CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells.

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.

Anatomic position determines oncogenic specificity in melanoma.

Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.

BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma.

DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Here, we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma, with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of the 5-hmC landscape in the melanoma epigenome. We show that downregulation of isocitrate dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy.

Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

BACKGROUND: Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation-induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life. RESULTS: A total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P = 0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups. CONCLUSIONS: In this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.).

Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy.

Inhibitors of the receptor tyrosine kinase c-MET are currently used in the clinic to target oncogenic signaling in tumor cells. We found that concomitant c-MET inhibition promoted adoptive T cell transfer and checkpoint immunotherapies in murine cancer models by increasing effector T cell infiltration in tumors. This therapeutic effect was independent of tumor cell-intrinsic c-MET dependence. Mechanistically, c-MET inhibition impaired the reactive mobilization and recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies. In the absence of c-MET inhibition, neutrophils recruited to T cell-inflamed microenvironments rapidly acquired immunosuppressive properties, restraining T cell expansion and effector functions. In cancer patients, high serum levels of the c-MET ligand HGF correlated with increasing neutrophil counts and poor responses to checkpoint blockade therapies. Our findings reveal a role for the HGF/c-MET pathway in neutrophil recruitment and function and suggest that c-MET inhibitor co-treatment may improve responses to cancer immunotherapy in settings beyond c-MET-dependent tumors.

IGFBP7 is not required for B-RAF-induced melanocyte senescence.

Induction of senescence permanently restricts cellular proliferation after oncogenic stimulation thereby acting as a potent barrier to tumor development. The relevant effector proteins may therefore be fundamental to cancer development. A recent study identified IGFBP7 as a secreted factor mediating melanocyte senescence induced by oncogenic B-RAF, which is found commonly in cutaneous nevi. In contrast to the previous report, we demonstrate that B-RAF signaling does not induce IGFBP7 expression, nor the expression of the IGFBP7 targets, BNIP3L, SMARCB1, or PEA15, in human melanocytes or fibroblasts. We also found no correlation between B-RAF mutational status and IGFBP7 protein expression levels in 22 melanoma cell lines, 90 melanomas, and 46 benign nevi. Furthermore, using a lentiviral silencing strategy we show that B-RAF induces senescence in melanocytes and fibroblasts, irrespective of the presence of IGFBP7. Therefore, we conclude that the secreted protein IGFBP7 is dispensable for B-RAF(V600E)-induced senescence in human melanocytes.

Author Correction: Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin.

Panel j was inadvertently labelled as panel k in the caption to Fig. 4. Similarly, 'Fig. 4k' should have been 'Fig. 4j' in the sentence beginning 'TNF-α-deficient gBT-I cells were…'. In addition, the surname of author Umaimainthan Palendira was misspelled 'Palendria'. These errors have been corrected online.

Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin.

The immune system can suppress tumour development both by eliminating malignant cells and by preventing the outgrowth and spread of cancer cells that resist eradication1. Clinical and experimental data suggest that the latter mode of control-termed cancer-immune equilibrium1-can be maintained for prolonged periods of time, possibly up to several decades2-4. Although cancers most frequently originate in epithelial layers, the nature and spatiotemporal dynamics of immune responses that maintain cancer-immune equilibrium in these tissue compartments remain unclear. Here, using a mouse model of transplantable cutaneous melanoma5, we show that tissue-resident memory CD8+ T cells (TRM cells) promote a durable melanoma-immune equilibrium that is confined to the epidermal layer of the skin. A proportion of mice (~40%) transplanted with melanoma cells remained free of macroscopic skin lesions long after epicutaneous inoculation, and generation of tumour-specific epidermal CD69+ CD103+ TRM cells correlated with this spontaneous disease control. By contrast, mice deficient in TRM formation were more susceptible to tumour development. Despite being tumour-free at the macroscopic level, mice frequently harboured melanoma cells in the epidermal layer of the skin long after inoculation, and intravital imaging revealed that these cells were dynamically surveyed by TRM cells. Consistent with their role in melanoma surveillance, tumour-specific TRM cells that were generated before melanoma inoculation conferred profound protection from tumour development independently of recirculating T cells. Finally, depletion of TRM cells triggered tumour outgrowth in a proportion (~20%) of mice with occult melanomas, demonstrating that TRM cells can actively suppress cancer progression. Our results show that TRM cells have a fundamental role in the surveillance of subclinical melanomas in the skin by maintaining cancer-immune equilibrium. As such, they provide strong impetus for exploring these cells as targets of future anticancer immunotherapies.

Development and validation of a novel model to predict recurrence-free survival and melanoma-specific survival after sentinel lymph node biopsy in patients with melanoma: an international, retrospective, multicentre analysis.

BACKGROUND: The introduction of adjuvant systemic treatment for patients with high-risk melanomas necessitates accurate staging of disease. However, inconsistencies in outcomes exist between disease stages as defined by the American Joint Committee on Cancer (8th edition). We aimed to develop a tool to predict patient-specific outcomes in people with melanoma rather than grouping patients according to disease stage. METHODS: Patients older than 13 years with confirmed primary melanoma who underwent sentinel lymph node biopsy (SLNB) between Oct 29, 1997, and Nov 11, 2013, at four European melanoma centres (based in Berlin, Germany; Amsterdam and Rotterdam, the Netherlands; and Warsaw, Poland) were included in the development cohort. Potential predictors of recurrence-free and melanoma-specific survival assessed were sex, age, presence of ulceration, primary tumour location, histological subtype, Breslow thickness, sentinel node status, number of sentinel nodes removed, maximum diameter of the largest sentinel node metastasis, and Dewar classification. A prognostic model and nomogram were developed to predict 5-year recurrence-free survival on a continuous scale in patients with stage pT1b or higher melanomas. This model was also calibrated to predict melanoma-specific survival. Model performance was assessed by discrimination (area under the time-dependent receiver operating characteristics curve [AUC]) and calibration. External validation was done in a cohort of patients with primary melanomas who underwent SLNB between Jan 30, 1997, and Dec 12, 2013, at the Melanoma Institute Australia (Sydney, NSW, Australia). FINDINGS: The development cohort consisted of 4071 patients, of whom 2075 (51%) were female and 1996 (49%) were male. 889 (22%) had sentinel node-positive disease and 3182 (78%) had sentinel node-negative disease. The validation cohort comprised 4822 patients, of whom 1965 (41%) were female and 2857 (59%) were male. 891 (18%) had sentinel node-positive disease and 3931 (82%) had sentinel node-negative disease. Median follow-up was 4·8 years (IQR 2·3-7·8) in the development cohort and 5·0 years (2·2-8·9) in the validation cohort. In the development cohort, 5-year recurrence-free survival was 73·5% (95% CI 72·0-75·1) and 5-year melanoma-specific survival was 86·5% (85·3-87·8). In the validation cohort, the corresponding estimates were 66·1% (64·6-67·7) and 83·3% (82·0-84·6), respectively. The final model contained six prognostic factors: sentinel node status, Breslow thickness, presence of ulceration, age at SLNB, primary tumour location, and maximum diameter of the largest sentinel node metastasis. In the development cohort, for the model's prediction of recurrence-free survival, the AUC was 0·80 (95% CI 0·78-0·81); for prediction of melanoma-specific survival, the AUC was 0·81 (0·79-0·84). External validation showed good calibration for both outcomes, with AUCs of 0·73 (0·71-0·75) and 0·76 (0·74-0·78), respectively. INTERPRETATION: Our prediction model and nomogram accurately predicted patient-specific risk probabilities for 5-year recurrence-free and melanoma-specific survival. These tools could have important implications for clinical decision making when considering adjuvant treatments in patients with high-risk melanomas. FUNDING: Erasmus Medical Centre Cancer Institute.

Size matters: integrating tumour volume and immune activation signatures predicts immunotherapy response.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, providing significant benefit to patients across various tumour types, including melanoma. However, around 40% of melanoma patients do not benefit from ICI treatment, and accurately predicting ICI response remains challenging. We now describe a novel and simple approach that integrates immune-associated transcriptome signatures and tumour volume burden to better predict ICI response in melanoma patients. RNA sequencing was performed on pre-treatment (PRE) tumour specimens derived from 32 patients with advanced melanoma treated with combination PD1 and CTLA4 inhibitors. Of these 32 patients, 11 also had early during treatment (EDT, 5-15 days after treatment start) tumour samples. Tumour volume was assessed at PRE for all 32 patients, and at first computed tomography (CT) imaging for the 11 patients with EDT samples. Analysis of the Hallmark IFNγ gene set revealed no association with ICI response at PRE (AUC ROC curve = 0.6404, p = 0.24, 63% sensitivity, 71% specificity). When IFNg activity was evaluated with tumour volume (ratio of gene set expression to tumour volume) using logistic regression to predict ICI response, we observed high discriminative power in separating ICI responders from non-responders (AUC = 0.7760, p = 0.02, 88% sensitivity, 67% specificity); this approach was reproduced with other immune-associated transcriptomic gene sets. These findings were further replicated in an independent cohort of 23 melanoma patients treated with PD1 inhibitor. Hence, integrating tumour volume with immune-associated transcriptomic signatures improves the prediction of ICI response, and suggest that higher levels of immune activation relative to tumour burden are required for durable ICI response.

Cutaneous melanoma.

Cutaneous melanoma is a malignancy arising from melanocytes of the skin. Incidence rates are rising, particularly in White populations. Cutaneous melanoma is typically driven by exposure to ultraviolet radiation from natural sunlight and indoor tanning, although there are several subtypes that are not related to ultraviolet radiation exposure. Primary melanomas are often darkly pigmented, but can be amelanotic, with diagnosis based on a combination of clinical and histopathological findings. Primary melanoma is treated with wide excision, with margins determined by tumour thickness. Further treatment depends on the disease stage (following histopathological examination and, where appropriate, sentinel lymph node biopsy) and can include surgery, checkpoint immunotherapy, targeted therapy, or radiotherapy. Systemic drug therapies are recommended as an adjunct to surgery in patients with resectable locoregional metastases and are the mainstay of treatment in advanced melanoma. Management of advanced melanoma is complex, particularly in those with cerebral metastasis. Multidisciplinary care is essential. Systemic drug therapies, particularly immune checkpoint inhibitors, have substantially increased melanoma survival following a series of landmark approvals from 2011 onward.

The Effect of Neoadjuvant Systemic Therapy on Surgical Outcomes After Lymph Node Dissections for Stage III Melanoma; An Australian Cohort.

BACKGROUND: Neoadjuvant systemic therapy (NAST) for patients with stage III melanoma achieves high major pathologic response rates and high recurrence-free survival rates. This study aimed to determine how NAST with targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) influences surgical outcomes after lymph node dissection in terms of complications, morbidity, and textbook outcomes. METHODS: Patients who underwent a lymph node dissection after either NAST in a clinical trial or upfront surgery for stage III melanoma between 2014 and 2022 were identified from an institutional research database. RESULTS: The study included 89 NAST-treated patients and 79 upfront surgery-treated patients. The rate of postoperative complications did not differ between the NAST- and upfront surgery-treated patients (55% vs. 51%; p = 0.643), and steroid treatment for drug toxicity did not influence the complication rate (odds ratio [OR], 1.1; 95% confidence interval [CI], 0.4-3; p = 0.826). No significant differences in postoperative morbidity were observed in terms of seroma (23% vs. 11%; p = 0.570) or lymphedema (36% vs. 51%; p = 0.550). The rate of achieving a textbook outcome was comparable for the two groups (61% vs. 57%; p = 0.641). CONCLUSIONS: The surgical outcomes after lymph node dissections were comparable between the patients who received NAST and those who had upfront surgery, indicating that surgery can be safely performed after NAST with TT or ICI for stage III melanoma.

Impact of an Online Risk Calculator for Sentinel Node Positivity on Management of Patients with T1 and T2 Melanomas.

BACKGROUND: Predicting which patients with American Joint Committee on Cancer (AJCC) T1-T2 melanomas will have a positive sentinel lymph node (SLN) is challenging. Melanoma Institute Australia (MIA) developed an internationally validated SLN metastatic risk calculator. This study evaluated the nomogram's impact on T1-T2 melanoma patient management at MIA. METHODS: SLN biopsy (SLNB) rates were compared for the pre- and post-nomogram periods of 1 July 2018-30 June 2019 and 1 August 2020-31 July 2021, respectively. RESULTS: Overall, 850 patients were identified (pre-nomogram, 383; post-nomogram, 467). SLNB was performed in 29.0% of patients in the pre-nomogram group and 34.5% in the post-nomogram group (p = 0.091). The overall positivity rate was 16.2% in the pre-nomogram group and 14.9% in the post-nomogram group (p = 0.223). SLNB was performed less frequently in T1a melanoma patients in the pre-nomogram group (1.1%, n = 2/177) than in the post-nomogram group (8.6%, n = 17/198) [p ≤ 0.001]. This increase was particularly for melanomas with a risk score ≥ 5%, with an SLN positivity rate of 11.8% in the post-nomogram group (p = 0.004) compared with zero. For T1b melanomas with a risk score of > 10%, the SLNB rate was 40.0% (8/20) pre-nomogram and 75.0% (12/16) post-nomogram (p = 0.049). CONCLUSIONS: In this specialized center, the SLN risk calculator appears to influence practice for melanomas previously considered low risk for metastasis, with increased use of SLNB for T1a and higher-risk T1b melanomas. Further evaluation is required across broader practice settings. Melanoma management guidelines could be updated to incorporate the availability of nomograms to better select patients for SLNB than previous criteria.

Role of Concurrent Ultrasound Surveillance of Sentinel Node-Positive Node Fields in Melanoma Patients Having Routine Cross-Sectional Imaging.

PURPOSE: In sentinel node-positive (SN+ve) melanoma patients, active surveillance with regular ultrasound examination of the node field has become standard, rather than completion lymph node dissection (CLND). A proportion of these patients now receive adjuvant systemic therapy and have routine cross-sectional imaging (computed tomography [CT] or positron emission tomography [PET]/CT). The role of concurrent ultrasound (US) surveillance in these patients is unclear. The purpose of our study was to describe the modality of detection of nodal recurrence in SN+ve node fields. METHODS: SN+ve melanoma patients who did not undergo CLND treated at a single institution from January 1, 2016 to December 31, 2020 were included. RESULTS: A total of 225 SN+ve patients with a median follow-up of 23 months were included. Of these, 119 (53%) received adjuvant systemic therapy. Eighty (36%) developed a recurrence at any site; 24 (11%) recurred first in the SN+ve field, of which 12 (5%) were confirmed node field recurrence only at 2 months follow-up. The nodal recurrences were first detected by ultrasound in seven (3%), CT in seven (3%), and PET/CT in seven (3%) patients. All nodal recurrences evident on US were also evident on PET/CT and vice versa. CONCLUSIONS: The high rate of recurrences outside the node field and the identification of all US-detected nodal recurrences on concurrent cross-sectional imaging modalities suggest that routine concurrent ultrasound surveillance of the node-positive field may be unnecessary for SN+ve melanoma patients having routine cross-sectional imaging.

Uncovering molecular mechanisms for amelanotic/hypopigmented primary cutaneous melanoma.

BACKGROUND: A portion of approximately 2-20% of cutaneous melanoma (CM) are diagnosed as amelanotic/hypopigmented melanoma (AHM) and represent a challenge for early diagnosis. OBJECTIVES: Since the degree to which somatic mutations and copy number aberrations (CNA) in genes associated with skin-lightening or albinism may contribute to the loss of tumour pigmentation in AHM samples has not yet been addressed, we have investigated loss of function mutations of key pigmentation genes in matched germline and AHM as well as pigmented melanoma (PM) tumour DNA samples. METHODS: An analysis of clinical and histopathological characteristics together with whole exome sequencing data of 34 fresh frozen primary CM, graded according to the amount of pigmentation present was performed. Together with germline and somatic variant analysis, 30 samples were previously analysed for CNA changes. This study focussed on germline and somatic variants in the coding region of 16 genes known to be associated with albinism/hypopigmentation or variation in human pigmentation in all samples. Chromosomal regions encompassing these 16 genes were examined for DNA copy loss or gain. RESULTS: The finding that red hair related MC1R and TYR R402Q loss of activity gene variant alleles and genotypes are associated with AHM was validated in this study. Germline AHM-related gene variants were enriched in 70% (n=7 of 10) of AHM patients vs 8.3% (n=2 of 24) of PM patients. This surprisingly high frequency of rare germline variants in AHM patients constitutes the "first hit" and confirms that AHM patients are more likely to be albinism allele carriers than patients with PM. Next, in CNA analysis of each tumour sample, 50% (n=4 of 8) AHM samples with a pigmentation gene variant had LOH in the region containing the corresponding gene, and 25% (=2 of 8) had loss-of-heterozygosity (LOH) in chromosomal regions of two AHM-related genes. CONCLUSIONS: This study proposes that the likely molecular mechanism for development of amelanogenesis in AHM is carriage of an albinism/hypopigmentation allele followed by LOH of the corresponding gene in the tumour.

Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.

Answer questions and earn CME/CNE To update the melanoma staging system of the American Joint Committee on Cancer (AJCC) a large database was assembled comprising >46,000 patients from 10 centers worldwide with stages I, II, and III melanoma diagnosed since 1998. Based on analyses of this new database, the existing seventh edition AJCC stage IV database, and contemporary clinical trial data, the AJCC Melanoma Expert Panel introduced several important changes to the Tumor, Nodes, Metastasis (TNM) classification and stage grouping criteria. Key changes in the eighth edition AJCC Cancer Staging Manual include: 1) tumor thickness measurements to be recorded to the nearest 0.1 mm, not 0.01 mm; 2) definitions of T1a and T1b are revised (T1a, <0.8 mm without ulceration; T1b, 0.8-1.0 mm with or without ulceration or <0.8 mm with ulceration), with mitotic rate no longer a T category criterion; 3) pathological (but not clinical) stage IA is revised to include T1b N0 M0 (formerly pathologic stage IB); 4) the N category descriptors "microscopic" and "macroscopic" for regional node metastasis are redefined as "clinically occult" and "clinically apparent"; 5) prognostic stage III groupings are based on N category criteria and T category criteria (ie, primary tumor thickness and ulceration) and increased from 3 to 4 subgroups (stages IIIA-IIID); 6) definitions of N subcategories are revised, with the presence of microsatellites, satellites, or in-transit metastases now categorized as N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes, if any; 7) descriptors are added to each M1 subcategory designation for lactate dehydrogenase (LDH) level (LDH elevation no longer upstages to M1c); and 8) a new M1d designation is added for central nervous system metastases. This evidence-based revision of the AJCC melanoma staging system will guide patient treatment, provide better prognostic estimates, and refine stratification of patients entering clinical trials. CA Cancer J Clin 2017;67:472-492. © 2017 American Cancer Society.

Comparison of clinicopathological features and treatment outcomes for cutaneous melanomas of the head and neck and melanomas arising at other sites: Implications for systemic therapy.

BACKGROUND: Melanoma is increasingly recognized as a heterogeneous disease, with conflicting evidence regarding whether cutaneous head and neck melanoma (CHNM) represents a distinct entity. OBJECTIVE: Comparison of clinicopathological features and treatment outcomes of CHNM and cutaneous melanomas of other sites (CMOS). METHODS: Patients with CHNM and CMOS diagnosed between 2000 and 2018 were included. Locoregional control, distant metastasis-free survival, melanoma-specific survival (MSS), and overall survival (OS) were described using the Kaplan-Meier method. Cox regression analyses were performed to examine associations between prognostic factors and outcomes. Additional analyses of survival from time of stage IV disease diagnosis were undertaken, stratified by receipt of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy. RESULTS: Of 3007 CHNM and 10,637 CMOS patients, CHNM had more adverse pathological features (median age 65.9 vs 58.5, P < .001; median Breslow thickness 1.7 mm vs 1.2 mm, P < .001; and ulceration 21.2% vs 18.2%, P < .001). CHNM had worse locoregional control (hazard ratio (HR) 1.17, P < .001) and distant metastasis-free survival (HR 1.25, P < .001) but there were no significant differences in MSS or OS. Among stage IV patients who received immune checkpoint inhibitor, CHNM had better MSS (HR 0.56, P = .001) and OS (HR 0.57, P < .001) on multivariable analyses. LIMITATIONS: Retrospective study, offset by prospective data collection. CONCLUSION: CHNM is associated with a distinct clinicopathological and prognostic profile.

Evaluation of Multiple Tissue Levels Frequently Upstages Patients With Clinically Localized Thin Primary Cutaneous Melanoma.

BACKGROUND: Breslow thickness (BT), ulceration, and microsatellitosis are critical prognostic parameters for cutaneous melanoma staging. These parameters can vary depending on the number of tissue levels examined from individual paraffin blocks. We sought to evaluate all prognostic histopathologic parameters in melanoma for their variations between levels, taken at regular intervals, in a single study. METHODS: We analyzed 40 consecutive cases of primary cutaneous (nonacral) melanoma through five hematoxylin and eosin sections, taken at 100 µm intervals, for staging and prognostic parameters. RESULTS: Examination of additional levels resulted in (a) an increase in BT in 47.5% (19 out of 40) of cases and (b) detection of ulceration in a further 5% (2/40). This resulted in upstaging for 20% (8 out of 40) of patients (15% because of BT, 2.5% because of ulceration, and 2.5% because of BT and ulceration). The upstaging effect was incremental, with approximately 5% of patients upstaged with each additional 100 µm interval (up to 400 µm). Incipient ulceration and epidermal consumption were infrequent (10% of cases); however, when present, ulceration was subsequently observed in half of cases. We encountered no cases where microsatellitosis was detected at deeper levels. CONCLUSION: The performance of additional tissue levels is a simple and inexpensive procedure that can improve the accuracy of staging for patients with thin (pT1) primary cutaneous melanomas. It may be pertinent for pathologists to consider additional levels for thin melanomas when a BT measurement is close to a staging threshold (e.g., within 0.1-0.3 mm for pT1a vs. pT1b, or pT1b vs. pT2a), or when incipient ulceration is encountered.

The Prognostic Significance of Tumoral Melanosis.

BACKGROUND: Tumoral melanosis (TM) is a histological term to describe a nodular aggregation of macrophages containing melanin pigment (melanophages) that is devoid of viable melanocytes. It is most often identified in skin, where it may be appreciated clinically as a pigmented lesion; however, it can also be found in other organs such as lymph nodes. The presence of TM is usually thought to signify the presence of a regressed melanoma or other pigmented tumor. Until recently, it was a relatively uncommon finding; however, with the use of effective systemic therapies against melanoma, its occurrence in histological specimens is more frequent. METHODS: We identified and reviewed all histopathological diagnoses of TM at any organ site reported at a single institution from 2006 to 2018. TM cases were paired with non-TM cases of cutaneous melanoma through propensity score matching at a 1:2 ratio, and their survival outcomes were compared. The clinical outcomes examined included recurrence-free survival (RFS), distant disease-free survival (DDFS), melanoma-specific survival (MSS), and overall survival (OS). RESULTS: TM was reported in 79 patients. Their median age was 65 years (range 22-88), with a 2:1 male predominance (51 out of 79, 65%). The most common organ involved was the skin (67%), with a third of all cases localized to a lower limb (36%). TM had a strong association with the presence of melanoma (91%) and regression at other sites of melanoma (54%), suggesting that it is part of a systemic immune response against melanoma. Most patients with TM either previously or subsequently developed histologically confirmed melanoma in the same anatomical region as the TM (89%). Thirty-five TM patients were matched with 70 non-TM cases. Patients with melanoma who developed TM without prior regional or systemic therapy showed improved MSS (p = 0.03), whereas no statistically significant differences were observed in terms of RFS, DDFS, and OS. CONCLUSIONS: TM usually occurs in the context of a previous or subsequent cutaneous melanoma and is associated with improved MSS. It is important that TM is recognized by pathologists and documented in pathology reports.