction between HGF and c‐Met varies among the various bone and soft tissue tumors including MFH, their signaling system may play an Important role in the development and progression of bone and soft tissue tumors.

Oyama, Tetsunari; Ichimura, Elji; Sano, Takaaki; Kashiwabara, Kenji; Fukuda, Toshio; Nakajima, Takashi

doi: 10.1111/j.1440-1827.1998.tb03835.xpmid: 9788259

It has become clear that papillary carclnomas of the thyroid often express the receptor for c‐Met/hepatocyte growth factor (HGF) receptor, but little Is known about the role of the HGF and c‐Met system In the pathogenesis of thyroid carcinoma. In this study, the expression of c‐MeUHGF receptor was evaluated in thyroid tlssue by western blot and immunohistochemistry, and compared with the concentration of HGF. Clinicopathologlcal characteristics were also compared. Fmeen of 20 papillary Carcinomas (75%) showed eMet bands of 145 kDa. No or only a low frequency of c‐Met expression was detected in healthy thyroid tissue (0/5), thyroiditis or Basedow's disease (0/2), adenomatous goiters (0/8), follicular adenomas (119, 11%) and undifferentiated carcinomas (0/2). These results were confirmed by immunohistochemistry, but a relatively higher frequency of c‐Met expression was detected in adenomatous goiters (25%), follicular adenoma (44%) ancl papillary Carcinoma (100%) using formalin‐fixed and paraffin‐embedded materials. A strong immunoreaction for c‐Met was observed In the tumor cytoplasm of paplllary carcinomas among the fibrous tissues situated at the perlphery of the tumor. The densito‐metrically measured expression of c‐Met had no relation to tumor stage in papillary carcinoma, but did correlate to the concentration of HGF in papillary carcinomas. In conclusion, in thyroid lesions, c‐Met was highly expressed specifically in the cytoplasm of papillary carcinomas. c‐Met expression was not related to the aggressiveness of the tumor but was related to the concentration of HGF, which was probably derived from the stroma. Also, the c‐Met system might play a role in the pathogenesis of papillary carcinoma of the thyroid.

Motoi, Toru; Ishida, Tsuyoshi; Kuroda, Masahiko; Horiuchi, Hajime; Oka, Teruaki; Matsumoto, Kunio; Nakamura, Toshikazu; Machinami, Rikuo

doi: 10.1111/j.1440-1827.1998.tb03836.xpmid: 9788260

Hepatocyte growth factor (HGF) is a heterodlmeric polypep‐tide growth factor that has pleiotropic roles, Including those of mitogen, motogen and morphogen. The HGF receptor Is characterized as a c‐Met proto‐oncogene product (c‐Met), which is a heterodimeric tyrosine kinase receptor. Hepatocyte growth factor acts as a mediator between the mes‐enchymal and epithelial tissues because HGF is produced by mesenchymal cells and c‐Met is mainly expressed on various epithelial cells. Furthermore, the HGF/c‐Met system plays an important role in embryogenesis and the regeneration of various organs. Synovial sarcoma (SS) are unique sarcoma that show epithelial differentiation, but little is known about their histogenesis. The expression of HGF and c‐Met was examined by immunohlstochemlstry In SS specimens from 12 patients (six each of biphasic and monopha‐sic fibrous types). lmmunohistochemical coexpression of HGF and c‐Met was demonstrated in the epithelial component of five biphasic SS, while only c‐Met was expressed in the epithelioid nests of three monophasic fibrous SS. The spindle cell component was negative for HGF and c‐Met. In SS, positivity for epithelial markers, such as cytokeratins and epithelial membrane antigen, was diffusely observed in the epithelial component and was focally observed In spindle cells, while vlmentin was positive predominantly in the spindle cell component. The areas expressing HGF and c‐Met corresponded to distinct epithelial structures; however, HGF and c‐Met expression were not found in any other tumor cells expressing epithelial markers in the spindle cell component of SS. Considering the morphogenlc effect of HGF, which has been known to be one of Its most important roles, the unique immunohlstochemical localization of HGF and c‐Met In SS suggests that the HGF/c‐Met system may be closely related to the formatlon of epithellal (glandular) structures In biphasic SS.

Kamoshida, Shingo; Tsutsumi, Yutaka

doi: 10.1111/j.1440-1827.1998.tb03837.xpmid: 9788261

Normal and mallgnant plasma cells (PC), follicular dendritic cells (FDC), myoflbroblasts (MFB) and perineurial cells (PNC) were Investigated for the expression of YUC‐1 glycoprotein (MUC‐1 gp) by immunohistochemical and immunoelectron microscopic techniques uslng monocional antibodies E29, 115D8, DF3 and a combination of the three. MUG1 glycoprotein‐positive PC detected by the combined antibodies were frequently seen in a variety of pathological lesions tested, including chronic cervicitls, chronic syno‐vitis, Hodgkin's disease, allergic rhlnitis and sinusitis, tuberculous lymphadenitis, foreign body granuloma, multiple myeloma, and chronic tonsillitis. In the lesions containing MUC‐1gp‐positive PC, the infiltration of immunoglobulin (lg) E PC and/or IgE‐bound mast cells was significantly increased, but MUC‐1gp‐positive PC did not contain any specific immunoglobulin heavy or light chains. The findings suggest that the expression of MUC‐1gp In PC, although not restrlcted to IgE‐class cells, may be Induced in an allergic status. Plasma cells and PNC mainly reacted with the antibodies E29 and 115D8, while FDC and MFB were principally reactive wlth the antibody DF3. In some cases of multiple myeloma, the neoplastic PC were predominantly immunoreactive with DF3. The results indicate: (i) the epitopic variability of MUC1gp molecules expressed on the non‐epithelial cells; and (ii) the epitoplc alterations during malignant transformation. It should also be noted that the expression of MUG‐1 gp in the nonepithellal cells represents a pitfall in histopathological diagnosis.

Onodera, Ken; Sasano, Hironobu; Ichinohasama, Ryo; Ooya, Kiyoshi

doi: 10.1111/j.1440-1827.1998.tb03838.xpmid: 9788262

The enzyme aromatase Is Involved In the conversion of androgens to estrogens and in the modulation of various androgenlc and estrogenlc actions. Abnormalities of estrogen metabolism have been postulated to play roles in the development and/or pathophyslology of Sjdgren's syndrome. In the present study, aromatase was immunolocal‐ized In 75 cases of Inflammatory disorders of human minor salivary glands of the lower lip. These included cases of primary Sjögren's syndrome (19 cases), of chronic slaladenitis (34 cases) and of mucous extravasation cysts (22 cases), in order to clarify the possible involvement of in situ estrogen production in primary Sjögren's syndrome. Aromatase Immunoreactlvlty was detected In myoepithelial cells of acini and in interstitial cells adjacent to acini and ducts In 13/19 (68%) cases of primary Sjögren's syndrome. In contrast, aromatase expression was detected In only six of 34 (18%) cases of chronic sialadenttis and in seven of 22 (32%) cases of mucous extravasation cyst. These results suggest that Increased aromatase expression in minor salivary glands with primary Sjogren's syndrome in premenopausal women may be involved in the biological features of primary Sjogren's syndrome through the production of estrogens in situ and possibly through the aggravation of the inflammatory reaction.

Fukuda, Takeaki; Tominaga, Kunihiko; Abe, Masafumi; Kusakabe, Takashi; Yamaki, Toshifumi; Hiraki, Hiroyuki; Itoh, Seiki; Suzuki, Toshimitsu

doi: 10.1111/j.1440-1827.1998.tb03839.xpmid: 9788263

Human acinic cell adenocarcinoma cell (HACC) line was established from the pleural effusion that contains meta‐static tumor cells of acinic cell adenocarcinoma of papillary and microcystic type originating from the parotid gland. The HACC cells grew in an adherent monolayer with a doubling time of 66 h. Implanted tumor of SCID mice revealed similar histologlcal findings to that of the primary tumor. The HACC cells produced mucin and expressed epithelial markers as well as α1‐antitrypsin and lysozyme, whereas salivary peptide P‐C was expressed in cultured HACC cells but not In the primary and Implanted HACC cell tumors. S‐100 protein was also expressed in both the primary tumor and HACC cell line. Neither amplification of common oncogenes nor expression of p53 was observed. The receptor for epidermal growth factor (EGF) was expressed, indicating EGF and transforming growth factor‐α (TGF‐α) enhanced the growth of the HACC line. Unexpectedly, tumor necrosis factor‐α (TNF‐α) also enhanced the growth of the HACC line significantly. However, there was no evidence of autocrine growth using these growth factors. In contrast, TGF‐β1 inhibited the growth of the HACC cell line through apoptosis. The HACC cell line has features similar to both acinar and intercalated ductal cells of the salivary gland. Epidermal growth factor, TGF‐α and TNF‐α are potential growth factors for the HACC cell line. The HACC cell line may be a good model for studying the biological behavior of salivary gland neoplasms.

Takasaki, Takashi; Akiba, Suminori; Sagara, Yoshiatu; Yoshida, Hiroki

doi: 10.1111/j.1440-1827.1998.tb03840.xpmid: 9788264

Fifty‐two mammary carcinomas, 2 cm or less in diameter, were examined in order to clarify the morphology and biology of microinvasion. The morphological characteristics of microinvasion of carcinomas include: (i) a loss of myoeplthelial cells and a rupture with concomitant loss of collagen IV and lamlnin in the basement membrane of involved mammary glands; and (ii) budding of carcinomas from the rupture into the stroma. When microinvasion was defined as a rupture of < 200 pm In the basement membrane with invasion, the number of microinvasions per 1 mm of basement membrane was larger in the tumors in which the area of invasion was larger. The prevalence of microinvasion showed a significant correlation with lymph node metastasis and the rate of histological deviation, while no correlation of expression of either estrogen receptors or progesterone receptors and c‐erbB‐2 protein was found. The study clarified that the early invasion of mammary carcinomas could be detected by the immunohistochemical method using anti‐smooth muscle actin, laminin and collagen IV antibodies. The study also suggested that microinvasion might be an indicator of lymph node metastasis in mammary carcinomas ≤ 2 cm diameter.

Lee, C. Soon; Gad, Jacqueline

doi: 10.1111/j.1440-1827.1998.tb03841.xpmid: 9788265

Differences In the Immunohlstochemlcal expression of the 17 kDa protein encoded by the human nm23‐H1 gene were studied In premallgnant lesions and Invasive squamous cell carcinoma (SCC) (N = 8) of the cervix using routine streptavldln‐blotln Immunohistochemlstry and a polyclonal antibody to the nm23‐H1 protein. The premalignant lesions were kollocytic atypla due to wart virus Infection (N = 5), low‐grade cervical intraepithelial neoplasia (CIN) (N = 7) and high‐grade CIN (N = 7). The carcinomas were either moderately (N = 3) or poorly differentiated (N = 5). The non‐neoplastlc controls were normal squamous epithelium from cases with uterine prolapse (N = 7) and normal squamous epithelium not affected by the Infective or neoplastic areas of some of the cases with wart virus Infection (N = 2) and carcinoma (N = 2). Moderate to strong cytoplasmic and, occasionally, nuclear Immunostainlng for the nm23‐H1 protein was seen in all cells above the basal layer of the normal squamous epithelium. However, most of the cervical SCC show a relative reduction in nm23‐H1 immunoreactivity (7/8 cases; 88%). This difference In nm23‐H1 expression was statistically significant (P = 0.0006; Chi‐squared test with continuity correction). All of the cases with wart virus Infection (N = 5; 100%) displayed moderately strong nm23‐H1 immunostaining throughout the squamous epithelium except for the basal layer where no staining was observed. The cases that had low‐grade squamous dysplasia of the cervix (CIN Ml) (N = 7; 100%) also displayed moderate to strong nm23‐H1 Immunoreactivity In the epithelium except for the basal layer (CIN I) or the lower two‐thirds of the epithelium (CIN II). nm23‐H1 Immunoreactivity was either absent or was significantly reduced in all of the high‐grade CIN (CIN III) cases (At = 7; 100%) in which only the non‐dysplastJc superficial third of the squamous epithelium displayed nm23‐H1 immunolabeling. The difference in nm23‐H1 expression between low‐grade and high‐grade CIN cases was statistically significant (P = 0.0013; Chi‐squared test with continuity correction). Similarly, the difference between low‐grade CIN and SCC cases in the expression of nm23‐H1 was also significant (P = 0.0041; Chi‐squared test with continuity correction). However, no statistically significant difference in nm23‐H1 immunoreactivity was found between cases of high‐grade CIN and SCC. In conclusion, nm23‐H1 protein immunoreactivity is reduced in high‐grade CIN and cervical SCC but not in low‐grade CIN. These findings suggest that reduced expression of the protein may be Important early in the sequential development of cervical squamous neoplasia.

Kuroda, Naoto; Hayashi, Yoshitake; Itoh, Hiroshi

doi: 10.1111/j.1440-1827.1998.tb03842.xpmid: 9788266

Chromophobe renal cell carcinoma (RCC), which has recently been recognized to be a distinct type of RCC, comprises approximately 5% of renal cell tumors. It has been hypothesized that the cells that comprise chromophobe RCC show a phenotype similar to that of intercalated cells of the collecting duct Although the number of research reports on this type of tumor has recently been increasing, only nine cases of chromophobe RCC showing sarcomatoid transformation have been described. Herein, a case of chromophobe RCC with sarcomatoid foci and a small daughter lesion is reported.

Lim, Sung‐Chul; Lee, Mi‐Ja; Lee, Mi‐Sook; Kee, Keun‐Hong; Suh, Chae‐Hong

doi: 10.1111/j.1440-1827.1998.tb03843.xpmid: 9788267

A giant hidradenocarcinoma presented by a 75‐year‐old female Is reported. The patient had a malignant transformation within a nodular hidradenoma involving the right postauricular area, which was treated by mass removal and a right radical neck dissection with a free‐flap covering. Malignant hidradenocarcinoma is the least common adnexal tumor of uncertain origin. They are usually malignant from their inception, but some develop from a benign counterpart. To the authors' knowledge, only three cases have been reported previously. Two histologically distinct components were seen in this tumor: (i) typical nodular hidradenoma, which constituted a small part of the tumor; and (ii) carcinoma with areas of transition. The secretory cells of hidradenocarcinoma showed decapitation secretion on light and electron microscopic observations, which is evidence of apocrine differentiation. Histologically, this case was concluded as a hidradenocarcinoma arising from a long‐standing nodular hidradenoma. A literature review is presented and the histological, immunohisto‐chemical and ultrastructural features are described.