Lymphadenopathy that can mimic malignant lymphoma associated with drug therapy, usually as a result of a hypersensitivity reaction. A wide variety of drugs can induce lymphadenopathy (Table 46.1). Of these, the anticonvulsant medications phenytoin and carbamazepine are the best known, and in this chapter, these drugs serve as models for other medication-associated lymphadenopathies.

Anticonvulsant hypersensitivity syndrome, phenytoin (Dilantin) lymphadenopathy, carbamazepine (Tegretol) lymphadenopathy, pseudolymphoma syndrome, DRESS (drug rash, eosinophilia, and systemic symptoms).

The causes of acute drug-induced lymphadenopathy, also known as anticonvulsant hypersensitivity syndrome (AHS), are poorly understood (1). The most likely explanation for AHS is a hapten-like interaction between a drug and an unknown host antigen. An allergic mechanism may explain why the development of lymphadenopathy does not depend on drug dosage or serum levels (2), and why rechallenge with a small amount of drug can fatally reinduce lymphadenopathy (3).

A genetic predisposition to drug-induced hypersensitivity appears to be involved. Anticonvulsant hypersensitivity syndrome runs in families, and siblings of an affected person have an increased risk of developing lymphadenopathy after exposure to phenytoin (4). This genetic predisposition may be related to defects in drug metabolism, resulting in the accumulation of toxic metabolites. Cytochrome P450 metabolizes phenytoin and carbamazepine to arene oxide derivatives that are normally detoxified by epoxide hydrolase. Some individuals with AHS have inherited defects in epoxide dehydrolase (5). Single nucleotide polymorphisms in the cytochrome P450 gene, CYP2C9, have been reported that impair phenytoin metabolism (6). These mechanisms are the likely explanation for the cross-reaction that occurs between anticonvulsant medicines: if a patient develops AHS in response to one anticonvulsant (e.g., phenytoin), he is likely to develop the same syndrome if treated with another (e.g., carbamazepine).

A recent study (7) has described an association between AHS and reactivation of human herpes virus-6 (HHV-6) and HHV-7 infection. In a study of 23 patients with AHS, including patients treated with carbamazepine, phenytoin, phenobarbital, and gabapentin, increased serum titers of anti-HHV-6 and anti-HHV-7 IgG antibodies were detected, associated with HHV-6 and HHV-7 DNA in serum in a small subset of patients (7). This study suggests that viral reactivation may contribute to the severity of AHS. Some patients with AHS have been reported with hypogammaglobulinemia as well as decreased numbers of circulating B cells, perhaps predisposing to viral reactivation (8). The significance of these observations needs further investigation.

A subset of patients develops lymphadenopathy after prolonged drug intake, and acute hypersensitivity may not be involved in pathogenesis. Instead, in these individuals, drug-induced immunosuppression or immunodysregulation may allow B- or T-cell clones to emerge, resulting in cases of “pseudolymphoma” or true lymphoma (9,10). Although the mechanisms are not understood, a similar syndrome can be induced in mice through the long-term administration of phenytoin (11).

The frequency of AHS is likely to be dependent on the drug used. In patients treated with phenytoin, Gennis and colleagues estimated that AHS occurs in the range of 1:1,000 and 1:10,000 drug exposures (4). The onset of AHS is acute; it usually occurs 2 to 8 weeks after beginning drug therapy, but AHS may rarely occur later (1,2,12,13,14). Fever, skin rash, and lymphadenopathy are common, but not invariable features of AHS. Other abnormalities may include facial edema and hepatosplenomegaly (12,13,14). Hepatitis is present to some degree in many patients; liver failure is rare but can be a cause of death (1). Gingival hyperplasia develops in some patients treated with long-term phenytoin; it regresses on drug withdrawal and is not specifically a part of AHS. Lymphadenopathy occurs in up to 75% of patients with AHS, and may be either localized or generalized (1,12,13,14). Skin lesions in AHS patients can be relatively nonspecific or mimic, in small or large part, mycosis fungoides (Fig. 46.1A and B) (15,16). Dermatopathic lymphadenopathy has been reported as part of AHS (17), but is probably secondary to the presence of skin lesions rather than being a direct effect of the drug.

The most common laboratory findings in patients with AHS include abnormal serum γ-globulin levels (hypo- or hypergammaglobulinemia) and hematologic abnormalities (1,12,13,14). The latter include eosinophilia (Fig. 46.2), leukocytosis or leukopenia, and atypical lymphocytosis (Fig. 46.3). Symptoms, including lymphadenopathy, usually regress after anticonvulsants are discontinued, but can reappear if the same drug or a cross-reacting drug is used again (1,2).