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Notes: Aims:  To clarify the cellular differentiation of colorectal villous tumours in malignant transformation, compared with that of tubular tumours (tubular adenoma and adenocarcinoma arising in tubular adenoma).Methods and results:  Forty-nine cases of colorectal villous tumours [six cases of low-grade villous adenoma, 21 of high-grade villous adenoma (VA), nine of invasive carcinoma in villous adenoma (CIVA), and 13 of pure villous carcinoma (PVC)] and 46 cases of tubular tumours [14 cases of low-grade and 17 of high-grade tubular adenoma (TA), and 15 cases of carcinoma in tubular adenoma (CITA)] were selected for this study based on their expression patterns of CD10 (small intestinal brush border), MUC2 (intestinal goblet cell), and HGM (gastric foveolar epithelium). HGM was more frequently expressed in the adenomatous components of villous tumours (63%) than in those of tubular tumours (14%) (P 〈 0.05). CD10 expression of high-grade TAs (47%) and carcinomas arising in TA (60%) was significantly higher than that of villous tumours (0%) (P 〈 0.05).Conclusions:  There were significant differences in the phenotypic expression of adenoma and adenocarcinoma between villous and tubular tumours, respectively. Villous tumours have a pathway of malignant transformation different from that of tubular tumours. Because of biological differences, colorectal villous tumours should be distinguished from tubular neoplasia. The analysis of the phenotype of colorectal neoplasms is useful for the evaluation of tumour progression.

Notes: c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma Aims: The c-erbB-2 and c-Met proto-oncogenes are important for tumour invasiveness and metastasis in many types of malignant tumours. Previous studies have indicated that these proteins are associated with carcinogenesis in intrahepatic cholangiocarcinoma. In this study, we examined c-erbB-2 and c-Met expression by immunohistochemistry in hepatolithiasis, intrahepatic cholangiocarcinoma and metastatic lymph node, in order to clarify whether these proteins play a role in carcinogenesis and tumour metastasis in intrahepatic cholangiocarcinoma. Methods and results: In hepatolithiasis, the staining for c-erbB-2 was positive in 14 of the 23 (61%) cases, while staining for c-Met was positive in eight of the 23 (35%) cases. In intrahepatic cholangiocarcinoma, staining for c-erbB-2 was positive in 45 of the 81 (55%) cases, while staining for c-Met was positive in 28 (35%) cases. The positivity of c-Met staining in intrahepatic cholangiocarcinoma was significantly higher in the differentiated type of cholangiocarcinoma than in the undifferentiated type. In addition, c-Met-positive staining had an inverted correlation with tumour size, the presence of perineural invasion and the presence of lymph node metastasis. c-Met staining had a significantly higher positivity in cases at an early stage of intrahepatic cholangiocarcinoma. In contrast, the positivity of c-erbB-2 staining in intrahepatic cholangiocarcinoma was significantly higher in cases with lymph node metastasis than in cases without. In metastatic lymph nodes, the staining for c-erbB-2 was positive in 20 of the 25 (80%) cases, while staining for c-Met was positive in six of the 25 (24%) cases. There was no difference in survival between c-erbB-2-positive and negative patients. However, the patients with c-Met-positive tumours had a significantly longer survival than those with c-Met-negative tumours in the medium survival term. The multivariate analysis showed the presence of lymph node metastasis, lymphatic permeation and histological differentiation to be independent prognostic factors. Conclusion: These results indicate that increased c-Met expression participates in cholangiocarcinogenesis and in the early developmental stages of intrahepatic cholangiocarcinoma, while increased c-erbB-2 expression contributes to the development of cholangiocarcinogenesis into an advanced stage associated with tumour metastasis.

Notes: Secondary malignant giant-cell tumour of bone: molecular abnormalities of p53 and H-ras gene correlated with malignant transformation Aims: We report two cases of secondary malignant giant-cell tumour occurring without irradiation therapy. To elucidate the mechanism of malignant transformation in this tumour, we searched for the molecular abnormalities of p53, MDM2 and the H-ras genes. Methods and results: These cases were retrieved after a review of 103 cases of primary giant-cell tumour of bone, registered in our institute. One case occurred in the distal femur of a 42-year-old female after surgical curettage, while the other arose in the acetabulum of a 25-year-old male after en bloc resection. Microscopically, the malignant tumour in the distal femur was composed of a proliferation of ovoid or fusiform cells arranged in fascicles with high mitotic activities. The malignant transformed tumour in the acetabulum was made up of pleomorphic tumour cells with atypical mitoses. In the tumour of the distal femur, both p53 and H-ras mutations were detected. Abnormal nuclear accumulation of p53 protein and c-myc expression were also revealed by immunohistochemistry. In both cases, the recurrent malignant tumour over-expressed MMP-9 and revealed a higher MIB-1-labelling index compared with the primary conventional giant-cell tumour. Conclusions: Our results suggest that multiple oncogene or tumour suppressor gene mutations may play an important role during malignant transformation in conventional giant-cell tumours.

Notes: Clinicopathological prognostic factors in soft tissue leiomyosarcoma: a multivariate analysis Aims: Prognostic factors affecting survival in cases of leiomyosarcoma of soft parts were investigated in this study. Methods and results: A retrospective study of 267 patients was carried out. This group comprised 142 females (53%) and 125 males (47%), whose ages ranged from 7 to 95 years (median 58 years). One hundred and five cases were superficially situated (arising from the skin or subcutis), while the remaining 162 cases were deeply situated (subfacial). Nineteen were cases of pleomorphic leiomyosarcoma where the diagnosis had been amended from malignant fibrous histiocytoma to leiomyosarcoma whilst under review. Of the 167 patients with follow-up data, 83 died of leiomyosarcoma. In univariate analysis, depth, tumour size (≥50 mm), mitotic rate of 〉20 per 10 high-power fields (HPF), tumour necrosis of 〉50% and a high stage according to the most recent American Joint Committee on Cancer (AJCC) staging for soft tissue sarcoma were found to lessen significantly the rate of survival (log rank test; P 〈 0.05). However, in multivariate analysis (Cox's proportional hazards model), tumour size and high AJCC stage were the only factors that were correlated independently with decreased survival. Conclusions: This study indicates that the most reliable prognostic parameters are tumour size and AJCC stage in leiomyosarcoma.

Notes: Recently, the expression of vimentin has been reported in some carcinomas. This study was designed to clarify the significance of vimentin expression in solid type poorly differentiated adenocarcinomas of the stomach. Immunohistochemically, 239 poorly differentiated adenocarcinomas with solid components of the stomach were stained for vimentin. Vimentin-positive cases were also stained by CAM 5.2 using serial mirror sections. We found 15 (6.3%) vimentin-positive cases. Twelve of them demonstrated varying amounts of rhabdoid-like cells. Eight cases diffusely co-expressed vimentin and cytokeratin simultaneously. In addition, four co-expressing cases showed positive staining with Keratin-903 which recognizes the high molecular-weight cytokeratin. Most of the co-expressing cases showed a diffuse proliferation of polygonal tumour cells with focal cell-to-cell contact. The prognosis of the co-expressing cases was poor in comparison with that of the 89 vimentin-negative tumours (P 〈 0.05).

Notes: A mapping study of cystectomy specimens in three cases of pure squamous cell carcinoma and 28 cases with transitional cell carcinoma with squamous differentiation is described, with an emphasis on the histogenesis of pure squamous cell carcinoma. Two of the three cases of pure squamous cell carcinoma had extensive benign keratinizing mucosa and an atypical squamous metaplastic mucosa contiguous with the tumour. These pure squamous cell carcinomas seemed to be derived from the squamous metaplasia. On the other hand, in all except one of the cases of transitional cell carcinoma with squamous differentiation, there was neither benign keratinizing nor atypical squamous metaplastic mucosa in the bladder.The quantitative amounts of both the transitional cell and squamous components differed from case to case in 28 cases with transitional cell carcinoma with squamous differentiation. Five of the 28 had a tumour composed predominantly of a squamous component with minute transitional cell components at the margin. In another two cases, transitional carcinoma in situ or satellite tumours of transitional cells were present adjacent to the main tumour which was composed of squamous cell carcinoma alone. We think these seven tumours originated as a result of extensive squamous differentiation in the transitional cell carcinomas. These features may indicate two forms of histogenesis of pure squamous cell carcinoma. The first is malignant transformation on the basis of squamous metaplasia of the bladder mucosa and the second is extensive squamous differentiation in a pre-existing transitional cell carcinoma.

Notes: Aims : ‘Scirrhous’ hepatocellular carcinoma (scirrhous HCC) is extremely rare and its characteristics remain unclear. We investigated the clinicopathological and immunohistochemical features of scirrhous HCC, compared with those of ordinary hepatocellular carcinoma (ordinary HCC).Methods and results : We compared the clinicopathological and immunohistochemical features of 20 resected cases of scirrhous HCC with those of 69 resected cases of ordinary HCC. Scirrhous HCC was characterized by its gross and histological findings, such as a higher proportion of contiguous multinodular type tumours, the absence of a complete fibrous capsule around the tumour, the absence of tumour necrosis and highly preserved portal tracts in the tumour. The immunohistochemical results revealed a significantly higher expression of cytokeratin 7 and a significantly lower expression of hepatocyte paraffin 1 in scirrhous HCC than in ordinary HCC (P 〈 0.0001, respectively). There were no significant differences in proliferative activity and survival curves between the patients with scirrhous HCC and those with ordinary HCC.Conclusion : Scirrhous HCC has several particular gross, histological and immunohistochemical features. In particular, we would like to emphasize the greater immunohistochemical expression of cytokeratin 7 and lower expression of hepatocyte paraffin 1 in scirrhous HCC than in ordinary HCC.

Notes: Aims : To evaluate the relationship between phenotypic expression and tumour progression as represented by macroscopic features, submucosal invasion and lymph node metastasis in early differentiated gastric adenocarcinoma.Methods : One hundred and fifty-five cases of early gastric differentiated adenocarcinoma without any poorly differentiated components were studied. The mucosal and submucosal components of carcinomas and lymph node metastatic lesions were classified into four categories, gastric type (G-type), incomplete intestinal type (I-type), complete intestinal type (C-type) and unclassified type (U-type), based on the combination of the phenotypic expression of HGM (gastric foveolar epithelium), MUC6 (gastric pyloric glands), MUC2 (intestinal goblet cells) and CD10 (small intestinal brush border). In addition, a new classification representing a phenotypic shift from mucosa to submucosa or from primary lesion to lymph node metastasis was established with the categories of preserved group (P-group), loss group (L-group) and acquired group (A-group).Results : (1) In submucosal carcinoma, U-type was more common in the submucosa (39%) than in the mucosa (9%). (2) U-type was more common in the metastatic lesions (42%) than in the primary lesions (5%). (3) The submucosal component and lymph node metastatic lesions were classified as P-group in 48% and 43% of cases, respectively, and as L-group in 50% and 52% of cases, respectively. (4) Lymph node metastatic lesions comprising undifferentiated carcinoma were classified as L-group in 100% of cases.Conclusion : During the course of tumour progression, early differentiated adenocarcinoma at first tends to lose its phenotypic expression despite preserving its morphology, but subsequently morphological dedifferentiation occurs.

Notes: Aims:  Only a few reports on renal cell carcinoma with rhabdoid features have been published. This study was performed to investigate the clinicopathological characteristics of renal cell carcinomas with rhabdoid features.Methods and results:  Among 253 cases of renal cell carcinoma in adults, eight cases with rhabdoid features were detected. Rhabdoid areas ranged from 10% to 90% of each of the cases. Seven of the eight cases were TNM stage III or IV, and four of the eight cases died within 8 months of surgery. Immunohistochemically, the rhabdoid areas were positive for CAM 5.2 (4/8), AE1/AE3 (6/8), epithelial membrane antigen (6/8) and vimentin (8/8), and negative for myogenetic markers (0/8). The mean MIB-1 labelling index in the rhabdoid areas was higher than that in the definite carcinomatous areas. Ultrastructurally, perinuclear whorls of intermediate filaments were demonstrated in three of the eight cases using paraffin-embedded blocks.Conclusions:  The rhabdoid areas in renal cell carcinoma have histological, immunohistochemical and ultrastructural similarities to malignant rhabdoid tumours. Renal cell carcinoma with rhabdoid features is a highly aggressive neoplasm and its malignant behaviour may be due to the high cell-proliferative activity of the rhabdoid areas. Rhabdoid features in renal cell carcinoma may represent the endpoint of clonal evolution of renal cell carcinoma (especially in clear cell type cases).