Are You Confident of the Diagnosis?
What you should be alert for in the history
–Solitary persistent lesion on the skin
–Sometimes several grouped lesions
–Generalized scattered lesions are uncommon
–Either itchy or asymptomatic
–Common triggers: arthropod bite, tattoos (particularly red dye), vaccinations, acupuncture, leech application, medications, Borrelia burgdorferi infection, ear piercing
–Many cases are idiopathic.
Characteristic findings on physical examination
–Well appearing patient
–Firm dome-shaped or annular papulonodules, plaques or small tumors
–Pink, violaceous, or red-brown
–Smooth, nonscaly, not ulcerated
–No lymphadenopathy or organomegaly
–Predilection for scalp, face, upper trunk but can occur anywhere
(Figure 1, Figure 2)
Expected results of diagnostic studies:
Pathology: Superficial and deep, “top-heavy,” dense, nodular or diffuse mixed infiltrates (lymphocytes, histiocytes, plasma cells, eosinophils) in the dermis with a Grenz zone. Formation of germinal centers/lymphoid follicles is common (Figure 3).
Immunohistochemistry: Mixed T- and B-cell lymphocytic infiltrate. Can see a normal germinal center phenotype (CD20+, CD10+, BCL-6+, BCL2-), no kappa or lambda light-chain restriction, normal proliferation markers, regular CD21+ follicular dendritic cell network. Prominent reactive T-cells are present.
Polymorphous inflammatory infiltrates can also be seen: Eosinophils, plasma cells, histiocytes, and granulomatous. A perifollicular predominance is occasionally observed. Some cases are T-cell predominant (T-cell cutaneous lymphoid hyperplasia).
Molecular: Polyclonal immunoglobulin heavy (IgH) chain and T-cell receptor (TCR) gene rearrangement of fresh tissue or paraffin block (in most cases), but some cases can show clonal IgH or TCR gene rearrangement populations.
Because of an overlap with low-grade cutaneous B-cell lymphoma (CBCL), if patient reports no “triggers,” can also check:
–CBC with differential
–Comprehensive metabolic panel
–Computed tomography (CT) or positron emission tomography (PET) CT scan
–CLH is sometimes associated with Borrelia burgdorferi infection (Europe); can check:
–Differential diagnosis: Low-grade CBCL: “bottom heavy,” more diffuse, predominantly lymphocytic rather than mixed cellular infiltrate, more monomorphous, no “normal” germinal center formation, immunophenotyping, light chain restriction, monoclonal IgH gene rearrnangement
–Non-mycosis fungoides cutaneous T-cell lymphoma (immunophenotyping, TCR gene rearrangement)
–Cutaneous metastases: histology will distinguish
–Adnexal tumors: histology will distinguish
–Lymphocytic infiltrate of Jessner (predominantly T-cell)
–Polymorphous light eruption – plaque form (seasonal, photodistributed, pathology shows dermal edema, perivascular T-lymphocytic infiltrate).
–Tumid lupus: photodistributed, superficial and deep perivascular’periadnexal lymphocytic infiltrate, mucin
Who is at Risk for Developing this Disease?
–Can occur at any age
–Women at greater risk than men
–Children are the main group affected by B burgdorferi-associated CLH.
What is the Cause of the Disease?
Most cases are idiopathic; some cases are the result of arthropod assault, B burgdorferi infection, vaccination, drugs, acupuncture, tattoos, ear piercing, leech therapy.
Benign but persistent locally reactive immunologic response to various antigenic stimuli
Systemic Implications and Complications
CLH is limited to the skin.
Treatment options for CLH are summarized in the Table 1.
|Intralesional steroid injection|
|Intralesional interferon injection|
|Topical steroids under occlusion|
|Topical tacrolimus||Localized radiation|
|Oral antibiotics (doxycycline)|
Optimal Therapeutic Approach for this Disease
Single small lesion:
–Surgical excision (or intralesional kenalog 3.3 to 5mg/mL if surgery is not feasible)
–If recurrent:: Intralesional kenalog 3.3 to 5mg/mL or superpotent topical steroids (clobetasol cream, gel, or ointment 0.05% twice daily for 2 to 4 weeks) under occlusion. If no improvement: Cryotherapy, localized low-dose electron beam radiation therapy
Single large lesion:
–Intralesional kenalog 3.3 to 5mg/mL or topical steroids under occlusion.
–If no improvement: Surgical excision or localized low-dose electron beam radiation therapy.
–Intralesional kenalog 3.3 to 5 mg/mL or topical steroids under occlusion.
–If no improvement: Can try cryotherapy, topical imiquimod cream 5% daily for 6 weeks, topical tacrolimus 0.1% daily for 2 months, topical nitrogen mustard ointment 0.01% every night and rinse in the morning for 2 months, or localized low-dose electron beam radiation therapy.
Scattered generalized lesions:
–Intralesional kenalog 3.3 to 5mg/mL or superpotent topical steroids (such as clobetasol cream, gel or ointment 0.05% twice daily for 2 to 4 weeks) under occlusion; if no improvement, can try cryotherapy
–Oral prednisone 0.5 to 1mg/kg tapered over 2 to 3 weeks.
–Oral doxycycline (for cases associated with B burgdorferi)
–Oral thalidomide (for refractory cases)
CLH is generally a benign reactive condition and usually resolves, sometimes spontaneously. If lesions persist, the patient needs to follow-up every few months. If the lesion(s) get larger or more prominent, rebiopsy over time to evaluate for evolving cutaneous lymphoma. Biopsies should be punch, incisional or excisional to ensure you obtain the deeper component of lesion.
Maintenance therapy: None
Unusual Clinical Scenarios to Consider in Patient Management
There is histologic overlap between some cases of CLH and low-grade indolent primary CBCL.
What is the Evidence?
Arai, E, Shimizu, M, Hirose, T. ” A review of 55 cases of cutaneous lymphoid hyperplasia: reassessment of the histopathologic findings leading to reclassification of 4 lesions as cutaneous marginal zone lymphoma and 19 as pseudolymphomatous folliculitis”. Human Pathol. vol. 36. 2005. pp. 505-11. (This study demonstrates how immunohistochemical and molecular techniques can assist in distinguishing between CLH and cutaneous lymphoma.)
Bergman, R, Khamaysi, Z, Sahar, D, Ben-Ariah, Y. “Cutaneous lymphoid hyperplasia presenting as a solitary facial nodule”. Arch Dermatol. vol. 142. 2006. pp. 1561-6. (Good review of CLH clinicohistopathologic presentation and work-up.)
Cerron, L, Gatter, K, Kerl, H. “Pseudolymphomas of the skin”. Skin lymphoma: The illustrated guide. 2009. pp. 231-62. (Excellent summary of the heterogeneous clinical manifestations of skin pseudolymphomas, including CLH/lymphocytoma cutis.)
Colli, C, Leinweber, B, Mullegger, R, Chott, Kerl, H, Cerroni, L. ” Borrelia burgdorferi-associated lymphocytoma cutis: clinicopathologic, immunophenotypic, and molecular study of 106 cases”. J Cutan Pathol . vol. 31. 2004. pp. 232-40. (Large series of B burgdorferi-associated CLH describes the most common sites of involvement (nipple, earlobe, genitals), and 5 of 106 cases had morphologic/immunophenotypic features that simulated large B-cell lymphoma, prompting the authors to state that integration of clinicopathologic, serologic, molecular data is necessary for correct diagnosis of this entity.)
Kluger, N, Vermeulen, C, Moguelet, P, Cotten, H, Koeb, MH, Balme, B. “Cutaneous lymphoid hyperplasia (pseudolymphoma) in tattoos: a case series in seven patients”. JEADV . vol. 24. 2010. pp. 208-13. (Similar to previous literature, T-cell predominant CLH was observed in tattoo-related cases. Red dye was the most common color associated with tattoo-associated CLH.)
Magro, CM, Crowson, AN. “Lymphomatoid tissue reactions mimicking cutaneous T and B cell lymphoma”. The cutaneous lymphoid proliferations. 2007. pp. 371-80. (A comprehensive textbook of lymphocytic infiltrates of the skin.)
Nihal, M, Mikkola, D, Horvath, N, Gilliam, AC, Stevens, SR, Spiro, TP. ” Cutaneous lymphoid hyperplasia: a lymphoproliferative continuum with lymphomatous potential”. Hum Pathol. vol. 34. 2003. pp. 617-22. (In their study of 44 patients with CLH over a 10-year period, 27% showed clonal IgH rearrangement, 30% showed clonal TCR rearrangement, 4% showed both IgH/TCR rearrangement. Two cases (4% of total) progressed to CBCL during the study period. The high prevalence of CLH in their study population is likely due to the sensitivity of their PCR-based technique and patient population, but the authors contend that CLH is on a continuous spectrum with clonal CLH and CBCL.)
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