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Unlabelled: BACKGROUND AND OBJECTS: Matrix degradation, which is a critical event in the process of tumor invasion and metastasis, is considered to be caused by the action of proteolytic enzymes., Methods: We examined the gelatinolytic activity of matrix metalloproteinase (MMP)-9, and the activity of active and inactive forms of MMP-2 in five thymi, five noninvasive thymomas, eight invasive thymomas, and five thymic carcinomas by quantitative gelatinolytic zymography., Results: The gelatinolytic activity of active MMP-2 in five thymi was zero. The mean gelatinolytic activity of active MMP-2 was 0.020 +/- 0.015 in noninvasive thymoma, 0.084 +/- 0.098 in invasive thymoma and 0.246 +/- 0.194 in thymic carcinoma. The gelatinolytic activity of active MMP-2 correlated with the invasiveness of thymic epithelial tumors (Spearman rank correlation: r-value = 0.532). The gelatinolytic activity of active MMP-2 in three thymoma cases with microscopic capsular invasion was the same as that of noninvasive thymoma. When thymoma cases showing microscopic capsular invasion were classified into the "macroscopically noninvasive thymoma" group, the gelatinolytic activity of active MMP-2 correlated with the invasiveness of thymic epithelial tumors (Spearman rank correlation: r-value = 0.621)., Conclusions: The gelatinolytic activity of active MMP-2 significantly correlated with the invasiveness in thymic epithelial tumors. J. Surg. Oncol. 2001;76:169-175., (Copyright 2001 Wiley-Liss, Inc.)

Background and Objectives: The exact role of ret/PTC in the development of papillary carcinoma remains unclear. Expression of the ret/PTC oncogene was examined immunohistochemically to address its role in the progression of thyroid carcinomas., Methods: Paraffin-embedded samples from 34 clinically evident thyroid papillary carcinomas and 19 occult papillary carcinomas were analyzed using an antibody raised against the ret tyrosine kinase domain., Results: Expression of ret/PTC was demonstrated in 6/19 (32%) occult carcinomas. The frequency of expression of ret/PTC in clinically evident carcinomas in 16/34 (47%) was significantly higher than in normal tissues (0%) and follicular adenomas (1/14, 7%, P < 0.01).ret/PTC expression was observed more frequently in the peripheral areas of clinically evident carcinomas (P < 0.01). Although there was no correlation of ret/PTC expression with tumor size, lymph node metastasis, or distant metastasis, the incidence of ret/PTC expression in tumors with extrathyroidal invasion (13/19, 68%) was significantly higher than those without extrathyroidal invasion (3/15, 20%, P < 0.01). Local invasion was found in none of the occult carcinomas. The frequency of expression in occult carcinomas was significantly lower than in clinically evident carcinomas with extrathyroidal invasion (P < 0.05)., Conclusions: The ret/PTC oncogene may be involved in the local invasion of thyroid papillary carcinomas.

Background and Objectives: Organ specificity has been demonstrated in the mode of CD44 expression among several cancers., Methods: We examined the expressions of CD44 standard (CD44s) and CD44 variants (CD44v) in 14 cell lines (small cell lung cancer (SCLC): 5, non-small cell lung cancer (NSCLC): 9 and 20 surgically resected samples (SCLC: 7, NSCLC: 13) of lung cancer using reverse transcription polymerase chain reaction and immunohistochemistry., Results: Although both NSCLC and SCLC expressed CD44s, the frequency and intensity of CD44s expression in NSCLC were different from those in SCLC: cell lines, 89% vs. 40%; tumor samples, 100% (diffusely stained) vs. 57% (focally stained). CD44s expression was partially or completely repressed in SCLC. However, NSCLC frequently expressed CD44v, but SCLC expressed infrequently: cell lines, 67% vs. 20%; tumor samples, 69% vs. 0%. The N-417 line, which only expressed some CD44v in SCLC, falls SCLC and NSCLC both in biomarkers and in growth patterns., Conclusions: CD44 expression was repressed in SCLC but was enhanced in NSCLC.

Mutations of the p53 tumor suppressor gene are frequent in lung cancers. It is suggested that p53 mutations are associated with smoking-induced lung carcinogenesis. We examined p53 mutations in 53 lung cancers by analyzing reverse transcription-polymerase chain reaction-single strand conformation polymorphism (RT-PCR-SSCP) to ascertain the association between p53 mutations and smoking. Twenty-five (47%) of 53 lung cancers carried p53 mutations. A discriminant analysis showed that the Brinkman index (0.156) and gender (0.140) significantly influenced p53 mutations. Furthermore, there was a dose-response relationship between the quantity of cigarettes consumed and the frequency of p53 mutations in lung cancer patients (P < 0.001). In patients with adenocarcinoma, the frequency of p53 mutations correlated with the amount of the tobacco smoked (P < 0.05). We suggest that the p53 gene is a target of particular carcinogen in tobacco smoke.

Seventy tumors of invasive ductal carcinoma of the breast were examined for p53 alteration by the RT-PCR-SSCP method. Sixty-five samples (92.9%) were investigated in the regions of codons 101-200 and 201-300. In total, 16 samples (24.6%) showed p53 gene alteration. We found that p53 gene alteration showed a correlation with (1) a negative ER status, (2) a negative PgR status, and (3) a high histologic grade (especially numerous mitotic figures) of the tumor. However, we found no correlation between p53 gene alteration and the lymph node status or clinical stage. Thus, p53 gene alteration in breast cancer may occur in highly malignant breast cancer other than advanced clinical stage cancer or node-positive cancer.

Forty consecutive cases with invasive ductal carcinoma of the breast (samples of both the primary invasive area and the involved node were available for 19 cases, multiple sections of breast tissue including both the primary invasive area and forefront intraductal cancerous area were available for 15 cases; and multiple sections of breast cancerous tissue and the involved node were available for six cases) were examined by immunohistochemical analysis for evaluation of their proliferation rate. In this study, we selected the PCNA index as a marker of the proliferation rate of the tumor cells. We demonstrated that the PCNA index of the primary invasive area was significantly higher than that of the forefront intraductal area (P = 0.0017), and the PCNA index of the involved nodes was significantly higher than that of the primary invasive area (P = 0.0004). These preliminary findings suggest that the progression from the tumor cells of the intraductal cancerous area to the metastatic tumor cells must be accompanied by two phases of increase in the proliferation rate.

The preoperative and pathological findings of 38 cases of small papillary carcinoma of the thyroid gland measuring < or = 10 mm in diameter and 74 cases of large papillary carcinoma measuring more than 10 mm were compared. In the small carcinoma cases, the sensitivity of palpation, ultrasonography, and fine-needle aspiration biopsy (FNAB) was higher than that of computed tomography and soft tissue roentgenography of the neck. Therefore, palpation, US, and FNAB should be instituted as reliable diagnostic methods, but other examinations seem unsuitable as methods for preoperative qualitative diagnosis. No definite correlation was found between the intraglandular dissemination and the size of the carcinoma, and the frequency of metastasis was relatively high even in the small carcinoma cases. If the patient elects to undergo surgery, subtotal thyroidectomy with lymph node dissection should be performed for small thyroid carcinomas as well as large carcinomas.

We have immunohistochemically examined estrogen receptors (ER) and estradiol (E2) on papillary thyroid carcinoma in young females under the age of 25 years. The 10 young females in this study were compared with 64 females 30 years of age or older who underwent surgery for treatment of papillary thyroid carcinoma. We did not find any significant difference in the incidences of positive staining for E2 between the two groups. Of the specimens obtained from the young patients, 80% (8/10) showed positive staining for ER; this was significantly higher (P < 0.01) than that observed in patients 30 years of age or older (25%). We think that, especially in youth, estrogen may play an important role as a promoting factor. This indication needs further study.

Local tumor extension was studied using a continuous series of multiple blocks of mastectomy specimens to assess malignancy remaining after breast-conserving surgery for early-stage breast cancer. In this study, 183 cases were chosen, consisting of 6 noninvasive ductal carcinoma cases and 177 invasive ductal carcinoma cases. The histopathology in 59 (32%) of the 183 cases corresponded to that showing extensions of more than 2.6 cm from the tumor margin. These wide extensions were also seen in 17% of breast cancers with a tumor size of less than 2 cm. The incidence of wide extension was higher in younger patients with cases of noninvasive ductal carcinoma. Extension to the nipple-areola was seen in 14% of cases with a tumor size of less than 2 cm. Breast cancers with multicentric development accounted for 3% of those with a tumor size under 2 cm. These findings suggest that if lumpectomy is performed with a margin of 2 cm for tumors with a size of 2 cm or less, a cancerous residue would be found in the surgical margin of 15-20% of the cases. The actual incidence was 23% of cases after breast-conserving treatment in our study. On the basis of the data, breast-conserving treatment with only local resection of the primary lesion showed cancerous residue such as intraductal cancerous extension in about 20% of cases. Therefore, it was concluded that, as part of breast-conserving therapy of early-stage breast cancer, radiation therapy of the whole breast should be performed after surgery with clear margins to control local recurrence.

There have been few reports of coexistence of secondary hyperparathyroidism (2 degrees HPT) and thyroid carcinoma. Eleven consecutive patients with 2 degrees HPT who underwent parathyroidectomy were analyzed. They consisted of six males and five females, whose age ranged from 34 to 55 years. None of the patients had a history of irradiation of the head or neck. Associated thyroid nodules were also present in seven patients (64%): four patients with benign nodules, and three patients with papillary carcinomas, and one with papillary carcinoma and two follicular adenomas. This incidence of thyroid carcinoma in the patient group with 2 degrees HPT (36%) was significantly higher than that of the autopsy group in the same geographical area (11%). The level of carboxyl-terminal parathyroid hormone in the patients with thyroid carcinoma was higher than that in the patients without thyroid carcinoma (P less than 0.05). The importance of searching for possible thyroid cancer in patients with 2 degrees HPT should be emphasized.

Sixty-two breast carcinoma patients underwent mastectomy and were analyzed for correlations between estrogen receptor (ER) status of the tumor and the histological findings of tumor, age, nodal status, and tumor size. An immunocytochemical assay for the detection of ER in breast carcinomas was used to evaluate the staining intensity index (SII) of the ER level of the tumors, which was calculated from the staining intensity of cancer cells and the percentage of ER-positive cancer cells. The histological differentiation of carcinomas showed a strong correlation with the SII. A statistically significant (F = 10.580, P less than 0.0005) negative correlation was found between the grade of malignancy and the SII. Patients under 50 years of age tended to have a lower SII, whereas patients over 49 years of age tended to have a higher SII. The tumor size, and nodal status showed no correlations with the SII in any of the patients. The histological differentiation of the tumor cells showed a strong correlation with the heterogeneity of the distribution of ER-positive cells in breast cancers.

The purpose of this study was to investigate the biological behavior of male breast cancer. We evaluated 11 cases of male breast cancer with respect to tumor growth, extent of disease, hormone receptor status, and histological grade of the malignancy, in comparison with 241 cases of female breast cancer. The duration of symptoms was 8.6 +/- 9.1 months in males and 8.5 +/- 18.6 months in females. The incidences of stages I, II, and III were 46%, 27%, and 27%, respectively, in male breast cancer, and 38%, 49%, and 13% in female breast cancer. Metastasis to the lymph node was negative in 60% of the male patients and 54% of the female patients. All cases of male breast cancer were histologically grade I according to Bloom's classification; the histological grades were as follows for the female breast cancer cases: grade I in 99 patients, grade II in 87, and grade III in 55. The rates of hormone receptor positively were 89% for ER and 86% for PgR in male breast cancer, and 64% for ER and 44% for PgR in female breast cancer. Therefore, there was no significant difference in the growth of male breast cancer and female breast cancer, but in male breast cancer the rate of hormone receptor positivity was high, endocrine therapy was effective, and the histological grade was low. Accordingly, the result following appropriate treatment of male breast cancer should be at least comparable to the results with female breast cancer.

Fifteen fetal thymuses and 100 thymomas were examined concerning the degree of differentiation of thymic epithelial cells by light and electron microscopy. The following results were obtained. The embryologic process of the fetal thymus was categorized into four stages (8, 12, 15, and 17 weeks or more of gestation) based on the morphological features of epithelial cells and the maturity of thymic tissues. Thymomas were classified into the undifferentiated, and poorly, moderately, and well-differentiated types by their morphological features in comparison with the fetal thymuses. The incidences of the respective types in the 100 thymomas were 5, 16, 68, and 11 cases. The moderately differentiated type was divided into three subtypes; namely, polygonal cell (49 cases), clear cell (6), and spindle cell type (13). The degree of differentiation of the thymomatous epithelial cells showed strong correlations with both the invasiveness and the prognosis of the thymoma. The ratios of invasive thymomas were 36, 47, 25, and 100% for the well-differentiated, moderately-differentiated, poorly-differentiated, and undifferentiated types, respectively. The 10-year survival rates were 87.5, 62.5, 46.9 and 0% for the well-differentiated, moderately-differentiated, poorly-differentiated, and undifferentiated thymomas.

The aim of this study was to establish the role of estrogen receptor (ER) and progesterone receptor (PgR) as prognostic indicators for early recurrence and survival. In all, among breast cancer patients, 166 patients who had undergone radical or extended radical mastectomy were studied. These patients were treated with adjuvant chemotherapy alone for 2-3 years after surgery. No patients had adjuvant endocrine therapy. Local recurrence and/or distant metastases were treated by endocrine therapy and/or chemotherapy. The relapse-free interval was not different between the ER-positive and ER-negative patients. The postrelapse survival curve was significantly different between the two groups. There was no significant difference in the relapse-free interval and the postrelapse survival curve between the PgR-positive and PgR-negative patients. These results suggest that ER is a good predictor of the response to endocrine therapy given after relapse, but not of early recurrence.

Serum carbohydrate antigen (CA) 19-9 was present at high levels in pulmonary sequestration, mediastinal bronchogenic cysts, and mediastinal mature teratomas. The fluid in the cysts of the lesions contained a high level of CA 19-9. After operation, the titer of serum CA 19-9 returned to normal ranges. Histological studies showed that mucosal epithelium stained positively for CA 19-9. We speculate that CA 19-9 concentrated in the cystic lesion might flow into the peripheral blood. Carcinoembryonic antigen (CEA) was also present at high levels in the cyst fluid. CEA was positively stained in the epithelial cells using a polyclonal antibody but not a monoclonal antibody. The CEA detected at high concentration in the fluid was considered to be immunologically cross-reacting CEA.

Of 134 patients with thymoma, 79 (59%) also had myasthenia gravis (MG). The thymoma with MG differed from that in the absence of MG in the following aspects: The ratio of lymphocytes to epithelial cells in the tumor was larger, the polygonal cell type was more prominent (i.e., in 83% of the MG patients this cell type predominated), and the differentiation of epithelial cells in the tumor was more advanced in the group with MG than in the group without MG. Furthermore, the clinical stage of thymoma was earlier, the recurrence rate was lower, and the survival curve was better in the group with MG than in the group without MG. These findings suggest that the thymoma with MG is less malignant than that without MG.

The case of a 12-year-old girl with an anterior mediastinal tumor is reported. A mass grew rapidly and occupied the anterior mediastinum after menarche. Resected material was diagnosed as a mature teratoma. Both estrogen receptors and progesterone receptors were detected in the resected tissue. The titer of estrogen receptors was 2-11.3 femtomoles per milligram of protein and that of progesterone receptors was 9.5-15.7 fmol/mg protein. Based on these data, it was surmised that sex hormones may affect the growth of the tumor in this case. The change in sex hormones after menarche may have played a role in the rapid growth of this tumor.

We diagnosed eight (8.9%) lung cancer patients in 90 workers exposed to chromate compounds. The duration of exposure ranged from 8 to 31 years, with a mean value of 18 +/- 8 years. The histological classification was squamous-cell carcinoma in seven patients and adenocarcinoma in one patient. The site of origin of the primary tumors was located peripherally in two (25%) and centrally in six (75%). All but one of these patients underwent surgery. In three (37.5%) of these patients, lung cancer foci were detected during the postoperative follow-up by sputum cytology and bronchoscopy. Two of these three patients had multicentric cancer foci: double primary early squamous-cell carcinoma in one and early squamous-cell carcinoma + small-cell lung cancer in the other. In a high-risk group such as chromate workers, we should emphasize early detection of lung cancer by serial sputum cytology, chest x-rays, and bronchoscopy. Lung cancer patients with chromate exposure should be treated with due regard to the possibility of synchronous or metachronous cancer.

The prognosis of patients with stage III nonsmall cell lung cancer was studied, with special attention to their biologic status prior to lung resection. The biologic status was estimated from the neutrophil/lymphocyte ratio in the peripheral blood, serum albumin level, and erythrocyte sedimentation rate. Among 46 patients who underwent potentially curative operations, 31 cases of biologic status A or B (more than two parameters normal) revealed 37.6% of a 5-year survival rate, whereas there was no 5-year survivor in 15 cases of biologic status C or D (more than two parameters abnormal). Of the 5-year survival rate in T3N0 disease of biologic status A or B, the 60% surviving (of 10 cases) was in marked contrast to the same stage disease of biologic status C or D where only 1 patient (of 10 cases) was still surviving at more than 30 months. In 30 patients with T3N0, T3N1, and T2N2 diseases of biologic status A or B, where long-term survivors were derived, the 5-year survival rate in 30 patients of biologic status A or B was 36.6% in contrast to no long-term survivor in the same stage diseases of biologic status C or D (n = 25). We conclude that surgical results in stage III nonsmall cell lung cancer will be beneficial in patients of biologic status A or B, but nonbeneficial in patients with the same stage of biologic status C or D.