Published on 19/03/2015 by admin
Filed under Dermatology
Last modified 22/04/2025
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Fiona J. Child and Sean J. Whittaker
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Lymphocytoma cutis (cutaneous lymphoid hyperplasia, cutaneous B-cell pseudolymphoma, Spiegler–Fendt sarcoid) is an entity encompassing a spectrum of benign B-cell lymphoproliferative diseases that share clinical and histopathologic features. Various stimuli can induce lymphocytoma cutis, but in most cases the cause is not known. It is more common in females, with a female-to-male ratio of 3 : 1. Most cases are characterized by localized erythematous, plum-colored nodules and plaques that may be difficult to distinguish from cutaneous B-cell lymphoma. Less frequently the generalized form may present with multiple miliary papules that measure a few millimeters in diameter. Lymphocytoma cutis secondary to Borrelia infection is most frequently seen at sites where skin temperature is low, such as the earlobes, nipples, nose, and scrotum.
A skin biopsy for histopathology and immunohistochemistry is required to confirm the diagnosis, but the distinction between lymphocytoma cutis and cutaneous B-cell lymphoma may be difficult on both clinical and histopathologic evaluation. There are no agreed histologic criteria; however, features that suggest lymphocytoma cutis include well-formed, non-expanded, reactive germinal centers, the majority of the infiltrate consisting of small round lymphocytes with a B:T cell ratio of <3 : 1 and polytypic expression of kappa and lambda light chains. A further feature is the presence of numerous tingible body macrophages within the lymphoid follicles. Molecular analysis of the immunoglobulin heavy chain gene has shown that a significant proportion harbor B-cell clones, which suggests that many cases previously thought to be lymphocytoma cutis represent indolent low-grade primary cutaneous B-cell lymphomas (PCBCL). Therefore, in cases with a detectable B-cell clone a careful evaluation to exclude systemic disease (a thorough clinical examination, thoracoabdominopelvic CT scan, and bone marrow biopsy) is required, with adequate long-term follow-up.
A history of possible stimuli known to cause lymphocytoma cutis should be sought; these include Borrelia burgdorferi infection, Leishmania infection, trauma, vaccinations, allergy hyposensitization injections, ingestion of drugs, arthropod bites, acupuncture, gold pierced earrings, tattoos, treatment with leeches (Hirudo medicinalis), and post herpes zoster scars, but the majority of cases are of unknown etiology.
The course of the disease varies but tends to be chronic and indolent, and some lesions may resolve spontaneously without treatment. There is no therapy of proven value for lymphocytoma cutis, with only anecdotal case reports and small series reported and no clinical trials in the literature.
If a cause can be identified, the causative agent should be removed. If infection with Borrelia burgdorferi is suspected, treatment with appropriate antibiotics (amoxycillin 500–1000 mg three times per day, or doxycycline 100 mg two to three times per day for at least 3 weeks) should be initiated.
Localized disease can be treated by simple excision and may respond to intralesional injection of corticosteroids, local irradiation, or intralesional interferon-α. More widespread (generalized) disease is traditionally treated with oral antimalarials, most commonly hydroxychloroquine (maximum dose 6.5 mg/kg/day); however, lesions may fail to respond to treatment or may recur following cessation of therapy. Other treatment modalities include subcutaneous interferon-α and oral thalidomide. Effective responses to destructive therapies, including cryotherapy and the argon laser, have been reported. A subtype of generalized lymphocytoma cutis may be exacerbated by light, and therefore sun avoidance and the use of sun block are important.
Serology for Borrelia burgdorferi (antibodies identified in 50% of patients with borrelial lymphocytoma)
Skin biopsy for histology, immunophenotype, and immunoglobulin gene analysis
Patch testing (if a possible contact allergen is suspected)
Hovmark A, Asbrink E, Olsson I. Acta Derm Venereol 1986; 66: 479–84.
Of 10 patients investigated, four reported a previous tick bite. Positive Borrelia serology was found in six of nine patients, and spirochetes were cultured from one of two skin biopsies.
Albrecht S, Hofstadter MD, Artsob H, Chaban RT. J Am Acad Dermatol 1991; 24: 621–5.
A child who developed lymphocytoma cutis on her ear following a tick bite 6 months previously had positive Borrelia serology, and a Borrelia-like organism was identified in skin biopsy sections. The lesion regressed during a 2-month course of penicillin V.
Baldassano MF, Bailey EM, Ferry JA, Harris NL, Duncan LM. Am J Surg Pathol 1999; 23: 88–96.
The histologic and immunophenotypic features of 14 cases of lymphocytoma cutis and 16 cases of cutaneous marginal zone lymphoma were compared.
Leinweber B, Colli C, Chott A, Kerl H, Cerroni L. Am J Dermatopathol 2004; 26: 4–13.
The histopathologic, immunophenotypic, and molecular features of Borrelia burgdorfori-associated lymphocytoma cutis, primary cutaneous follicle center cell lymphoma, and primary cutaneous marginal zone lymphoma were compared. Features that favored lymphocytoma cutis were the presence of tingible-body macrophages, strong proliferation rate of follicular cells, BCL-2-negative follicular cells, and the absence of monoclonality.
Colli C, Leinweber B, Müllegger R, Chott A, Kerl H, Cerroni L. J Cutan Pathol 2004; 31: 232–40.
A total of 106 cases of Borrelia burgdorfori-associated lymphocytoma cutis, in a region endemic for Borrelia infection, were studied retrospectively. The most common sites affected were the earlobe, genital area, and nipple (these locations may be due to the predilection of Borrelia burgdorfori spirochetes for cooler body sites). In some cases the histopathologic, immunophenotypic, and molecular features were misleading, and it was concluded that integration of all data is necessary to obtain the correct diagnosis.
Wood GS, Ngan BY, Tung R, Hoffman TE, Abel EA, Hoppe RT, et al. Am J Pathol 1989; 135: 13–19.
In this study, five of 14 cases with cutaneous lymphoid hyperplasia exhibited a clonal immunoglobulin rearrangement by Southern blot analysis. One of these evolved into a diffuse large B-cell lymphoma during a 2-year follow-up period, suggesting that monoclonal populations may exist in some cases of cutaneous lymphoid hyperplasia, and these may represent a subgroup more likely to evolve into lymphoma.
Hammer E, Sangueza O, Suwanjindar P, White CR, Braziel R. J Am Acad Dermatol 1993; 28: 426–33.
Of 11 patients with histologic and immunophenotypic features of lymphocytoma cutis, clonal rearrangements were detected in two, both of whom subsequently developed B-cell lymphoma.
Bouloc A, Delfau-Larue M-H, Lenormand B, Meunier F, Wechsler J, Thomine E, et al. Arch Dermatol 1999; 135: 168–72.
Twenty-four patients with a diagnosis of lymphocytoma cutis according to clinical, histopathologic, and immunophenotypic criteria underwent PCR analysis of the immunoglobulin heavy chain gene using DNA from lesional skin. In one patient a B-cell clone was detected. In the other 23 a polyclonal result was obtained.
Cutaneous B-cell lymphomas are known to have a relatively high false-negative rate using PCR owing to somatic hypermutation, which affects the variable region of the immunoglobulin heavy chain gene and may prevent primer binding. The number of false-negative results may be significantly reduced by using multiple primer sets for different parts of the variable region and for the kappa light chain gene. This paper only used one set of primers, and therefore the detection of only one B-cell clone may be a significant underestimate.
Arai E, Shimizu M, Hirose T. Hum Pathol 2005; 36: 505–11.
The histopathological features of 55 cases of cutaneous lymphoid hyperplasia were reassessed. Of these, nine were reclassified as marginal zone lymphoma, distinguished by patchy or diffuse centrocyte-like cells, with plasma cells at the periphery of the infiltrate, monotypic light chain restriction, and a clonal immunoglobulin heavy chain gene rearrangement.
Fleming C, Burden D, Fallowfield M, Lever R. Contact Derm 1997; 37: 298–9.
A rare entity characterized by nodules at sites of piercing with gold jewelry and the histologic features of lymphocytoma cutis. Patch tests to gold sodium thiosulfate are positive.
Stoll DM. J Am Acad Dermatol 1983; 8: 696–9.
A case report of a 40-year-old woman with generalized lymphocytoma cutis that cleared with 400 mg hydroxychloroquine daily.
Frain-Bell W, Magnus IA. Br J Dermatol 1971; 84: 25–31.
Patients with lymphocytoma and associated light sensitivity are reported and previous cases reviewed.
Kluger N, Vermeulen C, Moguelet P, Cotton H, Koeb MH, Balme B, Fusade T. J Eur Acad Dermatol Venereol 2010; 24: 208–13.
Two of seven patients with cutaneous lymphoid hyperplasia occurring within their tattoos were treated with CO2 or Nd:YAG laser with improvement.
Olson LE, Wilson JF, Cox JD. Radiology 1985; 155: 507–9.
Four cases of lymphocytoma cutis were treated with radiation therapy. Over a follow-up period of 8 months to 7 years there were no recurrences.
Pimpinelli N, Vallecchi C. Skin Cancer 1999; 14: 219–24.
Data from 115 patients with PCBCL produced a 98.2% complete remission rate and a median disease-free period of 55 months; recurrences were mostly limited to the skin. In view of the difficulties in distinguishing between PCBCL and lymphocytoma cutis, many groups have used superficial radiotherapy in cases of lymphocytoma cutis, although evidence remains anecdotal.
In our experience these cases are relatively radio-resistant compared to PCBCL.
Wheeland RG, Kantor GR, Bailin PL, Bergfeld WF. J Am Acad Dermatol 1986; 14: 267–72.
The argon laser improved cosmetic appearance and alleviated symptoms of lymphocytoma cutis but failed to provide complete histological clearing in a young man who had failed to respond adequately to initial therapy with hydroxychloroquine.
Kuflik AS, Schwartz RA. J Am Acad Dermatol 1992; 26: 449–52.
Five patients with lymphocytoma cutis underwent therapy with liquid nitrogen to individual lesions using a single cycle of 15–20 seconds per lesion, with complete clinical resolution of all lesions treated within 3 to 6 weeks.
Hervonen K, Lehtinen T, Vaalasti A. Acta Derm Venereol 1999; 79: 241–2.
Two men, who had generalized lymphocytoma cutis and had failed to respond to other therapies, were treated with subcutaneous interferon-α2b 2.5 MU three times per week, with complete resolution of all lesions by 3 months. However, lesions recurred in both men between 6 and 23 months after the completion of treatment.
Benchikhi H, Bodemer C, Fraitag S, Wechsler J, Delfau-Larue M-H, Gounod N, et al. J Am Acad Dermatol 1999; 40: 1005–7.
Two cases of lymphocytoma cutis involving the nose that showed complete regression following treatment with thalidomide for 3 months at a dose of 100 mg once daily for 2 months, and 50 mg once daily for the third month. There was no recurrence at respectively 36 and 31 months follow-up.
El-Dars LD, Statham BN, Blackford S, Williams N. Clin Exp Dermatol 2005; 30: 305–7.
Two cases of lymphocytoma cutis affecting the face were treated with topical tacrolimus 0.1% twice daily. In both cases the lesions completely resolved after 8 months application.
Martin SJ, Duvic M. Clin Lymphoma Myeloma Leuk 2011; 11: 286–8.
One case of lymphocytoma cutis was treated with intralesional rituximab with notable clinical improvement. Persistent and recurrent erythematous areas were subsequently treated with topical tacrolimus with further improvement.
Takeda H, Kaneko T, Harada K, Matsuzaki Y, Nakano H, Hanada K. Dermatology 2005; 211: 264–6.
Two females were treated with five treatments of topical δ-aminolevulinic acid photodynamic therapy (ALA-PDT) with dramatic clinical and histopathological improvement
Mikasa K, Watanabe D, Kondo C, Taneda Y, Matsumoto Y. J Am Acad Dermatol 2005; 53: 911–12.
A 51-year-old female with lymphocytoma cutis affecting the right cheek and dorsal nose underwent five treatments with ALA-PDT with complete clinical resolution and no clinical recurrence at 6 months follow-up.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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Excision
Topical corticosteroids
Intralesional corticosteroids
Oral antibiotics (if positive Borrelia serology)
CO2 or Nd:YAG laser (if occurring within a tattoo)
Antimalarials
Sun avoidance/sun block (light exacerbated)
Superficial radiotherapy
Intralesional interferon-α
Argon laser
Cryotherapy
Topical 0.1% tacrolimus ointment
Intralesional rituximab
Topical photodynamic therapy
Subcutaneous interferon-α2b
Thalidomide
