Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.
Background: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination antiprogrammed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS. Patients and methods: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n ¼ 29), cellular composition of the tumour bed was analysed by flow cytometry. Results: There was strong interobserver reproducibility in assessment of pathological response (k ¼ 0.879) and percentage residual viable melanoma (intraclass correlation coefficient ¼ 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P ¼ 0.008) and prolonged RFS (P ¼ 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had !70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P ¼ 0.002 and P 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P ¼ 0.046). Conclusions: There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of !70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.
Melanoma remains one of the most aggressive forms of cutaneous malignancies. While its diagnosis based on histologic parameters is usually straight forward in most cases, distinguishing a melanoma from a melanocytic nevus can be challenging in some instances, especially when there are overlapping clinical and histopathologic features. Occasionally, melanomas can histologically mimic other tumors and even demonstration of melanocytic origin can be challenging. Thus, several ancillary tests may be employed to arrive at the correct diagnosis. The objective of this review is to summarize these tests, including the well-established and commonly used ones such as immunohistochemistry, with specific emphasis on emerging techniques such as comparative genomic hybridization, fluorescence in situ hybridization and imaging mass spectrometry.
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