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Lymphomatoid papulosis


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

Lymphomatoid papulosis (LyP) is a chronic papulonodular disorder that consists of recurrent, self-healing crops of papulonodules characterized by a variable infiltrate of CD30+ lymphocytes on histopathology. In the World Health Organization/European Organization for the Research and Treatment of Cancer (WHO/EORTC) classification of cutaneous lymphomas, the disorder is defined as a benign clonal proliferation of T lymphocytes and is a distinct entity in the spectrum of cutaneous CD30+ lymphoproliferative disorders, which also includes primary cutaneous anaplastic large-cell lymphoma (pcALCL). Patients with LyP may present with very few or with multiple lesions, which may evolve into a crusted or necrotic stage, often healing with scarring. Less common presentations include regional, isolated acral, and oral disease. The lesions may cause pruritus. 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 hematologic malignancy, including systemic anaplastic large-cell lymphoma (ALCL), Hodgkin lymphoma, or a cutaneous T-cell lymphoma (CTCL) such as mycosis fungoides (MF). There may also be a slightly increased risk of a non-hematologic neoplasm. The same T-cell clone has been identified in some patients with LyP and the associated lymphoma (including MF and primary cutaneous anaplastic large-cell lymphoma [pcALCL]), supporting the concept that LyP lies within the spectrum of CTCL. Clinical and histologic features may overlap with arthropod bites, pityriasis lichenoides, and folliculitis.

Management Strategy

Management of LyP must take into consideration the natural history of the disease. LyP is defined as a recurrent, self-healing (remission of every individual lesion), papulonodular eruption, with histology suggestive of CTCL. There are six 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), type D (CD8/CD30+, resembles primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma), type E (CD30+ with angioinvasion), and type F (CD30+, follicular). A minor subset of LyP patients may have chromosomal rearrangements involving the DUSP22-IRF4 locus on 6p25.3, which has been observed in some pcALCL patients. Recognition of these different subtypes is essential to avoid misdiagnosis of other, more aggressive, forms of CTCL.

Clinical evaluation should include a complete history and examination assessing for atypical findings, including previous lymphoid neoplasms, constitutional symptoms, lymphadenopathy, or laboratory abnormalities in peripheral blood counts, blood chemistry, and lactate dehydrogenase. Patients with abnormal findings should undergo computed tomography (CT) or positron emission tomography (PET)/CT scanning to exclude a systemic lymphoma. Distinguishing LyP from pcALCL is important though somewhat challenging because of their clinical and histologic overlap. Persistent lesions greater than 2–3 cm in diameter are more consistent with pcALCL; however, some patients do not fit well into either category. Such ‘borderline’ cases exhibit similar biologic behavior to LyP and can be managed as such.

Treatment of LyP should be tailored to disease burden, as treatment has not been proven to alter the natural course of LyP, nor does it prevent the development of associated lymphomas. Treatment should be reserved for symptomatic or cosmetically bothersome cases. First-line therapies include topical corticosteroids, phototherapy, and low-dose methotrexate. A response may be seen within the first few weeks of treatment, yielding fewer lesions, quicker resolution of individual lesions, and occasionally complete remission. Large or borderline lesions may be treated with local radiation or excision. Therapies effective for MF may be used for LyP, including topical agents such as carmustine (BCNU), mechlorethamine (nitrogen mustard), bexarotene (retinoid X receptor agonist), and imiquimod. Systemic biologic agents such as interferon-α and oral bexarotene are also effective for suppressing lesions. The anti-CD30 antibody–drug conjugate brentuximab vedotin is highly effective; however, use of this agent may produce peripheral neuropathy and is only warranted in severe, refractory cases. 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

  • Biopsy and histologic review to confirm the diagnosis

  • Exclusion of constitutional (‘B’) symptoms, hepatosplenomegaly, lymphadenopathy, or laboratory abnormalities

  • Ongoing surveillance for a lymphoproliferative neoplasm

EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma

Kempf W, Pfaltz K, Vermeer M, et al. Blood 2011; 118: 4024–35.

These consensus guidelines provide recommendations for managing the spectrum of CD30+ cutaneous lymphoproliferative disorders. LyP does not require staging procedures if history and examination are unremarkable. Long-term follow-up is required for all subtypes.

Lymphomatoid papulosis. Reappraisal of clinicopathologic presentation and classification into subtypes A, B, and C

El Shabrawi-Caelen L, Kerl H, Cerroni L. Arch Dermatol 2004; 140: 441–7.

A retrospective review of 85 patients with LyP identified histologic overlap among subtypes A, B, and C, and between type B and MF. Eight percent of patients had more than one histologic subtype of LyP. The authors also stress the tight overlap between LyP and CD30+ CTCL such as pcALCL and MF with large-cell transformation. A variety of clinicohistopathologic presentations, including those with histology showing follicular mucinosis, syringotropism, vesicle formation, MF-like bandlike infiltrates, and associated keratoacanthoma, are discussed.

A variant of lymphomatoid papulosis simulating primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. Description of 9 cases

Saggini A, Gulia A, Argenyi Z, et al. Am J Surg Pathol 2010; 34: 1168–75.

A variant of LyP, termed LyP type D , is described in nine patients with clinical aspects of LyP but with histopathological features resembling primary cutaneous aggressive epidermotropic CD8+ cytotoxic lymphoma. LyP type D features medium-sized CD8+CD30+ pleomorphic cells with prominent, pagetoid reticulosis-like epidermotropism. None of the patients developed a lymphoproliferative malignancy during 84 months of mean follow-up.

Accurate clinicopathologic correlation is necessary to diagnose LyP type D and avoid a misdiagnosis of primary cutaneous aggressive epidermotropic CD8+ cytotoxic lymphoma.

Angioinvasive lymphomatoid papulosis: a new variant simulating aggressive lymphomas

Kempf W, Kazakov DV, Schärer L, et al. Am J Surg Pathol 2013; 37(1): 1–13.

Another variant of LyP, termed type E LyP, is described retrospectively in 16 patients with oligolesional papules that ulcerated with histopathology showing CD30+CD8+ angioinvasive medium-to-large anaplastic cells in the dermis and subcutaneous tissue. Such histology can overlap with cytotoxic cutaneous lymphomas such as extranodal natural killer/T-cell lymphoma (nasal type) or gamma/delta T-cell lymphoma. Despite the aggressive features, none of the patients developed extracutaneous disease.

Follicular lymphomatoid papulosis revisited: a study of 11 cases, with new histopathological findings

Kempf W, Kazakov DV, Baumgartner HP, et al. J Am Acad Dermatol 2013; 68(5):809–16.

Follicular LyP is a variant of LyP with involvement of hair follicles, manifesting as a perifollicular infiltrate with variable degree of folliculotropism. Other changes, including hyperplasia of the follicular epithelium, hair follicle rupture, and follicular mucinosis, are less common. Rarely, intrafollicular pustules can be seen in the follicular epithelium; such lesions manifest clinically as pustules.

Some propose that follicular LyP should be termed LyP type F, whereas others categorize it as a subtype of types A and C.

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, 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. Fifty-two of 118 patients were not treated, whereas others received various standard therapies, 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. Inducing remission of the secondary lymphoma had no effect on the natural course of LyP. The risk of extracutaneous disease was 4% at 10 years.

Lymphomatoid papulosis: treatment response and associated lymphomas in a study of 180 patients

Wieser I, Oh CW, Talpur R, et al. J Am Acad Dermatol 2016; 74(1): 59–67.

In this retrospective chart review of 180 patients diagnosed with LyP between 1995 and 2015 at a specialty cancer clinic, histologic type A was the most common (47.2%), followed by type C (22.8%), type B (17.2%), type D (7.8%), and type E (0.6%), as well as mixed type (4.4%). One hundred fourteen other lymphomas were observed in 93 patients (51.6%), of which the most common were MF (61.4%) and ALCL (26.3%). Risk factors for lymphoma included male sex and types B and C; patients with type D were less likely to have lymphoma. Number of lesions, symptom severity, and T-cell clonality were not associated with an increased risk of lymphoma. Treatment provided symptomatic relief but did not prevent progression to lymphoma.

The higher association (40%) with lymphoma compared with other studies may represent a referral bias.

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