Rapidly-growing hemangioma of the testicle clinically simulating an aggressive neoplasm. A case report.

We present a case of intraparenchymatous capillary-type hemangioma of the testicle in an adult. The patient was a 37-year-old man who showed a rapidly enlarging and palpable mass in left testicle. Radical orchiectomy was performed, and histological examination revealed an unencapsulated lobulated tumour with wide hemorrhagic portions. To our knowledge, the occurrence of rapid enlargement in a testicular hemangioma has not been previously reported, which might be explained by the development of intra-tumoural haemorrhage.

Giant genital cavernous haemangioma: case description and surgical management.

Giant genital haemangiomas are rare occurrences. Once properly diagnosed, they should be managed by surgery with wide and deep margins. We present a clinical case and provide suggestions for diagnosis and treatment of this unusual pathology.

Well-differentiated giant scrotal liposarcoma: case presentation and management.

Scrotal liposarcoma is an uncommon disease, usually found after the fifth decade. We describe the case of a well-differentiated scrotal liposarcoma associated with a considerable inflammatory reaction, treated with surgical ablation.

Opposite patterns of age-associated changes in neurons and glial cells of the thalamus of human brain.

In an autopsy series of 19 individuals, age-ranged 24-94, a relatively age-spared region, the anterior-ventral thalamus, was analyzed by immunohistochemical techniques to visualize neurons (neurofilament protein), astrocytes (glial fibrillary acidic protein), microglial cells (CD68) and amyloid precursor protein. The pattern of immunoreactivity was determined by surface fractal dimension and lacunarity, the size by the field area (FA) and the spatial uniformity by the uniformity index. From the normalized FA values of immunoreactivity for the four markers studied, a global parameter was defined to give an overall characterization of the age-dependent changes in the glio-neuronal networks. A significant exponential decline of the GP was observed with increasing age. This finding suggests that early in life (age<50 years) an adaptive response might be triggered, involving the glio-neuronal networks in plastic adaptive adjustments to cope with the environmental challenges and the continuous wearing off of the neuronal structures. The slow decay of the GP observed in a later phase (age>70 years) could be due to the non-trophic reserve still available.

Epidemiology of colorectal cancer: the 21-year experience of a specialised registry.

UNLABELLED: Cancer registries can be viewed as one of the main strategies for improving our understanding of cancer, as they may reveal the importance of specific trends in cancer incidence and survival; in addition, the information obtained from the registries can be translated into preventive measures that might lead to a better control of neoplasms. A colorectal cancer registry was instituted in Northern Italy in 1984. The purpose of this study is to provide a description of the main findings observed in a 21-year period of continuous registration. RESULTS: A total of 3951 malignancies of the large bowel were registered in 3817 patients, for a crude incidence rate of 75.1/100 000/year in men and 59.0 in women. Overall incidence (crude and age-adjusted) of colorectal tumours increased remarkably throughout the registration period. This increase was mainly due to early (Stage I and II) tumours and to lesions with lymph nodal involvement (Stage III). There was a tendency over time towards a progressive increase of colonic tumours, whereas the fraction of rectal neoplasms tended to decline. Colorectal cancer-specific survival increased significantly over time in each of the main TNM/Dukes classes (p<0.006 and <0.001 for Stage II and III tumours). Finally, surgery for colorectal tumours showed a tendency towards large operations (colectomy and hemicolectomy), which was parallel to a definite improvement of pathological staging. CONCLUSIONS: Despite the increasing incidence of colorectal cancer, there are several reasons for cautious optimism. Most of the lesions are now diagnosed at an early stage, and this is associated with a significant increase of survival. The disease is undoubtedly cured better than in the past; the main challenge for future years is to achieve a sustained reduction of mortality for colorectal neoplasms.

Frequency of constitutional MSH6 mutations in a consecutive series of families with clinical suspicion of HNPCC.

A large majority of constitutional mutations in hereditary non-polyposis colorectal cancer (HNPCC) are because of the MHL 1 or MSH 2 genes. In a lower fraction of cases, another gene of the mismatch repair (MMR) machinery, MSH6, may be responsible. Families with MSH6 mutations are difficult to recognize, as microsatellite instability (MSI) may not be detectable and immunohistochemistry (IHC) may give ambiguous results. In the present study, we proposed (i) to determine the frequency of MSH6 mutations in a selected population of colorectal cancer patients obtained from a tumor registry, (ii) to assess whether IHC is a suitable tool for selecting and identifying MSH6 mutation carriers. One hundred neoplasms of the large bowel from suspected HNPCC families were analyzed for MSI (BAT 25 and BAT 26 markers) and immunohistochemical expression of the MSH6 protein. We found on 12 tumors (from different families) showing instability or lack of MSH6 expression. Among these, four potentially pathogenic MSH6 mutations were detected (del A at 2984; del TT at 3119; del AGG cod 385; and del CGT cod 1242) by direct gene sequencing. These represented 12.9% of all families with constitutional mutations of the DNA MMR genes. Thus, some 5% of all HNPCC families are featured by constitutional mutation of the MSH6 gene. This appears, however, as a minimum estimate; routine use of IHC and the study of large numbers of individuals and families with little or no evidence of Lynch syndrome might reveal that mutation of this gene account for a large fraction of HNPCC.

Primary paraganglioma of the thyroid gland.

We describe the case of a 46-yr-old euthyroid woman, who was submitted to right lobectomy plus isthmusectomy because of a 30 mm large, rapidly growing thyroid nodule. Two cytological examinations of fine needle aspiration biopsy (FNAB) specimens were not diagnostic. Histology showed a neoplasm composed of nests of chief cells, almost completely replacing thyroid parenchyma, infiltrating the capsule and surgical resection margins, and invading perithyroid tissues. Immunohistochemical analysis revealed that the tumor stained positively to chromogranin, synaptophysin, NSE, S-100 protein and tyrosine hydroxylase, whereas no immunoreactivity was detected against cytokeratin, thyroglobulin, TTF-1, calcitonin and CEA. A diagnosis of thyroid paraganglioma (PG) was finally made. No complications developed following operation. Laboratory analysis and imaging study excluded multicentric disease, metastases to neck or extracervical organs, and multiple endocrine neoplasia (MEN). We report this unusual case, underscore its clinical and immunohistochemical features and discuss differential diagnosis.

Riedel's thyroiditis and fibrous variant of Hashimoto's thyroiditis: a clinicopathological and immunohistochemical study.

The aim of this study was to analyze and compare clinico pathological aspects of Riedel's thyroiditis (RT) and the fibrous variant of Hashimoto's thyroiditis (HTFV), and to show their immunohistochemical features. We reviewed 6 cases of HTFV and 4 cases of RT. Compared to RT, HTFV patients had hypothyroidism, no pressure symptoms, and frequently diagnostic fine-needle aspiration biopsy (FNAB) cytology. At histology, invasion of surrounding tissues and presence of occlusive phlebitis distinguished RT from HTFV. At immunohistochemistry, RT--compared to HTVF--was characterized by: 1) a more abundant fibrous reaction, and granulocytic, monocytic and eosinophil infiltration; 2) few plasma-cells, CD8+ T- and B-lymphocytes. The results of our study add further evidence regarding the separation of RT and HTFV in their peculiar clinical, laboratory, cyto-histological and immunohistochemical aspects.

P27Kip1 expression and survival in NO gastric carcinoma.

p27Kip1, a cyclin-dependent kinase inhibitor, is considered to be a tumor suppressor gene. Absent or reduced expression of the p27Kip1 protein has been reported being a negative prognostic marker in primary lung, breast, colon, bladder, and prostate carcinomas. p27Kip1 protein expression was evaluated in a series of 96 gastric carcinomas with no lymph node involvement (NO) to verify any impact on the clinical outcome. The analysis also considered the classic clinico-pathological parameters, such as age, sex, and depth of tumor invasion (pT). The most widely used classification systems for gastric carcinoma were adopted. The expression of p27pKip1 was related neither to the pT category nor to tumor histology. Kaplan-Meier analysis documented a significant impact of an advanced pT category (p < 0.0001) and p27Kip1-reduced expression (p < 0.0002) on survival. Multivariate analysis confirmed that the reduced p27Kip1 protein expression was a strong independent predictor of poor outcome, ranking second to the pT category only (p < 0.006 and p < 0.004 respectively). As reported for other neoplasms, the expression of p27Kip1 appears to be associated with the clinical outcome of gastric carcinoma.

Expression of p53 and bcl-2 in clinically localized prostate cancer before and after neo-adjuvant hormonal therapy.

The prognostic significance of p53 and bcl-2 expression in prostate carcinoma is currently under investigation. The aim of the present study was to analyze their expression in diagnostic biopsies and in prostatectomies performed after neo-adjuvant hormonal therapy to investigate their role in hormone resistance. One hundred and six patients with advanced prostate carcinoma were treated for 3 months with LHRH analogues before radical surgery. The expression of p53 and bcl-2 was analyzed by immunohistochemistry in all cases of prostatectomy and in available biopsies obtained before treatment, and was correlated with clinicopathologic parameters and follow-up. A significant increase in p53 expression was found following hormonal therapy, whereas no changes were observed in the expression of bcl-2. The increase in p53 did not correlate with the presence of therapy-induced morphological changes in prostate cancers, but it did correlate significantly with histologic grade and pathologic stage, biochemical progression of the disease, and short overall survival. At multivariate analysis, only grade and stage proved to be independent predictors of shorter survival. There were no correlations between bcl-2 and clinicopathologic variables whether in biopsies or in prostatectomies. The unfavorable clinical course associated with p53-positive carcinomas suggests that neo-adjuvant hormonal therapy may cause the selection of minor p53 mutated clones, rather than the induction of wild-type p53. In any case, the enhanced expression of p53 could label hormone-resistant cancers for further adjuvant therapy.

Loss of p21Waf1 expression is a strong predictor of reduced survival in primary superficial bladder cancers.

p21Waf1 is a downstream effector of p53 and belongs to the Cip1/Kip1 family of cyclin-dependent kinase inhibitors. Thus, it is a potential tumor suppressor gene and likely plays an important role in tumor development. Moreover, reduced expression of p21Waf1 has been reported to have prognostic value in several human malignancies. In this study, we evaluated the prognostic value of p21Waf1 in bladder cancer compared with other clinicopathological features and with p27Kip1 and p53 expression. A total of 96 superficial (pTa-1) human bladder carcinomas were immunohistochemically stained for p21Waf1 protein expression. Positive p21Waf1 staining (> or =5% positive nuclei) was observed in 68 of the 96 (71%) tumors. p21Waf1 expression was neither associated with tumor stage (P = 0.9) nor with tumor grade (P = 0.18) but was significantly associated with both p53 protein expression (> or =20% positive nuclei; P = 0.007) and with p53 gene mutations (P = 0.017). A significant correlation was also observed between positivity for p21Waf1 and high (>50% positive cells) p27Kip1 expression (P = 0.04). With regard to prognosis, patients whose tumors showed absence of p21Waf1 staining displayed a significantly shorter overall survival (P = 0.01 by log-rank test). However, p21Waf1 expression did not correlate with disease-free survival (P = 0.15 by log-rank test). On a multivariate analysis that also included p53 and p27Kip1 expression, negative p21Waf1 staining was an independent predictor of reduced overall survival (P = 0.004; relative risk, 5.32), stronger than age and tumor stage. These data indicate that expression of p21Waf1 protein strongly correlates with survival and might represent a useful prognostic marker in primary superficial bladder carcinomas.

Loss of p27Kip1 expression is a strong independent prognostic factor of reduced survival in N0 gastric carcinomas.

BACKGROUND: p27KiP1 is a cyclin-dependent kinase inhibitor and is a potential tumor suppressor gene. Reduced expression of p27Kip1 is a powerful negative prognostic marker in primary lung, breast, colon, bladder, and prostate carcinomas. In the current study, the prognostic value of p27Kip1 in gastric cancer was evaluated and compared with other histopathologic parameters and p53 expression. METHODS: p27Kip1 and p53 protein expression were determined by immunohistochemistry in 96 gastric carcinomas. The tumors were from a low incidence population and were selected for the absence of lymph node involvement. RESULTS: Reduced expression of p27KiP1 (< or = 50% positive cells) and nuclear p53 accumulation (> 30% positive cells) were observed in 67 (69.8%) and 9 (9%) tumors, respectively, and were not related to either the pT category or tumor histology. Kaplan-Meier analyses revealed a significant impact on survival by p27Kip1 (P = 0.0001 by log rank test), p53 (P < 0.0001) expression, and the pT category (P < 0.0001). On multivariate analysis, reduced p27Kip1 protein expression was the strongest independent predictor of reduced survival (P = 0.005; relative risk = 3.348) out weighing the pT category (P = 0.010; relative risk = 2.257) and p53 overexpression (P = 0.016; relative risk = 2.618). CONCLUSIONS: These data indicated that immunohistochemical detection of p27Kip1 could help to identify gastric carcinoma patients who are at high risk of death, even in the absence of lymph node involvement, and who might benefit from an adjuvant treatment following surgery.

Loss of P27Kip1 expression correlates with tumor grade and with reduced disease-free survival in primary superficial bladder cancers.

p27Kip1 is a member of the Cip1/Kip1 family of cyclin-dependent kinase inhibitors and is a potential tumor suppressor gene. We previously reported a deregulated expression of p27Kip1 in a series of human cancer cell lines and in primary breast and colon cancers. Moreover, p27Kip1 has been reported as an important prognostic factor in primary lung, breast, colon, and prostate cancers. In this study, we evaluated the prognostic value of p27Kip1 in a series of 96 superficial (pTa-1) human bladder carcinomas. High (>50% positive cells), moderate (25-50%), and low (<25%) p27Kip1 staining was observed in 39 (41%), 19 (20%), and 38 (39%) of the 96 primary superficial bladder cancers, respectively. No significant association was found between the expression level of p27Kip1 and tumor stage. Decreased p27Kip1 staining correlated with higher tumor grade (P = 0.001). Interestingly, a significant association was observed between increased expression of p27Kip1 and positivity for p53 (>20% positive cells; P < 0.001). A significant correlation was also observed between low expression of p27Kip1 and decreased disease-free survival (P = 0.0003 by log-rank test) and overall survival (P = 0.01 by log-rank test). Furthermore, on multivariate analysis, low p27Kip1 protein expression was an independent predictor of reduced disease-free survival (P = 0.018; relative risk = 1.95) second only to tumor stage. These data indicate that p27Kip1 protein is frequently expressed at low level in poorly differentiated tumors and suggest that this protein might represent a useful prognostic marker for disease recurrence and overall survival in superficial bladder carcinomas.

Detection of human papillomavirus DNA in urinary bladder carcinoma by in situ hybridisation.

AIMS: To investigate the sensitivity of an in situ hybridisation system to detect human papillomavirus (HPV) infection in transitional cell bladder cancer and to evaluate the advantages of analysing multiple biopsies; to examine the correlation between HPV tumour infection detected by in situ hybridisation and the presence of serum anti-HPV antibodies detected by enzyme linked immunosorbent assay (ELISA); and to relate the presence of viral infection to grade, stage, and follow up in cases of bladder cancer. METHODS: The in situ hybridisation technique was used with broad spectrum and type specific (6/11, 16/18, 31/33/35) probes against HPV DNA in formalin fixed, paraffin embedded tissues from 43 cases of bladder cancer. The results were analysed for the presence and type of papillomavirus and correlated with clinicopathological variables. RESULTS: The presence of HPV DNA was identified by the in situ hybridisation technique in 17 of 43 cases of bladder cancer; 12 of these were serum antibody positive and 10 had had multiple biopsies. Fifteen of the cases that were negative for HPV DNA by in situ hybridisation had positive serum serology when tested by ELISA. In 14 cases, the HPV was either types 16/18 or types 31/33/35, both of which carry high oncogenic risk. The stage (p < 0.05) and grade (NS) of the tumour and the outcome on follow up (p < 0.05) were correlated with the presence of HPV infection. CONCLUSIONS: ELISA is not useful in identifying patients with HPV positive bladder cancer, but the use of several probes and multiple biopsies increases the detection rate of HPV in neoplastic tissues. The association between tumour virus infection and high grade/high stage tumours and worse outcome suggests that HPV infection of neoplastic tissue has a negative effect on the behaviour and evolution of transitional cell bladder carcinoma.

Analysis of 4-ABP-DNA adducts and p53 alterations in urinary bladder carcinoma.

BACKGROUND: Activated intermediates of 4-aminobiphenyl (4-ABP) are able to covalently interact with DNA to form adducts. There is a large body of evidence indicating that carcinogen-DNA adduct formation can be one of the cancer initiating mechanisms. MATERIALS AND METHODS: (4-ABP)-induced DNA damage in association with p53 overexpression and mutations were evaluated in specimens of urothelial bladder cancers from 106 patients. RESULTS: 4-ABP-DNA adduct levels resulted higher in smokers compared to non smokers, with a borderline statistical value. p53 nuclear overexpression was related to tumor grading, while no significant correlation with stage, 4-ABP-DNA adducts, smoking habit, and disease recurrence could be observed. Concerning molecular analysis, p53 point mutations were found in 17 of 106 cases (16%) and mutational pattern was significantly associated both with higher grade and stage, but no correlation was found with disease recurrence. CONCLUSIONS: These results suggest that other sources, in addition to tobacco smoke, may contribute to 4-ABP-DNA adducts formation in bladder tissue and that p53 expression/mutation cannot be considered a prognostic factor in bladder cancer.

Does p53 immunostaining improve diagnostic accuracy in urine cytology?

The frequent change of the transitional cell carcinoma of the urinary tract accounts for the fact that cytological abnormalities in urinary specimens are often not sufficient to enable a definitive diagnosis of malignancy. The purpose of this work was to evaluate the possible use of p53 protein in increasing the diagnostic accuracy of urinary cytology. The expression of p53 was investigated by immunocytochemistry in two groups of urinary specimens, one cytologically positive and the other cytologically negative for cancer. Immunostaining was carried out using a monoclonal antibody to p53. In the positive group, in which bladder cancer was confirmed by cystoscopy and biopsy (31 cases), positive reaction for p53 was found in 55% of the cases (17 cases). In the negative group (92 cases), presence of cancer was histologically ascertained in 64 cases and in this group 15 cases (23.4%) showed positive p53 staining. In the remaining 28 cases of this group, where TCC was not present, 7 cases showed p53 positivity in non-neoplastic urothelial cells. This result shows that, while immunocytochemical detection of p53 in urinary specimens may be used for prognostic evaluation of patients with bladder cancer, it does not contribute to the diagnostic accuracy in cases with morphologically inconclusive or negative cytology. The sensitivity and specificity of the method in detecting bladder carcinoma were 23.5 and 75%, respectively.

[Molecular biology in bladder carcinoma: contributions of immunohistochemistry]. / Biologia molecolare nel carcinoma vescicale: contributi di immunoistochimica.

Despite the insights genetics and molecular biology have given to a better understanding of the mechanisms which lead to the onset and development of bladder carcinoma, the factors that influence its unpredictable and, at times, particularly aggressive outcome are still largely unknown. Also in bladder carcinoma the study of cellular differentiation markers has been replaced by that of genotypic alterations, and, mainly with the help of immunohistochemistry, of the expression of genes involved in cell proliferation and death, such as MTS1, TP53, Rb, c-myc, Bcl-2, c-erb-B2. So far, anyway, no independent and reliable indicator able to predict the outcome of the single tumour has been identified, and this issue seems to be best addressed by studies of the altered expression of more than one oncoprotein simultaneously. Fairly identical is the question arised by TP53 mutations, which, while worsening the evolution of advanced muscle-infiltrating tumours, hold a still unclear and debated meaning in superficial tumours. It is anyway clear that molecular analysis only may enable to reliably detect the presence of any TP53 mutations. As a matter of fact, the multiplicity of genetic mutations, the frequent transcript variations and the intrinsic limits of immunohistochemistry may explain the discrepancy between immunohistochemical and molecular analysis results, with specificity and sensitivity levels clinically not acceptable. To date, anyway, the biological and clinical meaning of this discrepancy has still to be clarified, as well as the clinical meaning, if any, of p53 overexpression in the absence of gene mutations.

Ontogeny of the circadian rhythm in medial basal hypothalamic beta-endorphin content in female rat.

The present study evaluated the possible role of estrogens in generating the circadian rhythm of medial basal hypothalamus content at the time of puberty in female rats. Accordingly, changes in medial basal hypothalamus beta-endorphin (beta-EP) content were investigated in female rats, before and at puberty. Groups of intact or ovariectomized rats were studied after estradiol-benzoate or placebo treatment. The results showed that circadian rhythm of beta-EP content of medial basal hypothalamus is absent in prepubertal rats, while it appears at puberty, associated to a significant increase of beta-EP concentration. The primary involvement of steroids in generating this circadian rhythm was supported by the finding that estradiol-benzoate treatment caused a precocious appearance of beta-EP hypothalamic diurnal changes in prepubertal rats. Moreover, estradiol-benzoate replacement restored the loss of beta-EP nocturnal increase induced by ovariectomy in pubertal animals. Therefore, these data support the significant role of estrogen in inducing the circadian rhythm of beta-EP content in medial basal hypothalamus at the time of puberty in female rats.

Gastric dysplasia. A follow-up study.

Gastric dysplasia is generally accepted as a precancerous lesion. Ninety-nine patients with an initial diagnosis of gastric dysplasia, based on examination of endoscopic biopsies taken because of symptoms of dyspepsia, were followed to define the magnitude of the neoplastic risk. The degree of dysplasia in the initial biopsy was mild in 73 cases, moderate in 16, and severe in 10. Mild dysplasia was no longer detected in 74% of patients, persisted in 19%, and progressed in 7% (in four cases, to carcinoma). Moderate dysplasia regressed to mild dysplasia in 31% of cases, it was no longer found in 56%, and progressed to cancer in 13%. Our data show that both lesions can progress slowly, although in most instances they remain stable or regress. Thus, annual endoscopic and histologic controls appear to be advisable. Severe dysplasia was no longer detected in 20% of cases, regressed to moderate in 10%, persisted in 10%, and progressed to cancer in 60%; in half of these patients, carcinoma was detected within 3 months. Thus, severe dysplasia indicates a high risk of cancer, often a synchronous one, and it requires gastrectomy when it persists in repeated biopsies.

Prognostic significance of nucleolar organizer regions in ovarian epithelial tumors.

Recent studies have shown that the silver-stained nucleolar organizer region (AgNOR) score is related to the cell growth rate in several neoplasms. In the work presented here, we tested the AgNOR technique in 79 ovarian epithelial tumors (13 benign, 10 borderline, 56 malignant) to evaluate the diagnostic potential of AgNOR count in distinguishing between ovarian borderline tumors and carcinomas and to assess its prognostic value in carcinomas. Ovarian carcinomas exhibited higher mean AgNOR values than borderline and benign tumors, but statistically significant differences were found only in the serous type. Statistical analysis showed a positive correlation of higher AgNOR score, advanced tumor stage, and adverse prognosis. On the contrary, low AgNOR counts identified stages I and II carcinomas with disease-free follow-up. These results suggest that the AgNOR count may improve the prognostic evaluation of ovarian epithelial tumors by representing a reliable indicator of survival.