Rheumatoid nodule and combined pulmonary carcinoma: topographic correlations; a case report and review of the literature.

An association between rheumatoid arthritis (RA) and malignancies has been ascertained and patients with RA appear to be at higher risk of lymphoma and lung cancer. The higher risk of the latter malignancy may be related to rheumatoid interstitial lung disease and immunosuppressive therapies. Herein we illustrate the case of a 59-year-old male smoker affected by RA and treated with cortisone, methotrexate and TNF-α antagonists, who underwent right lower lobectomy for a nodular lesion. On microscopic examination, the lesion consisted of two distinct areas: a central area of fibrinoid necrosis, bordered by histiocytes in a palisaded arrangement, lymphocytes and a 0.4 cm thick peripheral area constituted by a combined small cell anaplastic carcinoma, adenocarcinoma and squamous cell carcinoma. The combination of three histotypes is very rare in such a small tumour. In our case, it may be hypothesized that synchronous, heterogeneous mutations occurred in different type of committed cells or in stem cells, due to the production of cytokines by RA nodule histiocytes and lymphocytes, which are contiguous to the carcinomatous area. Since few studies have evaluated the topographic correlation between tumors and rheumatoid lung lesions, further morphological and molecular studies are needed to clarify this association and the pathogenetic relationship between RA and cancer of the lung.

Beclin 1 and LC3 autophagic gene expression in cutaneous melanocytic lesions.

Beclin 1 and LC3 autophagic genes are altered in several human cancer types. This study was designed to assess the expression of Beclin 1 and LC3 in cutaneous melanocytic lesions, in which they have not yet been investigated. In melanoma, we correlated their expression with conventional histopathologic prognostic factors. In 149 lesions, including benign nevi, dysplastic nevi, radial growth phase melanomas, vertical growth phase melanomas, and melanoma metastases, proteins were evaluated by immunohistochemistry, and, in representative cases of benign nevi, vertical growth phase melanomas and melanoma metastases were evaluated by Western blotting. In most lesions, messenger RNA level was also assessed by real-time reverse transcriptase polymerase chain reaction. Both genes were expressed in all the investigated conditions. Beclin 1 cytoplasmic protein and messenger RNA, as well as LC3 messenger RNA, significantly decreased with tumor progression (P < .05). The percentage of cases with high cytoplasmic expression of beclin 1 from 100% in benign nevi declined to 86.4% in dysplastic nevi, 54.5% in radial growth phase melanomas, 54.3% in vertical growth phase melanomas, and 26.7% in melanoma metastases. The lowest expression of LC3 II protein was observed in melanoma metastases (53.3% of cases) (P < .05); LC3 II protein overexpression was, however, found in several nonbenign lesions, with the highest percentage (45.5%) in radial growth phase melanomas. LC3 II protein expression was inversely correlated to thickness, ulceration, and mitotic rate. In a multivariate analysis, messenger RNAs for both genes discriminated between nonmalignant (benign and dysplastic nevi) and malignant (radial, vertical growth phase melanomas, and melanoma metastases) lesions. Our results, therefore, indicate that beclin 1 and LC3 II autophagic gene expression is altered also in melanocytic neoplasms.

Utility of tumour-infiltrating CD25+FOXP3+ regulatory T cell evaluation in predicting local recurrence in vertical growth phase cutaneous melanoma.

Tumour-infiltrating lymphocytes (TILs) represent the local immune response to cancer, however, their correlation with tumour behaviour is not unanimously considered in the literature. Most studies have not characterized TILs, that are known to comprise distinct subsets, bearing different roles in the complex tumour microenvironment. Characterization of patient lymphocytes has been mainly performed in peripheral blood, that is not always representative of the local immune status. Only few investigations have been performed at the tissue level in cancer, including melanoma. TILs encompass different populations of effector and regulatory T cells (Tregs), and the relevance of the latter in tumour progression is widely accepted. The transcription factor gene product FOXP3 is considered the most reliable marker of Tregs. However, it has not been extensively evaluated in primary cutaneous melanoma. We analyzed 66 vertical growth phase primary cutaneous melanomas, aiming at finding differences in TIL subsets between two groups of cases, that behaved differently in terms of local recurrence. In our study, the percentage of Tregs, as characterized by CD25 and FOXP3 expression, both among tumour cells, inside tumour parenchyma and at its periphery, and among TILs, at the tumour-stroma boundary, was significantly higher in cases that recurred than in those that did not (p=0.00065; p=0.00014; p<0.00001, respectively). TIL characterization by immunohistochemistry in melanoma diagnostic reports, could add further information. The analysis of a larger series of patients and correlation with other clinical parameters, such as distant metastases and/or patient survival, are mandatory for validating its use as a prognostic indicator.

Protein and mRNA expression of autophagy gene Beclin 1 in human brain tumours.

Beclin 1 is is an autophagy gene, the role of which as a tumour suppressor has recently been recognized in a few studies. We examined the expression of Beclin 1 protein in 212 primary human brain tumours, including 97 high-grade glial tumours, 29 low-grade glial tumours, 4 grade III meningiomas, 19 grade II meningiomas, 52 grade I meningiomas, and 11 medulloblastomas. In 94 cases, including 56 glial tumours, 35 meningiomas, and 3 medulloblastomas we also assessed Beclin 1 mRNA expression by real-time RT-PCR. In most high-grade astrocytic, ependymal neoplasms and atypical meningiomas we found a decrease of cytoplasmic protein expression that was, instead, high in the majority of low-grade tumours and in medulloblastomas. The expression level of Beclin 1 mRNA was significantly lower in glioblastomas than in grade II (p=0.04) and grade I (p=0.01) astrocytomas; in grade III than in grade I astrocytomas (p=0.01); in grade II than in grade I meningiomas (p=0.03); and in all glial tumours when compared to all meningiomas (p<0.0001). Cytoplasmic expression is thought to be linked to the functional protein. Our observations are in line with studies that demonstrated decreased expression of Beclin 1 in human breast, ovarian, prostate and ovarian cancer and furtherly support its involvement also in brain tumours, which had previously been demonstrated in a few experimental studies, both in spontaneous and in therapy-induced autophagy. Furthermore, our study suggests possible differences of Beclin 1 involvement and its role among the different histotypes of brain neoplasms. Further studies are needed to highlight Beclin 1 function in tumour suppression and/or in tumour survival through autophagy and other related programmed cell death processes in brain tumours.