Hypothesised cutaneous sites of origin of stage III melanomas with unknown primary: A multicentre study.

Based on molecular evidence that melanomas with unknown primary (MUPs) arise from the skin, we hypothesised that sites of MUPs are disproportionately on trunk and lower limbs, sites that are not readily visible to patients and clinicians. We tested this hypothesis by inferring the anatomic site of origin of MUPs from the corresponding known cutaneous sites of melanoma patients with known primary tumours (MKPs). We analysed data from three separate cohorts of patients from Brisbane, Australia (n = 236); Manchester, UK (n = 51) and Padova, Italy (n = 33), respectively, who first presented with stage III melanoma with lymph node metastases. We matched two MKP patients to each MUP patient based on lymph node dissection (LND) site, age and sex, and imputed cutaneous sites of origin of MUPs from their two matched MKPs for study countries, giving two possible sites for each MUP per centre. Overall, results showed that MUP patients were predominantly male, and trunk was the most likely origin, comprising around a third to a half of MUPs across the three cohorts. The remaining MUP inferred sites varied by country. In the Australian cohort, the legs accounted for a third of imputed sites of MUPs, while in the UK and Italian cohorts, the most frequent site was the arms followed by the legs. Our findings suggest the need for regular and thorough skin examination on trunk and limbs, especially in males, to improve early detection of cutaneous melanoma and reduce the risk of metastatic disease at the time of presentation.

Correction to: 1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study.

In the original article John F. Thompson was inadvertently omitted as an author. The author list is updated as shown in this correction.

1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study.

BACKGROUND: There is a lack of consensus regarding optimal surgical excision margins for primary cutaneous melanoma > 1 mm in Breslow thickness (BT). A narrower surgical margin is expected to be associated with lower morbidity, improved quality of life (QoL), and reduced cost. We report the results of a pilot international study (MelMarT) comparing a 1 versus 2-cm surgical margin for patients with primary melanoma > 1 mm in BT. METHODS: This phase III, multicentre trial [NCT02385214] administered by the Australia & New Zealand Medical Trials Group (ANZMTG 03.12) randomised patients with a primary cutaneous melanoma > 1 mm in BT to a 1 versus 2-cm wide excision margin to be performed with sentinel lymph node biopsy. Surgical closure technique was at the discretion of the treating surgeon. Patients' QoL was measured (FACT-M questionnaire) at baseline, 3, 6, and 12 months after randomisation. RESULTS: Between January 2015 and June 2016, 400 patients were randomised from 17 centres in 5 countries. A total of 377 patients were available for analysis. Primary melanomas were located on the trunk (56.9%), extremities (35.6%), and head and neck (7.4%). More patients in the 2-cm margin group required reconstruction (34.9 vs. 13.6%; p < 0.0001). There was an increased wound necrosis rate in the 2-cm arm (0.5 vs. 3.6%; p = 0.036). After 12 months' follow-up, no differences were noted in QoL between groups. DISCUSSION: This pilot study demonstrates the feasibility of a large international RCT to provide a definitive answer to the optimal excision margin for patients with intermediate- to high-risk primary cutaneous melanoma.

First evidence of genotype-phenotype correlations in Gorlin syndrome.

BACKGROUND: Gorlin syndrome (GS) is an autosomal dominant syndrome characterised by multiple basal cell carcinomas (BCCs) and an increased risk of jaw cysts and early childhood medulloblastoma. Heterozygous germline variants in PTCH1 and SUFU encoding components of the Sonic hedgehog pathway explain the majority of cases. Here, we aimed to delineate genotype-phenotype correlations in GS. METHODS: We assessed genetic and phenotypic data for 182 individuals meeting the diagnostic criteria for GS (median age: 47.1; IQR: 31.1-61.1). A total of 126 patients had a heterozygous pathogenic variant, 9 had SUFU pathogenic variants and 46 had no identified mutation. RESULTS: Patients with variants were more likely to be diagnosed earlier (p=0.02), have jaw cysts (p=0.002) and have bifid ribs (p=0.003) or any skeletal abnormality (p=0.003) than patients with no identified mutation. Patients with a missense variant in PTCH1 were diagnosed later (p=0.03) and were less likely to develop at least 10 BCCs and jaw cysts than those with other pathogenic PTCH1 variants (p=0.03). Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004). CONCLUSION: We propose that the clinical heterogeneity of GS can in part be explained by the underlying or SUFU variant.

Is skipped nodal metastasis a phenomenon of cutaneous melanoma?

BACKGROUND AND METHODS: Skipped nodal metastasis (SNM) is a recognized phenomenon of visceral cancers when metastases bypass the regional basin and skip to a distant nodal basin without evidence of distant metastases. Its occurrence is undocumented in cutaneous melanoma patients but of potential prognostic significance. We therefore assessed the frequency of SNM in a large series of patients with limb melanomas. PATIENTS AND METHODS: We studied melanoma patients attending a tertiary oncology hospital in northwest England using two approaches. First, we systematically searched medical records of an unselected patient sample treated 2002-2015, and second, we studied lymphoscintigrams of all patients with limb melanoma who underwent sentinel node biopsy 2008-2019. RESULTS: Of 672 melanoma patients whose clinical records were examined, 16 had regional nodal metastases without apparent visceral spread and one appeared to have SNM but further scans were uncovered that showed concurrent pulmonary metastases. Of 667 limb melanoma patients with lymphoscintigrams, 7 showed dual lymphatic drainage patterns to distal as well as regional nodal basins, but none had micro-metastases solely in the distant basin. CONCLUSION: Occurrence of SNM in cutaneous melanoma is highly unlikely.

Female Immunity Protects from Cutaneous Squamous Cell Carcinoma.

PURPOSE: Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation. EXPERIMENTAL DESIGN: We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing. RESULTS: We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. CONCLUSIONS: This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.

The modified bipedicled flap for reconstruction of oncological skin defects of the trunk and extremities.

BACKGROUND/AIMS: Oncological skin defects of the extremities and trunk can be challenging. Our modified bipedicled flap utilises the principle of the bipedicled advancement flap, but allows for direct closure of the donor site (as opposed to skin grafting). It does not rely on the preservation of perforators and it random pattern, making it extremely versatile. We aimed to assess the outcomes for patients reconstructed using the modified bipedicled flap technique including oncological safety and complications. METHODS: Consecutive patients were retrospectively identified from July 2011 to January 2019 using operative records. Demographics, operative details, oncological data and complications were recorded from patient records and the institution's internal electronic patient records system. No cases, having a modified bipedicled flap, were excluded from this study. RESULTS: One hundred flaps in 98 patients were included. Mean defect dimensions were 61.7 mm by 33.1 mm. Median length of stay was 1 day, time to discharge from dressing clinic was 15 days, and the length of follow-up was 6.0 years. Eight patients required oral antibiotics for suspected localised wound infection, and 6 patients had minor wound healing problems. There were no cases of flap failure, partial flap loss, returns to theatre for flap-related complications, or local disease recurrence. CONCLUSIONS: To our knowledge, this is the largest series of bipedicled flaps published to date. Our technique is easy to execute, versatile, and allows for direct closure of the secondary defect with excellent cosmetic results. It is oncologically safe, with a low incidence of complications. We commend it for use in the reconstruction of oncological skin defects of the trunk and extremities.

Reappraisal of giant basal cell carcinoma: Clinical features and outcomes.

BACKGROUND: Giant basal cell carcinoma (GBCC) is a rare subgroup of basal cell carcinomas with a diameter of >5 cm. Current evidence about determining factors is conflicting, suggesting patient neglect, on the one hand, and biologically aggressive behaviour, on the other, with outcomes varying from clearance to death. We aimed to clarify the natural history of GBCC and its response to treatment. METHODS: We extracted information from clinical records of all patients with GBCC treated from 1998 to 2017 in a tertiary oncology hospital in northwest England. Associations between patient and tumour characteristics were investigated, and modes of treatment and outcomes were assessed. RESULTS: In the 20-year study period, 43 patients (median age 76 years; 23 (53%) female), 3 of whom had Gorlin syndrome, were treated for GBCCs. Median diameter was 6.3 cm, and median time to presentation was 5 years. Seven (16%) GBCCs arose from recurrent BCC, while the majority (84%) presented de novo. The size of GBCC was significantly correlated with delay in presentation (p = 0.03) but not with age or sex. Of 41 patients receiving definitive treatment, 19 GBCCs were treated by excision with ≤1 cm margin and none recurred during follow-up, compared with 10 recurrences of 23 treated with photodynamic therapy (PDT), and 1 of 7 recurred after radiotherapy. Two of 43 patients with GBCC (<5%) presented with extensive local invasion, one of whom also had distant metastases, and both died of the disease. CONCLUSION: The majority of GBCCs are not clinically aggressive and respond to conservative surgical treatment with a low risk of recurrence.

Perioperative management of patients on anti-platelets and anti-coagulants presenting for dermatological surgical procedures. A UK survey.

There are an increasing number of our patients on antiplatelet and anticoagulant medications. In the absence of clear guidelines for the perioperative management of these patients presenting for operative dermatological procedures, we undertook a pilot survey of the current practices of dermatologists in the United Kingdom. The aims of our study were to determine whether there was uniformity of practice and whether the modes of practice differed from those outlined in the literature for other related specialities, and to debate whether there is a need for national guidelines with this regard. A postal survey of 185 dermatologists was conducted. The response rate was 50%. Overall, most respondents (61%) stated that their practice was primarily based on personal preference and only 30% stated that it was based on the local Unit policy. Only 34% of the Consultants based their practice on evidence-based medicine. There appeared to be significant variations in current practice amongst dermatologists. Some aspects of practice were found to vary from those recommended in the literature. The findings of this study emphasise the importance of national guidelines for the use of anti-platelet and anti-coagulant medications in cutaneous surgery specifically and in surgery in general.

Solitary plasmocytoma of frontal bone presenting as an asymptomatic forehead lump.

Solitary plasmocytoma of bone is a rare type of plasma cell tumor. We present a case of a solitary extramedullary plasmacytoma of the frontal bone presenting as an asymptomatic forehead lump with clinically benign characteristics. This case highlights the need for a high index of suspicion when dealing with enlarging subcutaneous lumps of the forehead and scalp. The significance of this lies in the appropriate sequencing of investigations and the implementation of the necessary treatment regimen.

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma.

UNLABELLED: Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell-derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma. SIGNIFICANCE: Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments.

Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome.

Gorlin syndrome is an autosomal dominant disorder, characterized by multiple early-onset basal cell carcinomas (BCCs) and jaw keratocysts. Through association studies in cohorts of sporadic BCC, nine genetic variants have previously been identified to increase the risk of BCC. The nine SNPs were genotyped by Taqman allelic discrimination in 125 individuals with Gorlin syndrome. Kaplan-Meier survival curves and Cox proportional-Hazard regression analysis were applied to determine the association between genotypes and age of first BCC in individuals with Gorlin syndrome. The p.(Arg151Cys) variant in MC1R (rs1805007) was associated with an earlier median age of onset of BCC of 27 years (95% CI: 20-34) compared with 34 years (95% CI: 30-40) for wild-type individuals (hazard ratio (HR)=1.64, 95% CI: 1.04-2.58, P=0.034). The risk allele of the variant at the chromosome 5p15 locus encompassing TERT-CLPTM1L (rs401681) was also associated with an earlier median onset of BCC, 31 years (95% CI: 28-37) compared with 41 years (95% CI: 32-48, HR=1.44, 95% CI: 1.08-1.93, P=0.014). In individuals with a risk allele at either rs1805007 or rs401681 the median time to BCC was 31 years of age (95% CI: 28-34) compared with 44 years of age (95% CI: 38-53) in wild-type individuals (HR=2.48, 95% CI: 1.47-4.17, P=0.0002). Our findings may have implications for future personalized risk estimates and BCC screening strategies in individuals with Gorlin syndrome.

Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations.

PURPOSE: Heterozygous germline PTCH1 mutations are causative of Gorlin syndrome (naevoid basal cell carcinoma), but detection rates > 70% have rarely been reported. We aimed to define the causative mutations in individuals with Gorlin syndrome without PTCH1 mutations. METHODS: We undertook exome sequencing on lymphocyte DNA from four unrelated individuals from families with Gorlin syndrome with no PTCH1 mutations found by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), or RNA analysis. RESULTS: A germline heterozygous nonsense mutation in SUFU was identified in one of four exomes. Sanger sequencing of SUFU in 23 additional PTCH1-negative Gorlin syndrome families identified a SUFU mutation in a second family. Copy-number analysis of SUFU by MLPA revealed a large heterozygous deletion in a third family. All three SUFU-positive families fulfilled diagnostic criteria for Gorlin syndrome, although none had odontogenic jaw keratocysts. Each SUFU-positive family included a single case of medulloblastoma, whereas only two (1.7%) of 115 individuals with Gorlin syndrome and a PTCH1 mutation developed medulloblastoma. CONCLUSION: We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome. Our study redefines the risk of medulloblastoma in Gorlin syndrome, dependent on the underlying causative gene. Previous reports have found a 5% risk of medulloblastoma in Gorlin syndrome. We found a < 2% risk in PTCH1 mutation-positive individuals, with a risk up to 20× higher in SUFU mutation-positive individuals. Our data suggest childhood brain magnetic resonance imaging surveillance is justified in SUFU-related, but not PTCH1-related, Gorlin syndrome.

Is superficial inguinal node dissection adequate for regional control of malignant melanoma in patients with N1 disease?

INTRODUCTION: The optimum extent of surgery for inguinal nodal metastases due to melanoma remains controversial. Recent evidence suggests a conservative superficial groin dissection (SGD) may provide adequate regional control. AIM: To evaluate patients with N1 stage disease treated with SGD to determine the recurrence rates and to evaluate whether SGD was adequate for regional control in these patients. MATERIALS AND METHODS: Patients undergoing SGD between April 2005 and April 2012 were retrospectively analysed from a prospectively collected database. RESULTS: Sixty patients were treated by SGD of which 40 had palpable disease and 20 had a positive sentinel node. Overall median follow-up was 38 months, with median follow-up for the SNB group being 29 months and that of the PD group 49 months. Three patients (5%) developed groin recurrence following SGD. All patients recurred within the superficial site of surgery; there was no deep inguinal or pelvic recurrence. Distant recurrence occurred in 22 patients (36.7%), with 21 of these patients coming from the PD group and one from the SNB group. This difference was statistically significant (p < 0.05). Overall survival at 5 years was 70.3%. Survival at 5 years in the PD group was 63.8% and in the SNB group it was 90.9%, this difference was approaching significance (p = 0.08). CONCLUSION: SGD appears adequate for local disease control in patients with N1 sentinel node positive disease. Longer term followup for N1 palpable disease is required to determine the suitability of SGD for this group of patients.