Cutaneous Pseudolymphoma

Updated: May 17, 2016
  • Author: Christine J Ko, MD; Chief Editor: William D James, MD  more...
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Overview

Background

Pseudolymphoma is not a specific disease but rather an inflammatory response to known or unknown stimuli that results in a lymphomatous-appearing but benign accumulation of inflammatory cells. [1] In cutaneous pseudolymphoma, resemblance to lymphoma is usually most apparent histologically, but some examples may also mimic lymphoma clinically. When known, the inciting agent should be included along with the diagnosis of cutaneous pseudolymphoma. The term pseudolymphoma without modification should be reserved for idiopathic cases.

Localized, nodular pseudolymphomas are more common and typically mimic B-cell lymphoma clinically and are sometimes called lymphocytoma cutis. A variety of specific diseases, such as actinic reticuloid, lymphomatoid contact dermatitis, pigmented purpuric dermatosis, and lymphomatoid drug eruptions, are sometimes referred to as pseudolymphomas. These disorders often show broad patches and plaques and often mimic lymphoma, specifically cutaneous T-cell lymphoma (CTCL), histologically. [2, 3] Note the images below.

This localized example of pseudolymphoma shows an This localized example of pseudolymphoma shows an ill-defined, thin, erythematous plaque.
Pseudolymphomatous drug eruption due to captopril, Pseudolymphomatous drug eruption due to captopril, marked by erythematous to purple papules, patches, and plaques.
This erythrodermic pseudolymphoma (T-cell pattern) This erythrodermic pseudolymphoma (T-cell pattern) typifies drug-induced pseudolymphoma, which is most often secondary to anticonvulsant therapy.
This example of lymphocytoma cutis shows a localiz This example of lymphocytoma cutis shows a localized, erythematous-to-brown, ill-defined plaque.
Lymphocytoma cutis of the shoulder, composed of fl Lymphocytoma cutis of the shoulder, composed of flesh-colored or erythematous nodules in small groups.
This photograph of lymphocytoma cutis caused by an This photograph of lymphocytoma cutis caused by an arthropod bite shows an erythematous scaling patch of the scalp with localized secondary alopecia.

Related Medscape Reference articles include Cutaneous B-Cell Lymphoma and Cutaneous T-Cell Lymphoma.

Nomenclature

The heterogenous clinical, histological, and etiologic nature of cutaneous pseudolymphoma along with the association of drug-induced hypersensitivity reactions has resulted in many different classification schemes and potentially confusing nomenclature. [4, 5, 6] The term drug-induced pseudolymphoma has been used to describe 2 kinds of adverse cutaneous drug reactions. The first is a subacute disease confined to the skin, which is the focus of this article. The second is an acute syndrome with a cutaneous eruption and associated systemic symptoms, also referred to as drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

The confusion is furthered because the prototypic drug stimulus in both is phenytoin. Bocquet et al proposed the acronym DRESS in 1996 to decrease the ambiguity of the term hypersensitivity syndrome. [5] The hypersensitivity syndrome has been postulated to represent a distinct clinical entity with a distinct biologic mechanism; however, the significant clinical overlap (ie, implicated drugs, symptomatology, and presentation) and histologic overlap make the nosologic distinction of these entities difficult to resolve. [2, 5, 6]

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Pathophysiology

In persons with pseudolymphoma, lymphocytes and other inflammatory cells are recruited to the skin in response to known or unknown stimuli. Most cases are idiopathic. Lymphocytoma cutis is not considered a lymphocytic response to malignancy. Cases of cutaneous pseudolymphoma with known etiology include reactions to tattoo dyes, jewelry (especially gold), insect bites, medications, [4] folliculitis, trauma, infections, vaccinations, [7] acupuncture, and contactants. A discrete subset of pseudolymphoma, borrelial lymphocytoma, primarily occurs in Europe in areas endemic for the tick Ixodes ricinus. Borrelial lymphocytoma is a response to infection by Borrelia burgdorferi subsp afzelius conferred by a tick bite. Another subset of pseudolymphoma is the result of an unusual systemic response to medications, typically anticonvulsants.

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. [8, 9] 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. [8, 10]

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. [4, 9] Supporting this theory are examples of antigen-driven lymphoproliferation and progression to lymphoma in other organ systems (eg, 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. [4]

Some authors believe the reported cases of transformation may have actually represented diagnostically challenging indolent B-cell cutaneous lymphomas. [4, 11] 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 infiltrates, 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. [5] 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 articles Cutaneous B-Cell Lymphoma and Cutaneous T-Cell Lymphoma may be of interest.

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Etiology

Most cases are idiopathic. Known inciting agents for lymphocytoma cutis include the following:

  • Tattoo dye [12]
  • Jewelry (eg, gold earrings)
  • Arthropod (insect and spider) bites
  • Medications [4] (see discussion of drug-induced pseudolymphoma below)
  • Folliculitis
  • Trauma
  • Vaccinations - Varicella-zoster virus vaccination [13]
  • Materials that come into direct contact with the skin or are injected into the skin (eg, gold, aluminum, liquid silicone [14] )
  • Infection (eg, varicella-zoster virus, Borrelia species, molluscum contagiosum, Helicobacter pylori) [4, 9, 15]
  • Sites where acupuncture needles were inserted
  • Therapy with medical leeches [16]

Drug-induced pseudolymphoma syndrome

Drug-induced pseudolymphoma syndrome refers to a benign, drug-induced lymphocytic infiltrate in the skin that mimics cutaneous lymphoma histologically, clinically, or both. [4, 8, 10] 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 [4, 8, 10, 17] and may recur with reinitiation of the implicated drug.

Since its initial report as a reaction to phenytoin more than 50 years ago, [11, 17, 18] 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.

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:

  • Anticonvulsants - Phenytoin, carbamazepine, butabarbital, lamotrigine, mephenytoin, methsuximide, phenobarbital, phensuximide, primidone, trimethadione, ethosuximide [4]
  • Antiarrhythmics - Mexiletine, procainamide
  • Antibiotics - Flucloxacillin, [4] dapsone, cefixime, nitrofurantoin, penicillin, sulfonamides
  • Anticoagulants - Fluindione [4]
  • 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
  • Bisphosphonates – Zoledronic acid [19]
  • Chemotherapeutics - Cyclosporine, methotrexate, imatinib (Gleevec), glatiramer acetate, oxaliplatin/5-fluorouracil/leucovorin [20]
  • CNS stimulants - Methylphenidate hydrochloride [21]
  • HMG-CoA reductase inhibitors - Lovastatin
  • Mast cell stabilizers - Cromolyn sodium
  • Sex steroids - Estrogen, progesterone
  • Topical agents - Etheric plant oil, menthol, hydroquinone cream [4]
  • Vaccines - Hepatitis A or B vaccine injection sites, varicella-zoster vaccination sites
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Epidemiology

US statistics

No data on US prevalence or incidence of lymphocytoma cutis are available.

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

International statistics

No frequency data are available. A discrete subset of lymphocytoma cutis, borrelial lymphocytoma, occurs primarily in Europe, in areas in which the I ricinus tick is endemic.

Racial differences in incidence

Although the majority of reported patients with pseudolymphoma are white, racial predilection has not been established.

No racial predilection is apparent for drug-induced pseudolymphoma syndrome. Drug-induced hypersensitivity syndromes may affect black patients more frequently than white patients. [5, 6] The familial aggregation seen may be due to inherited defects in drug metabolism, making some patients more susceptible.

Sexual differences in incidence

In reported cases of localized pseudolymphoma, the female-to-male ratio is approximately 2:1. No significant epidemiologic data are available regarding entities in the T-cell pattern pseudolymphoma spectrum.

Age-related differences in incidence

Individuals of any age may be affected, but localized, nodular pseudolymphoma is most common in early life. The mean age of onset is 34 years. Two thirds of patients are younger than 40 years at the time of biopsy. Approximately 8% of cases involve patients younger than 18 years. Borrelial pseudolymphoma is more common in children than in adults.

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. [4, 9]

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Prognosis

If the offending agent is removed, resolution of cutaneous pseudolymphoma is achieved. Idiopathic examples of cutaneous pseudolymphoma tend to be chronic and indolent. Spontaneous regression of cutaneous pseudolymphoma may occur over the course of months or a few years. Recurrence has been noted.

Following cessation of the implicated medications, complete clearance of drug-induced pseudolymphoma syndrome 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.

Occasional case reports of cutaneous pseudolymphoma have described evolution to lymphoma. A significant percentage of these cases may have represented histologically subtle lymphoma from the outset.

In rare instances, malignant lymphoma has appeared following apparent resolution of phenytoin- and carbamazepine-induced pseudolymphomas. These cases have been termed pseudo-pseudolymphomas. [5]

Mortality/morbidity

Pseudolymphoma is not associated with mortality. Localized variants rarely result in morbidity other than minor pain or pruritus.

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.

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Patient Education

If the inciting stimulus of the cutaneous pseudolymphoma is known, it should be subsequently avoided.

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