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// Alessandra Ulivieri 1, 2 , Giuseppe Cardillo 3 , Liborio Manente 1 , Gregorino Paone 4 , Andrea Petricca Mancuso 5 , Leonardo Vigna 5 , Enrico Di Stasio 6 , Rita Gasbarra 1 , Salvatore Girlando 7 , Alvaro Leone 1 1 Anatomic Pathology Unit, San Camillo-Forlanini Hospitals, Rome, Italy 2 Laboratory of Biomedical research “Fondazione Niccolo Cusano per la Ricerca Medico-Scientifica” Niccolo Cusano University of Rome, Rome, Italy 3 Thoracic Surgery Unit, San Camillo-Forlanini Hospitals, Rome, Italy 4 Department of Respiratory Diseases, San Camillo-Forlanini Hospitals, Rome, Italy 5 Department of Medical Oncology, San Camillo-Forlanini Hospitals, Rome, Italy 6 Institute of Biochemistry and Clinical Biochemistry, Universita Cattolica del Sacro Cuore, Rome, Italy 7 Anatomic Pathology Unit, S. Chiara Hospital, Trento, Italy Correspondence to: Alvaro Leone, e-mail: aleone@scamilloforlanini.rm.it Keywords: Pathology, melanoma, pulmonary metastases, BRAF, NRAS, EGFR Received: May 15, 2015 Accepted: June 20, 2015 Published: July 04, 2015 ABSTRACT Background: Melanoma is highly curable in early stages but holds devastating consequences in advanced phases with a median survival of 6–10 months. Lungs are a common metastasis target, but despite this, limited data are available on the molecular status of pulmonary lesions. Materials and Methods: 25 patients with surgically resected melanoma lung metastases were screened for BRAF, NRAS, CKIT and EGFR alterations. The results were correlated with time to lung metastasis (TLM), relapse-free survival after metastasectomy (RFS) and overall survival (OS). Results: BRAF or NRAS were mutated in 52% and 20% of cases while CKIT was unaffected. Chromosome 7 polysomy was detected in 47% of cases with 17.5% showing EGFR amplification and concomitant BRAF mutation. NRAS mutated patients developed LM within 5 yrs from primary melanoma with larger lesions compared with BRAF (mean diameter 3.3 ± 2.2cm vs 1.9 ± 1.1cm, p = 0.2). NRAS was also associated with a shorter median RFS and OS after metastasectomy. Moreover, Cox regression analysis revealed that NRAS mutation was the only predictive factor of shorter survival from primary melanoma ( p = 0.039, OR = 5.5 (1.1–27.6)). Conclusions: Molecular characterization identifies advanced melanoma subgroups with distinct prognosis and therapeutic options. The presence of NRAS mutation was associated to a worse disease evolution.

A 64-year-old woman, otherwise healthy, presented with multiple reddish-brown, slightly yellowish papules on the face and neck, which had developed 3 years earlier. The lesions were painless and nonpruritic and varied in diameter from 1 to 5 mm. Histological and immunohistochemical examination of cutaneous biopsies revealed a diffuse dermal infiltrate composed mainly of histiocytes which expressed both Langerhans cell as well as monocytic/macrophages cell marker characteristics. Electron microscopic studies revealed no Birbeck granules within the cytoplasm of the neoplastic cells, leading to a diagnosis of indeterminate cell histiocytosis. Indeterminate cell histiocytosis is a very rare disease characterized by the proliferation of indeterminate histiocytes which morphologically and immunophenotypically resemble Langerhans cells but lack Birbeck granules.

We analyzed microsatellite instability (MSI) and loss of heterozygosity (LOH) at 17 microsatellite markers located on chromosomes 2p, 3p, 5q, 6q, 9p, 9q, 17p and 18q in 19 randomly selected keratoacantomas (KAS), in one cutaneous lesion that histologically could not unequivocally be differentiated from squamous cell carcinoma, and in one patient with multiple KAs of longstanding duration. The goals of our study were to determine whether, in a similar manner to some visceral carcinomas, genomic instability could be detected in KAs and to clarify whether molecular analysis might be useful to further characterize KA. MSI was observed in 2 of 21 cases (9.5%) at 5 of 17 loci examined. In one patient with a solitary KA, the presence of MSI and a family history of visceral malignant tumours suggested that the patient might have belonged to a family with Muir-Torre syndrome. In one other MSI+ KA, a definite differential diagnosis in relation to squamous cell carcinoma could not be established. In addition, one sample displayed LOH at 2 of 17 loci analysed whereas in the patient with multiple KAs, LOH at one locus was the only alteration found. In conclusion, the low frequency of MSI and LOH detected in our study suggests that these genetic events are uncommon in KA unless it is associated with a familial disease (e.g. Muir-Torre syndrome) or it has more aggressive histological features.

Lymphoblastic lymphoma (LBL) is a neoplasm of lymphoid precursors presenting usually as acute leukemia with bone marrow and peripheral blood involvement. Primary cutaneous involvement of LBL with a pre-B phenotype has to be considered an extremely uncommon occurrence, accounting for less than 1% of all non-Hodgkin lymphomas. A child with an LBL involving a single cutaneous manifestation of 6 months duration is presented. At the time of presentation, the lesion consisted of a rapidly enlarging deeply infiltrated tumor on the upper arm. Immunophenotypic analysis performed an paraffin-embedded and frozen tissue sections revealed 2 pre-B phenotype of the tumor cells. Similar results were obtained from lymph node and bone marrow biopsy specimens. After 26 months of polychemotherapy, the patient is currently in complete remission. We wish to add this case to the current literature of LBL with cutaneous involvement, emphasizing the importance of a correct diagnosis and the excellent response to the therapeutic regimen.

The term “phacomatosis” refers to a growing number of sporadic genetic skin disorders characterized by the combination of two or more different nevi and possibly resulting from non-allelic twin spotting. While phacomatosis pigmentovascularis (PPV) and pigmentokeratotica represent the most common patterns, some patients do not fit with either condition and are temporarily classified as unique phenotypes. We report on an 8-year-old boy with striking right hemihypoplasia, resulting in limb asymmetry and fixed dislocation of right hip. Skin on the affected side showed three distinct nevi: (i) A whorled, hairless nevus of the scalp in close proximity with (ii) epidermal hyperpigmentation following lines of Blaschko on the neck and right upper limb, and (iii) multiple telangiectatic nevi of the right lower limb and hemiscrotum. Didymosis atricho-melanotica was proposed for the combination of adjacent patchy congenital alopecia and linear hyperpigmentation, while phacomatosis atricho-pigmento-vascularis appears to define the entire cutaneous phenotype, thus implying the involvement of three neighboring loci influencing the development of distinct constituents of the skin. Given the striking asymmetry of the observed phenotype, the effect of mosaicism (either genomic or functional) for a mutation in a single gene with pleiotropic action and influenced by the lateralization pattern of early development cannot be excluded. © 2012 Wiley Periodicals, Inc.

Polypoid Spitz nevus represents a spitzoid melanocytic neoplasm that frequently has worrying and challenging histopathological details. Distinction from polypoid melanoma may not be straightforward. Two cases of polypoid Spitz nevus with striking histopathological features were studied. One case had prolonged follow up (Case 1) and one patient had undergone sentinel lymph node biopsy (Case 2), and fluorescence in situ hybridization (FISH) analysis was also completed (both cases). Follow up and genetic analysis of three control cases of polypoid melanoma is also presented. Our clinical and genetic results suggest that both the polypoid Spitz nevi were benign. The patients are alive with no evidence of disease. FISH analysis did not show abnormalities with probes tested. This is in sharp contrast with the control cases of polypoid melanoma, wherein genomic alterations were detectable. Our data indicate that the two polypoid lesions presented here are most probably benign, despite their worrying histopathological features. More cases with long-term follow up and greater numbers of DNA probes are necessary to extend this conclusion to other ambiguous melanocytic tumors.

Biopsy of the heart has become a widely applied technique in circumstances such as detection of a transplant reject or histological diagnosis of masses. Biopsy is usually performed in the catheter laboratory (cath-lab) under fluoroscopic guidance. Echocardiography guidance is employed but as 'ancillary' comforting support to the cath-lab operator and for the early detection of complications. Until now, only a transesophageal approach has been used for guiding biopsy of intracardiac masses. Today, thanks to the current echocardiographic technology employing second harmonics, the definition of cardiac structures has consistently improved in the transthoracic approach, possibly allowing the full transthoracic procedure to be performed. We describe the biopsy of a large mass in the right ventricle, completely conducted without the help of fluoroscopy, and completed only under the help and guidance of transthoracic echocardiography.

Objective: To study the validity and feasibility of transferring images of cutaneous biopsy specimens via e-mail to remote physicians active in dermatopathology for teleconsultation. Design: Twenty skin specimens previously diagnosed at the Department of Dermatology, University of Graz, Austria, were subsequently sent for teleconsultation using the store-and-forward method. For each case, 3 or 4 images at different magnifications were sent by e-mail to 16 colleagues (11 dermatopathologists and 5 pathologists) in 15 centers in 6 different countries. Six weeks later each observer received the hematoxylin-eosin-stained specimens to render a conventional diagnosis. Setting: Dermatopathology and pathology units within institutional and private settings. Material: Twenty small skin biopsy specimens of cutaneous diseases were selected randomly from a study set of 80. Main Outcome Measure: Concordance between telepathologic diagnoses and conventional histopathologic diagnoses of 20 skin specimens. Results: On average, 78% of the telediagnoses were correct (range, 60%-95%), whereas 8510 of the conventional diagnoses were correct (range, 60%-95%). A perfect diagnostic concordance was obtained in 7 (35%) of 20 cases, and a significant difference was identified in only 1 case. Conclusions: Results suggest that telepathology performed by physicians active in dermatopathology may serve as a reliable technique for the diagnosis of cutaneous diseases when experts in dermatopathology are not available locally. Furthermore, teledermatopathology is attractive because it provides an opportunity to obtain timely consultation on difficult cases. RI Soyer, H. Peter/E-6000-2010

We report the unusual occurrence of Kaposi's sarcoma following asbestos-related malignant mesothelioma, in a human deficiency virus (HIV)-negative Italian man. Seropositivity to human herpes virus 8 (HHV8) was documented at the time of mesothelioma diagnosis and preceded the onset of Kaposi' sarcoma with a time lapse of 13 months. HHV8 DNA was detected by polymerase chain reaction in lesional Kaposi's sarcoma but not within mesothelioma. By immunostaining, mesothelioma cells expressed interleukin-6 and platelet-derived growth factor, which are important for survival of Kaposi's sarcoma cells. Besides the possibility of a casual association, we hypothesize that mesothelioma-linked factors may have contributed to the development of Kaposi's sarcoma in the presence of HHV8 infection.

A 13-year-old boy presented with a polypoid nodule localized in the groin. Although the clinical and histopathological features corresponded to previously described diagnostic criteria of epithelioid cell histiocytoma, immunohistochemical and ultrastructural findings suggested vascular differentiation of the epithelioid cells. In particular, the immunohistochemical negativity of the epithelioid cell elements for Factor XIIIa failed to substantiate the previously forwarded hypothesis that this lesion represents a dendrocytoma. Instead, the presence of histiocytoid, vacuolated cells occasionally containing sparse red blood cells, positive staining for Factor VIII-related antigen, and ultrastructural evidence of endothelial characteristics in epithelioid neoplastic cells favor the hypothesis that "epithelioid cell histiocytoma" is of endothelial origin. We suggest the descriptive term cutaneous histiocytoid hemangioendothelioma for this lesion.

We describe a patient with granulomatous slack skin (GSS) who has been followed for 15 years and present clinical, histological, immunohistochemical, ultrastructural, cytogenetic, and molecular findings. The clinical and pathological aspects of the 20 cases of GSS reported in the recent literature are reviewed and compared with those of the present case.

Aim and background To evaluate the characteristics of a case-series of 79 malignant mesothelioma patients collected from the main teaching hospital of Rome, Italy, and other local clinics of Latium Region and to assess the role of asbestos exposure, since previous studies on the occurrence of the disease in this area were lacking. Methods The study included cytohistologically diagnosed malignant mesothelioma (71 pleural, 7 peritoneal, and 1 testicular tunica vaginalis) detected or referred for consultation during the period 1980-1995. Information regarding occupational and/or nonoccupational exposures was derived from clinical records and interviews, when available. Results Patients were resident in Rome and other towns of Latium; a few were from other parts of central and southern Italy. Exposure to asbestos was assessed for 45.5% of patients, another 45.5% had unknown exposure, and for the remaining 9% such information was lacking. Occupational exposure occurred in 53% of men for whom information was available and nonoccupational exposure occurred in 20% of women. The study identified two clusters of cases from an asbestos-cement plant and a facility where asbestos was ubiquitous. Furthermore, most exposed subjects reported occupations in the construction industry, which is particularly active in the Latium Region; others were railroad workers, naval mechanics and navy personnel, bakers, explosive workers and car mechanics. A few patients reported indoor exposure to asbestos at home and/or in the workplace. Conclusions The study confirmed that mesothelioma risk is present in several job titles of the construction industry, and it is no longer confined to workers employed in the manufacture or application of asbestos products. The occurrence of malignant mesothelioma in patients with unexpected occupational and nonoccupational exposures indicates the need for further investigation on previously underestimated exposures.

e19033 Background: About 25% of pts will eventually develop lung metastases from primary melanoma. Activating mutations in BRAF, NRAS, CKIT and EGFR genes are involved in melanoma progression. Trials with drugs targeting oncogenic BRAF in melanoma have shown that a V600E mutation may identify a subgroup of pts with a high response rate. Methods: We analysedtheprevalence of BRAF, NRAS and CKIT mutations by direct sequencing and of EGFR copy number alterations by FISH, in pts affected by melanoma lung metastases, and explored their correlation with lung metastasis-free survival (LMFS) and post surgical progression-free survival (psPFS). Results: Over 10 years, 33 cases of pts with melanoma lung metastases were diagnosed at our institution, of which 22 underwent surgery with curative intent. The mean age was 64 years, and 19 (57.5%) were male. 51% carried a BRAF V600E mutation while 18% had a NRAS codon 61 mutation. The two events were mutually exclusive. No alterations were observed in exon 11 of the CKIT gene. FISH analysis indicated an EGFR low amplification in 3 cases and chromosome 7 polysomy in 13 cases. The presence of a BRAF V600E mutation was associated with a longer LMFS (median 6.1 vs 4.4 years, p

The Lukes and Collins system of classification was applied to 151 cases of non-Hodgkin's lymphoma who had bone marrow biopsies taken immediately after histologic diagnosis. Incidence and histologic pattern of bone marrow involvement at the time of initial diagnosis were determined for each subtype of lymphoma. Thirty-three patients (21.8 %) had bone marrow involvement. The frequency of bone marrow involvement was high for undefined and convoluted lymphocyte lymphomas (66.6 %) and low to intermediate for follicular centre cell (20.3 %) and small lymphocyte lymphomas (20.0 %). Within the FCC lymphomas the non-cleaved cell type had a higher incidence of marrow involvement than the cleaved cell type (41.6 % vs 8.9 %). The follicular and diffuse histologic patterns in the diagnostic node did influence the incidence of marrow invasion in the non-cleaved cell type (75 % vs 25 %). A low incidence of marrow involvement was observed for the immunoblastic lymphomas (14.2 %); evidence of marrow infiltration was never observed in patients with true histiocytic lymphoma.