Masazumi Tsuneyoshi

Background: Angiosarcomas are malignant mesenchymal neoplasms, including sarcomas of presumptive vascular endothelial origin and sarcomas of probable lymphatic origin. It is, however, often difficult to determine whether they are from blood vascular or lymphatic endothelium. The majority of angiosarcomas are thought to originate from vascular endothelia and spread via bloodstream to lung, but lymphatic metastases can occur.Methods: We investigated immunohistochemical expression of vascular endothelial growth factors (VEGF‐A, VEGF‐C) and their receptors (VEGFR‐1, VEGFR‐2, VEGFR‐3) in a series of 34 angiosarcomas.Results: VEGF‐A was expressed by 32/34 (94%), VEGF‐C by 4/34 (12%), VEGFR‐1 by 32/34 (94%), VEGFR‐2 by 22/34 (65%), and VEGFR‐3 by 27/34 (79%). Patients who expressed low or no VEGFR‐2 showed a significantly unfavorable prognosis by log‐rank test (P = 0.010) and multivariate analysis (hazard ratio, 5.16; 95% CI, 1.40–19.04; P = 0.014). VEGFR‐1 and VEGFR‐3 were not significantly associated with patients' prognosis.Conclusions: VEGF‐A and VEGFR‐1 were detected in diverse subtypes of angiosarcomas. In cooperation, VEGF‐A and VEGF‐C are likely to be involved in the development of angiosarcoma associated with lymphedema. VEGF‐C expression may cause susceptibility to lymphatic metastasis through tumor lymphangiogenesis. Angiosarcoma of the scalp, which is traditionally considered as a true hemangiosarcoma, may include some cases of lymphatic origin. J. Surg. Oncol. 2008;97:74–81.

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.

In myxoid/round cell liposarcoma (MLS/RCLS), the presence of a round cell (RC) component has been reported to correlate with a worse prognosis for the patients. However, little is known about the molecular genetic differences between conventional myxoid (MX) components and RC components in this tumour. The aim of this study was to investigate the possible implications of molecular alterations of G ₁ to S‐phase check‐point genes, especially in the RC component. We evaluated the immunohistochemical expression of p53, MDM2, p14 and p16 protein and assessed proliferative activities using MIB‐1 in 29 RC components and 81 MX components from 90 cases. Mutation of the p53 gene, amplification of the MDM2 gene, homozygous deletion, methylation status and mutation of the p16 ^INK4a /p14 ^ARF genes were also investigated, using concordant paraffin‐embedded and frozen material. The data were analysed together with clinicopathological factors to assess their prognostic implications in MLS/RCLS. Immunohistochemically, the over‐expression of p53 protein ( p = 0.01366) and the reduced expression of p14 ( p < 0.0001) and p16 ( p < 0.0001) proteins were significantly more frequently observed in RC components than in MX components. Reduced expression of p14 protein correlated significantly with hypermethylation of the p14 ^ARF gene promoter ( p = 0.0176) and over‐expression of p53 protein ( p = 0.00837). By univariate analysis, reduced expression of p14 and p53 missense mutation were found to reduce the rate of survival significantly ( p < 0.05). Multivariate analysis, including clinicopathological factors, revealed that tumour site ( p = 0.0251), the presence of an RC component ( p = 0.0113), high MIB‐1 labelling index ( p = 0.0005) and p53 missense mutation ( p = 0.0036) were adverse prognostic factors. In MLS/RCLS, reduction of p14 protein expression and p53 mutation were related to poor prognosis. Accordingly, the p14 ^ARF /p53 pathway may contribute to the presence of an RC component and malignant progression in this tumour. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Clear cell sarcoma (CCS) is a very rare soft tissue sarcoma with a poor prognosis. It has become apparent through immunohis‐tochemical, ultrastructural, and microarray analyses that CCS is a soft tissue melanocytic neoplasm. Alterations in the p16^INK4a/ p14^ARF gene are common in malignant melanoma, which is the prototypical melanocytic neoplasm. In the present study, we performed a clinicopathologic analysis and investigated p16 and cy‐clin D1 expression by immunohistochemistry in 14 cases. Furthermore, we investigated genetic changes of various tumor suppressor genes and an oncogene, including p16^INK4a/p14^ARF, p53, (‐catenin, and APC, in 11 cases. The 5‐year overall survival rate in all the patients was 33.3%. A high mitotic rate was a significant adverse prognostic factor (P=0.004). Decreased expression of p16 was observed in 4 (28.6%) of 14 cases. Overexpression of cyclin D1 was observed in 9 cases (64.3%). SSCP analysis followed by DNA direct sequencing revealed point mutations of the p16^INK4a gene in 2 of 11 cases (18.2%). In addition, one case with the p14^ARF mutation and 2 cases with the p53 mutation were observed. None of the cases harbored mutation of the (‐catenin or APC gene. Homozygous deletion of the p1ff^NK4a/p14^ARF gene was detected in one case. Methylation‐specific PCR did not reveal hy‐permethylation of the p16^INK4a/p14^ARF promoter region in any of the cases. Three cases harbored genetic alterations of the pl6^INK4a/ p14^ARF gene (27.3%). All tumors with genetic alterations of the p16^INK4a/p14^ARF or p53 gene showed a high mitotic rate or tumor necrosis. These alterations were considered to be influential in the poor prognosis of CCS patients.

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.

Aims:  The pathogenic mechanism and predictive indicators of biological behaviour of inflammatory myofibroblastic tumour are poorly understood. We investigated molecular abnormalities of p53 and MDM2 in order to assess whether these play an important role in pathogenesis, and whether they also contribute to clinicopathological aggressive phenotype in inflammatory myofibroblastic tumour.Methods and results:  We compared the immunohistochemical expression of calponin, h‐caldesmon, ALK, and p53 gene mutation and MDM2 gene amplification with clinicopathological findings in 15 cases of inflammatory myofibroblastic tumour. Histologically, cellular atypia was observed in five (33.3%) out of 15 cases. Local recurrences were observed in two (14.3%) of 14 informative cases, but no distant metastasis was observed. The expression of calponin (9/14; 64%) but not h‐caldesmon (0/14; 0%) was seen, which suggested myofibroblastic differentiation. ALK expression was seen in eight (53.3%) out of 15 cases, particularly in patients under 40 years old. Nuclear expression of p53 protein was recognized in only one (6.7%) of 15 cases, and polymerase chain reaction single‐strand conformation polymorphism followed by direct sequencing revealed p53 gene missense mutations in two (13.3%) of 15 cases. Nuclear expression of MDM2 was seen in four (26.7%) of 15 cases, and the MDM2 gene amplification was observed in two of the four cases.Conclusion:  Inflammatory myofibroblastic tumour shows a wide spectrum of cellular atypia and biological behaviour with p53 and MDM2 expression. However, the alterations in the p53 pathway seem not to play a major role in the pathogenesis of inflammatory myofibroblastic tumour.

To identify a characteristic cytogenetic aberration and cytogenetic‐morphological correlation in soft‐tissue leiomyosarcomas, a karyotypic and clinicopathological analysis of 15 cases of leiomyosarcoma was performed. The histological type was classical in nine cases, pleomorphic in three cases and myxoid in three cases. The histological grade was 1 in three cases, 2 in 10 cases and 3 in two cases. Nine of 15 tumors displayed an abnormal karyotype, whereas the other six tumors displayed a normal karyotype. The relative consistency of involvement of 3p, 3q, 6q, 7p, 7q, 9p, 10p, 11p, 11q, 12p, 16q, 17p and 19q was recognized, although characteristic chromosomal rearrangements were not detected. All six tumors that had a normal karyotype were of the classical type, whereas those displaying an abnormal karyotype contained another morphological type along with the classical type. The results of the present study suggest that chromosomal aberrations contribute to morphological changes in soft‐tissue leiomyosarcomas.

The tumor suppressor gene PTEN/MMAC1 was identified on chromosome 10q23.3, which is homozygously deleted in many human malignancies. The loss of chromosome 10q was also frequently reported in some types of soft tissue sarcomas. Our study was designed to investigate the frequency of PTEN/MMAC1 gene mutation and to evaluate the role of the PTEN/MMAC1 gene in the tumorigenesis of soft tissue sarcomas without specific balanced translocations. We analyzed 51 cases of soft tissue sarcomas without specific balanced translocations for PTEN/MMAC1 mutations by polymerase chain reaction‐single strand conformation polymorphism and direct sequencing. Mutations in the PTEN/MMAC1 gene were found in only 2 cases (3.9%). Both tumors with PTEN/MMAC1 mutation were leiomyosarcomas arising from the retroperitoneum and inferior vena cava, respectively. Two of 3 leiomyosarcomas arising from the intra‐abdominal cavity examined harbored mutations of this tumor suppressor gene. This result suggests that leiomyosarcomas derived from the intra‐abdominal cavity might have different tumorigenesis from those of an extremity or the trunk, from the viewpoint of PTEN/MMAC1 mutation, although PTEN/MMAC1 gene mutations are rare event in these soft tissue sarcomas.