AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Drug-induced pseudolymphoma syndrome refers to a benign, drug-induced lymphocytic infiltrate in the skin that mimics cutaneous lymphoma histologically, clinically, or both.^{1, 2, 3} While the clinical presentation can be highly variable, typically patients present with the insidious development of an asymptomatic singular lesion (papule, nodule, or plaque) following weeks to months of a drug exposure. Less often, multiple lesions or widespread skin involvement (erythroderma) is seen. The skin lesions typically resolve within several months of withdrawal of the offending agent.^{1, 2, 3, 4} and may recur with reinitiation of the implicated drug.

Since its initial report as a reaction to phenytoin more than 50 years ago,^{4, 5, 6} more than a dozen additional drugs have been implicated. Clinicians should consider this diagnosis in patients with the appropriate clinical presentation and a history of drug therapy with one or more of the implicated agents.
 
Drug-induced pseudolymphoma syndrome is a subtype of cutaneous pseudolymphoma (see Cutaneous Pseudolymphoma), a heterogenous group of benign T- or B-cell cutaneous lymphoproliferative processes with histologic features of malignancy but benign clinical behavior.¹ In most cases of cutaneous pseudolymphoma, the cause is unknown. When the cause is known, most experts suggest the inciting agent be stated in the diagnosis. Along with medications, other reported causes of cutaneous pseudolymphoma include photosensitivity, trauma, folliculitis, foreign agents (eg, tattoo dyes, insect bites, scabies, arthropod venom, vaccinations, hyposensitization injections, gold, acupuncture), and infections (eg, HIV, varicella-zoster virus, Borrelia burgdorferi).^{1, 7}

Pathophysiology

In contrast to classic drug eruptions, which develop minutes to days from drug ingestion and quickly resolve with drug discontinuation, the time course of drug-induced pseudolymphoma syndrome is prolonged and suggests a distinct biologic mechanism. Some postulate that drug-induced immunodysregulation results in the lymphoproliferative process.^{3, 7} Abnormally functioning lymphocytes may proliferate in response to an antigen from the drug itself, an antigen unmasked by drug metabolism, or another nonpharmacologic antigen. Supporting this theory, alterations in immune function have been demonstrated in vivo or in vitro for many of the causative agents.^{2, 3}
 
Usually, drug-induced cutaneous pseudolymphoma is a T-cell proliferation, but occasional B-cell–predominant forms have been reported. In general, evidence of T- or B-cell clonality (by polymerase chain reaction analysis of T-cell receptor or immunoglobulin H gene rearrangement or immunohistochemical light chain analysis) supports true lymphoma, whereas polyclonality supports a pseudolymphomatous proliferation; however, both polyclonal lymphomas and monoclonal pseudolymphomatous infiltrates have been well documented in the literature. Alone, clonality is insufficient to predict clinical behavior.

The emerging consensus is that pseudolymphomatous and lymphomatous proliferations represent 2 ends of a spectrum.^{1, 7} Supporting this theory are examples of antigen-driven lymphoproliferation and progression to lymphoma in other organ systems (ie, Helicobacter pylori–related gastric mucosa-associated lymphoid tissue [MALT] lymphoma). Transformation of drug-induced cutaneous lymphocytic infiltrates to malignant lymphoma has been reported with phenytoin; however, many of these cases predate the availability of current diagnostic standards and may have represented cases that would now be classified as hypersensitivity syndrome.¹
 
Some authors believe the reported cases of transformation may actually have represented diagnostically challenging indolent B-cell cutaneous lymphomas.^{1, 6} Similar cases involving pseudolymphomatous T-cell infiltrates progressing to true T-cell cutaneous lymphoma may potentially occur, but theses cases are less well-documented in the literature.
 
Individuals with a slow acetylator phenotype may be more susceptible to developing atypical lymphoid dyscrasias, owing to differences in drug metabolism kinetics, which may allow a pharmacologic antigen more opportunity to elicit an immune response or allow toxic drug metabolites to alter lymphocyte function.⁸ This proposed pathophysiology pertains primarily to drug-induced hypersensitivity syndrome. Thus, the details are not discussed extensively here; however, similar mechanisms of immunodysregulation have been suggested for drug-induced pseudolymphoma syndrome.

The eMedicine articles Cutaneous B-Cell Lymphoma and Cutaneous T-Cell Lymphoma may be of interest.

Frequency

United States

Although drug-induced pseudolymphoma remains a rare disorder, more than 100 individual cases have been reported in the literature worldwide. 

Mortality/Morbidity

In most cases, drug-induced pseudolymphoma regresses spontaneously following withdrawal of the offending agent. Misdiagnosis of these lesions as a malignant entity could lead to inappropriate chemotherapeutic treatment. 
 
Little is understood about the natural course of these lesions if drug exposure is allowed to continue. As discussed, transformation into malignant lymphoma has been reported in the literature, but many of these cases predate current diagnostic standards. Progression from a benign lymphocytic cutaneous infiltrate to cutaneous lymphoma remains poorly defined; however, close clinical follow up is prudent to monitor for such an event.

Mortality rates associated with drug-induced hypersensitivity syndrome can reach as high as 10%, and the condition requires specific therapy.⁸

Race

No racial predilection is apparent for drug-induced pseudolymphoma syndrome. Drug-induced hypersensitivity syndromes may affect black patients more frequently than white patients.^{8, 9} The familial aggregation seen may be due to inherited defects in drug metabolism, making some patients more susceptible.

Sex

Men and women are equally affected.

Age

In the largest published series, the average patient age was 61 years. Individual cases have been reported to range from childhood to the ninth decade of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

The onset of drug-induced pseudolymphoma is insidious. Most patients present with a single slowly enlarging papular, nodular, or plaquelike lesion several weeks following the initiation of implicated medications. However, several patients have demonstrated drug-induced pseudolymphoma after more than 5 years of therapy.

In the drug hypersensitivity syndrome, patients frequently report intermittent low-grade fever and local or diffuse lymphadenopathy. Constitutional symptoms may include headache, nausea, malaise, arthralgias, conjunctivitis, and pharyngitis.

Physical

Erythematous patches, similar to mycosis fungoides (MF), may be seen, but, in contrast to MF, they may be more localized and not restricted to sun-protected sites.¹ Frequently, a small number of erythematous indurated papules, plaques, or nodules are seen. Rarely, a solitary tumor may appear.

In the drug hypersensitivity syndrome, the patients may present with features of Sézary syndrome. Other physical findings associated with the hypersensitivity syndrome  include splenomegaly, marked localized or diffuse lymphadenopathy, and high-grade fever.⁹

Causes

Anticonvulsants, typically phenytoin and carbamazepine, are the most frequent cause of drug-induced pseudolymphoma. Nevertheless, the number of implicated agents reported to cause either drug-induced pseudolymphoma or drug-induced hypersensitivity syndrome is expanding.
Drug classes and the reported subclasses and agents are as follows:

• Antiarrhythmics - Phenytoin, carbamazepine, butabarbital, lamotrigine, mephenytoin, methsuximide, phenobarbital, phensuximide, primidone, trimethadione, ethosuximide,¹ mexiletine, procainamide
• Antibiotics - Flucloxacillin,¹ dapsone, cefixime, nitrofurantoin, penicillin, sulfonamides
• Anticoagulants - Fluindione¹
• Antidepressants - Amitriptyline, bupropion, desipramine, doxepin, fluoxetine, lithium, maprotiline
• Antihistamines
• • H1 blockers – Diphenhydramine
  • H2 blockers – Cimetidine, ranitidine
• Antihypertensives
• • Alpha agonists – Clonidine patch
  • ACE inhibitors – Benazepril, captopril, enalapril, lisinopril
  • Angiotensin receptor blockers – Losartan, valsartan
  • Beta-blockers – Atenolol, labetalol
  • Calcium channel blockers – Diltiazem, verapamil
  • Diuretics – Hydrochlorothiazide, hydrochlorothiazide with amiloride
  • Vasodilators – Hydralazine
• Antipsychotics - Phenothiazines (chlorpromazine, thioridazine, promethazine)
• Antirheumatics - Allopurinol, D-penicillamine, Gold, nonsteroidal anti-inflammatory drugs
• Benzodiazepines - Clonazepam, lorazepam
• Chemotherapeutics - Cyclosporine, methotrexate, imatinib (Gleevec), glatiramer acetate, oxaliplatin/5-fluorouracil/leucovorin¹¹
• CNS stimulants - Methylphenidate hydrochloride¹²
• HMG-CoA reductase inhibitors - Lovastatin
• Mast cell stabilizers - Cromolyn sodium
• Sex steroids - Estrogen, progesterone
• Topical agents - Etheric plant oil, menthol, hydroquinone cream¹
• Vaccines - Hepatitis A or B vaccine injection sites

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Although overlap exists between drug-induced pseudolymphoma syndrome and drug-induced hypersensitivity syndrome, distinguishing these entities is important because drug-induced hypersensitivity syndrome may be fatal. If associated symptoms include lymphadenopathy, organomegaly, diffuse lymphadenopathy, and constitutional symptoms, drug-induced hypersensitivity syndrome should be considered.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

Routine laboratory results most often remain within the reference ranges and play a limited role in diagnosis.⁸

• CBC count: Leukocytosis with eosinophilia may occur in severe cases.
• Liver-associated enzymes: Transaminitis has been reported; however, it is more prevalent in drug-induced hypersensitivity syndrome, and, when present, confers a worse prognosis, with one study reporting 10-50% mortality with severe hepatitis.¹⁰

Other Tests

Immunohistochemical stains are usually required to facilitate differentiation between pseudolymphomatous eruptions and lymphoma. Although none of these tests is perfectly specific or diagnostic alone, they may be particularly helpful in supporting or refuting a diagnosis of lymphoma in the appropriate clinicopathologic context.

Before advances in immunophenotyping and gene rearrangement analysis, the diagnosis was based on histologic findings and benign clinical behavior. Clinical follow up for 5 years following initial skin biopsy had been accepted as confirmation of the diagnosis⁷; however, both drug-induced pseudolymphoma and variants of cutaneous B-cell lymphoma, such as marginal zone, may have a similar indolent course.

• Cell surface marker analysis: True MF has a CD3⁺CD4⁺CD7^- immunophenotype. Most drug-induced pseudolymphomas also contain CD3⁺CD4⁺ T cells; however, CD7 is often retained. Because CD7 is lost in some pseudolymphomas and because it is not universally absent in cutaneous T-cell lymphoma (CTCL), the CD3⁺CD4⁺CD7⁺ phenotype is not 100% specific for pseudolymphoma.^{3, 6, 7} Loss of CD5 and restriction of the epidermotropic cells to a CD4 phenotype favors MF.
• T-cell receptor gene rearrangement studies: Polymerase chain reaction–based assessment of T-cell receptor gamma genes may be used to reveal a dominant clone of T-cells within a population. Because T-cell pseudolymphomas are most often polyclonal, demonstration of such a dominant clone favors a diagnosis of CTCL. Unfortunately, both rare monoclonal T-cell pseudolymphomas and polyclonal CTCL cases have been reported, thus decreasing the specificity of this assay.^{6, 13} Thus far, the identification of clonality in pseudolymphoma lesions has not been predictive of lymphomatous transformation.^{1, 4, 13}
• Immunoglobulin light-chain analysis: Some subsets of B-cell lymphoma exhibit a monoclonal restriction to either kappa or lambda light chains. Because B-cell pseudolymphomas tend to be polyclonal, detection of such a light-chain clone by immunohistochemistry favors true B-cell lymphoma.⁹

Procedures

Accurate histologic diagnosis of cutaneous pseudolymphoma requires a deep biopsy that includes subcutaneous fat. Avoidance of crush artifact is important because it impairs the diagnostic utility of a sample.

Histologic Findings

Drug-induced pseudolymphoma most often resembles the bandlike T-cell infiltrate of MF.^{1, 8} Less frequently, a nodular T- or B-cell infiltrate is seen. In all subtypes, frequent mitoses with nuclear and architectural atypia may occur, truly simulating their malignant counterparts.

In the most common variant, MF-like drug-induced T-cell pseudolymphoma, bands of small T lymphocytes invade the papillary dermis and disrupt the dermoepidermal junction. Epidermotropism, if present, is mild and generally lacks Pautrier microabscesses. Deep perivascular and periadnexal infiltrates may be observed. Dermal edema, acanthosis, and spongiosis may help to differentiate this condition from true CTCL. While similar in overall appearance, CTCL typically displays conspicuous epidermotropism and papillary dermal fibroplasia and exhibits minimal spongiosis. Close inspection of the lymphocytes to identify cerebriform cells is important because the predominance of these atypical cells in the epidermis favors MF.

In nodular drug-induced T-cell pseudolymphoma, nodular T-cell infiltrates may be either isolated or may appear concomitantly with MF-like lesions. They consist of small lymphocytes admixed with variable histiocytes, plasma cells, and eosinophils. Nuclear atypia, when present, is generally mild.¹

Nodular drug-induced B-cell pseudolymphoma is infrequently encountered.⁷ The nodules contain mildly atypical lymphocytes interspersed with a variety of mononuclear cells. An infiltrate containing well-formed germinal centers limited to the papillary and upper reticular dermis ("top heavy") favors pseudolymphoma,¹ although much more overlap exists between true cutaneous lymphoma (especially marginal zone type) and drug-induced cutaneous lymphoid hyperplasia.⁵

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

When the diagnosis of pseudolymphoma is suspected all implicated drugs should be discontinued. Because lesions are typically asymptomatic, no additional medical treatment is required. A short course of topical or intralesional steroids may  be attempted to hasten regression. The time course for lesion regression can range from 1-3 months. Careful follow up is prudent because a nonresolving lesion should prompt concern for a malignant process.

The Medscape Skin Cancer Resource Center may be of interest. 

Surgical Care

Lesions that interfere with function or are cosmetically undesirable may be surgically removed. No recurrence of excised lesions has been seen after withdrawal of the causative drugs. In cases of incomplete regression, external radiation therapy has also been reported to be successful.

The Medscape Dermatologic Surgery Resource Center may be of interest. 

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Deterrence/Prevention

In most cases, drug-induced pseudolymphoma regresses spontaneously following withdrawal of the offending agent.

Complications

In rare instances, malignant lymphoma has appeared following apparent resolution of phenytoin- and carbamazepine-induced pseudolymphomas. These cases have been termed pseudo-pseudolymphomas.⁸

Prognosis

Following cessation of the implicated medications, complete clearance is usually noted within 1-3 months. However, a few patients may require surgical excision or external radiation of one or more lesions. Recurrence following complete excision has not been reported.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

Because malignant lymphomas have been reported following clearance of pseudolymphoma, patients should be continually monitored for constitutional signs of lymphoma.

ACKNOWLEDGMENTS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous Chief Editor, William James, MD, to the development and writing of this article.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• References

1. Albrecht J, Fine LA, Piette W. Drug-associated lymphoma and pseudolymphoma: recognition and management. Dermatol Clin. Apr 2007;25(2):233-44, vii. [Medline].
2. Magro CM, Crowson AN. Drug-induced immune dysregulation as a cause of atypical cutaneous lymphoid infiltrates: a hypothesis. Hum Pathol. Feb 1996;27(2):125-32. [Medline].
3. Magro CM, Crowson AN, Kovatich AJ, Burns F. Drug-induced reversible lymphoid dyscrasia: a clonal lymphomatoid dermatitis of memory and activated T cells. Hum Pathol. Feb 2003;34(2):119-29. [Medline].
4. Bouloc A, Delfau-Larue MH, Lenormand B, Meunier F, Wechsler J, Thomine E, et al. Polymerase chain reaction analysis of immunoglobulin gene rearrangement in cutaneous lymphoid hyperplasias. French Study Group for Cutaneous Lymphomas. Arch Dermatol. Feb 1999;135(2):168-72. [Medline].
5. Baldassano MF, Bailey EM, Ferry JA, Harris NL, Duncan LM. Cutaneous lymphoid hyperplasia and cutaneous marginal zone lymphoma: comparison of morphologic and immunophenotypic features. Am J Surg Pathol. Jan 1999;23(1):88-96. [Medline].
6. Cerroni L, Kerl H. Diagnostic immunohistology: Cutaneous lymphomas and pseudolymphomas. Semin Cutan Med Surg. Mar 1999;18(1):64-70. [Medline].
7. Ploysangam T, Breneman DL, Mutasim DF. Cutaneous pseudolymphomas. J Am Acad Dermatol. Jun 1998;38(6 Pt 1):877-95; quiz 896-7. [Medline].
8. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg. Dec 1996;15(4):250-7. [Medline].
9. Callot V, Roujeau JC, Bagot M, Wechsler J, Chosidow O, Souteyrand P, et al. Drug-induced pseudolymphoma and hypersensitivity syndrome. Two different clinical entities. Arch Dermatol. Nov 1996;132(11):1315-21. [Medline].
10. Choi TS, Doh KS, Kim SH, Jang MS, Suh KS, Kim ST. Clinicopathological and genotypic aspects of anticonvulsant-induced pseudolymphoma syndrome. Br J Dermatol. Apr 2003;148(4):730-6. [Medline].
11. Addeo R, Montella L, Baldi A, Cennamo G, Guarrasi R, Faiola V. Atypical cutaneous lymphoid hyperplasia induced by chemotherapy in a patient with advanced colon carcinoma. Clin Colorectal Cancer. Nov 2007;6(10):728-30. [Medline].
12. Welsh JP, Ko C, Hsu WT. Lymphomatoid drug reaction secondary to methylphenidate hydrochloride. Cutis. Jan 2008;81(1):61-4. [Medline].
13. Bachelez H. The clinical use of molecular analysis of clonality in cutaneous lymphocytic infiltrates. Arch Dermatol. Feb 1999;135(2):200-2. [Medline].

Article Last Updated: Jun 19, 2008