Introduction

Drug-induced primary cutaneous B-cell lymphomas are rare.

Observation

A 63 year old woman was referred for a lumbar cutaneous lesion which had been rapidly growing for 1 month. Her past medical history included multiple allergies and a rheumatoid arthritis which was treated with oral methotrexate 10 mg per week and adalimumab. Mehtotrexate had been taken for 8 years, while adalimumab had been initiated 6 months earlier.
Physical examination revealed a solitary thick, violaceous plaque of 6 X 4 cm in diameters, without enlarged lymph nodes. No fatigue, fever or pruritus were present. The first clinical hypothesis was a cutaneous B-cell lymphoma.
The histological examination of a skin biopsy specimen showed a monomorphous dermal proliferation of large centroblast-like cells with large round, sometimes irregular, nuclei. Only rare reactive small cells were present. The infiltrate spared the epidermis, with a Grenz zone. The tumor cells were positive for CD45, CD20, bcl2, bcl6, MUM1, highly proliferating (Ki67 95%), and negative for CD3, CD30, CD10 and EBV / EBER. No CD21 or CD23 positive follicular dendritic cell network was identified. Fluorescence in situ hybridation showed no BCL2, BCL6 or CMYC rearrangement, whille high resolution melting identified the MYD88 L265P mutation. A B-cell rearrangement was detected in the lesion. Whole body FDG-PET/CT showed a single hypermetabolic activity corresponding to the cutaneous lombar lesion, without distant tumours.
Although the Borrelia burgdorferi serology was negative, a 15 days course of doxycyline 200 mg daily was given. Once the diagnosis of primary cutaneous large B-cell lymphoma, leg type (PCLBCL-LT) was made, adamimumab (but not methotrexate) was discontinued. The tumor compltely disappeared within 4 months. No other TNF inhibitors were later given. No recurrence was observed after a follow-up time of 4 years.

Discussion

PCDLBCL-LT are aggressive B-cell lymphomas mainly (but not exclusively) located on the leg, characterized by a monomorphous proliferation of large CD20+, Bcl2+, Mum1+, CD10 - B cells, frequently exhibiting the MYD88 L265P mutation, as observed in our patient. In contrast with indolent subtypes of primary cutaneous B-cell lymphomas, spontaneous regressions in PCLBCL-LT are exceptional, and constantly followed by recurrences.
Progression of undiagnosed cutaneous lymphomas after anti-TNF-alpha therapy (mainly cutaneous T-cell lymphomas misdiagnosed as psoriasis or eczema) have been reported.(1) However, the role of anti-TNF-alpha in the occurrence of new lymphoproliferative disorders remains controversial. (2) (3) To our knowledge, no PCLBCL-LT related to TNF-alpha inhibitors has been reported to date. Although methotrexate may have play a role as a cofactor for the development of this B-cell malignancy, the negative EBV staining and the long-term complete remission after adalimumab withdrawal while methotrexate was continued, strongly argue for a predominant role of the anti-TNF-alpha in the occurrence of this lymphoma.

1. Martinez-Escala ME, Posligua AL, Wickless H, Rutherford A, Sable KA, Rubio-Gonzalez B, et al. Progression of undiagnosed cutaneous lymphoma after anti-tumor necrosis factor-alpha therapy. J Am Acad Dermatol. juin 2018;78(6):1068‑76.
2. Hruska CJ, Bertoli RJ, Young YD, Burkhart PH, Googe PB. Primary cutaneous anaplastic large cell lymphoma in a patient receiving adalimumab. JAAD Case Rep. mars 2015;1(2):56‑9.
3. Muller M, D’Amico F, Bonovas S, Danese S, Peyrin-Biroulet L. TNF Inhibitors and Risk of Malignancy in Patients with Inflammatory Bowel Diseases: A Systematic Review. J Crohns Colitis. 4 mai 2021;15(5):840‑59.