Gordana Zamolo

p53 protein expression and cell proliferation in non-neoplastic and neoplastic proliferative skin diseases.

Aims and background The p53 protein is essential for the regulation of cell proliferation and its aberrant accumulation is usually seen in malignant tumors but also occurs in squamous epithelium of inflammatory skin diseases characterized by hyperproliferation. The aim of this study is to elucidate the role of the p53 tumor suppressor protein in the pathogenesis of different hyperproliferative, non-malignant and malignant skin diseases, and to determine the association between p53 overexpression and cell proliferation. We also investigated the influence of aging on p53 and Ki-67 protein expression. Methods One hundred and fifty skin specimens divided into 30 samples each of normal skin (NS), psoriatic skin (PS), keratoacanthomas (KA), basal cell carcinomas (BCC), and squamous cell carcinomas (SCC) were examined immunohistochemically to assess p53 and Ki-67 protein expression. Results p53 immunostaining of NS, PS, KA, BCC and SCC was detected in 39.0%, 46.7%, 66.7%, 80% and 86.7% of cases, respectively. Median values and ranges of p53 protein expression were as follows: 0.0% (range, 0.0–1.8%) in NS, 0.0% (range, 0.0–6.5%) in PS, 9.2% (range, 0.0–24.0%) in KA, 19.3% (range, 0.0–48.1%) in BCC and 30.1% (range, 0.0–68.1%) in SCC. p53- and Ki-67-positive cells were present in basal (NS) and suprabasal layers (PS), and not only in cancer nests of KA, BCC and SCC but also in dysplastic and even morphologically normal epidermis adjoining cancers. The positivity of p53 and Ki-67 proteins differed significantly among the groups, with no differences in p53 expression between NS and PS and in Ki-67 expression between PS and KA. Within all groups there was a significant correlation between p53 and Ki-67 expression. Lesion location and patient age, with the exception of location in PS and age in BCC, were significantly related to p53 and Ki-67 expression in all groups. Conclusions Our findings suggest that p53 overexpression occurs mainly in neoplastic skin lesions, although it may also occur in squamous epithelium of inflammatory skin diseases such as PS, as well as in normal skin epithelium. It is associated with cell proliferation in normal as well as altered epithelium. p53 protein overexpression is an age-related process and significantly associated with sun exposure, especially in NS and PS but also in KA and SCC. Our findings suggest that Ki-67 rate and p53 protein expression reflect the degree of malignancy in the examined cutaneous neoplasms.

Perforin expression is upregulated in the epidermis of psoriatic lesions.

Background  There are currently very few data regarding the role of cell‐mediated cytotoxicity in psoriasis. Both cytotoxic T lymphocytes and natural killer (NK) cells mediate cytotoxicity reactions, mainly by two distinct pathways, the perforin/granzyme and the Fas/Fas ligand pathway.

The first report of extraosseous Ewing's sarcoma in the rectovaginal septum.

Aims and Background To report an extremely rare case of Ewings sarcoma located in the rectovaginal septum. Ewings sarcoma is a highly malignant neoplasm of bone, which usually occurs during childhood. Common extraosseous localizations of Ewings sarcoma include the trunk, extremities, uterus, cervix and vagina. Methods A 45-year-old woman presented to us with a six-month history of pain in the lower abdomen during intercourse. Pelvic examination was performed and a palpable mass was found. The mass had a size of 9 × 6 cm, a soft tissue consistency, was partially movable and the patient felt the pain during palpation. Examination of the inguinal lymph nodes revealed no signs of inguinal adenopathy. The results of laboratory tests, rectoscopy, chest X-rays, barium enema and bone scan were normal. Computed tomography (CT) showed an inhomogeneous expansive mass in the rectovaginal septum measuring 8.7 × 6.1 cm, without any signs of rectum or bladder invasion. The vascular structures of the pelvis were normal. At laparotomy the process was judged inoperable and only biopsy of the tumor mass was carried out. Histology showed a neoplasm with small, round to oval cells with scarce cytoplasm. Immunohistology with the monoclonal antibody CD99 (MIC-2 gene product, Ewings sarcoma marker, clone 12E7, DAKO A/S, Glostrup, Denmark) revealed an extraosseous Ewings sarcoma. The patient was treated with chemotherapy followed by whole-pelvis external beam radiation and intracavitary brachytherapy. Results A residual mass measuring 3.5 × 2.5 cm was visible on a control CT scan 18 months after treatment; however, the patient was feeling well and refused surgery to remove the residual mass. Conclusions To our knowledge this is the first reported case of extraosseous Ewings sarcoma in the rectovaginal septum.

Perforin expression in peripheral blood lymphocytes and skin-infiltrating cells in patients with lichen planus

Background  Current evidence suggests that lichen planus is a T‐cell‐mediated autoimmune disease in which cytotoxic mechanisms have been poorly investigated.

The role of perforin-mediated apoptosis in lichen planus lesions

Lichen planus is recognized as a T-cell-mediated disease. Histologically, it is characterized by the formation of colloid bodies representing apoptotic keratinocytes. The apoptotic process mediated by CD8+ cytotoxic T lymphocytes (CTLs) and NK cells mainly involves two distinct pathways: the perforin/granzyme pathway and the Fas/FasL pathway. So far, little is known regarding the role of perforin-mediated apoptosis in lichen planus. In the present study, the expression and distribution of perforin, T and NK cell subsets in the epidermis and dermis of lesional and nonlesional lichen planus skin were studied. Skin biopsy specimens from lesional and nonlesional skin of ten patients with lichen planus and eight healthy persons were analysed by immunohistochemistry. Significant accumulation of T cells, particularly of CD4+ and CD8+ subsets, was found in both epidermis and dermis of lichen planus lesions compared with nonlesional and healthy skin. There were no significant differences in the incidence of NK cells (CD16+ and CD56+) between lesional, nonlesional and healthy skin. Perforin expression was significantly upregulated in the epidermis of lichen planus lesions. In conclusion, accumulation of perforin+ cells in the epidermis of lichen planus lesions suggest a potential role of perforin in the apoptosis of basal keratinocytes.

Salmonella infection-associated acute rhabdomyolysis. Some pathogenic considerations.

Rhabdomyolysis is a syndrome characterized by extended myolysis, elevation of serum aminotransferases and creatine kinase, and myoglobinuria. It is a rare but well-established complication of a spectrum of infectious diseases. Salmonella infections have been connected with this syndrome as well. We present here the case of a 58-year-old female affected by Charcot-Marie-Tooth (CMT) disease, a type of hereditary neuropathy, who presented with acute renal failure and rhabdomyolysis syndrome in the course of Salmonella infantis gastroenteritis. We formed some considerations on the pathogenesis of rhabdomyolysis in this specific setting based on certain experimental works on the Salmonella pathogenic cycle. We concluded that the calcium-dependent mechanism coupled with a predisposing factor might be of major significance in the development of this complication.

Spontaneous regression of Merkel cell carcinoma in a patient with chronic lymphocytic leukemia: a case report.

IntroductionMerkel cell carcinoma is a rare and aggressive primary cutaneous neuroendocrine malignant tumor. The tumor has a high rate of local recurrence after surgical removal. Spontaneous regression appears to be relatively common in this rare type of tumor.Case presentationWe describe the clinical course, cytological and histological findings of a Merkel cell carcinoma in a 70-year-old Caucasian woman, simultaneously diagnosed with chronic lymphatic leukemia. The tumor showed clinical regression after fine needle aspiration. At primary presentation, the tumor had no apparent leukocyte infiltration, but was completely cleared by T-cell mediated immunity within 3 weeks after fine needle aspiration.ConclusionFine needle aspiration may have acted as a mechanical trigger involved in the activation of cell-mediated immunity, leading to the clinical and histological regression of the tumor. To the best of our knowledge, this is the first case report of spontaneous regression of Merkel cell carcinoma in a patient with a co-malignancy, that is to say, chronic lymphocytic leukemia.

High grade angiosarcoma arising in fibroadenoma

Primary angiosarcoma of the breast is a rare tumour that account for fewer than 0.05% of all malignant mammary tumours. Angiosarcoma may have an perfidious clinical onset. Radiologic findings are often nonspecific and may appear completely normal in one-third of cases with primary angiosarcoma. The prognosis is usually poor because of the high rates of local recurrence and early development of metastases. Aggressive surgical resection is the mainstay of treatment. The role of adjuvant therapy has not yet been well established.Here we present a case of a 53 year old, postmenopausal women with primary angiosarcoma arising in fibroadenoma. To our knowledge, this is the first case described in the literature to date.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1812981492621981.

Cytomorphological variations, proliferation and angiogenesis in the prognosis of cutaneous melanoma

Summary Depth of invasion and stage of the disease are well known prognostic indicators in cutaneous melanoma (CM). However, the role of other parameters, such as the variations in cytomorphology of melanocyte tumours, mitotic activity and angiogenesis is still open to question. The aim of this study was to analyse proliferation by mitotic activity index (MAI) and immunostaining of proliferating cell nuclear antigen (PCNA), and the intensity of neovascularization (microvessel density; MVD) in CM clinical stage I in relation to epithelioid, spindle and nevoid cell type, histological type (superficial spreading melanoma and nodular melanoma), Clarks level and Breslow thickness. Finally, the role of all parameters in the prognosis of CM was evaluated. Statistical analysis demonstrated that cytological characteristics of CM correlate only with Clarks level, while histological types correlate with MAI, PCNA and MVD. MAI and PCNA also showed correlation between groups according to Clarks level and Breslow thickness. Finally, tumour cell PCNA was found to correlate with MVD. Survival of patients with CM correlated significantly with MAI. These results suggest that cytological variation, histological type, PCNA and MVD alone are not independent prognostic parameters, whereas MAI is a potentially important prognostic marker in CM.

Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis

The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1β production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS.