Yukio Shimosato

An immunoperoxidase study of S-100 protein distribution in normal and neoplastic tissues

ABSTRACTThe presence of S-100 protein was immunohistochemically studied in many types of formalin-fixed and paraffin-embedded tumors (260 cases). Peripheral nerve tumors, i.e., schwannomas, neurofibromas, granular cell tumors, and neurogenic sarcomas were demonstrated to contain variable amounts of S-100 protein in the tumor cell cytoplasm and nuclei. In ganglioneuromas and ganglioneuroblastomas, neoplastic Schwann cells or satellite cells were positive for S-100 protein. About one-half of the cases of carcinoid tumors stained weakly for S-100 protein. In addition to these nervous tissue and carcinoid tumors, chondrosarcoma, chordomas, pleomorphic adenomas of the salivary gland, and Langerhans cell granulomatosis were also shown to produce S-100 protein. In many types of breast tumors and other lesions, S-100 protein positive cells were likely to correspond to the distribution of myoepithelial cells. These results indicate that S-100 protein is not strictly specific to nervous tissue and its tumors; however, the immunohistochemical demonstration of S-100 protein can be a useful diagnostic tool in tumor diagnosis.

Early stages of multistep hepatocarcinogenesis: Adenomatous hyperplasia and early hepatocellular carcinoma

From a series of 320 heptocellular carcinoma (HCC) cases treated surgically, we selected small nodular lesions that had not destroyed the preexisting liver structure grossly. After excluding metastases and large regenerative nodules, 58 lesions from 41 cases were chosen. All the lesions were hypercellular. Among them, 33 lesions showing histologic features of very well-differentiated HCC (Edmondson grade I), that is, small hepatocytes with little cellular atypia but with structural atypia, such as a thin trabecular structure of acinar formation in some areas, were classified as early HCC (eHCC). In seven eHCCs, areas of overt carcinoma, classified as Edmondson grade II, were found in the background of Edmondson grade I carcinoma. The remaining 25 lesions lacked structural atypia and were classified as adenomatous hyperplasia (AH). Among the AHs, 10 nodules with a very focal abnormal structure were subclassified as atypical adenomatous hyperplasia (AAH). There was a tendency for the size and cellularity of the atypical lesions to increase in order from AH to AAH to eHCC. All nodules larger than 1.5 cm were eHCC. A degree of cellularity more than twice that of a regenerative nodular was suggested to be an indicator of HCC. All small nodular lesions were associated with chronic liver disease. These histologic observations appear to explain the stepwise development of overt HCC from very well-differentiated eHCC, and of eHCC from AH probably through AAH, at least in cases of HCC associated with chronic liver disease.

Pathology of small hepatocellular carcinoma. A proposal for a new gross classification

Review of 61 surgically resected small hepatocellular carcinomas (HCC) less than or equal to 3 cm in diameter yielded a simple gross classification system of five types based on tumor shape, which is highly correlated with microscopic and clinical features, including prognosis. Type 1 (single nodular type) tumors (n = 13) are expansile, roughly spheric, and often encapsulated. In Type 2 tumors (single nodular type with extranodular growth) (n = 21), replacing growth is often seen in the area of extranodular growth. Type 3 tumors (contiguous multinodular type) (n = 19) consist of small nodules growing in contiguity, often with replacing growth at the periphery. Type 4 (poorly demarcated nodular type) is a rare tumor showing infiltrating growth at its border. The authors define early HCC (n = 5) as the presence of tumor without destruction of the underlying liver structure. The lesions experienced are tiny (≤1.2 cm) and well differentiated. Poorly differentiated histologic characteristics and elevated alpha fetoprotein are more common in Types 2 and 3 than in Type 1. Type 1 has the highest rates of positive serum hepatitis B surface antigen and liver cirrhosis; portal vein tumor thrombus (PT) and/or intrahepatic metastasis (IM) is rare (7.7%), and the effect of transcatheter arterial embolization (TAE) is remarkable. This contrasts with Type 2, which has a high rate of PT and/or IM (71.4%) and multiple local recurrences (40%), and with Type 3, which shows a poor response to TAE.

Immunohistochemical demonstration of S 100 protein in malignant melanoma and pigmented nevus, and its diagnostic application

The presence of nervous tissue specific S100 protein was studied immunohistochemically in 47 cases of malignant melanoma and 25 pigmented nevi of various types by peroxidase‐antiperoxidase immunoenzyme method on routine paraffin sections of the surgical specimens. Of 47 cases of malignant melanoma, 44 were positively stained for S100 protein. The intensity of S100 protein immunostaining was suggested to be inversely proportional to the amount of melanin pigment. In ten cases of 12 amelanotic melanomas, the immunoreaction for S100 protein in tumor cells was stronger than that of normal Bergmann glial cell in human cerebellum. Intradermal nevi and juvenile melanomas were strongly positive for S100 protein, but blue nevi contained little or no S100 protein. Our results suggest that S100 protein is widely distributed among melanotic tumors and is also a very useful diagnostic indicator for malignant melanoma, especially of the amelanotic type.

Growth and spread of hepatocellular carcinoma: A review of 240 consecutive autopsy cases

All 240 consecutive cases of hepatocellular carcinoma (HCC) that underwent autopsy at the National Cancer Center Hospital (Tokyo, Japan) between September 1962 and August 1986 were reviewed. Among these cases, 162, for which photographs of cut surfaces of the primary tumors were available, were grossly classified using a combination of both Eggels classification and our own into three major types, i.e., nodular, massive, and diffuse as described by Eggel (Eggel H, Beitr Pothol Anat 1901; 30:506–604), and three subgroups of nodular type, i.e., single nodular type (type 1), single nodular type with extranodular growth (type 2), and contiguous multinodular type (type 3) by our classification (Kanai T et al. Cancer 60:810–819). Seventy‐eight cases were classified as nodular type, comprising seven cases of type 1, 61 cases of type 2, and ten cases of type 3. Sixty‐seven and 17 cases were classified as massive and diffuse type, respectively. of the 78 nodulartype tumors, 59 measured less than 10 cm, whereas 64 of 67 massive‐type tumors were 10 cm or more in size. the incidence of intrahepatic and extrahepatic tumor spread of HCC was significantly higher for tumors measuring more than 5 cm. As to the relationship between macroscopic type and tumor spread, the frequency of spread was lowest for type 1 tumors, and high for the other types. Intrahepatic melastasis was detected in 28.6% of type 1, 93.4% of type 2, 100% of type 3, and 98.5% of massive‐type tumors. Lymph node metastasis was detected in 14.3% of type 1, 24.6% of type 2, 70% of type 3, 38.8% of massive‐type and 52.9% of diffusetype tumors. Hematogenous extrahepatic metastasis was detected in 14.3% of type 1, 47.5% of type 2, 70% of type 3, 74.6% of massive‐type and 82.4% of diffuse‐type tumors. It appears that not only primary tumor size but also its macroscopic type has an important influence on the growth and spread of HCC.

Prognostic implications of fibrotic focus (scar) in small peripheral lung cancers.

ABSTRACT Peripheral lung cancers frequently possess a fibrotic focus or scar in their center or beneath the pleura. We reexamined 58 cases of peripheral lung cancer of less than 3 cm in diameter (48 adenocarcinomas, two large cell carcinomas and eight squamous cell carcinomas) which were removed surgically between June 1962 and July 1973. Analyses of the cases revealed that in adenocarcinoma with increased collagenization or hyalinization in the fibrotic focus, the degree of pleural invasion and incidence of lymph node metastasis and blood vessel invasion were greater and thus the prognosis of the patient was poorer than in cases with no or slight collagenization. The results also indicate that the characteristics of the central fibrotic focus are probably more important than the size of the tumor for estimating the prognosis of patients with peripheral adenocarcinoma of less than 3 cm in diameter. The same might be said of peripheral large-cell carcinoma. However, the prognostic importance of the fibrotic focus was not confirmed in cases of peripheral squamous-cell carcinoma. Although the central or sub-pleural scar has long been the basis of the scar cancer concept, alternate explanations were considered, namely, that scar formation occurred along with tumor development, rather than before, in the case of adenocarcinomas.

A review of 79 thymomas: modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma.

A clinicopathological study of surgically resected thymomas was performed using Masaokas staging and modified Masaokas staging systems, and the utility of these two staging systems was compared. The modification enabled adjustment for the disproportion in the number of cases between Stage I and Stage II. Analysis of survival rates, according to the tumor stage, indicated that the old classification should be reappraised, that is, division into non‐invasive and invasive thymomas, although staging may contribute to the indication for postoperative radiotherapy, especially for Stage II disease. Analysis of the cases showed a wide spectrum of aggressiveness, varying from cases showing slow progression with a relatively favorable prognosis, such as the spindle cell type, to cases with rapid progression leading to tumor death in a relatively short time, such as the epithelial cell predominant and polygonal cell type. The pathological stage at the time of first surgical resectlon would reflect the degree of aggressiveness of thymoma in many instances. Therefore, not only staging the tumor extent but also grading of its aggressiveness are needed in order to predict the prognosis of patients with thymoma. For the latter, histology and cytopathology are helpful.

Clonal Origin of Atypical Adenomatous Hyperplasia of the Liver and Clonal Identity With Hepatocellular Carcinoma

We present details of two separate nodular lesions of atypical adenomatous hyperplasia, within one of which a small area of overt hepatocellular carcinoma was detected. The patient was positive for serum hepatitis B surface antigen, and Southern blot analysis revealed that deoxyribonucleic acid from the lesions of hepatocellular carcinoma and surrounding atypical adenomatous hyperplasia showed the same restriction pattern of integrated hepatitis B virus deoxyribonucleic acid, indicating that the two lesions were derived from an identical clone. It was also indicated that the two separate lesions of atypical adenomatous hyperplasia were independently derived through clonal expansion of different cells.

Squamous cell carcinoma of the thymus. An analysis of eight cases.

Right cases of squamous cell carcinoma of the anterior mediastinum, most likely derived from the thymus, are presented. Seven were male and one female ranging in age from 39 to 65 years: the average was 55.5 years. There were no cases associated with any paraneo-plastic syndromes. They possessed common morphological characteristics. Grossly, the tumors resembled malignant thymoma. Invasion of the lung and metastases to regional lymph nodes were frequent. Often observed microscopically were foci of sharply defined kcratinization resembling Hassalls corpuscles, no radial arrangement of tumor cells at the periphery of nests, and broad, fibrotic, or hyalinized stroma. Admixture of a few lymphoid cells and some features transitional to thymoma were also observed in some parts of tumors. However, undoubtedly carcinomatous areas were present in some or large parts of all the tumors, where individual cells possessed a vesicular nucleus and a prominent round nucleolus. These features were distinct from those of bronchogenic squamous cell carcinoma and other thymic tumors, although they appeared to be related to thymoma. Treatment of choice is radical surgery and postoperative radiotherapy, because of relatively high radiosensitivity. Prognosis of patients was relatively good. From analyses of cases, it is concluded that squamous cell carcinoma of the thymus should be separated from ordinary thymoma of the epithelial type, and that squamous cell carcinoma involving both the thymus and lungs should be carefully examined for the primary site of growth.

Correlation between histologic grade of malignancy and copy number of c-erbB-2 gene in breast carcinoma. A retrospective analysis of 176 cases.

A system of histologic grade of malignancy in human breast carcinoma was devised by significantly modifying the way of evaluating number of mitoses and architectural atypia in the histologic grading of Bloom and Richardson. The modified grading system was applicable to all histologic subtypes of adenocarcinoma and showed a good association with prognosis of breast carcinoma patients in retrospective analysis of 176 consecutive surgical cases (P < 0.0001). Of the three components of histologic grade, architectural atypia and number of mitotic figures independently had a significant effect on the prognosis. The copy number of c‐erbB‐2, a prognostic factor independent of tumor size and nodal status, was strongly correlated with the histologic grade, number of mitotic figures, and degree of nuclear atypia (P < 0.001, each). Coxs regression model analysis showed that nodal status and histologic grade were two determinants of prognosis, and the independent effect of c‐erbB‐2 amplification was absorbed within that of the histologic grade. Although the importance of c‐erbB‐2 gene copy number seemed to be inferior to that of the histologic grade, both were shown to be strongly associated with the aggressiveness of the tumor itself rather than the extent of tumor spread.