Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma

Abstract

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.

Figure 1.

Gross assessment and sampling of lymphadenectomy specimens following neoadjuvant therapy. (A) Bisected lymph node with extensive melanin deposition grossly. (B) Bisected lymph node with morphologically distinct regions: viable tumor (black arrowhead) adjacent to necrotic tumor (white arrowhead). (C) Schema for processing grossly positive lymph nodes according to size. Lymph nodes ≤5 cm in greatest dimension are submitted entirely (top panel), whereas for lymph nodes >5 cm in greatest dimension, one tissue slice representing a complete cross section of the lymph node is submitted per cm (bottom panel; submission of one complete cross section is represented).

Figure 2.

Spectrum of pathologic responses observed following treatment with neoadjuvant dabrafinib-trametinib. Patterns of pathologic complete response (pCR) include (A, B) hyalinized fibrosis pattern in which lymph node parenchyma is replaced by dense hyalinized collagen (A, 40×; B, 100×; inset: 200×) with no residual viable tumor and (C, D) tumoral melanosis pattern where lymph node parenchyma is replaced by melanophages (C, 40×; D, 100×; inset: 200×). Patterns of incomplete pathologic response range from partial pathologic response (pPR) to pathologic non-response (pNR) (E–H) with variable densities of viable tumor cells in a background of necrosis, tumoral melanosis, fibrosis and lymphohistiocytic inflammation. Rare tumor cells evident in a background of necrosis and melanophages (E, 40×; F, 100×; inset: 400×), and clusters of tumor cells evident in a background of tumoral melanosis (G, 40×; H, 100×; inset: 200×). pNR (I, J) characterized by mostly viable tumor cells (I, 40×; J, 100×; inset: 200×). H&E staining, all panels.

Figure 3.

Spectrum of pathologic responses observed following treatment with neoadjuvant ipilimumab-nivolumab. (A, B) pCR characterized by replacement of lymph node with histologic features of immune-mediated regression with no residual viable tumor present (A, 100×; B, 200×). Inset shows multiple immune cell subsets, including foamy macrophages and plasma cells (600×). (C, D) pPR characterized by partial replacement of the lymph node architecture with histologic features of regression, including fibrosis, neovascularization, and lymphocytic infiltrate. Residual viable tumor is present (marked by asterisk). A cuff of normal lymph node architecture is seen adjacent to the area of regression (C, 50×; D, 100×). Inset shows residual viable tumor (Inset, D, 600×). (E, F) pNR characterized by mostly viable tumor cells abutting normal lymph node without any accompanying features of response (E, 20×; F, 100×; inset: 600×). H&E staining, all panels.