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. 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 ill-defined, thin, erythematous plaque.
Pseudolymphomatous drug eruption due to captopril, marked by erythematous to purple papules, patches, and plaques.
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 localized, erythematous-to-brown, ill-defined plaque.
Lymphocytoma cutis of the shoulder, composed of flesh-colored or erythematous nodules in small groups.
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.
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. 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]
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, folliculitis, trauma, infections, vaccinations, 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.
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. 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.
Most cases are idiopathic. Known inciting agents for lymphocytoma cutis include the following:
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:
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.
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.
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.
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.
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]
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.
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.
If the inciting stimulus of the cutaneous pseudolymphoma is known, it should be subsequently avoided.
Patients with B-cell pattern pseudolymphoma present with a nodule or a group of discrete nodules, usually with minimal associated symptoms. Occasionally, patients present with pruritus or pain. Patients with a T-cell pattern of cutaneous pseudolymphoma usually present with broader patches, which are often asymptomatic.
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.
Examination of patients with a B-cell pattern of pseudolymphoma usually reveals a single nodule, from one to several centimeters in diameter. Although the lesions may be soft, they are more often firm. Typically, the lesions are red to purple in color, but they may show no coloration. Approximately three quarters of cases of cutaneous pseudolymphoma are localized. The remaining cases usually show grouped papules in a single defined region. More disseminated cases are rare. The most common site of involvement in cutaneous pseudolymphoma is the face (70%), followed by the chest and the upper extremities. Cutaneous pseudolymphoma lesions are infrequent below the waist.
Sites of predilection for borrelial pseudolymphoma include the earlobe, the nipple, the areola, the nose, and the scrotum (sites of low skin temperature).
Patients with T-cell pattern pseudolymphoma typically present with broad, erythematous patches and/or plaques. Pseudolymphomatous actinic reticuloid affects sun-exposed areas. Lymphomatoid contact dermatitis demonstrates lesions in areas where the inciting agent has come in contact with the skin.
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. Frequently, a small number of erythematous indurated papules, plaques, or nodules are seen. Rarely, a solitary tumor may appear.
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. PD1+ cells are more common in pseudolymphomatous folliculitis compared with marginal zone lymphoma.
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 diagnosis ; however, both drug-induced pseudolymphoma and variants of cutaneous B-cell lymphoma, such as marginal zone, may have a similar indolent course.
In patients with borrelial pseudolymphoma, antibodies to Borrelia burgdorferi may be identified in 50% of cases. Additionally, the organism may be identified in tissue via polymerase chain reaction (PCR) analysis.
Routine laboratory results most often remain within the reference ranges and play a limited role in diagnosis.
Leukocytosis with eosinophilia may occur in severe cases.
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.
PCR-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.[11, 24] Thus far, the identification of clonality in pseudolymphoma lesions has not been predictive of lymphomatous transformation.[4, 17, 24]
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.
Biopsy is necessary to establish a diagnosis of pseudolymphoma. An adequate sample extending well into the subcutis with avoidance of crush artifact is essential.
Pseudolymphoma can be extremely difficult to differentiate from lymphoma on histologic grounds alone. For example, lymphocytoma cutis, a variant of pseudolymphoma with formation of B-cell germinal centers, is difficult to differentiate from follicular center lymphoma histologically. Histologically, the infiltrate simulates B-cell lymphoma and shows a nodular inflammatory infiltrate in the dermis. An infiltrate containing well-formed germinal centers limited to the papillary and upper reticular dermis (top-heavy) favors pseudolymphoma, although much more overlap exists between true cutaneous lymphoma (especially marginal zone type) and drug-induced cutaneous lymphoid hyperplasia.
The key histologic features that favor pseudolymphoma over lymphoma include the presence of a mixed infiltrate that includes histiocytes, eosinophils, and plasma cells, in addition to lymphocytes. The presence of tingible body macrophages, preserved and evenly spaced follicular dendritic cells (highlighted by CD21 immunohistochemical staining), preserved polarized germinal centers, and lack of BCL-2 staining favor pseudolymphoma, but clinical correlation and follow up is required for definitive diagnosis.
See the images below.
Biopsy specimens of pseudolymphoma vary substantially, but they most often exhibit a mixed inflammatory infiltrate with prominent lymphoid follicle fo....
A mixed inflammatory infiltrate with germinal centers is indicative of lymphocytoma cutis.
Drug-induced pseudolymphoma most often resembles the bandlike T-cell infiltrate of mycosis fungoides (MF).[4, 5] Some cases show a T-cell histologic pattern with a bandlike infiltrate in the papillary dermis, predominantly of small lymphocytes, with variable epidermotropism. 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. Although these features mimic MF, the clinical presentation is often characteristic.
Additionally, 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 CTCL, the CD3+ CD4+ CD7+ phenotype is not 100% specific for pseudolymphoma.[9, 8, 11] Loss of CD5 and restriction of the epidermotropic cells to a CD4 phenotype 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.
When the offending agent is known, its removal results in resolution of the cutaneous pseudolymphoma. Cases of cutaneous pseudolymphoma documented to occur as a result of infection should be appropriately treated. In idiopathic cases of cutaneous pseudolymphoma, treatment is not mandatory. Cures may be effected via surgical removal, cryosurgery, or local irradiation. Some reports have noted a response to topical or injected corticosteroids and topical immunomodulators such as tacrolimus.
Patients with presumed pseudolymphoma in whom the possibility of lymphoma cannot be excluded should be evaluated for the possibility of concurrent extracutaneous disease and followed for possible emergence of lymphoma.
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.
Case reports have suggested the efficacy of imiquimod. Antibiotics have been reported helpful in some reported cases associated with Borrelia infection. Subcutaneous injection of interferon-alfa has also cleared cutaneous pseudolymphoma.[28, 29] Photodynamic therapy has also been used.
The Medscape Skin Cancer Resource Center may be of interest.
In cutaneous pseudolymphoma, simple excision of the involved site can be curative in some cases.
Cryosurgery may be effective in some cases of lymphocytoma cutis.
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. Successful treatment of tattoo pigment–induced pseudolymphoma with fractional resurfacing and subsequent Q-switched Nd:YAG 532-nm laser treatments has been reported.
The Medscape Dermatologic Surgery Resource Center may be of interest.
Because malignant lymphomas have been reported following clearance of pseudolymphoma, patients should be continually monitored for constitutional signs of lymphoma.
The goals of pharmacotherapy for cutaneous pseudolymphoma are to reduce morbidity and to prevent complications.
Clinical Context: Hydrocortisone valerate is an adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. It has mineralocorticoid and glucocorticoid effects, resulting in anti-inflammatory activity. It is used to treat inflammatory dermatosis responsive to steroids. Hydrocortisone valerate decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.
Clinical Context: Betamethasone is for inflammatory dermatosis responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.
Clinical Context: Clobetasol is a class I superpotent topical steroid; it suppresses mitosis and increases the synthesis of proteins that decrease inflammation and cause vasoconstriction.
Clinical Context: Fluocinonide is a high-potency topical corticosteroid that inhibits cell proliferation; it is immunosuppressive and anti-inflammatory.
Clinical Context: Desonide stimulates the synthesis of enzymes that decrease inflammation. It suppresses mitotic activity and causes vasoconstriction.
Clinical Context: Fluocinolone is a fluorinated corticosteroid of moderate potency at the 0.025% concentration and low potency at the 0.01% concentration (class 6). It has anti-inflammatory, antipruritic, and vasoconstrictive properties.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body’s immune response to diverse stimuli.