To report the association of the development of a primary, cutaneous, anaplastic large-cell lymphoma after initiation of glatiramer acetate treatment of a patient with relapsing-remitting multiple sclerosis.
Dermatology outpatient clinic.
A 33-year-old white woman developed an erythematous nodule on her leg 4 months after starting treatment with glatiramer acetate. Biopsy showed primary, cutaneous, anaplastic large-cell lymphoma. Further evaluation showed no systemic involvement.
Radiation therapy induced a complete remission.
Several T-cell–mediated skin conditions have been associated with the use of glatiramer acetate, such as pseudolymphoma, drug eruptions, and erythema nodosum. We report the association of a T-cell malignancy with the use of glatiramer acetate.
Glatiramer acetate (GA) (Copaxone; Teva Pharmaceutical Industries Ltd, Kansas City, Missouri), an injectable polypeptide immunomodulatory agent, is currently approved for the treatment of relapsing-remitting multiple sclerosis. Although the exact mechanism of action remains unknown, GA appears to alter immune function by acting on CD8+ T cells, antigen-presenting cells, monocytes, and B cells and by altering T-cell differentiation.1 Reported cutaneous adverse events have included erythema at the injection site, local necrosis, and erythema nodosum.2,3 One patient was reported to develop a T-cell figurate erythemalike pseudolymphoma that resolved with continued treatment.4 We describe the clinicopathologic features of a CD30+, primary, cutaneous, anaplastic large-cell lymphoma developing after initiation of GA therapy.
A 33-year-old white woman began treatment with GA, 20 mg subcutaneously every day, 9 months after being diagnosed with multiple sclerosis. Four months after starting treatment, she developed an 8-mm, firm, nontender, erythematous papule at the left pretibial region. After slowly enlarging for 6 months it was surgically excised, with visible tumor extending to the fascia. The patient was otherwise healthy and without lymphadenopathy. Other medications included paroxetine hydrochloride and desogen, which are not known to cause lymphomas or pseudolymphomas. Family history was negative for lymphoproliferative disorders. Hematology-oncology consultation was obtained. Laboratory evaluation showed a normal complete blood cell count, serum chemistry results, lactate dehydrogenase level, and β2-microglobulin level. Results of computed tomography of the chest, abdomen, and pelvis were normal. Bone marrow biopsy and more extensive imaging were deferred, as was molecular analysis.
Hematoxylin-eosin–stained sections showed a diffuse, bottom-heavy, dermal, nodular infiltrate of atypical lymphoid cells extending into the subcutaneous tissue in sheets (Figure 1). The infiltrate was positive for CD3 and more than 75% positive for CD30 (Figure 2). Staining for anaplastic lymphoma kinase, epithelial membrane antigen, keratin, Ber-EP4, and CD15 was negative. Mitotic figures were frequent.
Diffuse infiltrate of large pleomorphic lymphoid cells (hematoxylin-eosin, original magnification ×400).
Staining with CD30 immunoperoxidase shows positive results for most of the anaplastic cells (original magnification ×100).
The clinical findings of a persistent, enlarging, solitary skin nodule along with the histologic features of an anaplastic CD30+ infiltrate present in sheets favor a diagnosis of primary, cutaneous, anaplastic large-cell lymphoma rather than lymphomatoid papulosis or pseudolymphoma.5
On subsequent examination, mild surrounding induration and smaller papules were noted in the edges of the surgical scar. Radiation therapy was administered and the residual lesion was completely resolved. Because of the limited nature of the lymphoma, good prognosis, and remarkable improvement of the patient's multiple sclerosis symptoms, GA treatment was continued.
Drug-associated, nodular, cutaneous T-cell pseudolymphomas are rare but have been reported with the use of anticonvulsants. Carbamazepine was reported to induce a CD30+, primary, anaplastic large-cell lymphoma.6 Differentiation of pseudolymphoma from lymphoma may be difficult and relies on the histologic pattern, cellular morphology, clonality, immunohistochemical markers, and clinical course. The development of our patient's primary, cutaneous, anaplastic large-cell lymphoma at a site distant from the injection would suggest a systemic effect by stimulation and/or selection of an aberrant clone of T cells.
Glatiramer acetate is a normally safe, well-tolerated, effective medication used in the treatment of multiple sclerosis. It is believed to alter immune function by causing a shift from reactive type 1 helper T cells to reactive type 2 helper T cells and ultimately dampening inflammation within the central nervous system.1 The temporal association of starting treatment with GA and the T-cell modulating properties of this drug implies a possible relationship with the development of the primary, cutaneous, anaplastic large-cell lymphoma in our patient. Clinicians should be aware of this potential association to better inform patients of the risks of using the drug.
Correspondence: David F. Butler, MD, Department of Dermatology, Scott and White Memorial Hospital, 2401 S 31st St, Temple, TX 76508 (firstname.lastname@example.org).
Accepted for Publication: June 2, 2008.
Author Contributions: All of the authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Madray and Butler. Acquisition of data: Madray and Greene. Analysis and interpretation of data: Madray, Greene, and Butler. Drafting of the manuscript: Madray. Critical revision of the manuscript for important intellectual content: Madray, Greene, and Butler. Administrative, technical, and material support: Greene and Butler. Study supervision: Greene.
Financial Disclosure: None reported.
Madray MM, Greene JF, Butler DF. Glatiramer Acetate–Associated, CD30+, Primary, Cutaneous, Anaplastic Large-Cell Lymphoma. Arch Neurol. 2008;65(10):1378–1379. doi:10.1001/archneur.65.10.1378