Melanoma antigen gene family (MAGE)-A4, a member of the cancer testis antigen family, has been reported in various cancers including melanoma, bladder, head and neck, oral, and lung, and is a potential target for T-cell-receptor–based immunotherapy. Baseline expression levels of the MAGE-A4 gene in thyroid cancer cell lines have not been previously studied thoroughly.Human thyroid cancer cell lines (8505c, HTh7, BCPAP, and TPC-1) were treated with either 10 μmol/L 5′-azacytidine (Aza) or 10 μmol/L 5-AZA-2′deoxycytidine (DAC) and evaluated for various MAGEA gene expression. Later melanoma cell lines A375 and 8505c were treated with PLX4720 in combination with DAC and evaluated for MAGE-A4 expression.Only BCPAP cells expressed moderate levels of MAGE-A3 and MAGE-A6 at baseline. Treatment with DAC/Aza induced the expression of MAGE-A4 and MAGE-A1 in 8505c cells. PLX4720 treatment did not affect MAGE-A4 expression in 8505c cells, but increased its expression in A375 cells. In contrast, addition of PLX4720 to DAC-treated 8505c cells decreased the previously induced MAGE-A4 expression by DAC in these cells. A similar decrease in MAGE-A4 expression by DAC was also seen in 8505cBRAF–/– cells. Although DAC treatment resulted in demethylation of the MAGE-A4 promoter in 2 CpG sites, PLX addition to DAC did not affect the demethylation status.Demethylating agents increased the expression of MAGE genes in thyroid cancer cells. The effect of BRAFV600E inhibitors on MAGE-A4 expression suggest the role of downstream MEK/BRAF signaling in its expression apart from promoter demethylation being the sole requirement. Expression of MAGE-A4 may make immunotherapeutic intervention possible in selected patients with thyroid cancer.

Background. Preoperative and intraoperative diagnosis of follicular carcinoma (FC), resulting in one-stage surgical treatment of follicular thyroid tumors, is an important issue in thyroid surgery.Methods. In the 10-year period there were 4158 operations performed on thyroid gland. There were 1559 patients with follicular tumors, 70 (4.4%) of them having FC. We analyzed the groups of patients with FC determined on frozen section (FS) and permanent section (PS) according to duration of clinical symptoms, ultrasound (US) examination, tumor size, patient gender and age, intensity of invasion, localization, and multiple or solitary occurrence of tumor.Results. FC was diagnosed in 39 (55.7%) patients on frozen section (IFS). Among the encapsulated (minimal invasion) carcinomas, the FS was accurate in 19 of 33 (57.6%) FC and in 5 of 15 (27.8%) Hurthle cell carcinomas (HCC); among extensively invasive carcinoma in 11 of 14 (78.6%) FC and in 4 of 5 (80.0%) HCC. FC was significantly more common in men (p < .001) and in the right lobe (p < .05). We did not find statistically significant differences concerning duration of symptoms, US examination, tumor size, patient age, and multiple or solitary occurrence of the tumor between the patients with FC diagnosed on FS and the patients with FC diagnosed on PS.Conclusions. The intraoperative diagnosis of FC is difficult. Although the percentage of false-negative results was relatively high (44.3%), there were no false-positive results. This means that the second operation was avoided in 55.7% of the patients, and no unnecessary thyroidectomies were performed. FS biopsy is an important method in surgery of follicular tumors. Improved technical support and the ability to analyze a greater number of slides will increase the accuracy of the method. (C) 2003 Wiley Periodicals, Inc.

By using monoclonal antibodies (mab) specific to HER-2 protein (Hercep Test DAKO, no. K5204), to MAGE family gene products (57B mab) (1) and to NY-ESO-1 (B9.8.1.1. mab) (2) an immunohistochemical analysis and comparison of the expression of these three antigens in cancer tissue in three groups of patients with invasive breast cancer was performed. All analyzed patients were treated at the University Hospital for Tumors, Zagreb, Croatia. 88 patients were studied. They were all operated, and had T1 to T3, N0 to N2, M0 tumors. As adjuvant therapy they all received postoperative irradiation and, if indicated, systemic therapy. In the majority of patients all these treatment modalities were performed in 1995. Regarding tumor relapse and the site of tumor relapse, based on the patients’ medical records from the Department of Radiation oncology after the minimum five years of the follow-up, these patients can be divided into three groups: a group without locoregional or bone metastases, a group with locoregional relapse, and a group with bone metastases. These three groups of patients were comparable in terms of tumor size, the number of involved axillary lymphnode metastases and tumor grade. Immunohistochemical analysis was performed on the patients’ archival paraffin embedded breast cancer tissues. MAGE antigen staining revealed a statistically significant difference in expression between the patients without locoregional relapse or bone metastases and the group with locoregional relapse (p=0.010). No significant difference was observed when these three groups of patients were compared for HER-2 or NY-ESO-1 expression. Obtained results confirm the observation (3) that the expression of MAGE gene products, detectable by routine immunohistochemical techniques on sentions could represent an important prognostic marker.

Parachordoma is a very rare soft tissue tumor with histological features similar to chordoma and chondrosarcoma. It should be distinguished from metastatic chordoma and extraskeletal myxoid chondrosarcoma because of its different treatment and prognosis. In this paper we report one case of parachordoma in a 20-year-old female patient. The tumor occurred in the subcutaneous tissue of the left hand as a painless, fixed, slow-growing mass. Pathologic analysis revealed a tumor composed of lobules of cells with variably vacuolated cytoplasm (physaliphorous cells) separated by fibrous septa, predominantly arranged in peculiar small or large alveolar structures. Immunohistochemistry showed positive staining of the tumor cells with cytokeratin 8/18, S-100 protein and vimentin. The patient is well and without recurrence 20 months after surgery.

MAGE (Melanoma antigen E) family gene products encompass tumour-associated antigens (TAAs) recognised by human leukocyte antigen (HLA)-restricted specific T-cells. Agents inducing DNA demethylation, an event typically detectable in cellular de-differentiation processes, were shown to induce the expression of MAGE genes. By using a monoclonal antibody specific for MAGE family gene products, we have studied the expression of these TAAs in a group of 144 patients with invasive ductal breast cancers. Immunohistochemical data were correlated with tumour differentiation, lymphatic vessel invasion, oestrogen receptor expression, intratumoural necrosis, lymphocytic infiltration, perineural invasion, tumour microcalcifications and axillary lymph node metastases. MAGE immunoreactivity was undetectable in non-neoplastic cells. In poorly differentiated cancers positive staining was observed in 30/63 cases (47.6%) as compared with 13/51 (25.4%) and 5/30 (16.6%) in moderately and well-differentiated tumours, respectively (P<0.05). In addition, MAGE immunoreactivity was significantly correlated with lymphatic vessel invasion and intratumoural necrosis. Moreover, a significant inverse relationship with oestrogen receptor expression was also observed. However, no significant correlation could be established between MAGE immunoreactivity and defined phenotypic characteristics of tumour infiltrating lymphocytes, including expression of CD3, CD4, CD8, CD20 or granzyme B. Thus, expression of MAGE family gene products in invasive ductal breast cancers appears to be associated with poorly differentiated histological phenotypes. These data support the concept of specific immunotherapy in highly aggressive forms of breast neoplasms. Furthermore, they suggest that MAGE immunoreactivity could represent a tumour marker of potential prognostic relevance.

The aim of this study was to determine the presence and histological grade of prominent ductal carcinoma in situ (DCIS) and the relationship between the histological grade of DCIS and the grade of invasive ductal carcinoma of the breast to local recurrence and survival. We have analysed 175 patients with stage I and II invasive ductal breast carcinoma who underwent breast-conserving therapy in the period 1987–1994. Patients were divided into those with carcinomas showing prominent DCIS (74 patients), and those with tumours without a DCIS component (101 patients). Ten patients developed recurrences and were treated by hormonal and/or chemotherapy. Local recurrence was observed in 2 (2%) patients without, and in 8 (10.8%) patients with prominent DCIS (χ2=12.954, P<0.005). There was a highly significant correlation between DCIS type and the histological grade of the infiltrating carcinoma (χ2=73.77, P<0.001). Our results suggest that the patients with poorly differentiated DCIS are significantly more likely to develop recurrence than patients with intermediately or well-differentiated DCIS.

In recent years, breast-conserving therapy and radiation therapy have become an important treatment option for patients with stage I and II invasive breast cancer. The results of long-term retrospective studies have demonstrated that this treatment can provide a high level of local tumor control with satisfactory cosmetic results. Numerous studies have shown that the presence of extensive intraductal component (prominent intraductal carcinoma) is highly associated with subsequent local recurrence. In this article we have stressed the value of the determination of the presence and the histologic grade of prominent intraductal component of invasive ductal breast carcinoma in the determination of the extent of surgery. We also point out the possibility of determination of prominent DCIS on frozen sections.

An unusual case of invasive ductal carcinoma of the breast associated with epitheloid granulomas is reported. Multinucleated giant Langhans'-type giant cells were found in the epitheloid granulomas in breast carcinoma, but there were not present in the breast tissue and axillary lymph nodes. Congo-red deposits were found haphazardly in the stroma between tumor cells and granulomas. Numerous mast cells were found surrounding granulomas. The patient lacked any clinical evidence of the systemic granulomatous disease. The presence of epitheloid granulomas, amyloid deposits and numerous mast cells in invasive breast carcinoma could be related to a host immune response towards the tumor.

Determination of pathohistologic diagnosis of encapsulated thyroid tumors, particularly follicular carcinoma, is sometimes very difficult, even for well-experienced pathologists. The analysis of intraoperative biopsies could be even more difficult. The importance of proper handling of bioptic material for correct interpretation of pathohistologic findings is not adequately stressed in our literature. In this article, we point out necessity of serial sections of encapsulated follicular tumors for correct diagnosis.

We report a case of salivary duct carcinoma in a 47-year-old woman. The patient presented with symptoms simulating acute appendicitis. Surgery revealed metastatic tumor in the wall of the small bowel. Two months later, a tumor of the right parotid gland was resected, and histologic analysis revealed a salivary duct carcinoma. To our knowledge, this is the first case of salivary duct carcinoma metastasizing to the small bowel with manifestations of metastatic disease as the prominent symptom.

The relationship between the grade of histologic differentiation of the tumor and estrogen (ER) and progesterone (PgR) receptor values was analyzed in 261 patients with breast cancer of the invasive duct type. There was a statistically significant difference in concentration and incidence of positive and negative ER and PgR with regard to histologic grade. The concentration and number of positive hormone receptors increased with better differentiation of the tumor. A statistically significant correlation between histologic grade, hormone receptor values and axillary nodal involvement was obtained only in patients with no metastases to axillary lymph nodes.

Histomorphological patterns of twenty primary medullary carcinomas of the thyroid were studied by light and polarized microscopy in relation to the content of calcitonin and thyroglobulin determined by the immunoperoxidase method: Out of 20 tumors, 10 showed classical, 7 glandular and 3 insular histomorphological pattern. In 19/20 cases, the cytoplasm of tumor cells contained various amounts of calcitonin, and the intensity of Immunoreaction was strong in 2/19, moderate in 7/19 and weak in 10/19 cases. Tumor stroma contained calcitonin in 7/20 cases. In 1/20 case, which did not show calcitonin immunoreactivity in the cell cytoplasm, the stroma contained a considerable amount of calcitonin. Thyroglobulin immunoreactivity was found in 4/20 tumors, 2 of them with classic and 2 with glandular histomorphological picture only in the cytoplasm of tumor cells. These tumors are considered medullary carcinomas with thyroglobulin immunoreactivity, since they do not fulfil the WHO criteria for "mixed medullary-follicular carcinomas".

Adenomas are the frequent tumors of the thyroid gland, which have different histological types, distinct criteria for pathohistological diagnosis, and distinct criteria for differentiation the follicular adenoma from follicular carcinoma of the thyroid gland. Authors have analyzed 63 patients with follicular adenomas of the thyroid gland which were diagnosed and treated at the Central Institute for Tumors and Allied Diseases in Zagreb in the period from 1986 to 1987, and on which had been done serial cuttings of the tumors for pathohistological diagnosis.

The authors describe angiosarcoma of the right breast, together with the pathohistologic and electron microscopic analysis and survey of the literature of this rare tumor. The greatest tumor diameter was 4.5 cms. Mastectomy and the axilla's dissection was performed and additionally, radiotherapy was undertaken. In the first biopsy the wrong diagnosis of ductal invasive carcinoma was made. Three years later a metastasis appeared in the left axilla when angiosarcoma was established. The revision of primary tumor of the right breast showed that previously it was angiosarcoma of the right breast, too. In this article the authors direct attention to the possibility of wrong diagnosis of benign or malignant tumor and list the results taken from the world literature. Following those results, the wrong diagnoses were made in 37% of the cases with breast angiosarcoma.

Hürthle cell tumors of the thyroid gland are rare. Their natural history remains incompletely understood what results in their different classification and therapy. The differentiation of benign from malignant Hürthle cell tumors is possible with classical, traditional histologic methods. Authors have analysed 53 patients with Hürthle cell tumor of the thyroid gland which were diagnostically evaluated and treated at the Central Institute for Tumors and Allied Diseases in Zagreb from 1975 to 1988.