Rubeta N. Matin

Melanoma in organ transplant recipients: clinicopathological features and outcome in 100 cases.

Organ transplant recipients have a higher incidence of melanoma compared to the general population but the prognosis of this potentially fatal skin cancer in this group of patients has not yet been established. To address this, we undertook a multicenter retrospective analysis to assess outcome for 100 melanomas (91 posttransplant and 9 pretransplant) in 95 individuals. Data were collected in 14 specialist transplant dermatology clinics across Europe belonging to the Skin Care in Organ Transplant Patients, Europe (SCOPE) Network, and compared with age, sex, tumor thickness and ulceration status‐matched controls from the American Joint Committee on Cancer (AJCC) melanoma database. Outcome for posttransplant melanoma was similar to that of the general population for T1 and T2 tumors (≤2 mm thickness); but was significantly worse for T3 and T4 tumors (>2 mm thickness); all nine individuals with a pretransplant melanoma survived without disease recurrence following organ transplantation. These data have implications for both cutaneous surveillance in organ transplant recipients and management of transplant‐associated melanoma.

iASPP/p63 autoregulatory feedback loop is required for the homeostasis of stratified epithelia

iASPP, an inhibitory member of the ASPP (apoptosis stimulating protein of p53) family, is an evolutionarily conserved inhibitor of p53 which is frequently upregulated in human cancers. However, little is known about the role of iASPP under physiological conditions. Here, we report that iASPP is a critical regulator of epithelial development. We demonstrate a novel autoregulatory feedback loop which controls crucial physiological activities by linking iASPP to p63, via two previously unreported microRNAs, miR‐574‐3p and miR‐720. By investigating its function in stratified epithelia, we show that iASPP participates in the p63‐mediated epithelial integrity program by regulating the expression of genes essential for cell adhesion. Silencing of iASPP in keratinocytes by RNA interference promotes and accelerates a differentiation pathway, which also affects and slowdown cellular proliferation. Taken together, these data reveal iASPP as a key regulator of epithelial homeostasis.

NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity

Background:Novel prognostic biomarkers and therapeutic strategies are urgently required for malignant melanoma. Ecto-5-prime-nucleotidase (NT5E; CD73) overexpression has been reported in several human cancers. The mechanism(s) underlying deregulated expression and the clinical consequences of changes in expression are not known.Methods:We used RT–PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse expression and regulation of NT5E in malignant melanoma cell lines and primary and metastatic melanomas.Results:NT5E is subject to epigenetic regulation in melanoma. NT5E mRNA is downregulated by methylation-dependent transcriptional silencing in the melanoma cell lines SKMel2, SKMel23, WM35, Mel501, Mel505 and C81–61 and expression is reactivated by azacytidine. In contrast, the CpG island is unmethylated and the gene expressed in cultured normal melanocytes. In clinical cases of melanoma, methylation in the NT5E CpG island occurs in both primary and metastatic melanomas and correlates with transcriptional downregulation of NT5E mRNA. Relapse with metastatic disease, particularly to the visceral sites and brain, is more common in primary melanomas lacking NT5E methylation. Primary melanomas with methylation in NT5E show limited metastatic potential or more commonly metastasise predominantly to nodal sites rather than viscera and brain (P=0.01).Conclusion:Deregulation of NT5E expression in melanoma occurs via epigenetic changes in the NT5E CpG island. Confirmation of our results in larger clinical series would support the candidacy of NT5E as a clinical biomarker in melanoma, which could be applied in both primary and relapsed disease. Inhibition of NT5E may have therapeutic potential in melanoma, particularly in patients with more aggressive disease metastatic to viscera or the brain.

Methylated Tissue Factor Pathway Inhibitor 2 (TFPI2) DNA in Serum Is a Biomarker of Metastatic Melanoma

Transcriptional silencing of tissue factor pathway inhibitor 2 (TFPI2) occurs in several human tumors including melanoma. We investigated methylated TFPI2 as a biomarker of metastatic melanoma using qRT-PCR to assess TFPI2 expression and pyrosequencing to analyze CpG island methylation in malignant melanoma cell lines, in benign nevi, in 112 primary and metastatic melanomas, and in serum from 6 healthy individuals and 35 patients: 20 patients with primary and 15 patients with metastatic melanoma. The TFPI2 CpG island is unmethylated in nevi but methylation is associated with metastatic melanoma. Circulating methylated TFPI2 DNA is undetectable in sera from healthy individuals and detectable in sera from patients with primary and metastatic melanomas, but the presence of methylated TFPI2 DNA in serum is strongly associated with metastatic disease (P<0.01). Detection of TFPI2-methylated DNA in the serum of patients with resected melanoma is a sensitive and specific biomarker of metastatic melanoma. Confirmation of our results in independent patient cohorts would encourage prospective evaluation as a biomarker of disease state.

Melanomas in renal transplant recipients: the London experience, and invitation to participate in a European study.

Sir, In response to the report of Le Mire et al.1 on the incidence of malignant melanoma in Oxford renal transplant recipients (RTRs), we detail our experience of melanoma in a series of RTRs at Bart’s and the London NHS Trust. Although incidence rates in our population were similar to those documented in the Oxford study, metastatic disease was more common, and we suspect that RTRs with melanoma may have a worse prognosis than their immunocompetent counterparts, although larger, multicentre studies are now required to confirm this. A retrospective clinical and histological review of melanomas diagnosed in patients attending a dedicated RTR dermatology clinic between 1990 and 2005 was performed. All specimens were resectioned and were assessed by an experienced dermatopathologist (R.C.). In a total population of 861 RTRs with a follow-up period of 8557 patient-years, there were seven cases of de novo melanoma (five invasive and two in situ) in three men and four women. All diagnoses were made in the RTR dermatology clinic. Clinicopathological data are presented in Table 1 and are illustrated in Figure 1. All patients were on prednisolone and azathioprine, with or without ciclosporin. The mean age at diagnosis was older than in Oxford [57·7 years (range 44-68) vs. 41] and the mean time from transplantation was shorter [102 months (range 10-247) vs. 132]. All patients had skin types I-III (although 20% of our RTR cohort have skin type V or VI). None had a family history of melanoma or fulfilled criteria for atypical mole syndrome, although two patients had several atypical naevi. A high proportion of patients had a history of other invasive skin tumours (five of seven vs. four of 10 in Oxford); in all but one patient (patient 1) these tumours arose prior to the diagnosis of melanoma. Melanomas were more commonly located on the head and neck in our series, with four of seven tumours occurring at this site, in contrast to the Oxford tumours which all occurred at extracephalic sites. Ten of 12 tumours in the Oxford series were superficial spreading melanomas, whereas this subtype accounted for two of our seven cases. As in the Oxford series, Breslow thickness in the majority of cases (five of seven) was < 1 mm, and an inflammatory response was either minimal or absent in all melanomas, as has previously been documented.2 A contiguous pre-existing naevus was present in only one case, and, similarly, was detected in only a minority (three of 12) of the Oxford cases, in contrast to a previous proposal that over half of all transplant melanomas arise in pre-existing naevi.2 All melanomas in our series were treated by complete surgical excision; sentinel lymph node biopsy was not available at the time these tumours were diagnosed. In most cases immunosuppression was reduced, but not stopped. Fig 1 Clinical and histological examples of melanoma in renal transplant recipients. (a) Patient 6: lentigo maligna melanoma on right side of nose, Breslow thickness 0·4 mm. (b) Patient 2: lentigo maligna on cheek. (c) Photomicrograph of histology, ... Table 1 Clinicopathological data This series represents an elevated incidence of melanoma in our London RTR cohort: the rate in 2003 for the general population in North East Thames was 6·5 and 8·1 per 100 000 population for men and women, respectively, and we would therefore have expected approximately 0·9 cases of melanoma to have arisen in our cohort (in which 64% are male). If in situ tumours are included, these 7 cases represent an approximately 7·8-fold increased incidence compared with the general population. This is remarkably similar to the eightfold increased rate found in Oxford, and is of the same order as that reported by Moloney et al.3 who reported a 6·6-fold increase in males with melanoma in an Irish transplant population. These more recent studies report rates higher than previous estimates.4-6 Three patients in our series, but only one patient in Oxford, died from metastatic melanoma. Two deaths occurred in RTRs with melanomas exceeding 2 mm Breslow thickness. In accordance with American Joint Committee on Cancer staging, the predicted 5-year survival for patient 3 was 67% and that for patient 4 was 63%,7 yet both died within approximately 2 years. Even more unexpectedly, patient 6 developed metastases from a lentigo maligna melanoma of Breslow thickness 0·4 mm, for which the expected 5-year survival is 95% or greater. Our series of patients is too small to give statistical confirmation of a poorer prognosis in RTRs and previous studies have also not had sufficient power to examine this, although a compromised outcome from melanoma has similarly been observed in individuals with human immunodeficiency virus infection or AIDS.8 The incidence of melanoma is rising faster than for any other major cancer and will continue to do so over at least the next 30 years.9 In conjunction with the steadily improving long-term survival from organ transplantation, it is likely that post-transplant melanoma will emerge as an increasing clinical problem in coming years. Many important questions have yet to be answered in this respect: whether prognosis is, indeed, worse for post-transplant melanoma, whether more aggressive management strategies are therefore required, and how reduction in immunosuppression should be approached. Although consensus statements such as those recently reported in this Journal are a useful guideline to management of post-transplant skin cancer,10 a firmer evidence base is now required. This is a particular priority for management of post-transplant melanoma, and sufficient power to reach meaningful conclusions is only likely to be achieved in the context of a multicentre study. Such a study is currently being coordinated within the SCOPE network (Skin Care in Organ transplant Patients, Europe: http://www.scopnetwork.org) by our centre, and we invite clinicians who are interested in participating to contact us.

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of nonmelanoma skin cancer (NMSC), and its incidence is increasing rapidly. Metastatic cSCC accounts for the majority of deaths associated with NMSC, but the genetic basis for cSCC progression remains poorly understood. A previous study identified small deletions (typically <1 Mb) in the protein tyrosine phosphatase receptor Type D (PTPRD) gene that segregated with more aggressive cSCC. To investigate the apparent association between deletion within PTPRD and cSCC metastasis, a series of 74 formalin‐fixed paraffin‐embedded tumors from 31 patients was analyzed using a custom Illumina 384 SNP microarray. Deletions were found in 37% of patients with metastatic cSCC and were strongly associated with metastatic tumors when compared to those that had not metastasized (p = 0.007). Subsequent mutation analysis revealed a higher mutation rate for PTPRD than has been reported in any other cancer type, with 37% of tumors harboring a somatic mutation. Conversely, bisulfite sequencing showed that methylation was not a mechanism of PTPRD disruption in cSCC. This is the first report to observe an association between deletion within PTPRD and metastatic disease and highlights the potential use of these deletions as a diagnostic biomarker for tumor progression. Combined with the high mutation rate observed in our study, PTPRD is one of the most commonly altered genes in cSCC and warrants further investigation to determine its significance for metastasis in other tumor types.

Trends in dermoscopy use in the UK: results from surveys in 2003 and 2012.

Background: Dermoscopy is a useful tool to aid diagnosis of pigmented and non-pigmented skin lesions, as well as many other dermatological conditions. Use of dermoscopy is increasing worldwide, but to date, there are no reported data on attitudes of dermatologists in the United Kingdom (UK) towards dermoscopy. Objective: To determine current attitudes of UK dermatologists towards dermoscopy and assess how these attitudes have changed over the last decade. Methods: In October 2012, an online survey was sent to members of British Association of Dermatologists over a 12-week period. Data were subsequently compared with data from a similar UK nationwide paper questionnaire distributed to members in 2003. Results: The 2003 survey collected 292 responses (uptake 42%), and in 2012 there were 209 responses (22%), predominantly from consultants and registrars. In 2012, 86% respondents reported increased use of dermoscopy over the previous decade with 98.5% of respondents reporting regular clinical use of dermoscopy, compared with 54% in 2003. Overall, 81% respondents in 2012 had received dermoscopy training, mainly from UK-based courses (62% of respondents) but increasingly via Internet-based resources (30% vs. 7% in 2003). However, 39% respondents lacked confidence when making a diagnosis based on their interpretation of dermoscopy findings. Conclusions: Over the last decade, use of dermoscopy has increased amongst UK dermatologists and the majority of respondents now employ dermoscopy in daily clinical practice. However, the use of dermoscopy in the dermatology community overall is not known and for those individuals there is a continued need for education.

Cutaneous mucinous carcinoma arising in extramammary Paget disease of the perineum.

We present the case of a 74-year-old woman with a 7-year history of an expanding vulval and perianal erythematous plaque, which failed to respond to topical treatments in the community. Biopsy of the affected skin showed typical features of extramammary Paget disease. No underlying associated malignancy was identified. After 2 months of treatment with 5% topical imiquimod, the patient developed a new tender nodule in the perineal region. Histological examination revealed a mucinous carcinoma, which, after careful clinical assessment, was deemed to be a primary cutaneous mucinous carcinoma. This is the second reported case of a primary cutaneous mucinous carcinoma arising on a background of extramammary Paget disease of the vulva and perineum.

Tests to assist in the staging of cutaneous squamous cell carcinoma: a generic protocol

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: To determine the diagnostic accuracy of sentinel lymph node biopsy (SLNB) for the detection of nodal metastases (in the investigated nodal basin) for the staging of cutaneous squamous cell cancer (cSCC). To determine the diagnostic accuracy of imaging tests, including ultrasound, computed tomography, magnetic resonance imaging and positron emission tomography, alone or in combination, for the detection of any metastasis for the staging of cutaneous squamous cell cancer. To determine the diagnostic accuracy of imaging tests for the detection of nodal metastases in the staging of cutaneous squamous cell cancer. To determine the diagnostic accuracy of imaging tests for the detection of distant metastases in the staging of cutaneous squamous cell cancer. We will estimate these separately for those undergoing primary staging and those who have experienced a disease recurrence. Sources of heterogeneity We will consider a range of potential sources of heterogeneity for investigation in each individual test review. These may vary between reviews but may include the following. i. Population characteristics • Primary tumour site (head and neck, trunk, limb, and other) • Primary staging versus mixed or unclear populations (i.e. including staging of recurrent disease) 1 Tests to assist in the staging of cutaneous squamous cell carcinoma: a generic protocol (Protocol) Copyright

KIT and BRAF Mutational Status in a Patient with a Synchronous Lentigo Maligna Melanoma and a Gastrointestinal Stromal Tumor

To the Editor: Molecular events may determine clinicopathologic types of melanoma. Aberrations affecting the KIT oncogene have been demonstrated in mucosal and acral melanomas and in melanomas on chronically sun-exposed areas. Improved understanding of such genotype-phenotype correlations impacts on the development of therapies. Similarly, progress has been achieved in targeted treatment with tyrosine kinase inhibitors (for example, imatinib) of gastrointestinal stromal tumors (GISTs), in which KIT mutations occur in up to 80% of cases. To date, significant responses to imatinib have also been demonstrated in melanomas harboring KIT mutations. We report the first case of synchronous GIST and lentigo maligna melanoma (LMM) in the same patient where oncogenic KIT may play an important role and in whommolecular genotyping was undertaken to determine whether targeted chemotherapy with imatinib might be justified. A 69-year-old woman presented with increasing pigmentation in a long-standing facial lesion. She had a history of high recreational UV exposure. She reported no family history of melanoma but her father had died aged 54 years from a gastric tumor, although the histology from this was not available. A skin biopsy of the lesion above her right lateral eyebrow revealed an LMM. A whole body CT scan revealed a polypoid lesion in the anterior stomach and a positron emission tomography scan excluded a melanoma metastasis. Histologic examination of the resected polyp revealed blunt-ended spindle cells with little nuclear pleomorphism. The tumor was strongly and diffusely positive for CD117 (c-kit) but negative for S100. Taken together, the histologic features and immunocytochemistry confirmed the diagnosis of a GIST with low-risk malignant features (size 3.7 cm; mitotic count 3/50 high-power field). We hypothesized a unifying molecular link through KIT for the synchronous occurrence of two uncommon tumors in the same patient. Germline KITmutations are observed in cases of multiple GISTs but these have not been previously described in concurrent GIST with other tumors. Supporting this, a study of familial GIST reported a KIT germline mutation associated with multiple GISTs, lentigines, and melanoma, although mutations inKITwere not analyzed in themelanoma. We undertook a molecular analysis of KIT in both tumor samples and a peripheral blood sample. Immunocytochemistry of the GIST tumor was strongly and diffusely positive for CD117 (figure 1a). The LMMwas also positive (figure 1b). In contrast with GISTs, overexpression of CD117 is reported in melanomas with a variable correlation between expression and mutational status ranging from poor to strong. Analysis of exons 9, 11, 13, 17, and 18 of the KIT gene was undertaken and the GIST sample showed a V559D (c.1676T>A) mutation of KIT that is a known