Lamotrigine-induced Hypersensitivity Syndrome with Histologic Features of CD30+ Lymphoma.

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome or drug-induced hypersensitivity syndrome (DIHS) is a severe adverse drug reaction. It can present with clinical, paraclinical, and histological findings mimicking skin and/or systemic lymphomas. We report the first case of a lamotrigine-induced DRESS with histologic features of a cutaneous CD30+ lymphoma. The patient responded well to a tapering course of oral steroids. This case highlights the atypical presentation of a lamotrigine-induced DRESS/DIHS in the presence of a cutaneous and a lymph node CD30 + lymphocytic infiltrate mimicking systemic lymphoma. Pathologists and clinicians must be aware of this "lymphomatous" presentation of drug reactions.

What was known?

Lamotrigine can induce drug rash with eosinophilia and systemic symptoms and pseudolymphomas

CD30 positivity is seen in lymphoproliferative disorders such as lymphomatoid papulosis, Hodgkin's disease, and primary cutaneous anaplastic large cell lymphoma but has not been reported with lamotrigine.

Introduction

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome or drug-induced hypersensitivity syndrome (DIHS) is a rare, life-threatening adverse drug reaction, mostly to anticonvulsants and sulfonamides that can present with clinical, paraclinical and histopathological findings similar to lymphomas.[1] Cases of antibiotic, antihypertensive, and antiepileptic drugs such as phenytoin, carbamazepine, lamotrigine-induced DRESS, and pseudolymphoma have in fact been reported.[2] We report here the first case of lamotrigine-induced DRESS with histologic features of a cutaneous CD30+ lymphoma.

Case Report

A 30-year-old woman presented to the hospital with a morbilliform and pruritic generalized rash [Figure 1], along with high-grade fever, fatigue, and malaise for 4 days. Physical examination and blood tests revealed enlarged cervical and inguinal nodes, leukocytosis (up to 66,800 white blood cell/mm3), and elevated levels of hepatic transaminases, lactate dehydrogenase, ß-2 microglobulin, and erythrocyte sedimentation rate. Serology results for hepatitis, syphilis, typhoid fever, and brucella were negative. The whole body computed tomography showed multiple neck, chest, and abdominal lymphadenopathy with splenomegaly suggestive of lymphoma [Figure 2a]. A skin biopsy specimen revealed epidermotropism of atypical lymphoid cells, with CD30 positive staining as well as a dense perivascular and perifollicular lymphoid infiltrate [Figure 2b]. An excisional biopsy of a 1.0 cm cervical node showed diffuse polymorphic lymphoid hyperplasia with effacement of the normal architecture with strong and diffuse staining for CD30 on immunohistochemistry, positive anti-leukocyte common antigen, and high proliferation index (Ki67 80%). All findings were consistent with lymphoma. However, osteomedullary biopsy showed no evidence of lymphoproliferative disorder, was absent for immunomarkers and high eosinophils proliferation rate. T-cell receptor rearrangement studies on the skin, lymph node, and bone marrow biopsies, failed to detect monoclonality. A detailed review of her past medical history revealed that she was started on lamotrigine 50 mg/day for somatization disorder 40 days prior to the onset of symptoms. Blood samples were positive for human herpesvirus 6 DNA. The diagnosis of DIHS/DRESS was made; lamotrigine was discontinued and treatment with oral corticosteroids (prednisolone, 60 mg/day) was started with rapid tapering. The patient made a full recovery with no organ deficit on follow-up visits at 1, 2, 4, and 6 months.

Figure 1

(a) Striking facial edema and erythema (b) morbilliform generalized desquamative rash

Figure 2

(a) Pelvic computed tomography scan showing inguinal lymphadenopathy (blue arrows) (b) skin biopsy showing lymphocyte epidermotropism and dense perivascular infiltrate (H and E, ×100)

Discussion

To our knowledge, this is the first case of a confirmed lamotrigine-induced DRESS with histologic features of a CD30+ cutaneous and systemic lymphoma. Because of the widespread lymphadenopathy, hepatosplenomegaly, leukocytosis, and the positive CD30 staining on both skin and lymph node biopsies, this case could have been easily mistaken for systemic lymphoma. DRESS/DIHS is, in fact, a severe adverse reaction associated with multisystemic involvement[2] that can present clinical and histopathologic features similar to lymphomas, with epidermotropism and cutaneous CD30+ lymphocytes. The latter is usually seen in lymphoproliferative disorders such as lymphomatoid papulosis, Hodgkin's disease, and primary cutaneous anaplastic large cell lymphoma but have been described in drug reactions.[3] Even monoclonal T-cell receptor have been seen with drug reactions,[3] rendering the diagnosis of DRESS versus lymphoma more difficult. Although both DRESS and pseudolymphoma are drug-induced have been reported with lamotrigine separately[3] and can present with histopathologic features of lymphoma, studies have shown that they can be differentiated on the basis of the clinical presentation. Compared to DRESS, patients with pseudolymphoma have less acute and less systemic involvement[2] but more severe lymph node distortion and atypical lymphocytes.[45] Our patient had features of both. This is not surprising since the mechanisms that have been implicated in the development of both entities include genetic predisposition and association with human leukocyte antigen, virus reactivation, and accumulation of reactive drug metabolites.[6] This case highlights the atypical presentation of a lamotrigine-induced DRESS/DIHS in the presence of a cutaneous and a lymph node CD30+ lymphocytic infiltrate mimicking systemic lymphoma. Pathologists and clinicians must be aware of this “lymphomatous” presentation of drug reactions.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

What is new?

Lamotrigine can induce drug rash with eosinophilia and systemic symptoms with features of CD30 + lymphomas

Any atypical presentation of systemic or skin lymphomas such as hyperacute presentation or absent T-cell receptor monoclonality should raise the suspicion of a drug reaction even in the presence of large anaplastic CD30 + cells.

Subjects have given their informed consent and that the study protocol has been approved by the Institute's Committee on human research.