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Eruptive melanocytic nevi (EMN) describes the sudden onset of cutaneous nevi over weeks or months. Such a clinical event is generally seen in young adult patients and may be related to several possible causes. We report here a case of EMN in an old male patient followed up for a thick amelanotic cutaneous melanoma. A few months after the eruption, multiple hepatic masses, diagnosed as melanoma metastasis, were detected. The presented case may suggest that EMN may be a paraneoplastic phenomenon of alert in patients being followed for melanoma or other malignancies.

Background: Recent studies have shown an increasing incidence of cutaneous adnexal carcinomas (CACs). Objectives: The aim of our study was to evaluate incidence and survival for cases of CACs and investigate their association with other skin neoplasms. Methods: We conducted a population-based study. Data on incident cases of CACs were obtained from the Tuscany Cancer Registry between 1985 and 2010. In order to determine whether the occurrence of squamous cell carcinoma (SCC) among patients with CAC is higher or lower than expected in the general population, the standardized incidence ratio (SIR) was calculated. Results: A total of 242 patients with CAC were observed; the age-standardized incidence rate was 3·8 cases per million person-years. From 1997 to 2010 crude incidence rates increased by 159%. Age-specific incidence was higher in men over 80 years old than in women of the same age and younger individuals. Carcinomas of sweat gland origin prevailed; the most common histotype was porocarcinoma and the most frequently affected site was the head/neck. Overall, 88% of CACs were diagnosed at a localized stage. The 5-year overall survival and disease-specific survival rates were 59% [95% confidence interval (CI) 53–65] and 94% (95% CI 91–98), respectively. In the observation cohort, the number of SCCs was significantly higher than expected as the SIR was calculated to be 33·7 (P < 0·001). Conclusions: Increasing incidence warrants awareness and early diagnosis of CACs. Increased SCC incidence among patients with these tumours highlights the relevance of careful skin examination and follow-up.

This study aimed to investigate the sentinel lymph node (SLN) tumour burden to predict the non-SLN positivity rate and the survival of melanoma patients to evaluate whether SLN microstaging could predict the prognosis, similar to what is currently performed by examining the lymph nodes excised by complete lymph node dissection. Of 1130 consecutive melanoma patients who underwent SLN biopsy, 226 were tumour-positive and 204 were included in this study. SLN metastases were classified on the basis of dimensional (Rotterdam) and topographic (Dewar) criteria either separately or combined. SLN metastases more than 1 mm in diameter had the highest non-SLN positivity rate (31%) compared with metastases 0.1-1 mm (10%) and less than 0.1 mm (4%). The non-SLN positivity rate was 45% for extensive metastases, 5% for subcapsular metastases and 23-29% for parenchymal, combined and multifocal classes, therefore suggesting a simplification of the parenchymal SLN metastases into only two classes: extensive and 'not extensive'. The dimension of the metastasis was correlated with a different non-SLN positivity rate only when the metastasis was in the parenchyma (20-36%) and not when it was in the subcapsular location (4-7%). Interestingly, the 5-year melanoma-specific survival (MSS) was 89% for patients with subcapsular less than 0.1 mm metastases and 45% for patients with nonsubcapsular more than 1 mm metastases (P=0.017). In the parenchyma, larger metastases (1 mm) were related to a lower 5-year MSS (46%) than smaller (1 mm) metastases (MSS 77%). SLN tumour burden characterization can be simplified and it can provide prognostic information on non-SLN positivity and survival, which is especially useful in patients who do not undergo complete lymph node dissection.

Electrochemotherapy (ECT) represents an effective local treatment for skin unresectable melanoma metastases with high overall objective response rate. ECT is based on the combination of anti-neoplastic drugs administration and cancer cells electroporation. Whether ECT can also activate the immune system is a matter of debate, however a significant recruitment of dendritic cells in melanoma treated metastases has been described. Herein we investigated immediate and late effects of ECT treatment on T cell subsets in ECT-treated lesions by fluorescent immunohistochemistry. Biopsies from melanoma patients (n = 10) were taken before ECT (t0), at d1 and d14 from treatment. At t0, CD3+CD4+ T cells were the most represented T cells, well detected in the perilesional dermis, particularly at tumour margin, while CD3+CD8+ T cells were less represented. CD4+FOXP3+ T regulatory (Treg) cells were present in the perilesional dermis and within the lesion. ECT induced a significant decrease of CD4+FOXP3+ Treg cells percentage in the perilesional dermis, observed at d1 and at d14 (p

Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression.

Background. Scalp/neck melanomas have a poor progno- sis, possibly because of a rich vascular supply that prompts tumor cells' dissemination. Methods. We compared the accuracy of immunohistochemical (IHC) staining with morphology for the identification of lymphovascular inva- sion in 156 scalp/neck melanomas. We then analyzed the association of vessel invasion and density with pathological features and survival. Results. IHC-detected lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) were identified in 34.6% and 13.5% of cases, respectively. IHC increased the LVI/BVI detection compared to morphology (40.4% vs 16.6%; p

Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas conventional naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion, may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or reduce and alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour genomics and progression will refine the classification of melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy.

Increasing evidences support the role of Merkel cell polyomavirus (MCPyV) and human papillomavirus (HPV) in non-cutaneous and cutaneous tumours. Porocarcinoma is a rare malignant neoplasm that arises from the intraepidermal ductal portion of the eccrine sweat glands. The aetiology of porocarcinoma is largely unknown and no systematic studies have been done to investigate the implication of infectious agents in the pathogenesis of this tumour.To investigate the possible association between MCPyV and/or HPV infection and porocarcinoma.Forty-four formalin-fixed paraffin-embedded (FFPE) porocarcinomas (40 primary and 4 metastatic) and 10 healthy skin specimens (controls), were analysed for the presence of MCPyV and HPV DNA using molecular detection methods.MCPyV DNA was found in 27/40 (68%) primary porocarcinomas and in 3/10 (30%) controls (Fisher exact test: p0.04). No significant difference in viral load was observed between tumours and healthy skin. Moreover, 2/40 primary porocarcinomas tested positive for high-risk HPV16. Cutaneous beta-HPV infection was detected in 16/40 (40%) porocarcinomas and in 6/10 (60%) controls. No particular beta-HPV types were significantly associated with tumour or with healthy skin. Two out of 4 metastatic biopsies were MCPyV DNA positive. All metastatic samples had mixed infections with cutaneous HPV types.This study demonstrated a significantly high prevalence of MCPyV and the presence of a broad spectrum of HPV types in porocarcinoma and provided the first available data about viral infections in this tumour. To understand the role, if any, of viral infections in the pathogenesis of porocarcinoma further studies are needed.

Introduction The diagnosis of cutaneous pigmented lesions remains a challenge for both dermatologists and pathologists. Our aim was to determine the diagnostic concordance between the conventional face-to-face diagnosis and the telediagnosis of 10 dermatologists with expertise in dermato-oncology of 10 challenging pigmented lesions. Methods Using a store-and-forward teledermatology method, clinical and dermoscopic digital images of all selected lesions were transmitted via e-mail to 10 dermatologists. Dermatologists were called to provide their telediagnoses with a step-by-step approach. When the dermatologists responded with their first clinical telediagnosis, they received a second email that contained dermoscopic images of the 10 cases. Final histopathological diagnosis was considered the gold standard for comparison with face-to-face and teledermatology diagnoses in statistical analysis. Results Face-to-face results indicated moderate agreement between clinical and histopathological diagnoses (K = 0.6). After the first clinical step, interobserver concordance of telediagnosis was lower than face-to-face diagnosis (K = 0.52). After the second dermoscopy step, the concordance declined further (K = 0.38). Conclusions Teledermatology was inferior to face-to-face dermatology. Moreover, the diagnostic concordance of telediagnosis decreased after the teledermoscopic step. This finding may be justified by the dermoscopic difficulty of the selected lesions, including Spitzoid proliferations and atypical melanocytic nevi of the elderly. These lesions may represent a potential diagnostic pitfall given their confounding dermoscopic aspects.

We report a 20-year-old male patient with an atypical Spitz tumor, located in the dorsal aspect of his left hand, and a positive sentinel axillary lymph node. After lymphadenectomy, 1 of 23 non-sentinel lymph nodes excised was found to contain small multiple deposits of large spindle atypical melanocytes. Reviewing the pertinent literature, 5 of 29 patients with atypical Spitz tumors and positive sentinel nodes who had undergone lymphadenectomy have shown non-sentinel node involvement (17.2%), a proportion similar to that reported in melanoma patients. The exact nature of atypical Spitz tumors and the interpretation of cell deposits detected in sentinel nodes are still debated; data regarding the non-sentinel lymph node involvement in patients with atypical Spitz tumors may contribute to better understand the real biological potential of such tumors.

Dermatofibrosarcoma protuberans (DFSP) is a rare skin cancer with intermediate malignancy, characterized by a progressive local growth and a propensity for local recurrence. DFSP is most frequent in adults; however, in recent years, DFSP in childhood emerged to be more common than previously believed. Unfortunately DFSP in children may be misdiagnosed, leading to a delay in the treatment. The authors report two cases of childhood DFSP with unusual clinical presentation: a congenital nodular variant and an atrophic variant developed at 2 years of age, both with acral localization. They highlight the importance of an early diagnosis by pediatricians and dermatologists to ensure an appropriate complete excision and reduce the risks of recurrences.

Tubular adenoma (TA) and syringocystadenoma papilliferum (SCAP) may show histopathological overlap, with some lesions having features of both neoplasms (SCAP + TA). TA has been recently suggested to represent a carcinoma. Four observers blindly assessed 67 cases of TA, SCAP, and their lookalikes (poroma, apocrine adenoma, apocrine carcinoma; all lesions focally featuring a pseudopapillary pattern), and classified the lesions into one of four categories: (1) TA, (2) SCAP, (3) SCAP + TA, and (4) others. Lesions were also classified as benign or malignant. In only 29 cases was there unanimous agreement among the four observers, who classified 22 lesions as TA, three as SCAP, and four cases as others. Of the 38 cases where there was interobserver diagnostic variation, in 30, the diagnosis varied between TA or SCAP or SCAP + TA; the remainder fell in the others category. Analysis of the factors leading to interobserver variability indicated that diagnostic problems occurred when there were any of the following: epidermal acanthosis, papillomatosis, connection of the neoplastic tubules to the overlying epidermis and/or follicular infundibula, and plasma cell infiltration. These features accounted for the morphological overlap between TA and SCAP. All observers agreed that the lesions were benign; the only apocrine carcinoma included was recognized as such by all observers. From the study, it was concluded that TA may arise in the deep dermis without any epidermal connection, or, in other cases, it may be more superficially located with or without an epidermal connection. It may be reasonably inferred that, possibly as a response to infection, there may be accompanying plasma cells and variable acanthosis and papillomatosis, such that the appearances are those of "pure" SCAP, or lesions may have features "intermediate" or overlapping between TA and SCAP.

Background Mucosal melanomas (MM) represent a heterogeneous tumour population that exhibits site-specific molecular profiles. Aims In a multicentre retrospective study, we investigated KIT aberrations in primary anorectal (AR) melanomas compared with melanoma metastatic to the gastrointestinal (GI) tract. Methods Primary AR MM (n=31) and GI metastatic melanoma (n=27) were studied for KIT mutations on exons 11, 13, 17 and 18 by high-resolution melting analysis, direct sequencing and c-KIT expression by immunohistochemistry. Selected cases were also investigated for increased KIT gene copy number by fluorescent in situ hybridisation. Results Functional KIT mutations were demonstrated in 11/31 (35.5%) of AR melanomas and in 1/26 (3.8%) of GI melanoma metastases (p=0.004). A significant difference emerged between primary and metastatic MM with regards to KIT-positive immunostaining (p=0.002). Immunohistochemical c- KIT protein overexpression did not correlate with KIT mutational status. Increased KIT copy number was demonstrated in 5/20 AR primary cases. Conclusions The rate of functional mutations in KIT is significantly higher in AR MM than in GI metastatic melanoma. KIT protein overexpression does not correlate with KIT mutations and cannot be used for screening purposes. Recognising the molecular heterogeneity of MM helps to identify patients who require a different therapeutic approach.

Testing for NRAS is now integral part in the assessment of metastatic melanoma patients because there is evidence that NRAS-mutated patients may be sensitive to MEK inhibitors, and RAS mutation is a common mechanism of acquired resistance during treatment with BRAF inhibitors. This study evaluated the sensitivity and specificity of immunohistochemical analysis using an N-Ras (Q61R) antibody to detect the presence of the NRASQ61R mutation in melanoma patients. A total of 98 primary cutaneous melanomas that have undergone examination of NRAS mutation were retrieved from a multicentric database. Formalin-fixed and paraffin-embedded melanoma tissues were analyzed for BRAF and NRAS mutations by independent, blinded observers using both conventional DNA molecular techniques and immunohistochemistry with the novel anti-human N-Ras (Q61R) monoclonal antibody (clone SP174). The antibody showed a sensitivity of 100% (14/14) and a specificity of 100% (83/83) for detecting the presence of an NRASQ61R mutation. Of the NRAS-mutated cases, none of the non-Q61R cases stained positive with the antibody (0/7). There were three cases with discordant NRAS mutational results. Additional molecular analysis confirmed the immunohistochemically obtained NRAS result in all cases, suggesting that a multiple analytical approach can be required to reach the correct sample classification. The reported immunohistochemical method is an accurate, rapid, and cost-effective method for detecting NRASQ61R mutation in melanoma patients, and represents a valuable supplement to traditional mutation testing. If validated in further studies, genetic testing would only be required for immunohistochemistry-negative patients to detect non-Q61R mutations.

The distinction between Spitz nevus and melanoma is currently possible, applying a set of definite histological criteria. However, in certain lesions deviating from the stereotypical morphology of classic Spitz nevi ("atypical Spitz tumors"), the differentiation between benign and malignant cases appears problematic because objective criteria for a reliable diagnosis are lacking. We report the clinicopathologic findings of 12 patients with atypical Spitz tumors, who underwent sentinel node biopsy. All the tumors, composed of spindle and/or epithelioid cells, histologically showed features referable to Spitz nevi mixed to features generally found in malignant melanomas. Nine patients were females and three males, ranging in age from 2 to 48 years (mean, 23.2 years). The size of lesions ranged from 5 to 9 mm, the thickness from 1.12 to 5.70 mm. Nodal micrometastases were found in 4 (33.3%) patients. Among the patients with positive sentinel node, two showed minimal nodal involvements; one patient showed additional tumor deposits in one nonsentinel regional node. All patients are alive and free of disease with a follow-up of 2 to 90 months (mean, 26.3 months). Metastasizing and nonmetastasizing cases appeared clinically and histologically indistinguishable. The statistical analysis showed no significant difference between the two groups. Results suggested that all the reported cases may constitute a relatively homogeneous morphological group of lesions with a relevant metastatic potential that may be underdiagnosed.

Background: Melanocytic nevi in the genital, acral, and flexural sites often display clinical and histologic features that may simulate melanoma. We verified whether this is the case also for nevi of the breast. Methods: Eleven dermatopathologists, from nine Italian Institutions, collected the specimens of melanocytic lesions from the breast and other body sites, excluding the acral, genital, and flexural areas, as controls. Cases and controls were matched for sex and age. All nevi were observed ‘blindly’ and simultaneously by all participants. For each lesion, 10 histological parameters were analyzed: asymmetry, absence of lateral demarcation of melanocytes, lentiginous proliferation, nested and dyshesive pattern, intraepidermal melanocytes above the basal layer, involvement of the hair follicle, absence of maturation of dermal melanocytes, melanocytic atypia, fibroplasia of the papillary dermis, and lymphocytic dermal infiltrate. Each parameter was scored 2 when present and 1 when absent or not valuable. A total score was calculated for each lesion. Results were statistically analyzed by the chi-square test and the Mann–Whitney U-test. Results: One hundred and one nevi came from the breast area and 97 from elsewhere. Breast nevi exhibited significantly more atypical features than nevi from other sites. In particular, breast nevi with intraepidermal melanocytes, melanocytic atypia, and dermal fibroplasia were significantly more numerous. We did not find any sexual difference. Conclusions: To avoid undue concerns, dermatopathologists should be aware that melanocytic nevi of the breast may show a high degree of atypical features.

The status and relevance of repetitive nucleotide sequences or microsatellite alterations in sporadic cutaneous melanoma has not been fully clarified. In this study we evaluated the presence of microsatellite alterations in a series of sporadic primary and metastatic melanomas in order to discover which genetic events may have a pathogenetic role in the development of this disease. Tumour samples were obtained from 21 patients with sporadic cutaneous melanoma, and from eight corresponding positive sentinel lymph nodes and one corresponding in-transit metastasis. In each specimen, selected neoplastic cells were procured by laser-assisted microdissection. Polymerase chain reaction-based microsatellite analysis was performed using a panel of 11 microsatellite markers, located at chromosome 2p, 4q, 9p, 16q, 17p and 21q. Overall, we found microsatellite alterations in five (23.8%) melanomas. Of these, one case showed alteration at marker D2S2182 and one at marker D17S261, whereas in another case alterations at three loci, D2S2182, D2S2291 and D9S171, were found. The fourth patient demonstrated an alteration at locus D9S171 both in the primary tumour and in the histologically positive sentinel lymph node. The fifth case was characterized by alterations at D2S2182 and at D17S250, whereas the corresponding in-transit metastasis showed the same alterations as the primary tumour and an additional alteration at IFN alpha. In conclusion, our study confirms previous observations that cutaneous melanomas demonstrate microsatellite alterations, although such instability occurs at a lower frequency than specific mismatch repair defects. Genetic analysis of metastatic lesions revealed that the same microsatellite alterations as in the primary tumour are seen, but additional genetic changes may develop during disease progression.

background. CO2 laser is currently one of the most versatile and useful laser devices in dermatologic practice in the fields of both cosmetology and oncology. The CO2 laser in a superpulsed mode enables the operator to effect precise and adequate vaporization of the affected area, with the possibility to appreciate visually the depth achieved, and, when necessary, to perform histologic and cytologic examination of the surrounding skin. objective. To show superpulsed CO2 laser treatment of basal cell carcinoma. methods. One hundred forty patients presenting single, multiple, superficial, or nodular basal cell carcinoma (BCC) have been treated with the superpulsed CO2 laser. Before the laser treatment the lesion was subjected to cytologic examination by scraping; this examination was then repeated when the papillary dermis was clinically detectable, and again when the operator considered the BCC completely vaporized. In selected subjects, histopathologic examination was done three times (biopsies were obtained at the same time as the samples for the cytologic examination). results. Recovery time was fast, with good healing outcomes. After 3 years follow-up no recurrences were seen. The cytologic and histopathologic examinations showed BCC in the specimens obtained prior to and during laser therapy, but not in those obtained after laser therapy. conclusion. This technique causes minimal thermal cellular damage and no severe morphologic cellular alterations. Thus it permits an intraoperatory cytologic and histopathologic examination. Finally, this technique enables the operator to recognize the different skin levels removed by vaporization and to stop the vaporization as soon as unaffected dermis has been reached, as shown by intraoperatory cytologic and histopathologic examination.

Context.—Several aspects of sweat gland carcinomas (incidence, classification, diagnosis, and behavior) have not been definitively clarified and need to be studied further. Objective.—The clinicopathologic findings of a large series of sweat gland carcinomas, collected during a period of 15 years, are presented. Methods.—Sixty sweat gland carcinomas (41 porocarcinomas, 3 syringomatous carcinomas, 8 ductal carcinomas, 5 adenoid cystic carcinomas, and 3 mucinous carcinomas) were analyzed histologically and immunohistochemically. Results.—Porocarcinomas were composed of eosinophilic and clear atypical cells arranged in solid-cystic lobular masses. These tumors were divided into 2 subgroups: horizontal porocarcinomas, showing a prominent intraepidermal component, and nodular porocarcinomas, which demonstrated predominant nodular growth. Syringomatous carcinomas presented keratinizing and nonkeratinizing cysts, dilated tubules (sometimes with a “tadpole” appearance), small neoplastic ducts, solid islands, and cellular cords. Ductal carcinomas were characterized by a prominent formation of tubules, solid islands, and cellular cords. Adenoid cystic carcinomas presented a characteristic pattern, showing basaloid monomorphous cells with moderately atypical nuclei, arranged in cribriform or solid islands and in tubular structures. Mucinous carcinomas were composed of moderately atypical cells with eosinophilic vacuolated cytoplasm, forming solid and cystic islands floating in large mucin pools. Immunohistochemically, cytokeratin was found in neoplastic cells in all cases, carcinoembryonic antigen was detected in 73% of cases, and actin-positive (myoepithelial) cells were not found. Conclusions.—Although numerous studies have been published in recent years, the histologic features, histogenesis, and classification of sweat gland carcinomas still remain controversial and need to be clarified by further studies.

The atypical histologic features considered to be specific to dysplastic (atypical) nevi have been reported to occur in nevi that are common nevi by all other clinical and histologic features. The distribution and mutual relations among such features in nevi need to be further studied. Six histologic features (dimension > 5 mm, lentiginous proliferation, disordered nested pattern, melanocytic dyskaryosis, dermal lymphocytic infiltrate, suprabasal melanocytes) were analyzed in 253 melanocytic nevi with different clinical appearances. Atypical histologic features, found in 72% of nevi, occurred singly or formed numerous and highly variable combinations. Nevi formed a complex histologic spectrum comprising lesions showing a progressively increasing incidence of atypical features rather than two classes (common and dysplastic nevi). To divide the investigated lesions in objectively defined groups, we used a scoring system. In each nevus, a numeric value of 1 was assigned when each of the studied parameters was present and a value of 0 was assigned when each of these parameters was absent; on the basis of the final scores, nevi were divided in six different classes (classes 0-5). Diagnostic categories such as dysplastic nevi and common nevi seem to be inappropriate, as they do not reflect the real histologic complexity of such lesions.

BACKGROUND The c-erbB-2 gene codes for a putative transmembrane protein, similar in structure to the epidermal growth factor receptor. Amplification and/or overexpression of the gene has been recently described with a prognostic significance in a variety of human adenocarcinomas. METHODS A monoclonal antibody against the c-erbB-2 oncoprotein has been used immunocytochemically in a retrospective study of formalin-fixed, paraffin-embedded samples from 28 consecutive intestinal-type adenocarcinomas (ITACs) of the nose and paranasal sinuses. RESULTS Nine out of 28 primary adenocarcinomas (32%) showed positive staining. Clinical follow-up data, available for all patients, suggested in a univariate analysis a correlation between c-erbB-2 expression and poor prognosis, as measured by 5-year disease-free (p = .02) and overall survival curves (p = .07) as well as by recurrence of disease and the appearance of regional and distant metastases (p = .08). In multivariate analysis, c-erbB-2 expression was statistically significant in terms of disease-free survival (p = .046) but not of overall survival (p = .091) in our series. CONCLUSIONS These data indicate that c-erbB-2 oncogene activation could be involved in sinonasal tract oncogenesis, with possible prognostic implications.

A 96-year-old man presented with a polypoid melanoma, which showed a prominent clear stroma, similar to that of myxoid melanoma, but stained negative for Alcian blue at pH 2.5 and for colloidal iron. It is not clear whether melanoma displaying pseudomyxoid features (pseudomyxoid melanoma) may represent a distinct histological variant of melanoma. However, it must be differentiated from true myxoid melanomas, in which Alcian blue-positive acid mucopolysaccharides are present. Urso C. Cutaneous melanoma with pseudomyxoid features.

Animal-type melanoma (ATM) is a rare tumor, characterized histologically by a predominantly dermal proliferation of heavily pigmented epithelioid and spindle dendritic melanocytes. Five patients with ATM, who had undergone sentinel node biopsy, were studied: three male and two female, between 4 and 62 years of age (mean, 28.0). Lesion size ranged from 4 to 18 mm and thickness from 0.7 to 5.1 mm. Nodal deposits were found in three patients. Of the patients with positive sentinel nodes, the first showed a minimal nodal involvement in one node, the second multiple deposits in one node, and the third multiple deposits in one sentinel node and a single deposit in another; this last patient also had additional tumor deposits in a nonsentinel regional node. Fluorescence in-situ hybridization tumor analysis proved negative in all cases. All patients are alive and free of disease at 36-95-month follow-up (mean, 53 months). Results showed ATM as a neoplasm characterized by a somewhat high rate of lymph node involvement but relatively low rate of visceral metastases and mortality, appearing as a low-grade malignant tumor.

Cutaneous melanoma represents the main cause of death among skin cancers. The thickness of the lesion at diagnosis is one of the most important prognostic indicators for survival, which is good for thin melanomas (≤1 mm) and worsens as thickness increases. Nevertheless, it is not rare to observe disease progression of thin melanomas or, conversely, a good outcome for those melanomas considered to be at high risk, according to the classical prognostic criteria. In the present paper, we analysed for the first time the expression of the hERG1 protein, a potassium channel frequently overexpressed and misexpressed in cancers, in cutaneous melanocytic lesions. The analysis was carried out on archival samples relative to (a) typical melanocytic nevi, (b) atypical melanocytic nevi, (c) thin (1 mm) melanomas from patients who survived at least 10 years after surgery, (d) thick (4 mm) melanomas from patients who died for melanoma and (e) melanoma metastases. Samples were analysed by immunohistochemistry using an hERG1-specific antibody. We showed that primary cutaneous melanomas with a thickness greater than 4 mm as well as metastatic melanoma lesions are characterized by a high level of hERG1 expression. Conversely, thin melanomas and benign melanocytic lesions (e.g. typical and atypical melanocytic nevi) express hERG1 at significantly lower levels. Although still preliminary, the data presented here enable us to consider hERG1 as a novel candidate biomarker for aggressive melanoma.

Electrochemotherapy (ECT) is a novel treatment for recurrent or in-transit unresectable melanoma metastases based on the administration of anti-neoplastic drugs followed by cancer cell electroporation. Whether ECT can also induce anti-tumour immunity is unclear. We addressed this issue investigating the presence of dendritic cells (DCs) in the inflammatory infiltrate of ECT-treated lesions. Biopsies from melanoma patients (n = 9) were taken before ECT (T0), at d7 and d14 after treatment and studied by immunofluorescence with DCs-related antibodies. Epidermal Langerin+ Langerhans cells (LCs) were the most represented subset before treatment. ECT induced a significant reduction in epidermal LCs number at d7 (p < 0.001), while they were completely replaced at d14. Similarly, the few LCs observed intermingled with metastatic melanoma cells at T0 decreased after treatment (p < 0.001), suggesting an ECT-induced activation of LCs. Consistently, at d1 after ECT (n = 3 patients), LCs were found to express CCR7, which mediates LCs migration to regional lymph nodes, and CD83, the typical DCs maturation marker. In contrast, plasmacytoid DCs (pDCs) were not present at T0, but significantly increased after ECT both in melanoma metastasis (p < 0.001) and perilesionally (p < 0.05). Similarly, CD1c+ dermal DCs (dDCs), observed in low number before ECT, strongly increased at d7 and even more at d14 (p < 0.05 and p < 0.001, respectively). Notably, some dDCs expressed CD83. These data suggest that ECT promotes LCs migration from the tumour to draining lymph nodes and pDCs and dDCs recruitment at the site of the lesion. These findings may help to design new strategies of in situ DCs vaccination in cancer patients.

The special types of breast cancer seem to have not only distinct morphological features but also distinct biological features. Women diagnosed with a first primary invasive breast cancer in the 2004–2005 period were identified through Tuscan Cancer Registry. Information on age, tumor size, lymph node status, histological type and grade, hormonal receptors, HER2 immunohistochemical expression were collected. Five subtypes were defined: luminal A, luminal B HER2+, luminal B HER2−, triple negative, and HER2 positive. The association between the histological type and molecular subgroups was assessed by a Fisher’s exact test, and a multinomial logistic regression model was used. Out of 1,487 patients, 34 % were luminal A subtype, 25 % luminal B HER2−, 11 % luminal B HER2+, 19 % triple negative, and 10.2 % HER2+; 58.5 % of cancers were ductal NOS types. With luminal A as reference, histological types distribution was significantly different between the subgroups. Mucinous, tubular, and cribriform histotypes were found among luminal A cancers more than in other subgroups; all medullary carcinomas were triple negative cancers. Pathological stage at diagnosis was more advanced, and histological grade was lower among subgroups other than luminal A. Significant association between breast cancer histotypes and molecular subgroups was found.

In a population-based screening program, a percentage of tumors remain undetected; these tumors comprise a heterogeneous group, and they are more likely to have adverse prognostic features. The aim of this study was to identify differences in biological characteristics of screen-detected versus interval breast cancers in a population-based screening program according to molecular subtypes.We analyzed the population-based data from a long-running screening program in the area of Florence. Data on screening history and on age, T and N status, grade, histotype, hormonal status and Ki-67 and HER2 expression were retrieved. Subtypes of breast cancer were defined on the expression of ER, PR, Ki-67 and HER2: luminal A if ER/PR+, HER2- and Ki6714 %, luminal B (HER2 negative) if ER/PR+, HER2- and Ki67 ≥14 %, luminal B (HER2 positive) if ER/PR+ and HER2+, triple negative if ER/PR-and HER2-, HER2 positive if ER/PR- and HER2+. Association between molecular subtypes and mode of detection will be evaluated by a logistic regression model adjusted for the potential confounding variables.Information about biomarkers was known for 277 cases, 211 screening-detected and 66 interval cancers. Among interval cases, the triple-negative cancers were more represented than luminal A (OR = 3.52; CI, 1.112-11.13; p = 0.0319), while the proportion of HER2+ was quite similar (OR = 1.57; p = 0.4709).Although made on a small number of cases, our results suggest a difference in distribution of molecular subtypes according to mode detection, confirming the results of earlier studies.

To the editor: The specific function of Langerhans cells (LCs) in the skin immune system is controversial and a matter of intense debate.[1][1] As epidermal LCs are potential targets for cancer immunotherapy, the topic is of primary importance.[2][2] Recently, van de Ven et al showed that LCs are

Summary The histological intraepidermal characteristics considered to be specific to dysplastic nevi(radial extension, lentiginous and disordered nest proliferations, cytological atypia or dyskaryosis) were investigated in a series of 114 acquired nevi showing various clinical appearances in an attempt to establish whether dysplastic nevi can be considered a homogeneous class of lesions, clearly distinct from common nevi. On the basis of the distribution of investigated architectural features, found singly or variously associated, the examined lesions were divided into 5 groups, showing an increasing incidence of dyskaryosis. Results suggest that acquired nevi, rather than two distinct classes (common and dysplastic nevi), form a histological spectrum of lesions, within which the border between lesions implying and not implying an increased melanoma risk cannot be objectively fixed.

Summary Background Although showing a rapidly rising incidence, paediatric melanoma is relatively rare, accounting for 1–4% of all cases of melanoma and for 1–3% of all paediatric malignancies. The overall survival rate in paediatric patients seems to be similar to that recorded in adults. ‘Animal-type' melanoma (ATM) is a rare melanoma subtype, occurring both in childhood and in adults, that shows a close histological resemblance to the heavily pigmented melanocytic tumours observed in grey and white horses. Case presentation We present a case of ATM of the scalp with satellitosis and two positive sentinel nodes in a 4-year-old male child. No other tumour deposits were found in the subsequent regional lymphadenectomy; the patient has been tumour free for 30 months. Conclusions We treated our case of ATM in a child as the other types of paediatric melanoma, therefore as an adult melanoma. ATM is generally considered a neoplasm with an indolent course, that occasionally shows an aggressive behaviour, and patient deaths of ATM have been reported. Due to the rarity of ATM, further studies are needed to better define the biological behaviour of this particular melanoma subtype and the therapeutic and follow-up strategies.

Seven cases of sweat-gland carcinomas showing eccrine ductal differentiation (ductal carcinomas) are presented. The tumors had a variable histological appearance, but were basically characterized by the following histological elements: (a) tubular structures, sometimes cystic or having a "tadpole" appearance; (b) solid islands of squamous, basaloid, or clear cells; (c) periodic acid-Schiff-positive endoluminal and/or intracellular material; and (d) infiltrating growth. Immunocytochemically, tumor cells were positive for keratin and negative for actin. Endoluminal material contained carcinoembryonic antigen in five of seven cases. Although it is not yet clear whether carcinomas exhibiting eccrine ductal differentiation may represent a specific histotype or a group encompassing several distinct clinicopathological entities, the histological analysis of the cases suggested that the wide spectrum of their histological appearances may be due to variable grades of differentiation.

Ten (dermato)pathologists studied 50 cutaneous melanocytic lesions including common naevocellular naevi, dysplastic naevi (DN), melanomas in situ and invasive primary melanomas, with emphasis on the histological criteria of DN. Using a standardised form, 20 defined histopathological features were scored (semi)quantitatively. Concordance of diagnosis, efficacy and reproducibility of features were investigated. DN were distinguished well from the other entities (mean Po 0.87). Agreement on the degree of atypia of DN was low. The reproducibility of the scoring was best for the following features: irregular nests, lymphohistiocytic infiltrate, marked junctional proliferation and large nuclei. The overall values of these features to discriminate between DN and non-DN were better than for the other features studied. Using the presence of at least three of the four features as a condition for the diagnosis of DN, values for sensitivity, specificity and positive and negative predictive values were 0.86, 0.91, 0.96 and 0.73, respectively. On the basis of the results these features seem best suited as histological criteria for the diagnosis of DN.

Pityriasis lichenoides et varioliformis acuta (PLEVA) is a disorder of unknown aetiology that occurs at any age and can be localized on the skin and on the mucosas. We report the case of a 24-year-old woman who presented PLEVA at her 20th week of gestation. This is, to our knowledge, the second case of PLEVA during pregnancy reported in literature. We report this case for the importance of the diagnosis of PLEVA during pregnancy because of the possible involvement of the mucosal membranes, and in particular of the vagina or cervical os of the uterus, where it may cause premature labour and/or premature rapture of the membranes.

The aim of this study is to evaluate the prognostic values of some biological parameters in a population based series of female breast cancer patients. Through the Tuscan Cancer Registry all the invasive breast cancer cases diagnosed during the period 2004–2005 in the provinces of Florence and Prato, central Italy, were retrieved. Molecular subtypes were analyzed defined by immunohistochemical markers, by age, tumor size, lymph node status, histotype, grade of differentiation and proliferative marker. Out of 1487 patients 70.3% were luminal A subtype (ER/PR + HER2-), 15.6% luminal B (ER/PR + HER2+), 8.1% triple negative (ER/PR-HER2-), 6.0% HER2+ (ER/PR-HER2+); the 3 year survival rates were 93.3%, 89.5%, 86.3%, 82.7% respectively (p < 0.001). Analysis of survival by the Cox proportional hazards model showed an independent prognostic value of molecular classification. Our study revealed significant differences in clinicopathological characteristics among breast cancer molecular subtypes and confirmed their prognostic independent role.

A retrospective evaluation of 201 stage I cutaneous melanomas was performed to investigate the prognostic significance of histological regression (present in 67 cases). Thin melanomas showed regression more frequently than thick lesions (48% less than or equal to 0.75 mm vs 12% greater than 3 mm). The mean disease-free interval was 33.53 months in regressing tumours and 19.9 in non-regressing tumours (p = 0.07): differences between the survival curves were not significant (p = 0.61). Metastases developed in 13 (19.40%) patients with regressing tumours and by 40 (29.85%) patients with non-regressing tumours. Although we observed a higher frequency of regression in thin melanomas we could not demonstrate an influence of regression on disease-free interval and survival.

Background: We tested the relevance of clinical information in the histopathologic evaluation of melanocytic skin neoplasm (MSN). Methods: Histopathologic specimens from 99 clinically atypical MSN were circulated among ten histopathologists; each case had clinical information available in a database with a five-step procedure (no information; age/sex/location; clinical diagnosis; clinical image; dermoscopic image); each step had a histopathologic diagnosis (D1 through D5); each diagnostic step had a level of diagnostic confidence (LDC) ranging from 1 (no diagnostic certainty) to 5 (absolute diagnostic certainty). The comparison of the LDC was employed with an analysis of variance (ANOVA) for repeated measures. Findings: In D1 (no information), 36/99 cases (36.3%) had unanimous diagnosis; in D5 (full information available), 51/99 cases (51.5%) had unanimous diagnosis (p for difference between proportions

• Intratumoral and peritumoral infiltration of T-zone histiocytes, mainly of mature Langerhans cells, was investigated in 88 patients with squamous cell carcinoma of the larynx by immunohistochemical methods using polyclonal antibodies against S100 protein and lysozyme. Granulocytic and lymphoid inflammatory infiltration and its relationship to the presence of Langerhans cells were also evaluated. Langerhans cells were present within the cancer tissues and showed a relationship with lymphoid infiltrate. No significant correlation was present among the density of Langerhans cells and the site of neoplastic growth (supraglottic or subglottic), granulocytic inflammatory infiltration, histological tumor grade, or clinical stage. Patients with high or intermediate density of Langerhans cells survived longer than those with low density (mean survival, 61%, 62%, and 0%, respectively). The number of Langerhans cells was relevant in patients with evident infiltration of lymphocytes and plasma cells, according to their ability to present antigens to sensitized T cells. Our results indicate that the presence of high or intermediate density of Langerhans cells and of marked lymphoid inflammation may be considered favorable prognostic factors for patients with squamous cell carcinoma of the larynx. ( Arch Otolaryngol Head Neck Surg . 1991;117:1007-1010)

The efficacy of the histological criteria currently used in the diagnosis of melanoma is still to be defined. We performed a quantitative analysis of 72 conventional (non-Spitzoid, nondesmoplastic) melanomas and 73 conventional melanocytic naevi, used as controls, for 13 histological diagnostic parameters (dimension6 mm, asymmetry, poor circumscription, irregular and confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, asymmetrical melanin, melanin in deep cells, cytological atypia, mitoses, necrosis and dermal lymphocytic infiltrate). Differences in the distribution of selected parameters between the two groups were investigated by Fisher's exact test; for each parameter sensitivity and specificity were calculated. Results showed that all parameters, except poor circumscription, seemed to be significantly associated with melanoma (P0.05). Cytological atypia, dermal lymphocytic infiltrate, asymmetry, dimension6 mm and absence of maturation showed a high sensitivity (90%); absence of maturation, mitoses, necrosis, asymmetrical melanin, suprabasal melanocytes and melanin in deep cells showed a high specificity (90%); irregular-confluent nests and single melanocytes predominating were poorly sensitive and poorly specific. In melanomasor =2 mm, two additional parameters were sensitive (or =90%): suprabasal melanocytes and single melanocytes predominating. We conclude that not all parameters showed to have the same diagnostic value. Absence of maturation and, limited to melanomasor =2 mm, suprabasal melanocytes were the most discriminating (sensitive and specific) histological features. Cytological atypia, dimension6 mm, suprabasal melanocytes and mitoses were additional reliable diagnostic features, showing a relatively high sensitivity and a relatively high specificity. Other useful features were dermal lymphocytic infiltrate and asymmetry (sensitive) and necrosis, asymmetrical melanin and melanin in deep cells (specific).