Are You Confident of the Diagnosis?

Cutaneous pseudolymphomas are benign reactive lymphocytic proliferations that mimic cutaneous lymphomas clinically and/or histopathologically. They encompass a large heterogeneous group traditionally divided between B and T-cell cutaneous pseudolymphomas. Distinguishing between cutaneous pseudolymphoma and true cutaneous lymphoma requires the complete synthesis of clinical, histopathologic, immunohistochemical, and molecular data; in many situations, patients need to be followed over time (particularly patients who present with a solitary small lesion) to determine which diagnosis fits best, especially given that many cutaneous lymphomas can take months to years to fully manifest themselves clinically.

Most common subtypes

Mycosis fungoides/Sezary Syndrome mimickers

Actinic reticuloid

Drug-induced pseudo-MF/SS

Lymphomatoid allergic contact dermatitis

Clonal erythroderma (including atypical pityriasis rubra pilaris)

Lymphomatoid lichenoid keratosis

Tattoo associated pseudolymphoma

Vaccination associated pseudolymphoma

HIV associated pseudolymphoma

Primary cutaneous CD30+ lymphoproliferative disorder mimickers

Atypical arthropod bites


PLEVA (pityriasis lichenoides et varioliformis acuta)

Infections (orf, milker’s nodule, molluscum contagiousum, herpes simplex/zoster)

Subcutaneous panniculitic T-cell lymphoma (alpha-beta) mimickers

Lupus panniculitis

Atypical lobular panniculitis

Cutaneous B-cell lymphoma (CBCL) mimickers

Cutaneous lymphoid hyperplasia (CLH, lymphocytoma cutis)

Borrelia-associated pseudolymphoma

Drug-induced pseudo-CBCL

Tattoo associated pseudolymphoma

Vaccination associated pseudolymphoma

Inflammatory morphea

Inflammatory pseudotumor (plasma cell granuloma)

Jessner-Kanof lymphocytic infiltration of the skin

What you should be alert for in the history

When questioned, patients may report a preceding inciting event: medications (over the counter, prescription,homeopathic, alternative medicine), arthropod assault, history of tickbite/Lyme disease, tattoo, metal piercing, vaccination, infection. Patients report two events (arthropod bite in setting of being on a new medication).

Characteristic findings on physical examination

Characterisitc findings include persistent skin papule, papulonodule, or plaque (Figure 1), OR clustered papules, OR generalized papules, OR erythroderma.

Figure 1.

Pseudolymphoma. Red dermal nodule. (Courtesy of Stuart Lessin, MD)

Diagnosis confirmation

The accurate diagnosis of cutaneous pseudolymphoma depends on critical elements from the clinical history, physical exam, histologic, and/or adjunctive studies that make the particular case fall short of the diagnosis of confirmed cutaneous lymphoma.

Cutaneous pseudolymphoma that mimicks cutaneous B-cell lymphoma (cutaneous lymphoid hyperplasia) is classically described as a dense nodular or diffuse dermal lymphocytic infiltrate that spares the epidermis, has a “top-heavy” overall architecture (Figure 2) (vs. “bottom-heavy” seen in fully developed cutaneous B-cell lymphoma) and often mixed B-cell and T-cell infiltrate on immunohistochemistry with a tendency to form germinal center follciles.

Figure 2.

Cutaneous lymphoid hyperplasia “Pseudolymphoma” Histology. Superficial and deep top-heavy lymphocytic infiltrate. (Courtesy of Stuart Lessin, MD)

Interpretation of molecular studies (most commonly polymerase chain reaction [PCR])–based assays for T-cell receptor and/or Immunoglobulin heavy chain gene rearrangement studies) MUST be interpreted in the context of other historical, clinical, and histologic data. This is crucial since a small subset of malignant lymphomas may have negative gene rearrangement studies and many reactive or “pseudolymphomas” will demonstrate monoclonal populations.

Basic bloodwork to check includes complete blood count with differential, comprehensive metabolic panel, lactate dehydryogenase.

Adjunctive studies to rule out underlying infection, inflammatory conditions can be done on a case-by-case basis (HIV, rapid plasma reagin (RPR), Lyme titer, connective tissue serologies).

If patients have large skin lesions, erythroderma, palpable lympadenopathy, unusual systemic symptoms (fatigue, fevers, chills, night sweats, unintentional weight loss), then further systemic evaluation can be pursued (such as computed tomography of neck, chest, abdomen, pelvis with contrast, whole body positron emission tomography/computed tomography [PET/CT] scan).

Who is at Risk for Developing this Disease?

Incidence/prevalence is uncommon, but precise numbers are not known.

Borrelia- associated cutaneous lymphoid hyperplasia (CLH).

Drug-induced pseudolymphomas are more commonly seen with certain agents (aromatic anticonvulsants, allopurinol, sulfa drugs, beta blockers, but have been reported with MANY other diverse medications including antihistamines, antipsychotropics, selective serotinin re=uptake inhibitors [SSRIs], and all antihypertensives).

What is the Cause of the Disease?




Systemic Implications and Complications

The majority of cutaneous pseudolymphomas have no systemic complications. Drug-induced pseudolymphomas can rarely cause reactive lymphadeopathy and/or atypical lymphocytosis in the peripheral blood (similar to certain cases of drug rash and eosinophilia with systemic symptoms, [DRESS]). Cutaneous pseudolymphomas due to underlying infections, inflammatory diseases (connective tissue disease) can manifest the expected systemic findings.

Treatment Options

Treatment options are summarized in Table I.

Table I.
Cutaneous pseudolymphoma clinical presentation Topical Agents and Other Options Systemic Medications
Single lesion Excision (when feasible)Intralesional steroidsTopical steroidsLocalized electron beam radiation therapy (EB/RT)  
Grouped or regional lesions Potent topical steroids under occlusionPhototherapy (PUVA, NBUVB)Localied EB/RT Tetracycline antibiotics (B-cell)HydroxychloroquineOral corticosteroidsOral weekly methotrexate
Generalized lesions PhototherapySoak and smear topical steroids (short term) Tetracycline antibiotics (B-cell)HydroxychloroquineOral corticosteroidsOral weekly methotrexate
Erythroderma Topical steroids soak and smearOral anti-staphyloccocal antibiotics (if clinical signs of fissuring, crusting, superinfection)Phototherapy Oral corticosteroidsOral retinoids (acitretin 10-50 mg daily, isotretinoin 1 mg/kg/day)Oral weekly methotrexateLow dose interferon alpha

EB/RT. electron beam radiation therapy; NBUVB, narrow beam ultraviolet B; PUVA, psoralen plus UVA.

Optimal Therapeutic Approach for this Disease

If applicable, stop the offending agent (medication, topical agent). For small lesions, surgical excision is the treatment of choice, and should be submitted for repeat histologic examination. For recurrent lesions, treatment is intralesional steroid injections (triamcinolone 5mg/ml on face, 10mg/ml elsewhere, to start). For regional or generalized lesions, treat with topical steroids (superpotent such as clobetasol cream, gel or ointment 0.05% twice a day for 2-4 weeks for regional lesions, midpotency triamcinolone cream or ointment 0.025 or 0.1% twice a day for 2-4 weeks for generalized lesions) or phototherapy initially.

If there is no improvement, then give oral corticosteroids (1 mg/kg/day for 3 weeks). If lesions recur, treat with steroid-sparing agents as listed above.

For erythroderma, a topical soak and smear regimen with topical triamcinolone ointment or cream 0.1% is very helpful for short-term management ( up to 1 month). If lesions recur, patients can be transitioned to phototherapy or a systemic steroid sparing agent.

General principles of treatment are as follows.

Rebiopsy frequently if the patient has persistent, recurrent progressive lesions. While patients can have certain subtypes of cutaneous pseudolymphomas for years (ie, some CLH cases), cutaneous pseudolymphomas likely reside in a spectrum of lymphoproliferative disorders and have a risk (although exact percentage is unknown) of evolving into true lymphoma.

Steroid=sparing immunosuppressive agents (such as mycophenolate mofetil, tumor necrosis factor (TNF) Inhibitors, cyclosporine, azathioprine) should be tried with caution in patients with cutaneous pseudolymphomas that mimick mycosis fungoides/Sezary syndrome (MF/SS).

Patient Management

After excision, patients with a single lesion can be followed up every 2 months for 6 months, then every 3 months for 6 months, then every 6 months for 1 year, then every year for 10 years. If no recurrence has occurred at that point, it is likely that lesions will not recur. Patients with persistent or recurrent lesions should be followed initially every 2-3 months.

Unlike simple morbiliform allergic drug eruptions, drug-induced pseudolymphomas will often NOT resolve quickly with simple cessation of the offending drug. Similar to many cases of DRESS, it may take weeks/months for the rash to subside, and more likely, additional treatment will often be necessary to clear the eruption. However, whenever possible, medications that are suspected culprits should be stopped for at least 2 months. Additional treatment should be initiated if no improvement after 2 months and suspect culprit medications should continue to be withheld if medically possible.

Risk of evolution into true cutaneous lymphoma is unknown but exists. Patients can be counseled that over time if their skin rash changes, gets worse, or keeps coming back, this warrants repeat sampling/skin biopsies. However, some cases of pseudolymphoma of the skin can persist for years (certain cases of CLH) – rebiopsy in that situation should occur when the clinical presentation/behavior appears to change from the initial presentation.

Unusual Clinical Scenarios to Consider in Patient Management

Clinicopathologic correlation is crucial for diagnosis of cutaneous pseudolymphoma vs. cutaneous lymphoma. Particularly in younger patients, an accurate diagnosis is crucial since the diagnosis of lymphoma can impact long term ability to qualify for life and disability insurance.

What is the Evidence?

Albrecht, J, Fine, AM, Piette, W. “Drug-associated lymphoma and pseudolymphoma: Recognition and management”. Dermatol Clin. vol. 25. 2007. pp. 233-44. (Excellent review of terminology and literature, with particularly comprehensive table updating the list of medications associated with cutaneous pseudolymphomas.)

Boer, A, Tirumalae, R, Bresch, M, Falk, TM. “Pseudoclonality in cutaneous pseudolymphomas: a pitfall in interpretation of rearrangements studies”. Br J Dermatol. vol. 159. 2008. pp. 394-402. (The authors note cases of pseudolymphomas in which clonality appears to be inconsistent between different samples taken from the same lesion over time (different size peak), defined as pseudoclonality.)

Cerron, L, Gatter, K, Kerl, H. “Pseudolymphomas of the skin (Chapter 22)”. Skin lymphoma: the illustrated guide. 2009. pp. 231-262. (Concise summary of the heteregenous clinical manifestations of skin pseudolymphomas, including CLH/lymphocytoma cutis.)

Magro, CM, Crowson, AN. “Lymphomatoid tissue reactions mimicking cutaneous T and B cell lymphoma (Chapter 5)”. The cutaneous lymphoid reactive proliferations. 2007. pp. 371-80. (A comprehensive textbook of lymphocytic infiltrates of the skin. In addition to lymphomatoid drug reaction, the authors discuss reactive lymphomatoid lesions in the setting of collagen vascular disease and viral infections. The case vignettes at the end of the chapter have excellent histopathology figures.)

Ploysangam, T, Breneman, D, Mutasim, D. “Cutaneous pseudolymphomas”. J Am Acad Dermatol. vol. 38. 1998. pp. 877-905. (Comprehenisve clinical and histopathologic review of cutaneous pseudolymphomas with well-balanced discussion regarding the pitfalls of clonality testing as a diagnostic tool in pseudolymphomas versus true lymphomas.)