Intralesional photodynamic therapy induces apoptosis in basal cell carcinoma and Bowen's disease through caspase 3 and granzyme B.

BACKGROUND: Photodynamic therapy (PDT) is used to treat cutaneous cancers. It may induce cell death through direct and indirect means, including apoptosis, inflammation and certain immune mechanisms, with the depth of penetration as a potential modifying factor. OBJECTIVES: To examine the pathways of apoptosis in the intralesional PDT of basal cell carcinoma (BCC) and intraepidermal squamous cell carcinoma (Bowen's disease). METHODS: Sixteen patients with superficial or nodular BCC and Bowen's disease were treated with intralesional aminolevulinic acid-PDT. Biopsies were taken at baseline and 24 h post-PDT, and sections were examined by immunohistochemistry for the expression of markers of apoptosis, such as caspase 3, involved in the intrinsic apoptotic pathway, granzyme B, a caspase-independent apoptotic mediator, and the proapoptotic markers BAX and BAK. RESULTS: Apoptotic cells stained with TUNEL showed statistically significant staining at 24 h post PDT (p < 0.01 in both BCC and Bowen's lesions). Caspase 3 (p < 0.01 in BCC and p < 0.05 in Bowen's) and granzyme B (p < 0.01 in BCC and p < 0.01 in Bowen's) were significantly increased at 24 h post-PDT. BAX expression was apparently increased compared to baseline in Bowen's lesions at 24 h post-PDT, whereas Bak was upregulated both in BCC and Bowen's disease at baseline and at 24 h post-PDT. CONCLUSION: Intralesional PDT induces apoptosis in BCC and Bowen's disease via common and alternative apoptotic pathways involving granzyme B. Proapoptotic factors Bak in both BCC and Bowen and Bax in Bowen's disease appear to increase by intralesional PDT at 24 h.

Primary small bowel melanoma. A case report and a review of the literature.

Primary malignant melanoma originating from the small intestine is extremely rare. Only a limited number of cases are described in the literature. Most commonly small intestine is affected by metastatic tumors from other primary lesions. We present a case of a 68-years old male diagnosed with primary malignant melanoma as an ulcerated and bleeding mass in the jejunum--located 40 cm away from the Treitz band. In our case the diagnosis was confirmed at laparotomy and enterectomy. Histology revealed a neoplastic infiltration involving the entire intestinal mucosa, with atypia of neoplastic cells and immunoreactivity to HMB45(+), Melan A(+) and S100(+), confirming the diagnosis of melanoma. There was not revealed a primary lesion in the skin, eye, anus, rectum or in other location by the post-operative investigation. An eleven-month close follow-up has not revealed any metastasis. Therefore a definitive diagnosis of primary malignant melanoma was set.

Carcinoma urotelial plasmocitoide de la vejiga con extensión peritoneal. Diagnóstico citológico en líquido ascítico / Plasmacytoid urothelial carcinoma of the bladder with peritoneal spread. Cytological diagnosis in ascitic fluid

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Infliximab restores the balance between pro- and anti-apoptotic proteins in regressing psoriatic lesions.

BACKGROUND: Psoriasis and psoriatic arthritis are treated very efficaciously with infliximab, a chimaeric human-murine antitumour necrosis factor (TNF)-α antibody. As we reported earlier, infliximab, besides its anti-inflammatory properties, induces a caspase-independent programmed cell death of psoriatic keratinocytes. OBJECTIVES: To elucidate this finding further, we investigated the epidermal expression of proteins involved in the mitochondria-dependent (intrinsic) pathway of cell death. METHODS: Quantification of proteins with pro- (p53, AIF, Bax) and anti-apoptotic functions (Bcl-2, Bcl-XL) and of NF-κB was performed by means of immunohistochemistry and digital image analysis of the staining of nonlesional skin and lesional psoriatic skin from patients treated with infliximab at weeks 0, 2 and 6. RESULTS: Serial biopsies from psoriatic plaques of samples taken at days 0, 5, 14 and 21 of therapy demonstrated a significant downregulation of anti-apoptotic proteins Bcl-2, Bcl-XL and NF-κB during treatment and, in parallel, a significant upregulation of pro-apoptotic proteins p53, Bax and AIF. These differences in expression correlated with decreases in epidermal thickness and clinical outcome (Psoriasis Area and Severity Index). At day 21, expression levels of apoptosis-related proteins in lesional skin approximated those found in nonlesional skin. CONCLUSIONS: Our data therefore suggest that TNF-targeting agents may induce the regression of psoriasis at least in part by normalizing the expression of apoptosis-related proteins in lesional keratinocytes.

Primary haemangiopericytoma of the parapharyngeal space: an unusual tumour and review of the literature.

Haemangiopericytoma is a rare soft tissue tumour, with great histological variability and unpredictable clinical and biological behaviour. The precise cell type origin is uncertain. One third of haemangiopericytomas occur in the head and neck area, but only a few cases have been reported regarding localization at the parapharyngeal space. Herewith, case is presented of a 54-year-old female, referred to our Department due to a parapharyngeal space tumour with non-specific imaging characteristics. The patient underwent radical excision of the tumour with a trans-cervical sub-mandibular approach. The histolopathologic examination revealed a neoplasm with the characteristic features of haemangiopericytoma. One year later, during the scheduled follow-up, the computerized tomography scan showed no evidence of recurrence or residual disease. The pre-operative evaluation of a haemangiopericytoma must include a thorough imaging evaluation with computerized tomography and magnetic resonance imaging, even if results may not be specific for haemangiopericytoma. Angiography and pre-operative embolization may be performed in cases of large tumours with significant vascularity. The treatment of choice is radical excision. The follow-up includes clinical evaluation every 6 months and annual magnetic resonance imaging for at least 3 years.

Apoptosis and cell proliferation correlated with tumor grade in patients with lung adenocarcinoma.

BACKGROUND: Apoptosis and cell proliferation in patients with adenocarcinoma of the lung have not been well described with relation to fine-needle aspiration biopsies (FNABs). To investigate the contribution of apoptosis to the growth of adenocarcinoma of the lung, both apoptosis and cell proliferation were analysed for correlation with the grade of the tumor. PATIENTS AND METHODS: Fifty tumors from 50 patients with adenocarcinoma of the lung were studied. Twelve tumors were well-differentiated, 22 were moderately differentiated and 16 were poorly differentiated. The detection of DNA fragments in situ using the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) assay was applied to investigate active cell death (apoptosis) and the MIB-1 antigen was used to investigate cell proliferation. RESULTS: The TUNEL indices were 0.55±0.09, 0.90±0.33 and 3.1±0.99 in well-, moderately and poorly differentiated adenocarcinoma of the lung respectively. The MIB-1 antigen labeling indices were 7.1±0.12, 14.3±3.5 and 28.7±6.9, respectively, in the same order of tumor differentiation. The differences in both TUNEL and MIB-1 labeling indices were significant between well-, moderately and poorly differentiated adenocarcinoma of the lung and a positive correlation was found between the TUNEL indices and the MIB-1 indices. CONCLUSION: Apoptosis (cell death) and cell proliferation increases as the grade of differentiation decreases in adenocarcinoma of the lung, suggesting a rapid turn over of the tumor cells in tumors with a lower grade of differentiation.

Infantile fibromatosis of the mandible: a case report.

We report an aggressive tumour in a 5-year-old girl causing facial disfigurement. Imaging confirmed a solid, diffusely enhancing mass at the right internal pterygoid muscle, infiltrating the adjacent bone. Surgical excision and reconstruction of the mandible were performed. Histology revealed aggressive infantile fibromatosis. No recurrence was noted 7 months later. Infantile fibromatosis may mimic malignancies and should be considered in aggressive mandibular soft tissue masses, in order to carefully plan biopsy and reconstructive surgery.

Prevalence of BK virus and human papillomavirus in human prostate cancer.

Polyomaviruses such as the BK virus (BKV), JC virus (JCV) and SV40, as well as the human papillomaviruses (HPV) are frequently detected throughout human populations, causing subclinical persistent infections and inducing oncogenesis in human and other cell lines. To test the involvement of these viruses in prostate tumorigenesis, we investigated the prevalence of BKV, JCV and HPV in a series of human prostatic malignancies. Forty-two samples of diagnosed prostatic malignancies were tested using standard polymerase chain reaction (PCR) protocols. Differentiation between BKV and JCV among the polyomavirus-positive samples was achieved after sequencing analysis of the PCR products. Reconstitution of BKV in vitro was performed and indirect immunofluorescence for the large T-antigen of the virus was applied to confirm the production of progeny virus. Detection and typing of HPV was carried out by PCR. The overall prevalence of polyomaviruses was 19% in the prostate cancer cases. Sequencing analysis of the polyomavirus-positive specimens revealed the presence of BKV in all samples. Reconstitution of the BKV from the BKV-positive prostate samples was successfully achieved in cell culture and progeny viral particles were obtained, confirming the presence of the virus in the human biopsies. HPV was detected in 4.8% of the samples, however, no HPV-11, HPV-16, HPV-18 or HPV-33 types were identified. BKV was frequently detected and could play a relevant role in the development and progression of human prostate cancer, whereas HPV does not seem to be implicated in this type of human neoplasia.

Correlation of heat shock protein (HSP70) expression with cell proliferation (MIB1), estrogen receptors (ER) and clinicopathological variables in invasive ductal breast carcinomas.

The aim of our study was to evaluate the relationship between the expression of HSP70 protein, cell proliferation, the expression of ER receptors and the clinicopathological variables Grade and LNS in breast invasive human tumors along with the role of HSP70 protein in the prognosis of human breast cancer. A strong association between HSP70 expression and ER content, in agreement with previous data, was found which revealed a statistically significant association between HSP70 positivity and ER expression (p<0.008) in 50 cases of invasive primary human breast cancers. We also found a strong correlation between HSP70 expression, Grade and LNS of invasive ductal breast carcinomas. This suggests that the expression of HSP70 plays a significant role in the progression of human breast cancer, and might prove useful in many other malignancies as an important marker for the outcome of the disease.

Metastatic uterine leiomyosarcoma coexisting with papillary carcinoma of the thyroid gland.

Metastatic leiomyosarcoma to the thyroid gland has rarely been described. We report a 54-year-old postmenopausal woman with uterine leiomyosarcoma, who presented with a single "cold" nodule in the right thyroid lobe 3 months after hysterectomy. The lesion was identified as a papillary thyroid carcinoma. In a separate area of the thyroid, a 1.2-mm area of a malignant mesenchymal neoplasm with morphologic and immunohistochemical features of leiomyosarcoma existed. Seven months after thyroidectomy the patient developed micronodular lung disease visible on successive chest computed tomography scans, consistent with metastatic disease from the primary uterine leiomyosarcoma that showed very good and prolonged response to chemotherapy. The thyroid papillary carcinoma was likely the recipient of an early and possibly the first metastasis of the patient's uterine leiomyosarcoma. This is the first report of metastatic leiomyosarcoma coexisting with a primary thyroid carcinoma and supports the possibility of a common pathway connecting thyroid gland neoplasms and sarcomas.

Telomerase activity as a marker of invasive ductal breast carcinomas on FNABs and relationship to other prognostic variables.

To study the activity of telomerase and the relationship between telomerase and other prognostic variables in cases of invasive ductal breast carcinomas, fifty fine-needle aspiration biopsies (FNABs) obtained from the same number of female patients, diagnosed cytologically and confirmed histologically after surgery, were examined. The same cases were studied immunocytochemically using monoclonal antibodies to telomerase, estradiol receptors (ER) and HER-2 (CB11) and a standard alkaline phosphatase (APAAP) method. Telomerase activity was found in 72% of the carcinomas studied. An association was found between telomerase activity, ER receptors and HER-2 expression (p <0.005). A relationship between telomerase activity, histological grade and lymph node status (LNS) was found as well (p<0.005). The above results seem to be significant prognostic factors and should be taken into consideration in the follow-up of patients after appropriate treatment for breast cancer.

Topoisomerase II alpha expression in breast ductal invasive carcinomas and correlation with clinicopathological variables.

Topoisomerase II alpha (topo IIa) is an enzyme that in normal cells is expressed predominantly in the S/G2/M-phase of the cell cycle. In malignant cells, in vitro studies have indicated that the expression of topo II alpha is both higher and less dependent on the proliferation state in the cell. To study the expression of topo IIa and the relationship between that expression-and other variables in cases of breast ductal invasive carcinomas, 50 fine-needle aspiration biopsies were performed from the same number of female patients, diagnosed cytologically and confirmed histologically after surgery. The same cases were studied immunocytochemically using monoclonal antibodies to topo IIa and Her2/neu (CB11) by the alkaline phosphatase method (APAAP). Topo IIa was found in 32 cases (64%) of the carcinomas studied. An overexpression between topo IIa and Her2/neu was found (p < 0.005). A relationship between topo IIa expression, histological grade and lymph node status (LNs) was also found (p < 0.005). Increased topo IIa expression seems to be related to an aggressive form of breast cancer featuring Her2 amplification and lymph node metastasis.

Ascites associated with the initial presentation of Crohn's disease.

We report a case of a 23-yr-old patient who was initially admitted with severe Crohn's ileocolitis complicated by a large amount of exudative ascites. There was no evidence of malignancy, portal hypertension, or inflammation in any organ other than the bowel. We present the clinical course and response to treatment and discuss the possible mechanisms by which Crohn's disease might contribute to the development of exudative ascites.

Proliferative patterns of rectal mucosa as predictors of advanced colonic neoplasms in routinely processed rectal biopsies.

OBJECTIVES: We sought to determine whether the evaluation of rectal cell proliferation in routinely processed rectal biopsies of apparently normal mucosa can predict the presence of advanced colonic neoplasms. METHODS: Fifty consecutive patients, who did not meet any of the following exclusion criteria, underwent total colonoscopy. Patients with nonadvanced adenomas, inflammatory bowel disease, hereditary predisposition to colonic cancer, or a history of colonic neoplasms were excluded. Patients with neoplasms in the distal 40 cm of the large bowel were also excluded. An adenoma was considered advanced if it had a diameter > 1 cm, or villous or severe dysplasia histology were present. In 26 of the 50 patients (Group A: 16 men, 10 women; mean age, 65 yr) advanced colonic neoplasms (advanced adenomas or cancer) were detected; in the remaining 24 (Group B: 13 men, 11 women; mean age, 66 yr) the large bowel was free of neoplasms. In all patients the proliferative patterns of apparently normal rectal mucosa were evaluated using the monoclonal antibody MIB-1 to assess the expression of Ki-67 antigen in routinely processed tissues. Proliferation index for the entire crypt, as well as proliferation indices for each of the five equal compartments, into which the crypt had been divided longitudinally, were calculated for each patient. RESULTS: The mean proliferation indices were similar between the two groups compared. The mean proliferation index for the upper crypt compartments (4 + 5) in the Group A patients was significantly higher than for those of the Group B patients (p < 0.01). Multivariate stepwise logistic regression analysis revealed that among gender, age, and proliferative parameters, the pattern of cell proliferation in the upper rectal crypt (4 + 5) compartment was the only predictor of advanced colonic neoplasms (beta = 11.01, p < 0.001). CONCLUSIONS: Our data suggest that the evaluation of the upward expansion of the rectal crypt proliferative zone in routinely processed rectal biopsies of apparently normal mucosa appears to predict the presence of advanced colonic neoplasms. These preliminary results should be confirmed in larger studies.

Primary angiosarcoma of the breast.

We report a case of a 44-year-old woman with primary angiosarcoma of the left breast. An excisional biopsy was performed initially and the mass was interpreted as angiosarcoma. The pre-operative staging provided no evidence of metastasis. The patient then underwent a left mastectomy with the placement of an expandable prosthesis. For 3 months the prosthesis was progressively expanded to the desired size and it was then replaced with a permanent one. Primary angiosarcoma of the breast is a rare and often misdiagnosed disease. Treatment options are numerous and conflicting. The diagnostic approach and treatment options from the literature are presented and discussed.

p53 protein expression in breast carcinomas. Comparative study with the wild type p53 induced proteins mdm2 and p21/waf1.

The aim was to investigate the pattern of expression of p53 protein and two wild-type (wt) p53-induced proteins (mdm2 and p21/waf1), as an indirect way of assessing p53 gene status in breast carcinomas. Formalin-fixed paraffin embedded tissue from 102 cases of breast carcinomas comprising mostly ductal carcinomas (88 cases) was stained by immunohistochemistry for p53, mdm2 and p21/waf1 proteins. We found p53, mdm2 and waf1/p21 protein expression in 33/102, 20/102 and 38/102 breast carcinomas, respectively. Parallel p53/mdm2 protein expression was found in 9 cases. Five were also p21/waf1 positive. Discordant p53+/ mdm2-protein expression was found in 24 cases. Nine were p21/waf1 positive and the remaining fifteen were p21/waf1 negative. The patterns mdm2+/p53-/p21- and p21+/p53-(+)/mdm2- were found in 6 and 20 cases, respectively. Parallel p53/mdm2/p21 protein expression may represent breast carcinomas with wt p53 gene since mdm2 and p21 proteins are inducible by wt p53 gene. In these cases p53 protein expression may be due to stabilisation to mdm2 protein. This could be important in the pathogenesis of these cases since mdm2 may deregulate the p53-dependent growth suppressive pathway. Discordant p53+/mdm2-/p21- protein expression may represent breast carcinomas with p53 gene mutations unable to activate expression of mdm2 and p21 proteins. Breast carcinomas with p53+/mdm2/p21+ protein expression may have either wt p53 with deregulated mdm2 gene expression or mutated p53 gene with p53-independent p21 expression. Cases with only mdm2 expression may represent tumours with mdm2 gene amplification or overexpression and cases with only p21 expression may reflect p53-independent regulation of p21 protein.

Expression of p53 and mdm-2 proteins in Hodgkin's Disease. Absence of correlation with the presence of Epstein-Barr virus.

The expression of p53 and mdm-2 proteins was analysed in parrafin sections from 39 cases of Hodgkin's disease (HD) and compared to the presence of Epstein-Barr Virus (EBV). P53 protein was found in Hodgkin and Reed-Sternberg (HRS) cells in 12/39 cases. Mdm-2 protein was found in HRS cells in 10/39 cases. EBV-encoded EBER1-2 mRNAs and LMP-1 protein expression were found in HRS cells in 16/39 cases. In view of the LMP-1 oncogenic potential in vitro, these findings suggest that EBV may be involved in the pathogenesis of a proportion of HD cases. The coexpression of mdm-2 and p53 proteins was found in HRS cells in 10 cases, whereas in 27 cases neither was identified and in 2 cases there was no coexpression of mdm-2/p53. The simultaneous p53/mdm-2 protein expression, in view of previous findings which showed that most cases of HD display no p53 gene mutations, suggests that mdm-2 protein expression may be one of the factors responsible for the stabilisation of p53 protein in these cases. This could be important, in the pathogenesis of these cases of HD, since mdm-2 may deregulate the p53 dependent growth suppressive pathway. Mdm-2-/ p53+ protein expression may reflect the stabilisation of p53 protein by proteins other than mdm-2, mutations in the p53 gene making it unable to activate mdm-2, or the deregulation of the mdm-2 gene. No relationship was found between the presence of EBV and the expression of p53 and/or mdm-2 proteins.