Histologic and tumor microenvironmental features as prognostic markers in mantle cell lymphoma: A digital pathology-based study

Mantle cell lymphoma (MCL) is a mature B-cell non-Hodgkin lymphoma with limited histopathologic markers for prognostication. We aimed to characterize histologic pattern and tumor microenvironment (TME) of MCL and evaluate their prognostic significance. A total of 33 cases of MCL (17 excisional biopsy and 16 needle biopsy specimens) were reviewed with pathologic slides and medical records. Survival outcomes including overall survival (OS) and progression-free survival (PFS) were calculated for 28 patients. CD4+, CD8+, and FoxP3+ T-lymphocytes, oncogene p53 expression patterns and Ki-67 proliferative index were assessed by immunohistochemistry, and quantified using Qupath digital image analysis. The median age of patients with MCL (n=33) was 69 years (range, 47-84), and 25 cases were male (75.8%). The majority of cases presented with advanced Ann Arbor stage (III-IV; 24/29, 82.8%). According to the Mantle Cell Lymphoma International Prognostic Index (MIPI), patients were categorized into low-risk (n=14, 46.7%), intermediate-risk (n=9, 30.0%), and high-risk (n=7, 23.3%) groups. Histologic patterns were evaluable in 30 cases, with 16 cases (53.3%) exhibiting a diffuse histologic pattern and 14 cases (46.7%) showing multinodular/mantle zone patterns. The diffuse histologic pattern was significantly associated with inferior PFS (p=0.011) and higher Ki-67 index (>30%, p=0.022). CD3+ cell density, defined as the number of CD3+ cells per square millimeter (cells/mm2), ranged from 576.2/mm2 to 8104.4/mm2 (median=1829.6/mm2). Higher CD3+ cell density was associated with worse OS (p=0.018). CD4+ cell density ranged from 0/mm2 to 6169.7/mm2 (median=508.5/mm2), and lower CD4+ cell density correlated with aberrant p53 expression, higher Ki-67 index and high-risk MIPI (p=0.012, 0.027 and 0.009, respectively). FoxP3+ cell ratio, defined as the proportion of FoxP3+ cells among total nucleated cells, ranged from 0% to 7.62% (median=1.20%). Higher FoxP3+ cell infiltration trended toward better PFS, without reaching statistical significance (p=0.099). Aberrant p53 expression (null/overexpression patterns; 5/33, 15.2%) was correlated with worse OS and PFS (p=0.005 and 0.038, respectively), and also with higher Ki-67 index (p=<0.001). CD4+/CD8+ cell ratio was highly variable (range, 0.01-7.53; median=0.77). In excisional biopsy specimens, cases with bone marrow involvement (4/17, 23.5%) exhibited higher CD4+/CD8+ cell ratio (p=0.028). Histologic pattern, tumor immune microenvironment and p53 expression pattern appear to have prognostic value in MCL. Quantitative assessment of TME using digital pathology methods may provide additional tools for predicting clinical behavior of MCL.