Plasma Cells in Primary Melanoma. Prognostic Significance and Possible Role of IgA

Francesca M Bosisio; James S Wilmott; Nathalie Volders; Marjorie Mercier; Jasper Wouters; Marguerite Stas; Willeke AM Blokx; Daniela Massi; John F Thompson; Richard A Scolyer; Nicolas van Baren; Joost J van den Oord

Disclosures

Mod Pathol. 2016;29(4):347-358. 

In This Article

Abstract and Introduction

Abstract

Melanoma is not only one of the most immunogenic cancers but also one of the most effective cancers at subverting host immunity. The role of T lymphocytes in tumor immunity has been extensively studied in melanoma, whereas less is known about the importance of B lymphocytes. The effects of plasma cells (PCs), in particular, are still obscure. The aim of this study was to characterize pathological features and clinical outcome of primary cutaneous melanomas associated with PCs. Moreover, we investigated the origins of the melanoma-associated PCs. Finally, we studied the outcome of patients with primary melanomas with PCs. We reviewed 710 melanomas to correlate the presence of PCs with histological prognostic markers. Immunohistochemistry for CD138 and heavy and light chains was performed in primary melanomas (PM) and in loco-regional lymph nodes (LN), both metastatic and not metastatic. In three PM and nine LN with frozen material, VDJ-rearrangement was analyzed by Gene Scan Analysis. Survival analysis was performed on a group of 85 primary melanomas >2 mm in thickness. Forty-one cases (3.7%) showed clusters/sheets of PCs. PC-rich melanomas occurred at an older age and were thicker, more often ulcerated and more mitotically active (P<0.05). PCs were polyclonal and often expressed IgA in addition to IgG. In LN, clusters/sheets of IgA+ PCs were found both in the sinuses and subcapsular areas. Analysis of VDJ-rearrangements showed the IgA to be oligoclonal. Melanomas with clusters/sheets of PCs had a significantly worse survival compared with melanomas without PCs while, interestingly, melanomas with sparse PCs were associated with a better clinical outcome (P=0.002). In conclusion, melanomas with sheets/clusters of PCs are associated with worse prognosis. IgG and IgA are the isotypes predominantly produced by these PCs. IgA oligoclonality suggests an antigen-driven response that facilitates melanoma progression by a hitherto unknown mechanism.

Introduction

Melanoma is not only one of the most immunogenic cancers but also one of the cancers that is most adept at circumventing host antitumor immunity.[1] In fact, the phenomenon of regression in primary melanomas is frequently only partial (23–58%), and complete regression is rare (12.4%), suggesting the presence of mechanisms that allow the tumor to resist immune attack.[2] In recent years, the immune response in melanoma has gained much attention owing to the efficacy of new therapies that act on its modulation by blocking immune check points.[3–7] The immune response is the result of complex interactions between different types of cells, which can result in an immune-stimulatory signal as well as an immune-suppressive signal. Moreover, the very same type of cell can be influenced by the microenvironment to polarize into different functional states according to the need for an active immune response or of immune tolerance at a certain moment. This has been demonstrated for macrophages (M1 and M2 polarization),[8–11] neutrophils (N1 and N2 polarization)[12,13] and T lymphocytes (Th1, Th2, Th17 responses).[14–16]

The role of T lymphocytes and macrophages has been extensively studied in melanoma,[13,17–22] whereas less is known on the role of B lymphocytes and plasma cells (PCs). Recently, B lymphocytes have turned out to constitute between 0 and 50% of the tumor-infiltrating lymphocytes,[23–25] but controversy exists as to their precise role in melanoma progression.[25–28] Furthermore, the role of PCs, the terminally differentiated form of B lymphocytes, has been the subject of two studies, one that links them with an increased risk of lymph node metastasis[29] and one that shows an association with poor survival,[30] but the mechanisms underpinning these observations remain obscure.

The aim of the current study was to identify melanomas with a significant PC component in the inflammatory infiltrate, to study their detailed clinico-pathological characteristics and immunoglobulin expression and to speculate on the origin of the PC response by examining the melanoma-draining loco-regional lymph nodes.

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