Introduction
The occurrence or the worsening of cutaneous T-cell lymphoma (CTCL) during or after a treatment with dupilumab has recently been reported in a limited number of patients including a small series of 7 patients, of whom 4 had been previously diagnosed with atopic dermatitis (AD).1 We hereby describe a previously unreported observation of systemic CD30+ lymphoproliferation occurring during treatment with dupilumab, adding to the literature of new-onset cutaneous lymphomas associated with dupilumab therapy.
Case report
A 50-year-old Caucasian woman with lifelong moderate-to-severe AD was referred for progressive worsening of her cutaneous condition despite an increasing use of superpotent topical steroids. She initially presented with pruritic, diffuse erythematous and squamous lesions involving 80% of total body surface area, including head and neck. Histopathologic examination demonstrated subacute eczema, consistent with AD. Owing to claustrophobia precluding the use of phototherapy, treatment with cyclosporin A 200 mg/d was successfully introduced after comprehensive pretreatment biologic and morphologic investigations, including normal chest x-ray, abdominal ultrasound, and Papanicolaou test. However, cyclosporin A was discontinued after 6 months due to dyslipidemia. Methotrexate 15 mg weekly was initiated, but treatment was interrupted after 2 months owing to liver toxicity. Dupilumab was then introduced according to guidelines and standard protocol (2 initial subcutaneous injections of 300 mg followed by injections of 300 mg every other week). After 5 months of dupilumab (and 13 months after the first systemic treatment was introduced), a complete response of skin inflammatory lesions was observed. However, she reported a new painful, erythematous and ulcerated plaque on her right breast with a diameter of 5 cm (Fig 1), which she had first noticed 3 weeks previously. Biopsy of the area was performed, and histopathology showed a focally ulcerated epidermis associated with a dense dermal infiltrate composed of medium-to-large–size mononuclear cells characterized by irregular nuclei and moderately abundant eosinophilic cytoplasm in some cells, surrounded by numerous neutrophils. Immunohistochemistry displayed a CD30+, CD2+, CD3+, CD5−, CD4+, and CD8− immunophenotype for atypical dermal cells. Antibodies against the pan B cell markers CD20, PAX5, and OCT2 were not detected. Multiple myeloma oncogene 1 and cytotoxicity markers (T cell–restricted intracellular antigen and granzyme B) were expressed, while activin A receptor–like type 1 was negative. In situ hybridization with Epstein-Barr–encoded RNA probe was negative. The Ki67 proliferation index was high (90%). Dupilumab was immediately interrupted. A positron emission tomography scan revealed multiple hypermetabolic lymph nodes in the left cervical, bilateral axillary, and right iliac and inguinal areas. Over all, these features were suggestive of an anaplastic large-cell lymphoma with cutaneous and systemic involvement. During the following month, the patient rapidly developed a similar skin tumor on her left forearm, and rapidly progressive inguinal lymph nodes were biopsied and proved infiltrated by the same lymphoproliferation. A partial response was achieved after 2 lines of systemic polychemotherapies with acyclophosphamide + doxorubicin + vincristine + prednisone chemotherapy regimen and a cyclophosphamide + doxorubicin + vindesine + prednisone chemotherapy regimen; bendamustin/brentuximab was introduced before autologous hematopoietic stem cell transplantation. However, this treatment resulted in protracted aplasia, and the patient died of pulmonary cytomegalovirus infection associated with severe hypoxemic infiltrative fibrosis, 12 months after the onset of the first specific cutaneous lesion.
Fig 1.
A, Painful, erythematous ulcerated plaque on the right breast. B, Corresponding pathologic findings of a primary cutaneous anaplastic large-cell lymphoma. C, Immunohistochemistry showing activin A receptor–like type 1–negative infiltrative cells. D, Immunohistochemistry showing multiple myeloma oncogene 1–positive infiltrative cells. (B, Hematoxylin-eosin stain; original magnifications: B, ×20; C, ×20; D, ×20.)
Discussion
The secondary occurrence of CTCL and especially of mycosis fungoides in patients with protracted benign skin inflammatory conditions, including AD (relative risk = 2), is a well-known circumstance. However, the underlying pathomechanisms remain a matter of debate because an initially indolent CTCL cannot be ruled out in some cases, whereas the coexistence of mycosis fungoides and AD in the same patient is also possible, as emphasized in several studies.2 On the other hand, at least 10 cases of primary or secondary cutaneous CD30+ lymphoproliferative disorders have been reported in severe, protracted AD evolving since childhood, including 4 patients previously treated with cyclosporin A. The latter cases are reminiscent of similar observations in solid organ transplant recipients receiving cyclosporin A but not dupilumab.3,4 Recently, a limited set of CTCL cases occurring during or after treatment with dupilumab for AD was reported along with some observations of established CTCL worsening after initial symptomatic improvement (Table I).5, 6, 7, 8, 9, 10 Our case differs from these previous cases of CTCL occurring in allegedly benign chronic conditions treated by dupilumab by its histopathologic subset, never specifically reported in this setting to date. However, overall it raises a similar hypothesis, including the selection and the promotion of a preexisting, initially inconspicuous dupilumab-resistant CD30+ T-cell clone through a dupilumab-induced depletion of tumor-infiltrating lymphocytes with tumor suppressive activity contributing to the emergence of the neoplastic clone. Alternatively, the transformation of an initially misdiagnosed mycosis fungoides appears less likely. The putative role of cyclosporin is questionable owing to the relatively long time interval between its discontinuation and the supposed lymphoma onset. An initial primary cutaneous anaplastic large-cell lymphoma with rapid secondary systemic involvement was initially suspected owing to the clinical course with primary skin lesions, secondary lymph node involvement, and the activin A receptor–like type 1–negative and multiple myeloma oncogene 1–positive phenotype. However, the latter pattern is not fully specific of primary involvement and an aggressive, primary nodal anaplastic large-cell lymphoma with skin extension revealing the disease cannot be ruled out.
Table I.
Previous reports of the use of dupilumab in diagnosed or undiagnosed cutaneous T-cell lymphomas
| Number of patients | Gender, age (y) | Indication of dupilumab | Treatments prior to dupilumab | Clinical response to dupilumab | Delay to diagnosis of CTCL | Patients outcome | Reference | |
|---|---|---|---|---|---|---|---|---|
| 1 | M, 43 | Atopic dermatitis | Systemic corticosteroids | Initial improvement in pruritus, then worsening | 2 mo, MF with 40% CD30+ | Brentuximab + pralatrexate, ongoing follow-up | 5 | |
| 1 | M, 64 | Atopic dermatitis | UV therapy | Erythroderma | 2 wk, Sezary syndrome | Bexarotene, extracoporeal photopheresis, ongoing follow-up | 6 | |
| 3 | M, 61; M, 52; F, 60 | Eczematous or psoriasiform dermatitis | UV therapy, guselkumab, and other biologic therapies | None | 6 wk, 3 mo | NA | 7 | |
| 2 | F, 37; M, 55 | Eczema; atopic dermatitis | UV therapy, methotrexate | None; improvement in pruritus and partial remission of MF | 2 mo, Sezary syndrome; NA, MF | Mogamulizumab, remission; partial remission | 8 | |
| 1 | F, 74 | Pruritus in Sezary syndrome | UV therapy, cyclosporin A, extracorporeal photopheresis (ongoing) | Improvement in pruritus | NA | Partial remission | 9 | |
| 7 | F, 3; M, 4; median age, 65.5 | 4 atopic dermatitis; 3 CTCL | Azathioprine, prednisone, methotrexate, interferon, intravenous immunoglobulin | Initial improvement in pruritus, then worsening | Mean, 3.6 mo; NA | 2 of the 3 patients with Sezary syndrome died | 1 | |
| 1 | M, 68 | Concomitant atopic dermatitis and CTCL | Bexarotene, interferon, UV therapy, total skin electron beam therapy, extracorporeal photopheresis | Improvement in pruritus and erythema | NA | Decrease in all CTCL specific treatments | 10 | |
| Total | 16 | SR, 0.625; mean age, 59.4 (range, 37-77) | On-label use for atopic dermatitis 50% | … | Worsening or leading to CTCL diagnosis 81% | Mean delay to diagnosis of CTCL 1 mo (range, 0.5-8) | … | … |
CTCL, Cutaneous T-cell lymphoma; F, female; M, male; MF, mycosis fungoides; NA, not available or not applicable; SR, sex ratio M/F; UV, ultraviolet.
Conflicts of interest
None disclosed.
Acknowledgments
We thank Dr Christophe Delfour, MD and Dr Aude Muslin, MD for their valuable help with pathologic data and figures.
Footnotes
Funding sources: None.
IRB approval status: Not applicable.
References
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