Lymphomatoid papulosis

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Lymphomatoid papulosis

Rachel S. Klein, Elisha Singer, Jacqueline M. Junkins-Hopkins, Carmela C. Vittorio, Alain H. Rook and Ellen J. Kim

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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Lymphomatoid papulosis (LyP) is a distinct subset of CD30+ lymphoproliferative disorders in the World Health Organization/European Organization for the Research and Treatment of Cancer (WHO/EORTC) classification of cutaneous lymphomas, defined histologically by a variable infiltrate of CD30+ lymphocytes, in conjunction with the clinical presentation of recurrent, self-healing papulonodules. The lesions evolve into a crusted or necrotic stage, which often heal with a scar. Less common presentations include regional and oral disease. LyP affects adults and children as young as 11 months of age and may persist for years to decades. Approximately 5–25% of patients with LyP may present with or develop a lymphoproliferative malignancy, such as mycosis fungoides (MF – cutaneous T-cell lymphoma, CTCL), anaplastic large cell lymphoma (ALCL), and Hodgkin’s or non-Hodgkin’s lymphomas. There may also be a slight risk of developing a non-hematologic neoplasm. The same clone has been documented in patients with LyP and the associated lymphoma (including MF and ALCL), supporting the concept that LyP lies within the spectrum of CTCL. Clinical and histologic overlap may also be seen with LyP and pityriasis lichenoides et varioliformis acuta.

Management strategy

Most importantly, the management of LyP begins with understanding the natural history of the disease. LyP is defined as a recurrent, self-healing (remission of every individual lesion), papulonodular eruption, with histology suggesting CTCL. There are four histologic variants, including type A (wedge-shaped infiltrate containing eosinophils and histiocytes), type B (epidermotropism, resembles MF), type C (cohesive sheets of CD30+ cells, resembles ALCL), and type D (CD8+, resembles primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma). Clinical evaluation should include a complete history assessing for atypical features, including previous lymphoid neoplasms, constitutional symptoms, lymphadenopathy, or laboratory abnormalities on complete blood counts, blood chemistry, and lactate dehydrogenase. Patients with abnormal findings should undergo CT or PET/CT scanning to exclude a systemic lymphoma. Distinguishing LyP from primary cutaneous ALCL is important, although this may be difficult because of clinical and histologic overlap, including spontaneous regression.

Persistent lesions greater than 2–3 cm in diameter favor ALCL; however, some patients do not fit well into either category. Such borderline cases have similar biologic behavior to LyP and can be managed as such. Treatment of LyP should be tailored to the disease burden, because most modalities have not been proven to alter the natural course of LyP, nor do they prevent the development of extracutaneous lymphomas. Treatment should be reserved for symptomatic or cosmetically bothersome cases. First-line therapies include topical corticosteroids, low-dose methotrexate, and 8-methoxypsoralen with UVA (PUVA). A response may be seen within the first few weeks of treatment, including the development of fewer lesions, shortening of the lifecycle of individual lesions, and occasionally induction of remission. Large or borderline lesions can be treated with local radiotherapy or excision. Therapies that are beneficial in MF may also be used, including topical carmustine (BCNU), topical mechlorethamine (nitrogen mustard), and biologic agents such as interferon-α, interferon-γ, and the retinoid X receptor agonist bexarotene. Topical bexarotene, in a region of localized disease, may prevent recurrence of the condition. Similarly, topical imiquimod cream 5% can hasten resolution of lesions. In severe cases, the anti-CD30 antibody, brentuximab, may also be efficacious; however, this must be balanced by the risks of peripheral neuropathy, neutropenia, and rarely, progressive multifocal leukoencephalopathy (PML). Multiagent chemotherapy is not indicated, despite histologic features that may suggest ALCL. LyP can recur for decades, requiring careful consideration of treatment side effects and continued monitoring for the development of lymphoma.

Specific investigations

Primary and secondary cutaneous CD30+ lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment.

Bekkenk MW, Geelen FAMJ, van Voorst Vader PC, Heule F, Geerts ML, van Vloten WA, et al. Blood 2000; 95: 3653–61.

Guidelines are proposed for the diagnosis and treatment of patients with CD30+ lymphoproliferative disorders based on long-term follow-up of 219 patients, 118 of whom had LyP (4% had tumors). Fifty-two of 118 patients received no treatment or topical corticosteroids. The remainder received a variety of standard treatments, none of which were associated with complete, sustained remission. Staging of patients with type C LyP failed to reveal extracutaneous disease. Nineteen percent developed an associated lymphoma. Induction of remission of the secondary lymphoma had no effect on the natural course of LyP. The calculated risk for extracutaneous disease was 4% at 10 years.

CD30+ cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma.

Liu HL, Hoppe RT, Kohler S, Harvell JD, Reddy S, Kim YH. J Am Acad Dermatol 2003; 49: 1049–58.

In 19 of 31 cases with LyP, a higher than previously reported associated coexisting hematolymphoid malignancy (61% with one or more) was noted. Most had MF, which occurred before, during, or after the diagnosis of LyP. Some had two hematolymphoid malignancies. Three progressed to ALCL, with an interval ranging from 77 to 152 months. The overall 5- and 10-year survival of patients with LyP was 100% and 92%, respectively, and none died of LyP. Those with ALCL had a favorable course. LyP subtype did not predict the risk of associated malignancy.

The higher association with malignancy may represent selection bias.

CD30-positive T-cell lymphoproliferative disorder of the oral mucosa – an indolent lesion: Report of 4 cases.

Agarwal M, Shenjere P, Blewitt RW, Hall G, Sloan P, Pigadas N, et al. Int J Surg Pathol 2008; 16: 286–90.

The authors report four cases of CD30+ oral tumors, three of which presented on the tongue and one on the buccal mucosa. All regressed, and none was associated with an aggressive course. One presented as an ulcer. The histology of two cases showed features typical of LyP.

If one is not aware of this presentation, oral CD30+ lymphoproliferative disorders may be erroneously diagnosed as T-cell lymphoma. This may or may not present in conjunction with cutaneous or genital mucosal lesions of LyP. The evaluation of patients with LyP should include examination of the oral mucosa. Isolated oral lesions with histology of LyP should be distinguished from ALCL and CD8+ aggressive epidermotropic CTCL, which may have overlapping clinical and histologic features.

First-line therapies

image Therapy not required B
image PUVA B
image Low-dose methotrexate B
image Topical corticosteroids E

Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30+ lymphoproliferative disorders.

Vonderheid EC, Sajjadian A, Kadin ME. J Am Acad Dermatol 1996; 34: 470–81.

A 20-year experience of methotrexate therapy in 45 patients with LyP, CD30+ lymphoma, and borderline cases is reviewed. Patients responded within 4 weeks (15–20 mg weekly). Maintenance doses were given at 10- to 14-day intervals (range 7–28 days); 29% had concomitant MF, requiring other therapies (mechlorethamine hydrochloride, carmustine, standard UV therapy, and PUVA), which offered some additional benefit, but the relative effectiveness was less than with methotrexate. LyP and CD30+ lymphoma responded similarly. Three patients had diminished responsiveness, suggesting resistance to methotrexate. Severe exacerbations occurred upon abrupt drug discontinuation.

This is considered first-line therapy for symptomatic disease, with disease control typical but remission off drug uncommon.

Second-line therapies

image Topical mechlorethamine (nitrogen mustard) B
image Topical carmustine C
image Topical bexarotene C

Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma.

Vonderheid EC, Tan ET, Kantor AF, Shrager L, Micaily B, Van Scott EJ. J Am Acad Dermatol 1989; 20: 416–28.

Seven patients with LyP and 17 with concomitant LyP and MF were treated with 10–20 mg of mechlorethamine dissolved in 40–60 mL water and applied once daily to the entire skin surface except for the genitalia, until at least 2 weeks after complete clearance of lesions. Four of the seven with LyP achieved a complete response (CR), with one lasting for more than 8 years of follow-up. A slightly increased risk of squamous and basal cell carcinomas, Hodgkin’s disease, and colon cancer was noted.

A common side effect of mechlorethamine therapy is an allergic hypersensitivity reaction, which may occur less frequently when mechlorethamine is prepared in an ointment base.

Third-line therapies

image Oral bexarotene C
image Recombinant interferon C
image Excimer laser E
image Radiotherapy E
image Topical methotrexate E
image Imiquimod cream E
image SGN-30 B

Therapeutic use of interferon-alpha for lymphomatoid papulosis.

Schmuth M, Topar G, Illersperger B, Kowald E, Fritsch PO, Sepp NT. Cancer 2000; 89: 1603–10.

Five patients were treated with subcutaneous interferon-α, 3–15 million IU three times per week. Three were treated for 12–13 months, and each achieved a CR that was durable for at least 1 year after discontinuation of therapy. Two were treated for 5 to 7 months: one had a partial response (PR) and one had CR; however, neither was durable after discontinuation of therapy. Only one of six controls achieved spontaneous remission.

Interferon-α is one of the few therapies that may have potential for altering the course of LyP. A superior benefit may be associated with long-term treatment courses, and the side effect profile at low doses is low, allowing for prolonged treatment course.

Persistent agmination of lymphomatoid papulosis: an equivalent of limited plaque mycosis fungoides type of cutaneous T-cell lymphoma.

Heald P, Subtil A, Breneman D, Wilson LD. J Am Acad Dermatol 2007; 57: 1005–11.

Seven cases of regional LyP were treated as if they were localized mycosis fungoides, with local radiotherapy, resulting in long-standing remissions. The radiation doses ranged from 30 to 46 Gy, in fractionated doses. One patient also had topical bexarotene and localized electron beam therapy. At follow-up (2 to 6 years), six of the seven had no recurrences. One patient with recurrence subsequently achieved complete remission with interferon-α and PUVA.

Treatment of regional LyP as if it were MF may offer remission of LyP, but, as demonstrated, these patients may develop lymphoma. Long-term follow-up is critical.

A phase 2 study of SGN-30 in cutaneous anaplastic large cell lymphoma and related lymphoproliferative disorders.

Duvic M, Reddy S, Pinter-Brown L, Korman N, Kennedy D, Lorenz J, et al. Clin Cancer Res 2009; 15: 6217–24.

SGN-30, an anti-CD30 antibody, was administered to 23 patients with PCALCL, LyP, or transformed MF. Overall, 16/23 (70%) responded, including 10 CRs and six PRs. Overall response rates per disorder were 82% for PCALCL (9/11), 67% for LyP (2/3), 33% for MF (1/3), and 67% for patients with multiple diagnoses (4/6). With regard to LyP in particular, three patients had a primary diagnosis of LyP and six had LyP in addition to another CD30+ disorder. Within these groups, four patients had a CR and two had a PR, for an overall response rate of 67%. The remaining three patients were categorized as non-responders because they flared after the first dose of SGN-30. Subsequently, each achieved a durable remission; it was postulated that these patients had a delayed response to SGN-30 and that the disease flare resulted from the required methotrexate washout prior to initiation of the trial.

Many of the trials on SGN-30 and SGN-35 (discussed below) focus on Hodgkin’s lymphoma and ALCL; however, their findings may also be pertinent to other CD30+ disorders, such as LyP.

Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas.

Younes A, Bartlett N, Leonard J, Kennedy D, Lynch C, Sievers E, et al. N Engl J Med 2010; 363: 1812–21.

To improve efficacy, the anti-CD30 antibody was conjugated with monomethyl auristatin E, an antitubulin agent, resulting in the drug SGN-35, or brentuximab vedotin. This drug was studied in a cohort of 45 patients with refractory CD30+ lymphoproliferative disorders, including Hodgkin’s lymphoma, systemic ALCL, and angioimmunoblastic T-cell lymphoma. The maximum tolerated dose was found to be 1.8 mg/kg every 3 weeks. The most common side effects included fatigue, fever, diarrhea, nausea, neutropenia, and peripheral neuropathy. The overall response rate was 38%, including 2/2 patients with ALCL, 15/42 patients with Hodgkins’s lymphoma, and 0/1 patient with angioimmunoblastic T-cell lymphoma. The median duration of response was 9.7 months.

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