Lentigo maligna (LM) and lentigo maligna melanoma (LMM) arise from chronically sun-damaged skin. LM/LMM incidence continues to increase, particularly in Utah, where melanoma rates are twice the national average. The melanocortin-1 receptor (MC1R) has been studied in melanocyte pigmentation and DNA repair but has yet to be thoroughly investigated in LM/LMM. We investigated allele and genotype frequencies of germline MC1R variants among 175 Utah patients diagnosed with LM/LMM and 402 Utah reference individuals. The comparative analysis demonstrated an increased frequency of the D294H allele (0.046; P = 0.0042) and a decreased frequency of the V60L allele (0.074; P = 0.034) in patients with LM/LMM. The LM/LMM group demonstrated a higher OR compared with the Utah reference group associated with R151C homozygosity compared with heterozygous R151C [OR = 5.6; 95% confidence interval (CI), 0.98-32; P = 0.052] and R151C homozygosity compared with wild type (OR = 5.7; 95% CI, 1.1-30; P = 0.042). D294H heterozygosity was strongly associated with LM/LMM (OR = 3.8; 95% CI, 1.3-11; P = 0.014). Conversely, V60L heterozygosity was less strongly associated with LM/LMM (OR = 0.52; 95% CI, 0.26-1.1; P = 0.072). Stratified analyses showed no significant differences in age or gender across the key MC1R variants studied. These data highlight significant differences in MC1R allele frequencies in patients with LM/LMM, demonstrating that D294H is associated with increased LM/LMM risk, whereas the V60L variant is inversely associated with risk. This study provides the first comprehensive analysis of specific high-risk MC1R variants in patients with LM/LMM in Utah.Significance: Our study is the first comprehensive analysis of MC1R germline variants in patients with LM/LMM in Utah, a region with an exceptionally high melanoma incidence. We draw new risk associations in LM/LMM, identifying an increased risk with the D294H and R151C variants. We also describe a novel inverse association for V60L, warranting further investigation. This study contributes to improved targeted risk stratification and an increased understanding of an understudied melanoma subtype.

Abstract: In this unusual case, a 73-year-old woman presented with bloody discharge from her right breast and skin thickening was observed on subsequent imaging. Clinically, the findings raised concern for Paget disease. A skin punch biopsy was performed, revealing a high-grade infiltrating carcinoma with squamous features. Metaplastic carcinoma was a differential diagnosis, given that this patient had a history of invasive ductal carcinoma and radiation treatment in the same breast. A subsequent central lumpectomy confirmed the diagnosis of invasive squamous cell carcinoma of the nipple, occurring in the context of Bowen disease as a precursor lesion. Notably, there was no evidence of ductal carcinoma in situ in the background breast tissue or conventional invasive ductal carcinoma component. Both in situ and invasive forms of squamous cell carcinomas have been rarely reported in the nipple. This case highlights the importance of considering such a rare diagnosis, especially in patients with a history of breast cancer.

Supplementary Figure 3. Phospho-FAK (P-FAK) and paxillin are candidate factors in tumor progression.

Supplementary Figure 7. AKT1E17K does not promote cell proliferation compared with controls.

Supplementary Figure 4. P-FAK and P-paxillin are elevated in tumors that express AKT1E17K.

AbstractAlterations in the PI3K/AKT pathway occur in up to 70% of melanomas and are associated with disease progression. The three AKT paralogs are highly conserved but data suggest they have distinct functions. Activating mutations of AKT1 and AKT3 occur in human melanoma but their role in melanoma formation and metastasis remains unclear. Using an established melanoma mouse model, we evaluated E17K, E40K, and Q79K mutations in AKT1, AKT2, and AKT3 and show that mice harboring tumors expressing AKT1E17K had the highest incidence of brain metastasis and lowest mean survival. Tumors expressing AKT1E17K displayed elevated levels of focal adhesion factors and enhanced phosphorylation of focal adhesion kinase (FAK). AKT1E17K expression in melanoma cells increased invasion and this was reduced by pharmacologic inhibition of either AKT or FAK. These data suggest that the different AKT paralogs have distinct roles in melanoma brain metastasis and that AKT and FAK may be promising therapeutic targets.Implications:This study suggests that AKT1E17K promotes melanoma brain metastasis through activation of FAK and provides a rationale for the therapeutic targeting of AKT and/or FAK to reduce melanoma metastasis.

<p>Supplementary Figure 7. AKT1E17K does not promote cell proliferation compared with controls.</p>

Supplementary Figure 5. Tumors cluster based on gene expression profile.

Supplementary Figure 1. RCAS mutant AKT viruses infect TVA+ melanoma cells.

Supplementary Materials and Methods

Supplementary Figure 2. Kinase-dead AKT1E17K (AKT1E17K, K179M) and wild type AKT1 expressing melanomas do not impact survival compared with Cre-only controls (BRAFV600E;Cdkn2a-/-;Pten-/-).

Supplementary Figure 6. Expression of AKT1E17K promotes the dysregulation of integrins.

Supplementary Table 1. Summary of tumor formation in Dct::TVA mice. .

ABSTRACT:Nevi of specialized sites (NOSS) occur on the scalp, ears, flexural, acral, and genital areas and display atypical clinical and histologic features. We assessed NOSS recurrence and progression to melanoma, management patterns, and associations between histologic features and treatment recommendations. We queried all histologic diagnoses of NOSS (n = 275) from 2012 to 2017 from a large U.S. academic medical center with reference dermatopathology laboratory and matched these to clinical records. A blinded panel of dermatopathologists re-evaluated lesions, catalogued histologic findings, and gave management recommendation. Associations with dermatopathologist decision and concordance between new and original recommendations were assessed. Of 117 cases with follow-up, 2 locally recurred (1.46%) and none eventuated in melanoma. Clinical features were not associated with original treatment recommendations. After histopathologic review, large melanocytes [odds ratio ratio (ORR) = 8.00, 95% CI, 1.35-47.4] and junctional mitotic figures (ORR = 65.0, 6.5-650) predicted excision recommendation. Likewise, accumulation of many (>9) high-risk features was associated with excision recommendation. Panel review changed treatment recommendation in 27% of cases. Fair concordance existed between original and panel recommendations (κ = 0.29, 0.15-0.44). The low rate of recurrence and lack of melanoma occurrence suggest that despite an atypical clinical and histopathologic appearance, these nevi have limited potential for malignant transformation. Histopathologic findings seem to be principal drivers behind the recommendation for excision in this analysis. Variability existed in treatment recommendations; the panel's consensus recommendation tended to downgrade treatment. This highlights the importance of further outcomes-based studies to identify true high-risk features and refine management guidelines.

With a 34-percent increase in dermatology residency applications in the past decade, residency programs are increasingly faced with the daunting task of reviewing more applications for a relatively fixed number of residency positions. Other specialty programs, including otolaryngology, orthopedics, plastic surgery, and ophthalmology, have called for limiting the number of residency applications. Dermatology programs have developed various ways to decrease the number of reviewed applications, from cutoffs for Step 1 board scores to Alpha Omega Alpha membership to secondary applications. While this can decrease the applicant pool, it limits a more holistic review of applications. We propose an application cap of 20 programs, which will decrease the number of applications each program receives 3- to 5-fold. Each applicant can approach the process more thoughtfully in choosing the best programs for them and will save money in application fees. As program directors rank "perceived interest" in their residency program as a primary factor for selecting applicants, a cap will allow program directors to know that all applicants are interested in their specific program. Ultimately, we contend that application caps would improve match outcomes with applicants receiving training in the best program for them, increasing the likelihood of successful fit for clinical training, opening the field to a more diverse set of applicants, and saving everyone time and money.

BACKGROUNDPrescription opioids play a large role in the opioid epidemic. Even short-term prescriptions provided postoperatively can lead to dependence.OBJECTIVETo provide opioid prescription recommendations after Mohs micrographic surgery (MMS) and reconstruction.METHODSThis was a multi-institutional Delphi consensus study consisting of a panel of members of the American College of Mohs Surgery from various practice settings. Participants were first asked to describe scenarios in which they prescribe opioids at various frequencies. These scenarios then underwent 2 Delphi ratings rounds that aimed to identify situations in which opioid prescriptions should, or should not, be routinely prescribed. Consensus was set at ≥80% agreement. Prescription recommendations were then distributed to the panelists for feedback and approval.RESULTSTwenty-three Mohs surgeons participated in the study. There was no scenario in which consensus was met to routinely provide an opioid prescription. However, there were several scenarios in which consensus were met to not routinely prescribe an opioid.CONCLUSIONOpioids should not be routinely prescribed to every patient undergoing MMS. Prescription recommendations for opioids after MMS and reconstruction may decrease the exposure to these drugs and help combat the opioid epidemic.

Abstract Hyper-activation of the PI3K/AKT signaling pathway occurs in most metastatic melanomas and increased PI3K/AKT pathway activity correlates with disease progression. The serine/threonine kinase, AKT, represents a major signaling hub within the pathway and consists of three highly conserved paralogs that have both distinct and overlapping functions. Activating mutations of AKT1 and AKT3 occur in human melanoma but their role in melanoma formation and metastasis remains unclear. Using an established melanoma mouse model, we evaluated the ability of constitutively active E17K, E40K, or Q79K mutants of each AKT paralog to promote tumor progression and metastasis in the context of BRAFV600E expression and loss of Cdkn2a and Pten. Expression of AKT1E17K promoted highly aggressive melanomas that metastasized to the lungs and brain. This metastatic phenotype was not significantly observed in the case of other mutant AKT-positive tumors, suggesting that the AKT paralogs have distinct, non-overlapping roles in the development of melanoma metastases. AKT1E17K-positive tumors showed AKT1E17K-dependent up-regulation of multiple focal adhesion (FA) factors, which are key components of focal adhesions and established stimulators of cell motility, as well as phosphorylation of focal adhesion kinase (FAK). Ectopic expression of AKT1E17K in non-metastatic melanoma cells increased cell invasion, a phenotype abrogated by pharmacological inhibition of AKT or FAK. These findings strongly suggest that one mechanism by which AKT1 promotes melanoma metastasis is through regulation and activation of proteins involved in focal adhesions. This has important implications for the development of therapeutic strategies aimed at preventing or treating disseminated disease. Citation Format: David A. Kircher, Kirby A. Trombetti, Mark R. Silvis, Gennie L. Parkman, Grant M. Fischer, Stephanie N. Angel, Christopher M. Stehn, Sean C. Strain, Allie H. Grossmann, Keith L. Duffy, Martin McMahon, Michael A. Davies, Michelle C. Mendoza, Matthew W. VanBrocklin, Sheri L. Holmen. AKT1E17K activates focal adhesion kinase and promotes melanoma brain metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2736.

BACKGROUND Cellular dermatofibromas, a variant of dermatofibroma, are reported to recur at rates of 26% to 50%. OBJECTIVE To determine whether there are distinct clinical or histological differences between cellular dermatofibromas that recur versus those that do not. To determine recurrence rates in a real-world clinical setting. MATERIALS AND METHODS A retrospective analysis of the medical records and skin biopsies of cellular dermatofibroma in the University of Utah Health system between December 2011 and 2016. Clinical and dermatopathological features were evaluated to find distinct differences between the cellular dermatofibromas that recurred compared with those that did not. RESULTS There were no significant differences in histology between the primary lesions in recurrent and nonrecurrent cases. One factor that seemed to be associated with a greater likelihood of recurrence was an initial lesion size greater than 1 cm. The authors' data suggest that if the margins are involved on initial biopsy, there is a 10% chance of recurrence. This percentage is far less than the 26% to 50% reported in the past literature. CONCLUSION If a patient presents with a cellular dermatofibroma larger than 1 cm and positive margins at initial biopsy, a careful discussion should be had between the provider and patient about the low risk of local recurrence.

We present a case of recalcitrant, localized patch disease in a patient with stage IB (T2, N0, M0) mycosis fungoides (MF) that clinically responded to treatment with topical gentian violet (GV) after undergoing several other therapies, including narrowband ultraviolet B (UVB) therapy and topical clobetasol, bexarotene, and mechlorethamine. A reduction of erythema of her treated patches was noted within 2 months of once-daily application of topical GV, and there was no disease progression. However, subsequent biopsy of the most prominent patch found the presence of active disease despite reduction of erythema.

Secondary cutaneous involvement by mantle cell lymphoma (MCL), an uncommon aggressive B-cell malignancy, predominantly involves the dermis, with few reports of pannicular involvement. Lymphocytic infiltration of subcutaneous tissue is associated with inflammatory panniculitides and certain T-cell lymphomas, primarily subcutaneous panniculitis-like T-Cell lymphoma (SPTCL), which is characterized by rimming of adipocytes by tumor cells. We report the case of a 69-year-old man with a history of systemic nodal MCL who presented with subcutaneous nodules on his lower extremities after receiving multi-agent chemotherapy. Biopsies showed a dense infiltrate of atypical, mitotically active, monomorphic, medium-sized lymphoid cells in the subcutaneous fat with prominent rimming of the adipocytes by the tumor cells. These features were not morphologically typical of MCL. Immunohistochemistry showed these cells to be CD20+, CD5+ B-cells with strong cyclin D1 expression; fluorescence in situ hybridization (FISH) analysis was positive for t(11;14)(q13;32), confirming the diagnosis of secondary cutaneous involvement of MCL. This represents an exceptional report of cutaneous MCL presenting clinically and histologically with a panniculitis-type pattern and adipocyte rimming, histomorphologically mimicking SPTCL. Noteworthy examples, such as this report, support the practice of utilizing clinical correlation, immunohistochemistry, and/or molecular cytogenetics to confirm the diagnosis of any case suspicious for cutaneous lymphoma.