Panel Sequencing of Primary Cutaneous B-Cell Lymphoma

SIMPLE SUMMARY: Primary cutaneous follicular B-cell lymphoma (PCFBCL) is a rare lymphoma subtype of the skin. Its biological behavior is mostly indolent, with slowly growing skin lesions exhibiting high response rates to topical or systemic therapy. Owing to the fact that there are only few studies addressing the underlying molecular basis of PCFBCL, the purpose of our study was to investigate the presence of oncogenic mutations in 10 cases of PCFBCL. By using hybridization-based panel sequencing of 40 lymphoma-associated genes, we identified genetic alterations within 15 of the selected target genes. Somatic mutations in TNFRSF14, CREBBP, STAT6 and TP53 genes were among the most commonly identified oncogenic alterations. The presence of any of these mutations was not associated with clinical features such as relapse or extent of skin lesions. To conclude, the identification of such genetic alterations helps to discriminate PCFBCL from cutaneous pseudo-lymphoma, and thus provide an additional diagnostic tool in difficult-to-diagnose cases. ABSTRACT: Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin’s lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low propensity for systemic dissemination or fatal outcome. Up to now, only few studies have investigated underlying molecular alterations of PCFBCL with respect to somatic mutations. Objectives: Our aim was to gain deeper insight into the pathogenesis of PCFBCL and to delineate discriminatory molecular features of this lymphoma subtype. Methods: We performed hybridization-based panel sequencing of 40 lymphoma-associated genes of 10 cases of well-characterized PCFBCL. In addition, we included two further ambiguous cases of atypical B-cell-rich lymphoid infiltrate/B-cell lymphoma of the skin for which definite subtype attribution had not been possible by routine investigations. Results: In 10 out of 12 analyzed cases, we identified genetic alterations within 15 of the selected 40 target genes. The most frequently detected alterations in PCFBCL affected the TNFRSF14, CREBBP, STAT6 and TP53 genes. Our analysis unrevealed novel mutations of the BCL2 gene in PCFBCL. All patients exhibited an indolent clinical course. Both the included arbitrary cases of atypical B-cell-rich cutaneous infiltrates showed somatic mutations within the FAS gene. As these mutations have previously been designated as subtype-specific recurrent alterations in primary cutaneous marginal zone lymphoma (PCMZL), we finally favored the diagnosis of PCMZL in these two cases based on these molecular findings. Conclusions: To conclude, our molecular data support that PCFBCL shows distinct somatic mutations which may aid to differentiate PCFBCL from pseudo-lymphoma as well as from other indolent and aggressive cutaneous B-cell lymphomas. While the detected genetic alterations of PCFBCL did not turn out to harbor any prognostic value in our cohort, our molecular data may add adjunctive discriminatory features for diagnostic purposes on a molecular level.