B A van de Wiel

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma

Background Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. Results Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. Conclusions 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.

Comment: Detailed Pathologic Examination of Completion Node Dissection Specimens and Outcome for Melanoma Patients with Minimal (< 0.1 mm) Sentinel Lymph Node Metastases

We read with interest the recent article by Holtkamp et al. and the accompanying editorial by Alistair Cochran. The authors re-assessed 21 tumor-negative completion lymph node dissection (CLND) specimens of patients with minimal tumor burden sentinel node (SN) for the presence of non–sentinel-node (NSLN) metastases using a more detailed pathology protocol with increased sampling and immunostaining rather than bivalving and hematoxylin and eosin (H&E) staining alone. Only 1 of 343 assessed NSLNs was found to harbor a metastasis. On the basis of these results, the authors concluded that nodal clearance is the safest option for patients with minimal SN tumor burden. The authors state that other studies on minimal SN tumor burden are underpowered or lack follow-up evaluation. However, already in 2009, we showed in a multicenter study that patients with an SN tumor burden smaller than 0.1 mm (n = 67) had a mean follow-up period of 61 months and a median follow-up period of 57 months. The 5-year melanoma-specific survival (MSS) rate was 94%, and NSLN positivity occurred in 5% of the patients. In the current study, we retrospectively analyzed a cohort of patients with minimal SN tumor burden treated at our institution from 2004 to the present, In this study, 11 patients did not undergo CLND and were observed. For this group, the mean follow-up period was 6.4 years, and the median follow-up period was 6.5 years. The estimated 5-year survival rate was 87.5%. No nodal recurrences were seen in this cohort. However, one patient died of distant metastases (without nodal recurrence), and another is alive at this writing with irresectable satellite and in-transit metastases. This is identical to clinical behavior observed in SN-negative patients. Therefore, we find the authors’ conclusions to be incorrect; First, only 0.29% of the examined NSLNs contained a metastasis in a more detailed examination, which demonstrates a negligible benefit from the more detailed protocol. This undermines the authors’ hypothesis that the NSLN positivity rate was underestimated in previous studies about this subject. Second, six patients experienced disease recurrence, and five patients died of melanoma metastases. None of these patients had additional nodal metastases in the CLND. Thus, these patients did not benefit from CLND. Our small cohort without CLND demonstrated the same recurrence pattern. Currently, the accrual of the Multicenter Selective Lymphadenectomy Trial II (MSLT-2) has been completed, and the results are pending. At the same time, the European Organisation for Research and Treatment of Cancer (EORTC) 1208 study (Minitub, NCT01942603), which is a prospective registry of minimal SN tumor burden, still is ongoing at this writing. Until these trials have demonstrated unequivocal significant results in favor for CLND, nodal observation with ultrasound still is to be considered a viable alternative to CLND, especially for patients with minimal SN tumor burden. Considering the potentially serious complications of a CLND, surgeons can decide that it is in their patients best interest to refrain from surgery when minimal SN tumor burden is found. Society of Surgical Oncology 2017