Phenytoin Induced Cutaneous B Cell Pseudolymphoma.

Cutaneous pseudolymphomas are benign lymphoproliferative processes mimicking lymphomas clinically and histologically. One of the precipitating factors for pseudolymphoma is drugs like anticonvulsants, antidepressants and angiotensin-converting enzyme inhibitors. According to existing literature phenytoin-induced cutaneous pseudolymphomas are usually T-cell predominant. Most often withdrawal of the drug with or without short-course systemic steroids can attain a cure. Rarely malignant transformation has been reported years later despite withdrawal of the offending drug, which necessitates a long-term follow up of the affected. We report an 80-year-old male patient who was receiving phenytoin sodium and who presented with diffuse erythema and infiltrated skin lesions which histologically resembled cutaneous B-cell lymphoma. Substituting phenytoin with levetiracetam achieved resolution of symptoms. Further evaluation was suggestive of a reactive process. A detailed drug history is of paramount importance in differentiating drug-induced pseudolymphoma from lymphoma. Searching literature we could not find any previous reports of phenytoin-induced cutaneous B-cell pseudolymphoma.

What was known?

Cutaneous T cell pseudolymphoma is a rare, but well known complication of phenytoin therapy.

Introduction

Cutaneous pseudolymphomas are a group of benign reactive T-cell or B-cell lymphoproliferative processes of varying etiologies that can mimic lymphoma.[12] One of the precipitating factors for pseudolymphoma is drugs like anticonvulsants, antidepressants, angiotensin-converting enzyme inhibitors and antihistamines.[2] We report an 80-year-old male patient on phenytoin who presented with skin lesions resembling cutaneous lymphoma which showed complete resolution on withdrawal of the drug.

Case Report

An 80-year-old male patient presented with pruritic rash of 1 month duration without any constitutional symptoms. He received treatment with antihistamines and systemic steroids (prednisolone 30 mg for 5 days) from a nearby hospital; there was temporary relief during steroid therapy, but the symptoms reappeared on its withdrawal. He was receiving phenytoin sodium 100 mg three times daily since 2 years for late onset seizures. A neurology work up at that time identified ischemic infarct to be underlying cause for seizures. He was not on any other drugs.

At the time of admission, his vitals were stable and there were multiple, firm, mobile, non-tender and enlarged axillary nodes. He also had diffuse erythematous rash with infiltrated papules and plaques on the face [Figure 1a], trunk and limbs with relative sparing of distal extremities. Systemic examination revealed no abnormality.

Figure 1

(a) Diffuse erythema and infiltrated plaques on the face of a patient with phenytoin induced B cell pseudolymphoma. (b) The same patient showing complete resolution of the rash two weeks after withdrawing phenytoin. (c) Skin biopsy from an infiltrated plaque on the chest showing dense perivascular and periappendageal lymphoid infiltrate (H and E, ×40); Inset: High power view of the same revealing the infiltrate to be composed of large atypical cells admixed with small mature lymphocytes (H and E, ×400)

Complete hemogram was normal except for an elevated erythrocyte sedimentation rate (ESR) at 60 mm/hour. Urine microscopy, random blood sugar, liver and renal function tests, lactate dehydrogenase level, chest radiography and ultrasonography of abdomen and pelvis were within normal limits. Peripheral smear showed no atypical cells or blast forms.

A biopsy from an infiltrated plaque on the chest showed normal epidermis with pronounced perivascular and periappendageal lymphocytic infiltrate [Figure 1c] composed of moderate to large sized (two to three times the normal size) lymphocytes [Figure 1c] having fine chromatin. Many cells showed small nucleoli. Occasional mitotic figures were seen. Many normal looking lymphocytes were also seen. Immunohistochemistry revealed most of the large cells to be CD 20 positive [Figure 2a] and CD 10 and bcl2 negative. A significant portion of normal sized, CD 3 [Figure 2b] and CD 5 positive cells [Figure 2c] were also noted. Contrast-enhanced tomogram of thorax and abdomen did not detect any abnormality. Biopsy and immunohistochemistry of axillary lymph node revealed paracortical widening and retention of follicles [Figures 3a and b] with CD 20 positive follicular cells [Figure 3c] and CD3 positive paracortical cells [Figure 3d]. Bone marrow study, though offered, was refused by the patient.

Figure 2

(a) Immunohistochemistry of a skin biopsy specimen demonstrating CD 20-positive large atypical lymphoid cells (immunohistochemistry, DAB Chromogen ×400). (b) Immunohistochemistry showing the atypical lymphoid cells to be CD 3 negative, whereas background lymphocytes are CD3 positive (immunohistochemistry, DAB Chromogen ×400). (c) Atypical lymphoid cells are negative for CD 5 immunostaining, whereas background lymphocytes are positive (immunohistochemistry, DAB Chromogen ×400)

Figure 3

(a) Section from lymph node showing interfollicular expansion with mottled appearance (H and E, ×40). (b) High power view of interfollicular area showing proliferation of immunoblasts (H and E, ×400). (c) Follicles highlighted using CD 20 immunostaining (immunohistochemistry, DAB Chromagen ×40). (d) Interfollicular area highlighted using CD 3 immunostaining (immunohistochemistry, DAB Chromagen ×40)

Considering the differential diagnoses of cutaneous B-cell lymphoma and phenytoin-induced cutaneous B-cell pseudolymphoma, phenytoin was substituted with levetiracetam and the patient was managed with antihistamines and emollients. Complete resolution of the rash was attained in 2 weeks [Figure 1b] and the ESR value came down to 20 mm/hour. He was reviewed once in every 2 weeks and was carefully assessed for any reappearance of the rash, progression of lymphadenopathy and organomegaly. Complete hemogram and peripheral smear analysis were repeated at each visit. At the end of 2 months, the patient remained asymptomatic with normal blood parameters with complete regression of axillary Lymphadenopathy.

Considering the prompt, complete and sustained improvement observed after withdrawing phenytoin and the normal histology and immunohistochemistry of a lymph node specimen, we made a final diagnosis of phenytoin-induced B-cell cutaneous pseudolymphoma. He is kept under regular follow up for early detection of any malignant transformation.

Discussion

Phenytoin-induced cutaneous lymphoproliferative disorders include benign lymphoid hyperplasia, pseudolymphoma, pseudo-pseudolymphoma and malignant lymphoma.[23] Drug-induced pseudolymphoma manifest with predominant or exclusive skin involvement without any constitutional symptoms or systemic involvement.[245] An interval of up to 7 years (between the onset of drug intake and the appearance of symptoms) has been reported in drug-induced pseudolymphoma as in our case.[2]

Presence of medium- to large-sized lymphocytes, that may appear atypical, with many ordinary small lymphocytes (as observed by us) is cited as the histology feature that distinguishes pseudolymphoma from other benign cutaneous inflammatory cell infiltrates.[6] Distinguishing pseudolymphomas from true lymphomas is difficult as both may show atypical cells and mitotic figures. Immunoglobulin and T-cell gene rearrangement studies may aid in distinguishing between the two, but polyclonal cutaneous lymphomas and monoclonal pseudolymphomas are rarely encountered.[2] Hence, response to drug withdrawal (occasionally systemic steroids may be required to achieve control of the disease process)[2] is taken as the reliable indicator to determine the benign or malignant nature of the disease. A long-term follow up is recommended following reports of malignant lymphoma after an initial resolution in few of these patients, who are categorized as having pseudo-pseudolymphoma.

Depending on the predominant cell, pseudolymphomas are classified into T-cell and B-cell types. Drugs well known to induce cutaneous B-cell pseudolymphomas are antidepressants, whereas phenytoin-induced cutaneous pseudolymphomas are mostly T-cell predominant.[7] We believe ours to be B-cell pseudolymphoma as majority of the atypical cells were CD20 positive. Usually B-cell pseudolymphomas appear as solitary lesions, but rarely can occur with multiple papules and plaques as observed by us.[26]

It is proposed that pseudolymphomas are induced by drugs that facilitate blast transformation and disrupt T-cell suppressor function eliciting an exaggerated lymphocyte response to exogenous antigens which could be the drug itself or a nonpharmacological agent.[2]

Phenytoin-induced cutaneous T-cell pseudolymphomas are well reported. Though lymph node biopsy specimen from patients with phenytoin-induced lymphadenopathy has revealed features of B-cell pseudolymphoma, to the best of our knowledge cutaneous B-cell pseudolymphoma induced by phenytoin is hitherto unreported.[8]

We report this case to highlight the significance of a thorough drug history in patients who develop atypical cutaneous infiltrates and the importance of a long-term follow up even in patients who show complete clinical resolution.

What is new?

To the best of our knowledge, cutaneous B-cell pseudolymphoma induced by phenytoin is hitherto unreported.