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Abstract: Deep penetrating nevi (DPN), particularly those showing combined features, or combined deep penetrating nevi (CDPN), may show histopathological resemblance to blue nevus (BN) and melanoma. Preferentially Expressed Antigen in MElanoma (PRAME) is a marker that helps distinguish melanoma from benign melanocytic lesions. Lymphoid enhancer-binding factor 1 (LEF1) has been proposed to be used in conjunction with β-catenin for diagnosis of DPN. The immunohistochemical expression of PRAME and LEF1 was evaluated in 10 DPN (including 6 CDPN and 2 DPN-like proliferations with atypical features), 16 BN (including combined and cellular BN), and 2 melanomas with features of DPN or BN. PRAME was negative in most DPN (n = 10/10, n = 9/10, one case with discrepancy between readers) and all BN (n = 16/16), while the 2 melanomas included were positive (n = 2/2). All DPN were positive for LEF1 (n = 9/9) while only a subset of BN were positive (n = 6/16, P = 0.0028; n = 5/16, P = 0.001, per both readers). LEF1 seemed to be easier to interpret than β-catenin because of its nuclear pattern of expression. The expression of LEF1 in the regular nevus component of combined BN presents a potential pitfall in practice because it may lead to misinterpretation of LEF1 as positive in the BN component of the lesion. However, a subset (approximately one-third) of combined BN seemed to show true LEF1 expression. Taking into account pitfalls in interpretation, the combinatorial panel of PRAME and LEF1, in addition to conventional histopathological features, may be useful to distinguish CDPN from combined BN and other benign and malignant mimics., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In areas without convenient access to dermatology care, primary care providers (PCPs) serve as an important patient resource for early skin cancer detection. To determine the most effective strategy for skin cancer detection training in PCPs, we conducted a systematic review of educational interventions and performed a meta-analysis on sensitivity and specificity outcomes in PCPs., Objectives: To summarize data on skin cancer sensitivity and specificity outcomes for PCP-targeted training programs and diagnostic algorithms. Our PCP cohort included practicing physicians, trainee physicians, and advanced practice practitioners., Methods: A literature search was performed in MEDLINE, Embase, Web of Science, and the Cochrane Library for relevant English-language articles published worldwide from 2000 onward. Results were screened for eligibility, and overlapping datasets were reconciled. Data extracted included the educational intervention, diagnostic algorithm, and outcomes of interest (sensitivity and specificity). Outcomes were pooled across interventions that taught the same diagnostic algorithm. A bivariate model was fit to compare different interventions/algorithms. This review followed the PRISMA guidelines., Results: In total, 21 articles were included in this review, encompassing over 58,610 assessments of skin lesions by about 1529 participants worldwide. Training programs that implemented the triage-amalgamated dermoscopic algorithm (TADA) demonstrated high pooled sensitivity (91.7%) and high pooled specificity (81.4%) among PCPs., Conclusions and Relevance: Overall, this systematic review and meta-analysis showed that dermoscopy training in PCPs was generally associated with gains in skin cancer sensitivity without loss of specificity. Clinically, this correlates with fewer skin cancers overlooked by PCPs and fewer excisions of benign lesions., (© 2022. The Author(s) under exclusive licence to American Association for Cancer Education.)

Background: The adoptive transfer of tumor-infiltrating lymphocytes (TIL) has demonstrated robust efficacy in metastatic melanoma patients. Tumor antigen-loaded dendritic cells (DCs) are believed to optimally activate antigen-specific T lymphocytes. We hypothesized that the combined transfer of TIL, containing a melanoma antigen recognized by T cells 1 (MART-1) specific population, with MART-1-pulsed DC will result in enhanced proliferation and prolonged survival of transferred MART-1 specific T cells in vivo ultimately leading to improved clinical responses., Design: We tested the combination of TIL and DC in a phase II clinical trial of patients with advanced stage IV melanoma. HLA-A0201 patients whose early TIL cultures demonstrated reactivity to MART-1 peptide were randomly assigned to receive TIL alone or TIL +DC pulsed with MART-1 peptide. The primary endpoint was to evaluate the persistence of MART-1 TIL in the two arms. Secondary endpoints were to evaluate clinical response and survival., Results: Ten patients were given TIL alone while eight patients received TIL+DC vaccine. Infused MART-1 reactive CD8 + TIL were tracked in the blood over time by flow cytometry and results show good persistence in both arms, with no difference in the persistence of MART-1 between the two arms. The objective response rate was 30% (3/10) in the TIL arm and 50% (4/8) in the TIL+DC arm. All treatments were well tolerated., Conclusions: The combination of TIL +DC showed no difference in the persistence of MART-1 TIL compared with TIL therapy alone. Although more patients showed a clinical response to TIL+DC therapy, this study was not powered to resolve differences between groups., Trial Registration Number: NCT00338377., Competing Interests: Competing interests: CLH is on the SAB for Briacell. PH consulting agreement with Immatics, Dragonfly, Sanofi, GSK. CB is on the SAB of Myst therapeutics and received research funding from Iovance biotherapeutics., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Checkpoint blockade has revolutionized the treatment of melanoma; however, it benefits only the minority of patients. Several agents have been combined with immunotherapy to improve T-cell activation and persistence including growth factor, chemotherapy, and radiation. Preclinical data suggest that temozolomide, which metabolizes to the same active compound as dacarbazine, selectively depletes regulatory T cells. This potential immunomodulatory effect of temozolomide provides rationale for combination with ipilimumab. We performed an open-label single-arm phase II study of ipilimumab plus temozolomide in the frontline setting for patients with metastatic melanoma and LDH ≤2× upper limit of normal. Ipilimumab was given at 10 mg/kg on day 1 and temozolomide 200 mg/m 2 orally days 1-4 every 3 weeks for four doses followed by maintenance ipilimumab every 12 weeks plus temozolomide every 4 weeks. The primary objective of the study was 6-month PFS. A total of 64 patients were enrolled and the 6-month PFS was 45% with median OS of 24.5 months. There were 10 (15.6%) confirmed partial responses and 10 (15.6%) confirmed complete responses. Duration of response amongst responders is 35 months with 10 patients demonstrating an ongoing response at median follow-up of 20 months. There were no deaths or unexpected toxicities on study. The most common gastrointestinal side effects were nausea and constipation rather than diarrhea or colitis. These results suggest that the combination of induction ipilimumab plus temozolomide could potentially be an effective strategy to enhance antitumor activity with a manageable toxicity profile. These findings warrant further evaluation in a large prospective study.

Background: BRAF V600 , NRAS, TP53, and BRAF Non-V600 are among the most common mutations detected in non-acral cutaneous melanoma patients. Although several studies have identified clinical and pathological features associated with BRAF V600 and NRAS mutations, limited data are available regarding the correlates and significance of TP53 and BRAF Non-V600 mutations., Methods: This study analyzed the patient demographics, primary tumor features, and clinical outcomes of a large cohort of non-acral cutaneous melanoma patients who had undergone clinically indicated molecular testing (n = 926)., Results: The prevalence of BRAF V600 , NRAS, TP53, and BRAF Non-V600 mutations was 43%, 21%, 19%, and 7%, respectively. The presence of a TP53 mutation was associated with older age (P = .019), a head and neck primary tumor site (P = .0001), and longer overall survival (OS) from the diagnosis of stage IV disease in univariate (P = .039) and multivariate analyses (P = .015). BRAF Non-V600 mutations were associated with older age (P = .005) but not with primary tumor features or OS from stage IV. Neither TP53 nor BRAF Non-V600 mutations correlated significantly with OS with frontline ipilimumab treatment, and the TP53 status was not significantly associated with outcomes with frontline BRAF inhibitor therapy. Eleven patients with BRAF Non-V600 mutations were treated with a BRAF inhibitor. Three patients were not evaluable for a response because of treatment cessation for toxicities; the remaining patients had disease progression as the best response to therapy., Conclusions: These results add to the understanding of the clinical features associated with TP53 and BRAF Non-V600 mutations in advanced cutaneous melanoma patients, and they support the rationale for evaluating the prognostic significance of TP53 in other cohorts of melanoma patients. Cancer 2017;123:1372-1381. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

There is an urgent need for new clinically applicable drug-delivery methods to enhance accumulation of immune-activating drugs in tumors. We synthesized a poly(L-glutamic acid)-CpG ODN2216 conjugate (PG-CpG) and injected it intratumorally into C57BL/6 mice bearing subcutaneous B16-ovalbumin melanoma. PG-CpG elicited the same potent antitumoral activity as CpG with respect to reducing tumor growth and triggering antigen-specific CD8 T-cell responses in this well-established solid tumor model. Moreover, PG-CpG was retained significantly longer in both tumor and draining lymph nodes than was free CpG after intratumoral injection. Specifically, 48 hours after injection, 26.5%±16.9% of the injected PG-CpG dose versus 4.72%±2.61% of free CpG remained at the tumor, and 1.53%±1.22% of the injected PG-CpG versus 0.37%±0.33% of free CpG was retained in the draining inguinal lymph nodes. These findings indicate that PG is an effective synthetic polymeric carrier for delivery of immunostimulatory agents to tumors and lymph nodes., Competing Interests: D.Z. is President of NanoCruise Pharmaceutical Suzhou Ltd., a consultant for BioTex, Houston, Texas, and an inventor involved in patents related to technologies mentioned in this study, issued or in application. C.L is a co-inventor involved in patents related to technologies mentioned in this study, issued or in application.

TPI 287 is a synthetic taxane derivative with structural modifications allowing for central nervous system penetration and potential circumvention of multidrug resistance efflux pump mechanisms. The aim of this phase I study was to determine the maximum tolerated dose of the combination of TPI 287 and temozolomide in metastatic melanoma. Patients with stage IV unresectable or recurrent stage III melanoma were eligible. Stable untreated or treated brain metastases were allowed. Patients with previous taxane exposure were excluded. TPI 287 was administered intravenously on days 1, 8, and 15 and temozolomide was taken orally daily on days 1-5 of a 28-day cycle. Responses were assessed every two cycles according to WHO criteria. A total of 21 patients were enrolled. The maximum tolerated dose of the combination at this schedule was determined to be 125 mg/m intravenous of TPI 287 and 110 mg/m of oral temozolomide. The dose-limiting toxicity was neuropathy and six patients experienced grade III neuropathy. All patients were evaluable for tumor response. There were no complete responses; there were two partial responses and seven patients had stable disease (overall response rate 9.5% and disease control rate 42.9%). Three patients had stable disease in the brain despite progressive extracranial disease. The combination of TPI 287 and temozolomide is well tolerated in patients with metastatic melanoma, with the exception of neuropathy. The central nervous system penetration of both agents makes this a rational combination for further testing in primary and metastatic brain lesions.

Purpose: Merkel cell carcinoma (MCC) is an aggressive cancer with frequent metastasis and death with few effective therapies. Because programmed death ligand-1 (PD-L1) is frequently expressed in MCC, immune checkpoint blockade has been leveraged as treatment for metastatic disease. There is therefore a critical need to understand the relationships between MCPyV status, immune profiles, and patient outcomes., Experimental Design: IHC for CD3, CD8, PD-1, PD-L1, and MCPyV T-antigen (to determine MCPyV status) was performed on 62 primary MCCs with annotated clinical outcomes. Automated image analysis quantified immune cell density (positive cells/mm 2 ) at discrete geographic locations (tumor periphery, center, and hotspot). T-cell receptor sequencing (TCRseq) was performed in a subset of MCCs., Results: No histopathologic variable associated with overall survival (OS) or disease-specific survival (DSS), whereas higher CD3 + (P = 0.004) and CD8 + (P = 0.037) T-cell density at the tumor periphery associated with improved OS. Higher CD8 + T-cell density at the tumor periphery associated with improved DSS (P = 0.049). Stratifying MCCs according to MCPyV status, higher CD3 + (P = 0.026) and CD8 + (P = 0.015) T-cell density at the tumor periphery associated with improved OS for MCPyV + but not MCPyV - MCC. TCRseq revealed clonal overlap among MCPyV + samples, suggesting an antigen-specific response against a unifying antigen., Conclusions: These findings establish the tumor-associated immune infiltrate at the tumor periphery as a robust prognostic indicator in MCC and provide a mechanistic rationale to further examine whether the immune infiltrate at the tumor periphery is relevant as a biomarker for response in ongoing and future checkpoint inhibitor trials in MCC. Clin Cancer Res; 22(22); 5553-63. ©2016 AACR., (©2016 American Association for Cancer Research.)

Importance: Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi)-refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development., Objective: To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractory metastatic melanoma., Design, Setting, and Participants: Single-center, single-arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy., Interventions: Patients were treated with dabrafenib (150 mg, twice daily) and trametinib (2 mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600., Main Outcomes and Measures: The primary end point was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points., Results: A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73% vs 11% for ≤6 months; P = .02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75% vs 18% for no decrease; P = .02) but not with pretreatment mitogen-activated protein kinase (MAPK) pathway mutations or activation. Biopsy specimens obtained during treatment demonstrated that CombiDT therapy failed to achieve significant MAPK pathway inhibition or immune infiltration in most patients., Conclusions and Relevance: The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT in patients with BRAFi-refractory metastatic melanoma. Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of CombiDT in this setting. Circulating BRAF V600 is a promising early biomarker of clinical response., Trial Registration: clinicaltrials.gov Identifier: NCT01619774.

The diagnosis of melanocytic lesions remains a formidable challenge in dermatopathology. For diagnostically challenging lesions, ancillary tests are available to inform the diagnosis, including immunohistochemistry and molecular testing (particularly fluorescence in situ hybridization [FISH]). However, the test result that most robustly informs the diagnosis remains controversial. Thirty-seven diagnostically challenging melanocytic lesions from our consultation service were reviewed. Histopathologic, immunohistochemical, and second-generation FISH results (NeoGenomics; probes 6p25, 8q24, 11q13, 9p21, and centromere 9) were correlated with the final consensus diagnosis and clinical follow-up using logistic regression and Fisher exact test. Based on histopathologic and immunohistochemical features, cases were designated as "favor benign" (n=19) or "favor malignant" (n=18) by a consensus group of up to 7 dermatopathologists. The sensitivity of FISH for the diagnosis of melanoma was 39%, and the specificity was 84%. Univariate logistic regression models for a final diagnosis of melanoma showed that only increased Ki-67-positive dermal tumor cells (≥5%; P=.01) significantly correlated with the diagnosis of melanoma. FISH result did not correlate with the final diagnosis (melanoma or nevus; P=.26). Follow-up (range, 8-29months) was available for 35 cases (19 diagnosed as nevus and 16 as melanoma), and metastases (restricted to sentinel lymph nodes) were detected from 5 melanomas (3 FISH negative and 2 FISH positive). Only increased dermal mitotic figures (>1/mm(2)) correlated with metastases to sentinel lymph nodes (P=.04). Thus, in the classification of diagnostically challenging melanocytic lesions, indices of proliferation emerge as the most informative diagnostic adjuncts-correlating with diagnosis and clinical behavior, respectively., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Inflammatory marker expression in stage III melanoma tumors was evaluated for association with outcome, using two independent cohorts of stage III melanoma patients' tumor tissues., Experimental Design: Fifteen markers of interest were selected for analysis, and their expression in melanoma tissues was determined by immunohistochemistry. Proteins associating with either overall survival (OS) or recurrence-free survival (RFS) in the retrospective discovery tissue microarray (TMA; n = 158) were subsequently evaluated in an independent validation TMA (n = 114). Cox proportional hazards regression models were used to assess the association between survival parameters and covariates, the Kaplan-Meier method to estimate the distribution of survival, and the log-rank test to compare distributions., Results: Expression of CD74 on melanoma cells was unique, and in the discovery TMA, it associated with favorable patient outcome (OS: HR, 0.53; P = 0.01 and RFS: HR, 0.56; P = 0.01). The validation data set confirmed the CD74 prognostic significance and revealed that the absence of macrophage migration inhibitory factor (MIF) and inducible nitric oxide synthase (iNOS) was also associated with poor survival parameters. Consistent with the protein observation, tumor CD74 mRNA expression also correlated positively (P = 0.003) with OS in the melanoma TCGA data set., Conclusions: Our data validate CD74 as a useful prognostic tumor cell protein marker associated with favorable RFS and OS in stage III melanoma. Low or negative expression of MIF in both TMAs and of iNOS in the validation set also provided useful prognostic data. A disease-specific investigation of CD74's functional significance is warranted, and other markers appear intriguing to pursue. Clin Cancer Res; 22(12); 3016-24. ©2016 AACR., (©2016 American Association for Cancer Research.)

Recent investigation has identified association of IL-12p40 blood levels with melanoma recurrence and patient survival. No studies have investigated associations of single-nucleotide polymorphisms (SNPs) with melanoma patient IL-12p40 blood levels or their potential contributions to melanoma susceptibility or patient outcome. In the current study, 818,237 SNPs were available for 1,804 melanoma cases and 1,026 controls. IL-12p40 blood levels were assessed among 573 cases (discovery), 249 cases (case validation), and 299 controls (control validation). SNPs were evaluated for association with log[IL-12p40] levels in the discovery data set and replicated in two validation data sets, and significant SNPs were assessed for association with melanoma susceptibility and patient outcomes. The most significant SNP associated with log[IL-12p40] was in the IL-12B gene region (rs6897260, combined P=9.26 × 10(-38)); this single variant explained 13.1% of variability in log[IL-12p40]. The most significant SNP in EBF1 was rs6895454 (combined P=2.24 × 10(-9)). A marker in IL12B was associated with melanoma susceptibility (rs3213119, multivariate P=0.0499; OR=1.50, 95% CI 1.00-2.24), whereas a marker in EBF1 was associated with melanoma-specific survival in advanced-stage patients (rs10515789, multivariate P=0.02; HR=1.93, 95% CI 1.11-3.35). Both EBF1 and IL12B strongly regulate IL-12p40 blood levels, and IL-12p40 polymorphisms may contribute to melanoma susceptibility and influence patient outcome.

Background: High mitotic figure count (MFC) correlates with low survival rate in Merkel cell carcinoma (MCC). However, the prognostic impact of histone biomarkers as surrogates of MFC in MCC is unknown. We evaluated the prognostic significance of the immunodetection of mitotic figures and of G2+ tumor nuclei with histone-associated mitotic markers H3K79me3T80ph (H3KT) and phosphohistone H3 (PHH3) in MCC., Methods: Immunohistochemical analyses of H3KT and PHH3 and proliferative marker Ki-67 were performed in a series of 21 cases of MCC. The significance of the pathologic data and immunoreactivity with these markers was evaluated with Pearson correlation and paired Student t-test. Univariate Cox proportional hazards regression models were performed to assess the relationships between these markers and survival., Results: H3KT detected a higher number of mitotic figure (p<0.0001) and G2+ tumor nuclei (p<0.0052) than did PHH3. Furthermore, the MFC combined with G2+ tumor nuclei detected with H3KT compared to PHH3 and manual MFC was a significant predictor of impaired survival in patients with MCC (p=0.035; HR=1.0172), corresponding to a 1.72% increased risk of death for each unit increase in H3KT., Conclusions: Biomarker analysis of proliferative rates with histone markers may have relevance in stratifying risk in patients with MCC., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Poorly differentiated, cytologically malignant, spindle cell neoplasms of the skin may present a diagnostic challenge with important clinical consequences. In particular, the distinction between poorly differentiated cutaneous spindle cell squamous cell carcinoma (SpSCC) and atypical fibroxanthoma (AFX) remains controversial, but with important clinical implications: SpSCC exhibits an increased tendency for both local recurrence and metastasis compared with AFX. AFX is generally accepted as a diagnosis of exclusion based on negativity for a broad panel of immunohistochemical markers, including multiple cytokeratins, melanocytic markers, muscle markers, and vascular markers. As cytokeratins can also be occasionally lost in SpSCC, it would be of tremendous diagnostic value if there were additional specific markers to facilitate the distinction of lineage in this differential diagnostic context. Initial studies demonstrated p63 to be of utility in distinguishing AFX from SpSCC; however, p63 has proved to lack specificity, as it also exhibits variable reactivity in a subset of AFX. Recent studies have shown p40 immunohistochemistry to be a more specific marker than p63 for the designation of squamous differentiation in carcinomas involving other organ systems. In the current study, we define the utility of p40 immunohistochemistry among common cutaneous spindle cell malignancies, and, specifically, we compare the diagnostic accuracy of p40 and p63 in distinguishing AFX from SpSCC. We show that p40 and p63 exhibit comparable sensitivity, but p40 exhibits superior specificity in the distinction of AFX from SpSCC.

The survival advantage of women over men with cutaneous melanoma and the reports of accelerated progression of melanoma during pregnancy have led to studies of the effect of hormones and hormone receptors on the development and progression of melanoma. However, the results are inconclusive. We therefore evaluated the expression of estrogen receptor α, estrogen receptor β, and androgen receptor in melanomas of stage- and age-matched pregnant women, nonpregnant women, and men by immunohistochemical analysis of formalin-fixed, paraffin-embedded archival tissues. In addition, we also assessed the mitotic rate using the antiphosphohistone H3 antibody by immunohistochemistry. Our data showed a trend of more frequent expression of estrogen receptor β in the melanomas of pregnant patients than in the melanomas of male patients, without a significant difference observed between pregnant and nonpregnant women. However, no association between the expression of estrogen receptor β and survival was observed. The small cohort may have limited the statistical power of the study, and large-scale studies are needed to elucidate the potential role of estrogen receptor β as a prognostic marker of melanoma.

Background: Hotspot mutations in BRAF and NRAS are the most common somatic events in patients with melanoma. These mutations occur at highly conserved residues, but include several different substitutions. To determine whether specific mutations are clinically important to differentiate, tumor characteristics and clinical outcomes were compared among patients with advanced melanoma with 1) BRAF V600E versus V600K mutations and 2) NRAS exon 1 versus exon 2 mutations., Methods: Retrospective clinical and pathologic data were collected for patients with advanced melanoma with BRAF or NRAS mutations. The demographics, tumor characteristics, and clinical outcomes of the patients were compared to identify significant mutation-specific associations., Results: Among 302 patients with activating BRAF mutations, 76% had BRAF V600E and 24% had V600K substitutions. Compared with V600E, the presence of a V600K mutation was significantly associated with older age (median, 60.0 years vs 44.7 years; P < .001), male sex (80% vs 59%; P = .001), head/neck primary tumor location (30% vs 15%; P = .0026), shorter interval to stage IV disease (0.98 years vs 2.8 years; P = .015), and a shorter overall survival from the time of diagnosis of stage IV disease (median, 2.44 years vs 1.25 years; hazards ratio, 1.68 [P = .014]). Comparison of 136 patients with NRAS exon 1 (18%) and exon 2 (82%) mutations found an association with primary tumor histology (P = .0096) only., Conclusions: The presence of different substitutions at BRAF V600 correlates with patient demographics, tumor characteristics, and prognosis. These findings demonstrate the presence of mutation-specific clinical differences between different BRAF genotypes in patients with melanoma, and support the incorporation of this information in patient evaluation and clinical trial design., (© 2013 American Cancer Society.)

In the American Joint Committee on Cancer (AJCC)-TNM (2009) staging system, the key prognostic factor in cutaneous melanoma is the depth of dermal invasion (Breslow thickness) with further refinement according to the presence of epidermal ulceration or dermal mitoses. Immunodetection of phosphohistone H3 has been shown to facilitate the identification of mitotic figures in various neoplasms. We selected 120 cases of primary cutaneous melanoma with completely annotated histopathologic parameters and clinical outcomes and performed double immunohistochemical staining for MLANA (Mart-1/Melan-A) and phosphohistone H3. One hundred and thirteen cases were amenable to antiphosphohistone H3 staining from 66 men and 47 women, with mean age of 64 years (9-93), including 61 superficial spreading type, 24 nodular, 6 lentigo maligna, 8 acral lentiginous, and 14 unclassified. The mean Breslow thickness was 2.53 mm (0.20-25), ulceration was present in 25/113 (22%) and the mean mitotic count was 3.2/mm(2) (<1-29/mm(2)). In 27/113 (24%) of the cases, antiphosphohistone H3 failed to highlight mitotic figures anywhere in the tissue (normal or tumor cell), whereas in 86/113 (76%) antiphosphohistone H3 detected at least one mitotic figure. Among the latter, antiphosphohistone H3 did not detect mitotic figures in dermal tumor cells in 37/86 cases (43%), whereas anti-PHH3 identified at least one melanocytic mitotic figure in the other 49/86 cases (57%; range: 1-66/mm(2)). The relationship between phosphohistone H3 and manual mitotic count was statistically significant (Pearson correlation=0.59, P<0.0001). Logistic regression analyses demonstrated an association between the development of subsequent metastatic disease and the following variables: mitotic figures (odds ratio (OR)=5.7; P=0.0001); phosphohistone H3-positive mitotic figures (OR=3.0; P=0.008); Breslow thickness (OR=4.0 per mm; P=0.0002); ulceration (OR=3.94; P=0.008). The application of phosphohistone H3 immunohistochemistry to the description of primary cutaneous melanoma is useful in identifying mitotic figures, improves upon the specificity of this designation when used together with MLANA, and correlates with an increased risk for metastasis in univariate analyses.

Background: There is a need for improved prognostic markers in melanoma. In this study, the authors tested the prognostic significance and clinicopathologic correlations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations in patients with metastatic melanoma., Methods: Clinical and pathologic data were collected retrospectively on melanoma patients who were clinically tested for BRAF (exon 15) and NRAS (exons 1 and 2) mutations at The University of Texas M. D. Anderson Cancer Center. Analyses were performed to identify significant associations of mutations with tumor and patient characteristics and with survival from the diagnosis of stage IV disease., Results: The genotypes of the full cohort (n = 677) were 47% BRAF mutation, 20% NRAS mutation, and 32% wild-type for BRAF and NRAS ("WT"). Tumor mutation status was associated (P = .008) with the risk of central nervous system involvement at the diagnosis of stage IV disease, with a higher prevalence observed in BRAF-mutant (24%) and NRAS-mutant (23%) patients than in WT patients (12%). Among patients with nonuveal melanoma who underwent mutation testing within 6 months of stage IV diagnosis (n = 313), patients with NRAS mutations had a median survival of 8.2 months from stage IV diagnosis, which was shorter than the median survival of WT patients (15.1 months; P = .004). Multivariate analysis of this population incorporating age, sex, metastases (M1) category, serum lactate dehydrogenase level, and mutation status confirmed that NRAS mutations are associated independently with decreased overall survival (vs WT; P = .005; hazard ratio, 2.05)., Conclusions: Patients with BRAF or NRAS mutations were more likely than WT patients to have central nervous system involvement at the time they were diagnosed with distant metastatic disease. NRAS mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma., (Copyright © 2011 American Cancer Society.)

The purpose of this study is to identify clinical and molecular characteristics of melanoma patients that predict response to high-dose interleukin-2 (HD IL-2) to improve patient selection for this approved but toxic therapy. We reviewed the records of 208 patients with unresectable stage III/IV melanoma treated with HD IL-2 at the University of Texas M.D. Anderson Cancer Center (n=100) and the Beth Israel Deaconess Medical Center (n=108) between 2003 and 2009. The BRAF and NRAS mutation status of the tumors was determined for patients with available tissue samples and the mutation status and clinical characteristics were compared with clinical outcomes. Pretreatment serum lactate dehydrogenase levels were available for most patients (n=194). Tissue was available for mutational analysis on a subset of patients (n=103) and the prevalence of mutations was as follows: BRAF 60%, NRAS 15%, WT/WT 25%. In the subset of patients for which mutational analysis was available, there was a significant difference in the response rate based on the mutation status: NRAS 47%, BRAF 23%, and WT/WT 12% (P=0.05). Patients with NRAS mutations had nonstatistically longer overall survival (5.3 vs. 2.4 y, P=0.30) and progression-free survival (214 vs. 70 d, P=0.13). Patients with an elevated lactate dehydrogenase level had a decreased progression-free survival (46 vs. 76 d, P<0.0001), decreased overall survival (0.56 vs. 1.97 y, P<0.0001), and trended toward a decreased response rate (7% vs. 21%, P=0.08). NRAS mutational status is a new candidate biomarkers for selecting patients with melanoma for HD IL-2 treatment.

Although pelvic computed tomography (CT) scans are frequently performed as a part of routine surveillance, the evidence for or against the routine use of these scans in patients with primary melanoma in the head and neck is weak. We conducted a retrospective study to evaluate the value of pelvic CT scans as routine surveillance in patients with primary melanoma in the head and neck. We identified 146 patients with either primary or mucosal primary melanoma who had adequate follow-up evaluation for at least 5 years at our institution. Among them, 33 patients (23%) had stage III melanoma, and four (3%) had stage IV melanoma at the time of diagnosis. At a median follow-up duration of 49 months, 110 patients (75%) had developed recurrences, and the median time to the first recurrence was 13 months. A total of 82 (56%) patients had eventually developed distant metastases, but only 10 (7%) had developed metastases in the pelvis, and none had developed pelvic metastases as the first and the only site of recurrence. If the true rate of finding the pelvic metastasis as the first and the only recurrence was at least 3%, the probability of seeing 0 events of the 146 patients was 1.17%. This study, which is the largest series to evaluate the value of pelvic CT scans in this patient population to date, suggests that the routine use of a pelvic CT scan as a surveillance method does not have any impact on the management in patients with primary melanoma in the head and neck.

Background: The most common cutaneous T-cell lymphomas (CTCLs) are mycosis fungoides and Sézary syndrome., Aim: To determine whether blood stage and other prognostic variables affect overall survival (OS) in CTCL., Methods: We studied retrospectively 1197 CTCL patients seen at the M.D. Anderson Cancer Center since 1987., Results: We identified 124 (10.3%) patients with erythrodermic CTCL (E-CTCL), 63% of whom had positive gene rearrangements in skin and 19 of whom had no evidence of hematologic involvement. The median age at diagnosis was 63 years (range, 26-90 years); the male to female ratio was 1.3 : 1. OS curves were estimated by the Kaplan-Meier method and compared using log-rank tests. The median OS in all 124 E-CTCL patients was 5.1 years (range, 0.4-18.6 years) regardless of the cause of death or blood involvement. Patients were stratified by the H0-H4 staging system with manual or flow cytometric determination of Sézary cell counts (Russell-Jones R, Whittaker SJ. Sézary syndrome: diagnostic criteria and therapeutic options. Semin Cutan Med Surg 2000; 19: 100-108). The median OS was 7.6 years for H0-H2 (< 1000 Sézary cells/L) (n = 23), 5.4 years for H3 (>or= 1000 to or= 10,000 Sézary cells/L) (n = 22) (P = 0.011). Treatment with systemic steroids, age, serum lactate dehydrogenase, and white blood cell count >or= 20,000 microL were significant prognostic factors, but large cell transformation, T-cell receptor gene rearrangement, tumor-node-metastasis stage, treatments, and CD4 : CD8 ratio were not. In multivariate analysis, advanced age and elevated lactate dehydrogenase were the strongest predictors of a poor prognosis., Conclusions: Serum LDH and age were the strongest predictive factors for OS in E-CTCL.