BCL-2 expression in primary cutaneous follicle center lymphoma is associated with a higher risk of cutaneous relapses: A study of 126 cases

Bcl-2 protein is an anti-apoptotic molecule overexpressed in many cancers1 investigated both for its potential prognostic and therapeutic role.2-6 Primary cutaneous follicle centre lymphoma (PC-FCL) represents 50–60% of all the cases of cutaneous B-cell lymphoma.2 At immunohistochemistry PC-FCL expresses germinal centre markers such as Bcl-6, CD20 and CD79a. Although most cases lack BCL-2 expression, cases featuring BCL-2 expression both at mRNA and surface expression levels have been described.2, 7-10 However, it is not known whether BCL-2+ PC-FCL cases are associated with a higher risk of relapses. The present paper aims to evaluate whether Bcl-2 immunohistochemical expression correlates with a higher risk of cutaneous relapses in PC-FCL. We performed a retrospective search from the databases of the cutaneous lymphoma tertiary services of the Dermatology Units of Florence and Bologna. We selected all cases with a proven diagnosis of PC-FCL made between 01/01/2000 and 30/12/2019 with adequate clinical and histological data. We retrieved 128 patients, 77 males, 51 females, with a median age at diagnosis of 55 years. Median follow-up data were 126 months (range 12–384 months,). Sixty-nine (54%) lacked BCL-2 expression, 20 had a scarce (more than 10 but less than 50%) expression of BCL-2 (16%), 11 (8%) displayed more than 50% and up to 75% of the neoplastic infiltrate with an expression of the BCL-2 molecule, 26 (20%) had a positivity >75% (Fig. 1a-l). Related to treatment, a complete response was achieved in all cases. In order to avoid confounding bias due to immunohistochemistry intensity only cases featuring BCL-2 superior to 75% of all the tumour cells were selected for statistical analysis and compared with those lacking BCL-2 expression. In the 26 cases with BCL-2 staining superior to 75% of all the tumour cells, 13 (50%) relapsed (showing the same high BCL-2 expression), while only 16 relapsed in 69 cases without BCL-2 expression (23%, P = 0.016, Fig. 2). The overall RFI was 881 days (601–1540). No differences in RFI were observed among BCL-2+ cases and BCL-2- (P = 0.45). After 1 year, 70% were still free from relapses, 57% after 2 years, 42% after 3 years and 31% at 5 years. To the best of our knowledge, this is the first study analysing the potential correlation between BCL-2 expression and cutaneous relapse rates in PC-FCL. BCL-2 positive cases were more likely to have a cutaneous relapse than those without BCL-2 expression. A possible explanation may be that BCL-2 expression may give some biological advantage to the neoplastic cells, thus favouring skin relapse. Furthermore, in all relapsed BCL-2+ cases, the marker expression was the same as the original lesion, configuring BCL-2 expression as an intrinsic trait of the tumour. In none of the patients was a lymph node or internal organ involvement observed, corroborating prior data that BCL-2 positivity should not be considered as a marker of more aggressive biology.2-4 In the relapsed group, approximately 50% of patients showed new lesions within the first 2 years of follow-up. To conclude, our series shows that in PC-FCL the expression of BCL-2 may be associated with a higher risk of skin relapses, especially within the first 2 years of follow-up.