Primary cutaneous CD30 + anaplastic large-cell lymphoma associated with fingolimod

Dear Editor, Fingolimod, a disease‐modifying treatment licensed (approved by the Food and Drug Administration in 2010) for relapsing‐remitting multiple sclerosis, is a modulator for four of the five known sphingosine‐1‐phosphate (S1P) receptor subtypes widely expressed in tissues, including endothelial cells, lymphocytes, smooth muscle and neural cells.1 S1P receptor type 1 is predominantly expressed by lymphocytes and represents the key molecular target for the therapeutic effect of fingolimod in multiple sclerosis (MS), by acting as a functional antagonist of the S1P receptor causing inhibition of lymphocyte egress from lymph nodes. This prevents the migration of lymphocytes into the peripheral tissues, including the central nervous system, which reduces the expression of proinflammatory cytokines involved in the pathogenesis of MS. Common side‐effects include infections and lymphopenia.1 We report a case of fingolimod‐induced primary cutaneous CD30+ anaplastic large‐cell lymphoma (pcALCL). A 51‐year‐old woman presented with a lesion on the posterior aspect of the right shoulder in May 2017 (Fig. 1a). She had started fingolimod in April 2016 and in February 2017 developed an erythematous, eroded plaque on the right upper back. Examination revealed a painful ulcerated tumour (5 cm diameter), which persisted, despite use of topical steroids and multiple courses of oral antibiotics. (a) At presentation: erythematous ulcerated plaque on right upper back. (b) Two months after withdrawal of fingolimod: healing with scarring, leaving atrophic skin. (c) A skin punch biopsy showing the infiltrate is composed of numerous atypical large lymphoid cells with nucleoli and atypical mitoses (haematoxylin and eosin × 400). (d) The atypical lymphoid cells were positive for CD4 (× 400), (e) negative for CD8 (× 400) and (f) expressed CD30 with a characteristic membranous and Golgi pattern (× 400), with (g) a high proliferation index (× 400). A diagnostic biopsy showed a dense dermal lymphoid infiltrate consisting of large atypical CD30+ T cells (CD2+ CD3+ CD4+ ALK1–) with an anaplastic morphology and high proliferation rate. (Fig. 1c–g). A staging positron emission tomography computed tomography scan was normal. Human T‐lymphotropic virus 1 and HIV were negative, and a full blood count, lactate dehydrogenase and lymphocyte subpopulations were unremarkable. These findings were diagnostic for pcALCL. After withdrawal of fingolimod, there was rapid resolution of the tumour within 2 months, with scarring, which left atrophic skin (Fig. 1b). An expectant approach was adopted and no recurrence was noted 12 months later. Extranodal lymphoma has been reported recently as a rare side‐effect of fingolimod. Six of the nine cases reported, including this one, consist of primary cutaneous CD30+ lymphoproliferative disorders (three anaplastic large‐cell lymphomas and three lymphomatoid papulosis). The other cases consisted of one patient with mycosis fungoides (CD30+) and two patients with B‐cell lymphomas, namely a conjunctival mucosa‐associated lymphoid tissue lymphoma and a primary cutaneous diffuse large‐cell lymphoma (Epstein Barr Virus+ CD30+).2,3,4,5,6 Animal models have shown that fingolimod predisposes to lymphoproliferative disorders by reducing immune surveillance of neoplastic lymphoid clones in the periphery, through modulation of the peripheral T‐cell microenvironment.7 Fingolimod inhibits lymphocyte egress from lymph nodes through modulation of SIP receptors and thereby prevents lymphocyte migration to peripheral tissues. Fingolimod also induces differentiation of peripheral T cells towards a regulatory T‐cell phenotype, through impairment of the physiological inhibitory activity of S1P1 on the Akt/mammalian target of rapamycin pathway and increased forkhead box P3 expression.8 The drug can also impair antigen presentation by inhibiting Langerhans cell migration to lymph nodes. Several questions remain, notably whether there will be an increased incidence in epithelial malignancies in patients on long‐term fingolimod and it is unclear why fingolimod appears to be most frequently associated with primary cutaneous CD30+ T‐cell lymphomas, rather than other extranodal lymphomas also known to originate from tissue‐resident memory T cells. While other immunosuppressive drugs have been associated with lymphoma, fingolimod has a unique action, which provides critical insight into the potential mechanisms underlying the impairment of tumour immune surveillance in extranodal lymphomas.