Lymphomatoid Papulosis

Background

Lymphomatoid papulosis (LyP) is a chronic papulonecrotic or papulonodular skin disease with histologic features suggestive of a malignant lymphoma. The disease is characterized by recurrent crops of pruritic papules at different stages of development that predominantly arise on the trunk and limbs. The papules heal spontaneously over 1-2 months, usually leaving slightly depressed oval scars.

The term lymphomatoid papulosis originally was used by Macaulay^[1] in 1968 to describe "a self-healing rhythmical paradoxical eruption, histologically malignant but clinically benign." Due to the typical waxing and waning clinical course, lymphomatoid papulosis was previously considered a pseuodolymphomatous inflammatory process. However, the classification system for cutaneous lymphomas has evolved rapidly, and, during consensus meetings in 2003-2004, the World Health Organization—European Organization for Research and Treatment of Cancer (WHO-EORTC) classification grouped lymphomatoid papulosis among the indolent cutaneous T-cell lymphomas. These classifications were updated in 2008 by the WHO-EORTC,^{[2, 3, 4]} and they were updated in 2016 by the WHO.^[5] The 2016 classification described new subtypes of lymphomatoid papulosis with similar clinical behavior but atypical histologic/immunophenotypic features. It classifies lymphomatoid papulosis as an indolent T-cell lymphoproliferative disorder of the skin, under primary cutaneous CD30⁺ T-cell lymphoproliferative disorders, along with primary cutaneous anaplastic large cell lymphoma (pcALCL). The rationale for classifying lymphomatoid papulosis as a cutaneous lymphoma is its association with other malignant lymphoproliferative disorders; however, some experts hesitate to classify this chronic skin disease as a true malignancy because of its spontaneous resolution and benign clinical course.^{[6, 7, 8, 9]}

Lymphomatoid papulosis is part of a spectrum of CD30 (Ki-1)–positive cutaneous lymphoproliferative diseases (CD30⁺ LPDs), including lymphomatoid papulosis, pcALCL, and borderline CD30⁺ lesions. Also see Cutaneous CD30+ (Ki-1) Anaplastic Large-Cell Lymphoma.

Also see the Medscape articles Cutaneous Melanoma, Malignant Melanoma, and Cutaneous T-Cell Lymphoma.

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Pathophysiology

The CD30 antigen is a type 1 transmembrane glycoprotein of the tumor necrosis factor receptor superfamily. In addition to the CD30⁺ lymphoproliferative diseases, malignant lymphomas such as Hodgkin disease (HD), node-based systemic anaplastic large cell lymphoma (ALCL), and mycosis fungoides (MF) with large cell transformation may express the CD30 antigen.

The pathophysiology of CD30⁺ LPDs, including lymphomatoid papulosis (LyP), is largely unknown. CD30 signaling is known to have an effect on the growth and survival of lymphoid cells, and one hypothesis is that genetic instability and accumulated genetic defects may have a role in the development of lymphomatoid papulosis and the progression to associated neoplasms. In a 2005 study, the 30M377 allelic form of the CD30 promoter microsatellite repressive element was associated with the development of lymphomatoid papulosis, and the 30M362 allelic form was associated with progression to other CD30⁺ lymphomas in lymphomatoid papulosis patients.^[10]

Genetic instability of tumor cells may lead to altered expression of apoptotic proteins and immune-regulatory molecules, such as transforming growth factor-beta. Other research has found overexpression of JunB,^[11] part of the AP-1 transcription factor complex involved in cell proliferation and apoptosis, in virtually all CD30⁺ lymphomas. Consequently, JunB is a potential target for experimental therapy in patients with these tumors.

Spontaneous regression of lymphomatoid papulosis is seen almost universally, whereas regression occurs in approximately 25% of pcALCL cases. Therefore, the higher apoptotic index found in lymphomatoid papulosis compared with pcALCL is not surprising. The proapoptotic protein Bax is also expressed at high levels in CD30⁺ cutaneous lymphoproliferative diseases and may play a crucial role in mediating apoptosis of tumor cells. Another study suggested that the death-receptor apoptosis pathway mediated by Fas-associating protein with death domain (FADD) may be responsible for the varying biologic behaviors of CD30⁺ LPDs involving the skin.^[12]

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Etiology

The etiology of lymphomatoid papulosis is unknown. Debate persists over whether (1) lymphomatoid papulosis is a benign chronic disorder of activated T cells responding to external or internal stimuli or (2) lymphomatoid papulosis is an indolent T-cell malignancy localized to skin and held in check by the host immune system.

A few investigators have discovered viruslike particles in lymphomatoid papulosis lesions examined under electron microscopy.^[13]

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Epidemiology

US frequency

The prevalence of lymphomatoid papulosis is estimated to be 1.2-1.9 cases per million population. The CD30⁺ cutaneous lymphoproliferative disorders account for approximately 25% of cutaneous T-cell lymphoma cases.

Race

Black persons may be less affected by lymphomatoid papulosis than persons of other racial groups.

Sex

No consistent sex predominance is found in studies of lymphomatoid papulosis, but some studies have reported a male-to-female ratio of 1.5-2:1.

Age

Lymphomatoid papulosis may develop at any age, but the peak incidence occurs in the fifth decade.

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Prognosis

The prognosis of lymphomatoid papulosis (LyP) is good because most patients have a chronic, indolent course. A retrospective cohort analysis found that no patients with lymphomatoid papulosis died of the disease, and the overall survival rate was 92% at 5 and 10 years.

Physicians are guardedly optimistic about the prognosis because estimates indicate that as many as 4-25% of patients have a history of associated malignant lymphoma (ALCL, HD, MF) prior to, concurrent with, or subsequent to the diagnosis of lymphomatoid papulosis.^{[14, 15]} Unfortunately, no clinical or histologic factors analyzed to date are predictive of worse outcomes in persons with lymphomatoid papulosis. A study suggested that fascin expression is increased in lymphomatoid papulosis cases associated with a malignant lymphoma.^[16] Alterations in transforming growth factor-beta signaling are hypothesized to play a role in the progression of lymphomatoid papulosis to malignant lymphoma. Additionally, data have shown an increased risk of associated lymphomas in lymphomatoid papulosis cases with CCR3⁺ atypical cells or the 30M362 allelic form of the CD30 promoter.

Primary cutaneous anaplastic large cell lymphoma (pcALCL) is more likely than mycosis fungoides (MF) to manifest as an ulcerated tumor and palpable lymph nodes. MF is the most common variant of cutaneous T-cell lymphoma and is characterized by the development of red patches or plaques in sun-protected areas. MF is more likely to manifest as patches and plaques than tumors. Disease-specific survival at 5 and 10 years for pcALCL was 85% in a 2003 study.^[17]

Associated lymphomas more rarely include immunoblastic lymphoma, lethal midline granuloma (currently considered as natural killer cell lymphoma in many patients), and systemic lymphocytic lymphoma. In most patients, the malignancy develops many years after the diagnosis of lymphomatoid papulosis.

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Patient Education

Instruct patients that they are not an infectious risk to others.

Instruct patients about local wound care of open crusted lesions. Lesions should be cleaned with mild soap and water twice daily, and topical petroleum ointment should be applied to prevent infection and aid healing. Crusted lesions should be covered with a loose adhesive bandages until healed.

Instruct patients to contact their physician if any of the following symptoms or signs develop that may herald the onset of infection or associated malignancy:

• Fever, chills, night sweats, or weight loss
• Persistent skin nodules or patches that do not regress over a 2- to 3-month period
• Enlarged lymph node glands in the neck, groin, or axillae

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History

Most patients with lymphomatoid papulosis (LyP) describe the gradual onset of an asymptomatic to mildly pruritic papular eruption. Papules appear in crops and resolve spontaneously within 2-8 weeks. Waxing and waning of the crops of papules may continue for decades.

Unless accompanied by systemic lymphoma, most patients have no constitutional symptoms.

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Physical Examination

Unless accompanied by systemic lymphoma, physical findings are limited to the skin and, very rarely, the oral cavity.^{[18, 19]}

Each erythematous papule evolves into a red-brown, often hemorrhagic, papulovesicular or papulopustular lesion over days to weeks, as demonstrated in the images below.

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Lymphomatoid papulosis type C on the upper back of a 65-year-old woman with waxing and waning papulonodular eruptions for almost 10 years. The eruptio....

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Lymphomatoid papulosis type A showing a cluster of pink papules and 2 crusted papules that resolved spontaneously in the left axilla of a 68-year-old ....

Some lesions develop a necrotic eschar before healing spontaneously. Occasionally, noduloulcerative lesions may be present, as in the image below.

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Crusted ulcerated papule of lymphomatoid papulosis on the left hip of a 47-year-old woman with a longer than 20-year history of recurrent papulonodula....

Each papule heals within 2-8 weeks, leaving a hypopigmented or hyperpigmented, depressed, oval, and varioliform scar.

Large nodules and plaques may take months to resolve. Carefully evaluate solitary ulcerated nodules, plaques, or masses for CD30⁺ ALCL (see image below), MF, or rarely, HD.

View Image

Large indurated plaques of anaplastic large cell lymphoma of 2-months' duration on the left lateral thigh of a 57-year-old man with a 5-year history o....

The skin distribution of lesions, characteristically, is on the trunk and extremities, although the palms and/or soles, face, scalp, oral mucosa,^[20] and anogenital area also may be involved.

Evolving lesions have been described under dermoscopy. The initial papular lesion showed a vascular pattern of tortuous vessels radiating from the center. A white structureless area was seen around the vessels. More mature lesions, hyperkeratotic papules, looked similar except the vascular pattern in the center of the lesion was obscured. As the lesions progressed to necrotic ulcerations, the vascular pattern was only seen at the periphery, while the center of the lesions was a structure of brownish-gray areas. The final, or cicatricial phase, was similar except no vessel pattern was seen.^[21]

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Laboratory Studies

No WBC count or serum chemistry abnormalities are expected in lymphomatoid papulosis (LyP) patients. However, they may be abnormal in patients with an associated lymphoma. Therefore, complete blood cell count and differential, blood chemistries, including lactate dehydrogenase (LDH), are recommended at baseline. Serology for human T-cell lymphotropic virus-1/2 is recommended only in areas with endemic human T-cell lymphotropic virus infection to identify adult T-cell lymphoma/leukemia, in which expression of CD30 by tumor cells can occur.^[14]

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Imaging Studies

No imaging studies are indicated for newly diagnosed patients with lymphomatoid papulosis (LyP), unless there are clinical concerns for a secondary lymphoma.

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Procedures

Obtain skin biopsy specimens from two or more fully developed inflammatory papules without necrosis or excoriation.

Skin biopsy is indicated to confirm the diagnosis and to exclude primary cutaneous ALCL, if possible. Because histologic distinction may be difficult, consult a dermatopathologist with experience in diagnosing lymphoproliferative skin disorders.

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Histologic Findings

Upon low-power histologic examination, lymphomatoid papulosis shows a wedge-shaped dense dermal infiltrate of lymphoid cells with numerous eosinophils, neutrophils, and atypical lymphocytes. As much as 50% of the infiltrate shows the atypical lymphocytes. Epidermotropism of lymphoid cells may occur. Dermal vessels may show endothelial swelling, fibrin deposition, and red blood cell extravasation.

Histologically, lymphomatoid papulosis is divided into the following subtypes^{[27, 28]} :

• Type A is characterized by large (25-40 µm) CD30⁺ atypical cells intermingled with a prominent inflammatory infiltrate. The large tumor cells have polymorphic convoluted nuclei with a minimum of 1 prominent nucleolus and resemble Reed-Sternberg cells when binucleate, as is seen in HD. Type A lymphomatoid papulosis is the most common histologic variant and accounts for 75% of all lymphomatoid papulosis specimens.
• Type B is characterized by smaller (8-15 µm) atypical cells with hyperchromatic cerebriform nuclei resembling the atypical lymphocytes in MF. CD30⁺ large cells are rare, but epidermotropism is more common in this variant. There is some concern that Type B lymphomatoid papulosis may be better classified as a papular variant of MF.
• Type C (diffuse large cell type) is characterized by sheets of CD30⁺ anaplastic large cells indistinguishable from ALCL, with the exception of the minimal subcutaneous invasion. These lesions resolve spontaneously and are therefore classified as lymphomatoid papulosis; however, some authorities view this histologic variant as borderline ALCL or, perhaps, pcALCL.^[29]
• Type D epidermotropic CD8 variant of lymphomatoid papulosis mimics primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma histologically with CD8⁺ CD30⁺ atypical T cells infiltrating the epidermis. Clinically, patients present with rapidly ulcerating papulonodules.^[30]
• Type E angioinvasive lymphomatoid papulosis is characterized by an angiodestructive infiltrate of small-to-medium atypical lymphocytes with CD30⁺ and often CD8⁺ staining.^[31]

Uncommonly, patients may have more than one histologic subtype of lymphomatoid papulosis. In 2013, 11 cases with spontaneously regressing papules were described harboring chromosomal rearrangements of the DUSP22-IRF4 locus on 6p25.3.^[32] The overall findings suggest that these cases may represent a newly recognized of lymphomatoid papulosis subtype characterized by 6p25.3 rearrangements.

Immunophenotyping and molecular findings

CD 30 (Ki-1) expression is characteristic. The atypical lymphocyte is predominantly a CD4⁺ helper/inducer T cell with HLA-DR and interleukin 2 receptor (CD25) expression and variable loss of CD5 and/or CD7 antigen expression. CD30⁺ expression is characteristic, but, paradoxically, the small tumor cells in lymphomatoid papulosis type B are usually CD30 negative. Tumor cells in lymphomatoid papulosis may express cytotoxic molecules such as CD56, TIA-1, and granzyme B. CXCR3, a Th1 cell marker, is expressed in up to 85% of lymphomatoid papulosis cases. Emergence of CCR4 positivity, a Th2 marker common in pcALCL, has been hypothesized as a risk factor for malignant progression. CD8 lymphomatoid papulosis is now considered a distinct clinical entity.

Clonality in lymphomatoid papulosis is controversial, and not all cases of lymphomatoid papulosis in the literature are clonal as detected by analysis of T-cell antigen receptor genes. However, monoclonal rearrangement of the T-cell antigen receptor has been detected in 40-90% of lymphomatoid papulosis lesions, and identical clones have been demonstrated in the peripheral blood cells of patients with severe disease. One investigation suggested that the cell infiltrate in lymphomatoid papulosis comprises a mixture of polyclonal large atypical cells (CD30⁺) and smaller monoclonal T cells (CD30-negative). The (2;5)(p23;q35) translocation is not detected.

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Staging

No staging scheme has been described for lymphomatoid papulosis.

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Medical Care

Localized mildly pruritic skin lesions may be treated with mid- to high-potency topical steroids to hasten resolution. Some authorities are more inclined to treat widespread lesions with systemic or more aggressive topical therapies, including phototherapy, to suppress the disease and the possibility of progression to Hodgkin disease (HD), anaplastic large cell lymphoma (ALCL), or mycosis fungoides (MF).

Low-dose weekly methotrexate (MTX)^{[33, 34, 35, 36]} is a safe and effective treatment for suppressing lymphomatoid papulosis (LyP)^{[37, 38]} ; however, the disease recurs within 1-2 weeks after discontinuing the medication.

Oral psoralen plus UVA (PUVA) phototherapy also effectively treats and suppresses the disease.

One report describes successful treatment of recalcitrant lymphomatoid papulosis in using PUVA-bath photochemotherapy in a pediatric patient.^[39]

A few reports also have found that topical carmustine, topical nitrogen mustard, topical MTX, topical imiquimod cream,^[40] intralesional interferon, low-dose cyclophosphamide, chlorambucil, medium-dose UVA-1 therapy, excimer laser therapy,^[41] photodynamic therapy,^[42] and dapsone help disease suppression.

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Consultations

Consultation with a dermatologist is recommended for evaluating clinical findings and obtaining skin biopsy specimens of appropriate lesions. Ideally, consult a dermatologist with experience in the management of cutaneous lymphomas.

Consultation with a dermatopathologist is recommended for histologic evaluation of skin biopsy specimens, with occasional consultation by a hematopathologist for patients with borderline biopsy results.

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Activity

Lymphomatoid papulosis mandates no activity restrictions.

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Long-Term Monitoring

Patients with lymphomatoid papulosis (LyP) require long-term follow-up, preferably twice yearly, to monitor the disease and evaluate for the development of associated lymphoma.

Patients on systemic therapy or PUVA phototherapy require closer monitoring for adverse effects.

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Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

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Methotrexate (Folex, Rheumatrex)

• Dosing, Interactions, etc.

Clinical Context:  Methotrexate is an antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells; it may suppress the immune system. Methotrexate is a first-line oral agent for the treatment of LyP. The disease usually is sensitive to low, weekly oral doses. Adjust the dose gradually to attain a satisfactory response.

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Class Summary

Antimetabolites inhibit cell growth and proliferation by blocking key steps of the cell cycle.

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Methoxsalen (8-MOP, Oxsoralen)

• Dosing, Interactions, etc.

Clinical Context:  Methoxsalen inhibits mitosis by binding covalently to pyrimidine bases in DNA when photoactivated by UVA. In Europe, this modality is more popular than MTX for treating LyP. It is available in a 10-mg capsule.

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Class Summary

Phototherapy agents induce apoptosis in activated T cells. PUVA phototherapy effectively treats and suppresses disease.

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