A case of severe nivolumab-induced lichen planus pemphigoides in a child with metastatic spitzoid melanoma.

Dermatologic reactions are among the most common adverse events of antiprogrammed cell death-1 (anti-PD-1) monoclonal antibodies agents and include maculopapular rash, psoriasiform rash, lichenoid eruptions, autoimmune bullous disorders, and vitiligo. Here, we present a case of a 12-year-old African American male with metastatic spitzoid melanoma treated with nivolumab who developed a mild lichenoid eruption that progressed to a severe case of lichen planus pemphigoides (LPP). Management was complex given the patient's age and history and included hospitalization for intravenous steroids, an intensive topical steroid regimen, methotrexate, and discontinuation of nivolumab. This case illustrates a rare but dramatic progression from a mild LP-like eruption to severe bullous lichenoid eruption, most consistent with LPP, as well as the diagnostic and treatment challenges in the setting of a pediatric patient on nivolumab.

Concordance of Squamous Cell Carcinoma Histologic Grading Among Dermatopathologists and Mohs Surgeons.

BACKGROUND: Current staging systems for cutaneous squamous cell carcinoma (cSCC) incorporate histologic grade. There are no universally agreed on criteria to define differentiation for cSCC. OBJECTIVE: To determine the interrater and intrarater reliability among dermatopathologists and Mohs surgeons in grading histological differentiation for cSCC. METHODS AND MATERIALS: One hundred thirty-one archived slides were selected. Three dermatopathologists and 3 Mohs surgeons graded the tumors in a blinded manner (Round 1). In an attempt to improve concordance, all 6 participants were then asked to regrade the tumors based on a devised quantitative grading scale (Round 2). RESULTS: For Round 1, overall κ was 0.56 corresponding to a weak agreement. κ for well, moderate, and poorly differentiated tumors was 0.68, 0.39, and 0.59, respectively, corresponding to moderate, minimal, and weak concordance. For Round 2 of the study, overall κ was 0.60, with κ = 0.75, 0.46, and 0.61 for well, moderate, and poorly differentiated tumors, respectively. Overall intrarater reliability was 0.70 (κ = 0.70, 0.77, 0.68, 0.71, 0.56, and 0.75), corresponding to a moderate concordance. CONCLUSION: Overall concordance for cSCC histologic grading is weak to moderate among the experimental group. Substantial differences in concordance exist among histological degrees of differentiation, with lowest agreement in moderately differentiated tumors.

Utility of TERT Promoter Mutations for Cutaneous Primary Melanoma Diagnosis.

Telomerase reverse transcriptase (TERT) promoter mutations are commonly found in malignant melanomas but rare in melanocytic nevi. To assess its potential diagnostic utility for the distinction of melanoma from nevus, we determined the TERT promoter mutation status of 86 primary melanomas, 72 melanocytic nevi, and 40 diagnostically problematic melanocytic proliferations. Of the 86 melanomas, 67 (77.9%) were TERT-positive, defined as harboring a hotspot TERT promoter mutation at positions -124C>T, -124_125CC>TT, -138_139CC>TT, or -146C>T. Of the 72 nevi, only 1 (1.4%) was TERT-positive. Of the 40 diagnostically uncertain melanocytic proliferations, 2 (5.0%) were TERT-positive. TERT positivity as a test for melanoma versus nevus had an accuracy of 87.3% [95% confidence interval (CI), 81.1-92.1], a sensitivity of 77.9% (95% CI, 68.9-85.4), a specificity of 98.6% (95% CI, 95.8-100), a positive predictive value of 98.5% (95% CI, 95.6-100), and a negative predictive value of 78.9% (95% CI, 72.6-85.4). Our results indicate that hotspot TERT promoter mutation status may be a useful ancillary parameter for the diagnosis of melanoma. In particular, the high specificity of these mutations for melanoma indicates the presence of a TERT promoter mutation in a melanocytic neoplasm associated with diagnostic controversy, or uncertainty should increase concern for a melanoma.

Pigmented epithelioid melanocytoma (animal-type melanoma): An institutional experience.

BACKGROUND: Pigmented epithelioid melanocytoma (PEM) is an uncommon, recently described entity with unknown biologic behavior. There is a high rate of regional metastases, but limited evidence of distant metastases or disease-related death. OBJECTIVE: We sought to report our series of patients given a diagnosis of PEM at our institution and provide mutational analysis of genes commonly implicated in melanoma in 2 cases. METHODS: The pathology database was queried for cases of PEM diagnosed at the University of Rochester. Charts were reviewed for follow-up information. Mutational analysis of melanoma-associated genes was performed on 2 cases. RESULTS: Nine cases of PEM were retrieved in a 10-year retrospective review. Five patients underwent sentinel lymph node biopsy with 3 of 5 having a positive sentinel lymph node. All 9 patients are alive and disease-free with average follow-up of 38.75 months. Two tumors were tested for common melanoma-associated mutations, and were negative, except for a telomerase reverse transcriptase promoter deletion detected in 1 sample. The deletion has not been associated with melanoma, and therefore its biologic significance is unclear. LIMITATIONS: Small sample size, retrospective nature, and single institution experience are limitations. CONCLUSIONS: PEM appears to have an indolent behavior. However, currently the evidence is too limited to provide insight into its true biologic potential.

Lymphomatoid Papulosis Type D: Report of a Case in a Child and Review of the Literature.

Lymphomatoid papulosis (LyP) is a cutaneous CD30-positive T-cell lymphoproliferative disorder that occurs primarily in adults and presents with crops of papules that become necrotic and spontaneously regress. It is classified according to the histopathologic findings; currently recognized subtypes include A, B, C, D, and E. LyP is uncommon in children. Herein we describe a child with an unusual clinical presentation of LyP type D and review the literature of reported cases in children.

Outbreak of Mycobacterium chelonae infection associated with tattoo ink.

BACKGROUND: In January 2012, on the basis of an initial report from a dermatologist, we began to investigate an outbreak of tattoo-associated Mycobacterium chelonae skin and soft-tissue infections in Rochester, New York. The main goals were to identify the extent, cause, and form of transmission of the outbreak and to prevent further cases of infection. METHODS: We analyzed data from structured interviews with the patients, histopathological testing of skin-biopsy specimens, acid-fast bacilli smears, and microbial cultures and antimicrobial susceptibility testing. We also performed DNA sequencing, pulsed-field gel electrophoresis (PFGE), cultures of the ink and ingredients used in the preparation and packaging of the ink, assessment of source water and faucets at tattoo parlors, and investigation of the ink manufacturer. RESULTS: Between October and December 2011, a persistent, raised, erythematous rash in the tattoo area developed in 19 persons (13 men and 6 women) within 3 weeks after they received a tattoo from a single artist who used premixed gray ink; the highest occurrence of tattooing and rash onset was in November (accounting for 15 and 12 patients, respectively). The average age of the patients was 35 years (range, 18 to 48). Skin-biopsy specimens, obtained from 17 patients, showed abnormalities in all 17, with M. chelonae isolated from 14 and confirmed by means of DNA sequencing. PFGE analysis showed indistinguishable patterns in 11 clinical isolates and one of three unopened bottles of premixed ink. Eighteen of the 19 patients were treated with appropriate antibiotics, and their condition improved. CONCLUSIONS: The premixed ink was the common source of infection in this outbreak. These findings led to a recall by the manufacturer.

Mutations of the TERT promoter are common in basal cell carcinoma and squamous cell carcinoma.

Telomerase is frequently expressed in cancer and contributes to carcinogenesis. Two recent publications report the identification of a set of recurrent mutations in melanoma in the promoter of the telomerase reverse transcriptase gene (TERT) that appears to be the result of mutagenesis from ultraviolet (UV) radiation. Both groups reported that the mutations increase the transcription of TERT. This prompted our search for similar mutations in two other UV-related skin cancers, basal cell carcinoma, and squamous cell carcinoma. We found that the activating TERT promoter mutations reported in melanoma are also frequent in squamous cell carcinoma (50%) and basal cell carcinoma, the latter including both sporadic tumors (78%) and tumors from patients with nevoid basal cell carcinoma syndrome (68%). These mutations were found in only 1 of 11 Bowen's disease (squamous cell carcinoma in situ) specimens, and in none of 15 non-malignant skin specimens and 57 blood specimens. The mutations were frequently homozygous or hemizygous, with little or no normal signal at the mutated positions. These data suggest that TERT promoter mutations are the most frequent putative oncogenic mutations in cutaneous cancer.

Cutaneous metastasis from penile squamous cell carcinoma resembling carcinoma en cuirasse.

Penile squamous cell carcinoma is a rare malignancy seen more frequently in developing nations. Metastasis occurs in a predictable manner, with superficial lymph node involvement occurring first, followed by deep lymph node involvement, and then distant spread. Brain, lung, liver, and bone are the typical sites of distant metastasis. We present the unusual case of an 81-year-old man with penile squamous cell carcinoma requiring total penectomy who developed a confluent red to violaceous, indurated suprapubic plaque with satellite papules and bulky inguinal lymphadenopathy. The shield-like clinical presentation and infiltrating strands and cords on histology resembled carcinoma en cuirasse, a rare form of cutaneous metastasis frequently associated with breast cancer but not reported with penile squamous cell carcinoma.

Characterizing Granuloma Annulare in 73 Pediatric Patients.

Background: Granuloma annulare (GA) is a common, benign, idiopathic inflammatory dermatosis. Aside from case reports and small studies, there are limited data about the characteristics of GA in children. Objective: This study aimed to better characterize the epidemiologic and clinical features, triggering factors, disease associations, and outcomes of GA in the pediatric population. Methods: We conducted a retrospective study of 73 pediatric patients diagnosed with GA at the University of Rochester Medical Center over a 7-year period. Results: The most common subtype was localized GA (71.2%, n = 52), followed by subcutaneous (also known as "deep GA"; 16.4%, n = 12) and generalized (12.3%, n = 9) subtypes. Over 90% of patients had idiopathic GA, with the remaining patients reporting viral infection or trauma as triggers. Half of the patients studied had comorbid conditions, most frequently atopic dermatitis (17.8%, n = 13), obesity (9.59%, n = 7), asthma (6.85%, n = 5), and allergic rhinitis (6.85%, n = 5). The median duration of the disease was 11.00 months (interquartile range (IQR) 15.75 months); generalized GA had the shortest duration (median 10.00 months, IQR 15.50 months), while subcutaneous GA had the longest duration (median 12.00 months and IQR 29.00 months). Although recurrence rates for subcutaneous and generalized GA were high at 45.5% and 33.3%, respectively, most patients achieved clearance or improvement with treatment. Conclusion: Most cases of GA in our study were idiopathic, with no clear differences between GA subtypes and associated comorbidities. Topical steroids were the most prescribed treatment with mixed efficacy.

Primary cutaneous Nocardia brasiliensis infection isolated in an immunosuppressed patient: a case report.

Cutaneous nocardiosis is a rare infection that may manifest as a superficial skin lesion, lymphocutaneous infection, mycetoma, or diffuse cutaneous infection from a disseminated systemic infection. We report a case of a 65-year-old immunocompromised man with persistent primary cutaneous Nocardia brasiliensis infection following a motor vehicle collision. A high degree of suspicion is needed to diagnose Nocardia infection because of its resemblance to other bacterial infections. Nocardiosis should be included in the differential diagnosis of chronic cutaneous infections, especially when the response to antibiotics is inadequate or when the patient is immunocompromised. Because Nocardia may take several weeks to grow in standard bacterial culture media, laboratories should be notified of the suspicion so that culture plates are held for longer time periods. Long-term therapy, usually with sulfonamides, often is necessary.

Prominent B-Cell Signature Differentiates Discoid from Subacute Cutaneous Lupus Erythematosus.

Although B cells account for a significant proportion of the lymphocytic infiltrate in discoid lupus erythematosus (DLE), their contribution to pathogenesis is unknown. In this study, we compare the immune landscape of 17 subjects with DLE with that of 21 subjects with subacute cutaneous lupus erythematosus using transcriptomic and histologic analyses of lesional skin. A few of the subjects (3 of 17 subjects with DLE, and 5 of 21 subjects with subacute cutaneous lupus erythematosus) had concomitant systemic lupus erythematosus. Using a modified Autoimmune Profiling Panel (NanoString Technologies, Seatle, WA), we show that B-cell‒specific genes, including canonical pan‒B cell markers CD19 (P = 0.0060), MS4A1 (CD20) (P = 0.0047), and CD79a (P = 0.0201), are among the most upregulated genes in DLE. Numerous other genes encoding B-cell‒associated proteins, including Igs, BAFF receptors, and FCRL family members, are similarly enriched. Relative cell type scoring reveals that among various inflammatory cell types, only B cells are more prevalent in DLE. Digital whole-image slide analysis of immunohistochemistry for B cells (CD20) and T cells (CD3) supports our gene expression findings of a disproportionately greater B-cell infiltrate in DLE lesions. Overall, this study identifies a B-cell‒predominant signature unique to DLE and highlights the importance of studying the role of cutaneous B cells in DLE pathogenesis.

Characterization of the CpG Island Hypermethylated Phenotype Subclass in Primary Melanomas.

Cutaneous melanoma can be lethal even if detected at an early stage. Epigenetic profiling may facilitate the identification of aggressive primary melanomas with unfavorable outcomes. We performed clustering of whole-genome methylation data to identify subclasses that were then assessed for survival, clinical features, methylation patterns, and biological pathways. Among 89 cutaneous primary invasive melanomas, we identified three methylation subclasses exhibiting low methylation, intermediate methylation, or hypermethylation of CpG islands, known as the CpG island methylator phenotype (CIMP). CIMP melanomas occurred as early as tumor stage 1b and, compared with low-methylation melanomas, were associated with age at diagnosis ≥65 years, lentigo maligna melanoma histologic subtype, presence of ulceration, higher American Joint Committee on Cancer stage and tumor stage, and lower tumor-infiltrating lymphocyte grade (all P < 0.05). Patients with CIMP melanomas had worse melanoma-specific survival (hazard ratio = 11.84; confidence interval = 4.65‒30.20) than those with low-methylation melanomas, adjusted for age, sex, American Joint Committee on Cancer stage, and tumor-infiltrating lymphocyte grade. Genes hypermethylated in CIMP compared with those in low-methylation melanomas included PTEN, VDR, PD-L1, TET2, and gene sets related to development/differentiation, the extracellular matrix, and immunity. CIMP melanomas exhibited hypermethylation of genes important in melanoma progression and tumor immunity, and although present in some early melanomas, CIMP was associated with worse survival independent of known prognostic factors.

Microarray comparative genomic hybridization detection of copy number changes in desmoplastic melanoma and malignant peripheral nerve sheath tumor.

Desmoplastic melanoma (DM) and malignant peripheral nerve sheath tumor (MPNST) can appear morphologically and immunophenotypically similar. We attempted to determine whether microarray comparative genomic hybridization could detect copy number differences between them to aid in the diagnosis. S-100 immunohistochemistry was performed on 5 cases of DM and 9 cases of MPNST using formalin-fixed paraffin-embedded specimens. Genomic DNA was extracted from microdissected cells. Whole genome amplification was performed on 5 of 5 DMs and 6 of 9 MPNST cases. A multiplex polymerase chain reaction assay was used to determine the quality of the DNA samples, which were run on the Spectral Chip 2600 bacterial artificial chromosome array platform. DM showed gains involving chromosomes 1p, 2p, 9q, 13q, 14q, and 20q and losses involving chromosomes 5p, 11p, 12q, 15q, and 18q. Several cancer-associated genes were involved, including gain of BCL2L1, ARTN, AMPK, NRAS, and CCNA1 and loss of IGF2, CDKN1C, PAX6, WT1, TRAF6, MAPK8IP1, and IMP3. MPNST had gains involving chromosomes 1p, 2q, and 19p and loss of chromosome 21q. Gains of MUM1, APC2, MAP2K2, JMJD2B, SP110, PTMA, GPI, and CDKN2D were detected. DM and MPNST have chromosomal alterations detected by array comparative genomic hybridization that might be useful in distinguishing these 2 tumors, although further studies with a larger sample size will be needed to test this.

A Rare Case of Porocarcinoma and Trichoblastoma Arising in a Nevus Sebaceus of Jadassohn.

Nevus sebaceus of Jadassohn, or "organoid nevus," is a common, benign hamartoma of the skin consisting of epithelial and adnexal components. Its natural history and association with neoplastic growths is well documented. The majority of concomitant neoplasms are benign-trichoblastoma and syringocystadenoma papilliferum are most frequently discovered-but malignant tumors have been described. We present the case of a 58-year-old male with a congenital nevus sebaceus of Jadassohn on his left parietal scalp that had been enlarging, changing color, and bleeding over the prior year. Clinical exam and histology disclosed the presence of a trichoblastoma and porocarcinoma arising within the nevus sebaceus. Porocarcinoma is a rare, intermediately aggressive, malignant eccrine gland tumor that is frequently metastasized at presentation. Otolaryngology performed wide local resection with sentinel lymph node biopsy. This case highlights the diversity of tumors associated with nevus sebaceus of Jadassohn, potential for malignant expansion, and necessity for close monitoring and maintaining a low threshold for biopsy in evolving lesions.

Picomets: Assessing single and few cell metastases in melanoma sentinel lymph node biopsies.

BACKGROUND: Lymph node involvement is a significant prognostic factor for melanoma. Both number of positive nodes and disease burden within a lymph node affects survival. However, the significance of few tumor cells within a single node and subsequent optimal management remains without consensus. We investigated the implications of minimal nodal disease on clinical outcomes. METHODS: We reviewed 752 patients who underwent lymph node sampling at time of primary melanoma resection at our institution over 15 years. We deemed patients who had 1 node with 1 to 4 atypical cells staining positive for either Melan-A or Sox-10 as having "picomets." We examined the initial clinicopathological features, subsequent management, and outcomes. RESULTS: Thirty-three patients (4%) met criteria for having picomets. The most common number of positively staining atypical cells was 1 (n = 13). Nodal staging at initial pathology review varied, and overall stage ranged from IA to IIIC. Four patients underwent further therapy, none of whom had recurrent disease. Of the 29 patients undergoing observation/surveillance only, 5 had disease recurrence (17%). CONCLUSION: Although patients with picomets had better outcomes than historical stage matched cohorts, a small subset had recurrent disease. Staging patients with picomets as "N0" may not reflect the true negative prognostic significance of picomets. A larger population of patients meeting picomets criteria is needed to draw further conclusions.

Diagnostic utility of IMP3 in segregating metastatic melanoma from benign nevi in lymph nodes.

Depending on the Breslow depth of the primary melanoma, sentinel lymph node biopsy is considered as standard of care for the staging of cutaneous melanoma, and is one of the most important prognostic factors. The histologic analysis of these specimens becomes difficult to interpret when benign intranodal nevic cells mimic metastases. Insulin-like growth factor-II messenger RNA (mRNA)-binding protein-3 (IMP3), also known as K homology domain-containing protein overexpressed in cancer or L523S, is a member of the insulin-like growth factor-II mRNA-binding protein family and has been shown to have diagnostic utility in distinguishing cutaneous melanoma from benign nevi. In this study, 43 sentinel lymph node biopsy specimens, including 13 with benign intranodal nevi and 30 with metastatic melanoma (two cases containing both benign nevi and metastatic melanoma), from 41 patients were immunohistochemically analyzed with a monoclonal antibody against IMP3. None of the benign intranodal nevi expressed IMP3, whereas 21 out of 30 (70%) of the lymph nodes containing metastatic melanoma did. It seems that IMP3 is helpful in distinguishing benign intranodal nevi from metastatic melanoma in sentinel lymph node biopsy specimens, and could be a valuable diagnostic adjunct in sentinel lymph node biopsy assessment in which questions arise as to the malignancy of the melanocytes present.

Identification of a Robust Methylation Classifier for Cutaneous Melanoma Diagnosis.

Early diagnosis improves melanoma survival, yet the histopathological diagnosis of cutaneous primary melanoma can be challenging, even for expert dermatopathologists. Analysis of epigenetic alterations, such as DNA methylation, that occur in melanoma can aid in its early diagnosis. Using a genome-wide methylation screening, we assessed CpG methylation in a diverse set of 89 primary invasive melanomas, 73 nevi, and 41 melanocytic proliferations of uncertain malignant potential, classified based on interobserver review by dermatopathologists. Melanomas and nevi were split into training and validation sets. Predictive modeling in the training set using ElasticNet identified a 40-CpG classifier distinguishing 60 melanomas from 48 nevi. High diagnostic accuracy (area under the receiver operator characteristic curve = 0.996, sensitivity = 96.6%, and specificity = 100.0%) was independently confirmed in the validation set (29 melanomas, 25 nevi) and other published sample sets. The 40-CpG melanoma classifier included homeobox transcription factors and genes with roles in stem cell pluripotency or the nervous system. Application of the 40-CpG melanoma classifier to the diagnostically uncertain samples assigned melanoma or nevus status, potentially offering a diagnostic tool to assist dermatopathologists. In summary, the robust, accurate 40-CpG melanoma classifier offers a promising assay for improving primary melanoma diagnosis.