Myofibroblastic stromal reaction and expression of tenascin-C and laminin in prostate adenocarcinoma.

The aim of this study was to analyse relationship between changes of the stroma and expression of tenascin-C (TN-C) and laminin in prostate carcinoma. Tenascin-C immunostaining was increased, and laminin decreased in carcinomas compared with peritumoral tissue and benign prostate hyperplasia (P<0.05). Statistical analysis confirmed connection between stromal changes and TN-C expression in prostate carcinoma (P<0.05). Gleason pattern 3 carcinomas showed more pronounced stromal reaction and TN-C expression compared with Gleason pattern 4 carcinomas (P<0.05). The main cells in prostate cancer stroma are myofibroblasts that are also responsible for tenascin production. Degradation of laminin was not connected with myofibroblastic stromal changes.

Primary glomangioma of the esophagus mimicking esophageal papilloma.

We report a case of glomangioma of the esophagus in a 28-year-old woman who presented with a 3-year history of vague discomfort, pain and heat in the neck. At initial gross examination, the tumor mimicked an esophageal papilloma. The resected esophageal specimen contained a polypoid, whitish-gray mass, which measured 3 cm in maximum diameter. Microscopically the tumor consisted of loose fibrovascular stroma heavily infiltrated with mononuclear inflammatory cells and covered with focally hyperkeratotic, parakeratotic and acanthotic squamous epithelium without atypia. In the deeper area immediately above the true muscular layer of the esophageal wall, microscopical examination revealed the neoplasm consisting of numerous, small-to-medium branched vessels covered by regular endothelium and filled with erythrocytes. The loose stroma around the vessels contained poorly circumscribed nests of small, round to oval cells with a uniform appearance. Immunohistochemically, the tumor cells were immunoreactive for smooth muscle actin and vimentin and non-immunoreactive for CD34, CD117, desmin, pan-cytokeratin, synaptophisin, neuron-specific enolase and S-100 protein. Despite its bland histology, the infiltrative growth pattern was suggestive of aggressive behavior; thus, an appropriate clinical follow-up was recommended. An accurate diagnosis and an understanding of the behavior of these rare tumors, especially in an unusual location, are crucial to their management and clinical outcome.

Correlation between Bcl-2 and Bax in atrophic and hypertrophic type of actinic keratosis.

BACKGROUND: Recent investigations consider actinic keratosis (AK) as an earliest visible pattern of squamous cell carcinoma (SCC). We have analysed the expression of apoptosis-related proteins TP53, Bcl-2 and Bax in 30 atrophic and 30 hypertrophic AK cases. MATERIAL AND METHODS: Immunohistochemical analysis was performed following microwave streptavidin immunoperoxidase protocol on DAKO TechMate Horizon automated immunostainer (DAKO, Copenhagen, Denmark). Monoclonal antibody for TP53 and Bcl-2 and polyclonal antibody for Bax (DAKO, Copenhagen, Denmark) were used. RESULTS: Expression of TP53 showed no significant differences between two analysed groups (chi2-test, P = 0.35636) whereas expression of Bcl-2 and Bax protein was significantly higher in atrophic compared to hypertrophic AK (chi2-test, P = 0.01458 and P = 0.00358, respectively). Comparison of Bcl-2 : Bax ratio in two analysed AK showed significantly higher value in hypertrophic compared to atrophic AK (Mann-Whitney U test, P = 0.02272). Statistical analysis did not show any correlation between patient's sex and age, localization and size of the lesion with expression of investigated oncoproteins (anova, P > 0.05). CONCLUSIONS: Our results may indicate higher resistance of keratinocytes on apoptotic stimuli in hypertrophic compared to atrophic AK. Thus, we suppose that keratinocytes in hypertrophic AK live longer and probably have higher propensity for additional mutations and conversion to overt SCC.

Renal artery changes in patients with primary renal cell carcinoma.

Arterial fibromuscular dysplasia (FMD) is a noninflammatory, nonatherosclerotic, occlusive condition of the systemic arteries, most frequently affecting renal arteries. Renal cell carcinoma (RCC) might be associated with arterial hypertension; however, there are no data in the literature regarding the relationship between RCC and associated renal artery changes. We analyzed a consecutive series of 57 (35 male and 22 female) patients aging from 35 to 79 years (mean 58.9 years) who underwent nephrectomy due to RCC in the year 2003. The patients had RCC measuring from 2 to 16 cm (mean 7.1 cm). Specimens were routinely fixed, embedded in paraffin, cut, and stained with hematoxylin and eosin, Mallory trichrome method, and orcein. Renal arteries of 26 patients (20 male, 6 female) showed no changes. In these patients, RCC measured 2.5-11 cm in largest diameter (mean 6.6 cm). In 24 patients (10 male, 14 female), renal arteries showed FMD. RCCs in these patients measured between 2 and 16 cm (mean 8.0 cm). Seven patients had atherosclerotic changes in renal arteries. In this series, FMD was found in a significant proportion of patients with RCC, mainly in women. The cause of such changes and their relationship with RCC and systemic hypertension should be further analyzed.

Sudden cardiac death due to physical exercise in male competitive athletes. A report of six cases.

In the period of 30 years, i.e. from 1973 to 2002, we noticed in Croatia 6 sudden and unexpected cardiac deaths in male athletes during or after training. Two were soccer players, 2 athletic runners, one was a rugby player and one was a basketball player. All of them were without cardiovascular symptoms. At the forensic autopsy, the first athlete, aged 29, had chronic myocarditis and thickened left ventricular wall of 15 mm. The second, aged 21, had an acute myocardial infarction of the posterior wall with normal coronaries and thickened left ventricular wall of 15 mm. The third aged 17, had hypoplastic right coronary artery and narrowed ascending aorta, suppurant tonsillitis and subacute myocarditis. Two athletes, aged 29 and 15, had hypertrophic cardiomyopathy and normal coronaries, and one dilated aorta. The sixth, aged 24, had arrhythmogenic cardiomyopathy of the right ventricle. All the 6 athletes died suddenly, obviously because of malignant ventricular arrhythmias. In Croatia the death rate among athletes reached 0.15/100 000, in others who practice exercise reached 0.74/100,000 and the difference is highly significant (c2=14.487, Poisson rates=3.81, P=0.00014) and in physicians-specialists reached 33.6/100,000. Preventive medical examinations are essential, especially in athletes before physical exercise, as are other investigations in every case suspicious of heart disease, including electrocardiogram (ECG), stress ECG, echocardiography and stress-echocardiography and other findings if indicated. Physical exercise is contraindicated in acute respiratory infection: in 2 of those cases had been a cause of death as a trigger.

[Carcinoma of the urinary bladder resembling lymphoepithelioma]. / Karcinom mokracnog mjehura slican limfoepiteliomu.

Lymphoepithelioma-like carcinoma of the bladder is rare and has only recently been described at this site. We report a case of lymphoepithelioma-like carcinoma of the urinary bladder in a 70-years old male patient who presented with painless hematuria lasting for one month. The patient underwent transurethral resection two times. Histopathologic diagnosis was transitional cell carcinoma. Histopathologic examination of the third biopsy showed tumor tissue with typical syncitial growth pattern of atypical, large, epitheloid cells with ill-defined cytoplasmic borders, prominent nucleoli and numerous mitoses. A prominent lymphocytic infiltrate was found as a component of the tumor. Immunohistochemistry showed positive reaction for cytokeratin and epithelial membrane antigen, and negative results for leukocyte common antigen, CD3, CD20, CD30, CD68 and PSA. The lymphoid infiltrate was an admixture of T and B cells. The tumor invaded the muscle wall. After last surgery the patient underwent chemotherapy by local application of Adriablastine. At present the patient is without recurrence 10 months after the last surgery.

Correlation between vimentin expression and morphological features of renal cell carcinoma.

The aim of this study was to analyze the correlation between the expression of vimentin and morphological features of renal cell carcinoma (RCC). We analyzed tumor tissue of 20 patients with RCC. There were 13 female and 7 male patients with RCC confined to the kidney (pT1, pT2). They were ranging in age from 36 to 80 years (mean age 60.6 years). Thirteen tumors measured > 5 cm and 7 tumors < 5 cm in diameter. Two tumors were papillary and 18 tumors showed a non-papillary pattern. Six tumors were composed of granular cells and 14 tumors of clear cells. Formalin fixed, paraffin-embedded tumor tissue was cut at 5 microns, deparaffinized, and stained with a monoclonal antibody to vimentin (Dako, Denmark). There were 4 tumors with nuclear grade I, 3 with grade II, 11 with grade III, and 2 with grade IV. Histopathologic examination showed vimentin expression in eight cases (40%), while 12 tumors (60%) were negative. Positive reaction for vimentin was observed in all four grade I tumors, none of three grade II tumors, four of 11 grade III tumors and in none of 2 nuclear grade IV tumors. In our study, there was no statistically significant difference between the expression of vimentin and morphologic features of RCC. Our study showed the lack of correlation between the expression of vimentin and nuclear grade, cell type and histologic pattern of RCC. Further studies on a larger series of tumors as well as follow-up of patients are obviously needed.

Basaloid squamous cell carcinoma of the larynx: report of two cases.

AIM: To present two patients with basaloid squamous cell carcinoma of the larynx, a rare, highly aggressive variant of the squamous cell carcinoma. METHODS: Surgical excision of the polypoid tumor of the anterior comissure of the larynx was performed in a 62 year-old male, and in the second case, total laryngectomy with radical dissection of the neck was performed in a 66 year-old male with supraglottic tumor of the larynx and enlarged lymph nodes of the neck. Histopathological analysis of biopsy specimens was performed on routine hematoxylin-eosin stained sections and on sections stained with antibodies to cytokeratin, epithelial membrane antigen, S-100 protein, neuron-specific enolase, and chromogranin. RESULTS: In both cases, the tumors were composed of moderately pleomorphic basaloid cells forming nests, cords, and cribriform patterns with foci of necrosis, squamous differentiation, and small cystic spaces containing mucin-like material. Surface mucosa showed squamous dysplasia. Cytokeratin and epithelial membrane antigen were positive. After surgery, both patients recieved radiotherapy and had no signs of tumor recurrence or metastases 12 and 15 months later, respectively. CONCLUSION: Basaloid squamous cell carcinoma has a potential for diagnostic confusion because of its basaloid and squamous component. It should be distinguished from adenoid cystic carcinoma that is much less aggressive.

Apoptosis in human gastric polyps and adenocarcinomas: a stereological analysis.

BACKGROUND/AIM: The occurrence of apoptotic cells was analyzed in human normal gastric mucosa, polyps and adenocarcinomas. METHODOLOGY: Histological classification was carried out on hematoxylin and eosin stained slides. The tissue was classified as follows: Normal gastric mucosa or adenomatous polyps. Gastric carcinoma specimens were histologically classified according to Lauren's classification into: A: Diffuse adenocarcinoma without metastasis, B: Diffuse adenocarcinoma with metastasis, C: Intestinal adenocarcinoma without metastasis, D: Intestinal adenocarcinoma with metastasis, E: Mixed adenocarcinoma without metastasis and mixed adenocarcinoma with metastasis. The counting of apoptotic cells was performed using the 40X objective with a calibrated eyepiece Weibel's multi-purpose M 42 stereological test system. Each group was evaluated stereologically, determining numeric density of apoptotic cells. RESULTS: The results show the progressive and statistically significant increase of apoptotic numeric densities from normal gastric epithelium to adenomatous polyp and finally to cancer, which contained the highest number of apoptotic cells. Comparing gastric carcinoma with and without metastasis in intestinal and diffuse adenocarcinoma there was statistically significant difference. In these two groups, carcinomas with metastasis contained higher number of apoptotic cells than without metastasis. Gastric cancer according to numeric densities of apoptotic cells can be separated in tree statistically different groups: A: Intestinal type gastric cancer with metastasis (the highest number of apoptotic cells), B: Intestinal type gastric cancer without metastasis and diffuse gastric cancer with metastasis (medium number), C: Diffuse type gastric cancer without metastasis, mixed gastric cancer with and without metastasis (the lowest number of apoptotic cells). CONCLUSION: These results suggest that numeric densities of apoptotic cells are associated with tumor progression in human gastric carcinogenesis and can be used as prognostic mark.

Epithelial hyperplastic lesions of the larynx in biopsy specimens.

Surgical biopsy files for the period 1991-92 were reviewed to determine the relative proportion and types of epithelial hyperplastic lesions of the larynx as well as sex and age distribution and correlation between clinical and histopathological diagnoses. In this period 203 laryngeal biopsies from 187 patients were analyzed. Epithelial hyperplastic lesions were found in 42 males and 9 females. There were 39 cases with keratosis and 12 cases showing keratosis with atypia. Correlation between clinical diagnoses and pathohistological findings was established in only 5 cases (9.8%), clinically diagnosed as leukoplakia; an additional 5 cases (9.8%) were clinically diagnosed as chronic laryngitis. The majority of clinical diagnoses in cases with epithelial hyperplastic lesions were laryngeal neoplasm (29, 56.9%) followed by laryngeal polyp in 9 cases (17.6%). We conclude that for correct diagnosis the biopsy should be performed in all patients with clinical symptoms showing laryngoscopic alterations that suggest a potentially malignant lesion.

Multiple genetic alterations in malignant metastatic insulinomas.

Proto-oncogenes, growth factors/receptors, and tumour suppressor genes were analysed in malignant metastatic insulinomas. Normal pancreas showed only a moderate immunoreaction for c-myc proto-oncogene and a strong reaction for insulin. Benign insulinomas were slightly or moderately positive for transforming growth factor alpha (TGF alpha), weakly positive for epidermal growth factor receptor (EGF-R), and strongly positive for c-myc and insulin. In malignant insulinomas, besides a strong immunoreaction for c-myc and TGF alpha, activation of c-K-ras and overexpression of p53 protein were found. Insulin reaction was moderate or strong. Three out of six malignant insulinomas displayed a c-K-ras point mutation at codon 12. All mutations were guanine to cytosine transversion, resulting in amino acid substitution, glycine to arginine. Mutations were present in metastatic insulinomas only. Patients with mutated c-K-ras oncogene had overexpression of p53 protein as well as c-myc and TGF alpha overexpression. Our results support the view that malignant progression is a consequence of more than one genetic lesion and suggest that activation of myc, TGF alpha an ras genes plays a role in a multistep process of tumour progression, perhaps serving as an initiating event.

Balkan endemic nephropathy: still a mysterious disease.

Balkan endemic nephropathy (BEN) is an acquired, environmental, polytopical disease of the entire urinary tract, with long latency. Tubulointerstitial chronic nephritis, urotheliomas of all localities, and renal cell carcinoma occur with a significantly higher frequency in the affected population. These represent only clinical manifestations of one unique nosological entity. BEN occurs in focuses. Within them, it agglomerates in households, without any evidence of hereditary background. Patients with various clinical manifestations of the disease can be simultaneously found within one single household. BEN appears equally among members of different ethnic groups. Its aetiology is not clear enough. There is no evidence of a causal relationship with silicon compounds, heavy metals and viruses. Much attention has been recently focused on research of the aetiological role of mycotoxins, mainly ochratoxin A. Toxic and carcinogenic agents of natural origin are commonly accepted as the major cause of BEN.

Interferon reduces recurrences of basal cell and squamous cell cancers.

BACKGROUND: Interferon is considered to be an important curative agent for dermatologic diseases. We report the follow-up experience of patients with basal cell or squamous cell carcinomas treated with human natural leukocyte interferon (HNLI). RESULTS: Among 52 patients with basal cell carcinoma (BCC) treated with HNLI more than 10 years ago, and among 58 treated more than 5 years ago, only 2 recurrences were observed. There were no recurrences in 75 patients who had a complete response to HNLI treatment, nor were there any in 20 patients with either a partial or complete response to r.IFM alpha 2c treatment. Of 52 patients with squamous cell carcinoma (SCC), 31 had been treated more than 10 years earlier, two recurrences of the disease at the site of the original lesion were observed. CONCLUSION: Interferon treatment makes it possible to achieve a persistent cure in patients with BCC and SCC in a high proportion of cases. The potential advantage of nonsurgical treatment are an enhancement of cosmetic results through the prevention of destruction of important anatomic structures.

[Interferon in the treatment of solid tumors]. / Interferon u lijecenju solidnih tumora.

Discovered almost four decades ago, interferons were being investigated as potential anticancer agents from early sixties, because of their antiviral antiproliferative and immunomodulating properties and their relatively modest toxicity. Unlike very good effects on some lymphoproliferative disorders where complete durable remissions were observed, results of their application in solid tumors are not so unambiguous. Among large number of tumors investigated so far, the best, reproducible, although modest, activity was found against melanoma, renal cell carcinoma and Kaposi's sarcoma. There are still many doubts concerning their optimal doses, sequencing and schedules, most probably in combination with other biological response modifiers and/or cytotoxic agents, which have to be clarified in further clinical trials, together with investigation of more reliable biological indicators of response to interferons in vivo.

Pathomorphology of Balkan endemic nephropathy.

Within the county of Slavonski Brod, Yugoslavia hyperendemic areas of Balkan endemic nephropathy (BEN) have been recognized for a long time. As the Department of Pathology and Forensic Medicine of the Medical Centre in Slavonski Brod is responsible for all diagnostic post-mortem examinations in the county, and at the same time is engaged in surgical pathological diagnosis, a considerable amount of material relating to BEN and concomitant urinary-tract tumours has been collected during a 16-year period. This material has been classified and used for pathological, anatomical and histological investigations. In this paper the most relevant findings are described and briefly discussed, without the intention to speculate on possible aetiology of BEN. As the origin of BEN and of the high frequency of urinary tumours among the people from the endemic areas are still unexplained, and uniform criteria for the pathomorphological diagnosis of BEN are badly needed, the proposal to set up an archive encompassing cases from all the centres investigating BEN is supported.

Basal cell carcinoma treated with interferon.

Human natural leukocytic interferon (HNLI) and recombinant interferon (rIFN) alpha 2c can be used in the therapy of basal cell carcinoma. Seventy-two patients were treated for 3 to 6 weeks with a single dose of 400,000 to 1,200,000 units (HNLI) and 2,000,000 to 5,000,000 units (rIFN alpha 2c). According to histopathologic and clinical findings, 52 patients were cured, and cancer cells were not found in the biopsy material taken after HNLI treatment for the second biopsy. In nine of 72 patients the cancer lesion was reduced 25% to 90%. In 11 patients it was not reduced or was reduced less than 25%. With rIFN alpha 2c therapy given five times per week for 4 weeks, histopathologic and clinical findings showed that five patients out of 12 were cured, and cancer cells were not found in the biopsy material taken after treatment. In seven patients out of 12 the cancer lesion was reduced 25% to 90%. Both types of interferons are effective in the treatment of basal cell carcinoma. Side effects were mild.

Interferon therapy for basal cell carcinoma and squamous cell carcinoma.

Totally 161 basal cell and squamous cell carcinoma (BCC, SCC) patients were treated with human natural leucocytic interferon (HNLI) and recombinant IFN alpha 2c. After HNLI treatment, 61 out of 86 BCC patients and 29 out of 45 SCC patients were cured according to histopathologic and clinical findings. In 13 BCC and 13 SCC patients, the cancer lesion was reduced 25%-90%. After recombinant IFN alpha 2c treatment, 14 of 20 BCC patients and 4 of 10 SCC patients were cured according to histopathologic and clinical findings. In 6 BCC patients and 5 SCC patients the cancer lesion was reduced 25% to 90%. Both types of interferons are effective in the treatment of BCC and SCC patients. Local application of interferon stimulates immune reaction at the site of the tumor. There is a marked difference between the spontaneous macrophage activity and that induced by interferon. The interferon activated macrophages are significantly larger, the number of lysosomes and the density of macrophages is increased. In difficult locations intralesional therapy can be considered to avoid disfigurement of the patients with or without surgery.