Lymphomatoid Papulosis

Practice Essentials

Lymphomatoid papulosis (LyP) is a chronic papulonecrotic or papulonodular skin disease with histologic features suggestive of a malignant lymphoma. It is characterized by recurrent crops of papules at different stages of development that predominantly arise on the trunk and limbs; commonly, these are pruritic, but they may be asymptomatic. Eroded or ulcerated lesions may be painful. The papules heal spontaneously over 1-2 months, usually leaving slightly depressed oval scars.^[1] LyP is part of a spectrum of CD30 (Ki-1)–positive (CD30⁺) cutaneous lymphoproliferative disorders (LPDs) that also includes primary cutaneous anaplastic large cell lymphoma (pcALCL) and borderline CD30⁺ lesions.

The 2016 World Health Organization (WHO) classification of lymphoid neoplasms described newer subtypes of LyP with similar clinical behavior but atypical histologic or immunophenotypic features. It classified LyP as an indolent T-cell LPD of the skin, under primary cutaneous CD30⁺ T-cell LPDs, along with pcALCL.^[2] The 2018 WHO–European Organization for Research and Treatment of Cancer (EORTC) classification categorized LyP similarly.^[3]

The rationale for classifying LyP as a cutaneous lymphoma is its association with other malignant LPDs; however, some experts have hesitated to classify this chronic skin disease as a true malignancy, because of its spontaneous resolution and benign clinical course.^{[4, 5, 6, 7]}

LyP is not a homogeneous syndrome; the diagnosis requires a combination of clinical features and histopathologic and immunohistochemical findings.^[8] Six different histologic subtypes have been recognized by the WHO-EORTC: A, B, C, D, E, and LyP with rearrangement 6p25.3.^[3] Subtype A is the most common one, accounting for 75-80% of cases.^[8] Single cases with a combination of subtypes have also been reported.^[8] Several rare variants—such as folliculotropic (subtype F),^[9] acral,^[10] syringotropic, spindle cell, angioinvasive, pseudoepitheliomatous, intralymphatic, and granulomatous eccrinotropic^[11] —have been reported but have not been formally recognized.

See also Cutaneous CD30+ (Ki-1) Anaplastic Large-Cell Lymphoma, as well as Cutaneous Melanoma, Malignant Melanoma, and Cutaneous T-Cell Lymphoma.

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Background

The term lymphomatoid papulosis (LyP) originally was used by Macaulay^[12] in 1968 to describe "a self-healing rhythmical paradoxical eruption, histologically malignant but clinically benign." Because of its typical waxing and waning clinical course, LyP was previously considered a pseuodolymphomatous inflammatory process.

Subsequently, however, classification of cutaneous lymphomas evolved rapidly, and during consensus meetings in 2003-2004, the World Health Organization (WHO)–European Organization for Research and Treatment of Cancer (EORTC) classification grouped LyP among the indolent cutaneous T-cell lymphomas. These classifications were subsequently reviewed and updated by the WHO-EORTC in 2008,^{[13, 14, 15]} by the WHO in 2016,^[2] and again by the WHO-EORTC in 2018.^[3]

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Pathophysiology

The CD30 antigen is a type 1 transmembrane glycoprotein of the tumor necrosis factor (TNF) receptor superfamily. In addition to the CD30⁺ LPDs, 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⁺ lymphoproliferative disorders (LPDs), including 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 LyP 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 LyP, and the 30M362 allelic form was associated with progression to other CD30⁺ lymphomas in LyP patients.^[16]

Genetic instability of tumor cells may lead to altered expression of apoptotic proteins and immune-regulatory molecules, such as transforming growth factor (TGF)-β. Other research has found overexpression of JunB,^[17] 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 LyP is seen almost universally, whereas regression occurs in only about 25% of primary cutaneous ALCL (pcALCL) cases. Therefore, the higher apoptotic index found in LyP as compared with pcALCL is not surprising. The proapoptotic protein Bax is also expressed at high levels in CD30⁺ cutaneous LPDs 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.^[18]

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Etiology

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

A few investigators have discovered viruslike particles in LyP lesions examined under electron microscopy.^[19]

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Epidemiology

US statistics

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

Age-, sex-, and race-related demographics

LyP may develop at any age, but the peak incidence occurs in the fifth decade. No consistent sex predominance has been established in studies of LyP, but some studies have reported a male-to-female ratio of 1.5-2:1. Black persons may be less affected by LyP than persons of other racial groups.

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Prognosis

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

Physicians tend to be guardedly optimistic about the prognosis because an estimated 4-25% of patients have a history of associated malignant lymphoma (ALCL, HD, or MF) before, concurrently with, or after the diagnosis of LyP.^{[20, 21, 22]} Unfortunately, no clinical or histologic factors analyzed to date have proved to be predictive of worse outcomes in persons with LyP. Fascin expression may be increased in LyP cases associated with malignant lymphoma.^[23] Altered TGF-β signaling may play a role in the progression of LyP to malignant lymphoma. Additionally, LyP cases with CCR3⁺ atypical cells or the 30M362 allelic form of the CD30 promoter.have shown an increased risk of associated lymphomas.

pcALCL is more likely than 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 as tumors. Disease-specific survival at 5 and 10 years for pcALCL was 85% in a 2003 study.^[24]

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 LyP.

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Patient Education

Patients should be informed that they do not pose an infectious risk to others. They should be educated regarding 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 bandage until healed.

Patients should know 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 LyP is accompanied by systemic lymphoma, most patients have no constitutional symptoms.

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Physical Examination

Unless LyP is accompanied by systemic lymphoma, physical findings are limited to the skin and, very rarely, the oral cavity.^{[25, 26]}

Each erythematous papule evolves into a red-brown, often hemorrhagic, papulovesicular or papulopustular lesion over days to weeks (see 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 (see 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⁺ anaplastic large cell lymphoma (ALCL; see the image below), mycosis fungoides (MF), or, rarely, Hodgkin disease (HD).

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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 characteristic skin distribution of lesions is on the trunk and extremities, though the palms or soles, the face, the scalp, the oral mucosa,^[27] or the anogenital area also may be involved.

Evolving lesions have been described under dermatoscopy.^[28] 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 that the vascular pattern in the center of the lesion was obscured. As the lesion progressed to necrotic ulceration, the vascular pattern was seen only at the periphery, and the center of the lesion contained a structure of brownish-gray areas. The final (cicatricial) phase was similar, except that no vessel pattern was seen.

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Approach Considerations

Diagnosis of lymphomatoid papulosis (LyP) can be challenging. The clinical features can vary, with some patients presenting with few lesions (paucilesional LyP), and the multitude of histologic patterns necessitates expert dermatopathologic and clinicopathologic correlation. Some cases are labeled as indeterminant because even with extensive immunohistochemistry, a definitive diagnosis may not be achieved.

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Laboratory Studies

No white blood cell (WBC) count or serum chemistry abnormalities are expected in LyP patients, but these values may be abnormal in patients with an associated lymphoma. Accordingly, a complete blood count (CBC) with differential and blood chemistries (including lactate dehydrogenase [LDH]) are recommended at baseline. Serology for human T-cell lymphotropic virus (HTLV) 1 and 2 is recommended only in areas with endemic HTLV infection to identify adult T-cell lymphoma or leukemia, in which expression of CD30 by tumor cells can occur.^[20]

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Imaging Studies

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

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Procedures

Skin biopsy is indicated to confirm the diagnosis and to exclude primary cutaneous anaplastic large cell lymphoma (pcALCL), if possible. Specimens should be obtained from two or more fully developed inflammatory papules without necrosis or excoriation.

Because histologic distinction may be difficult, it is advisable to consult a dermatopathologist with experience in diagnosing lymphoproliferative disorders (LPDs) of the skin.

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Histologic Findings

Upon low-power histologic examination, LyP 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, LyP is divided into the following subtypes^{[3, 34, 35, 36]} :

• Subtype A - This 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 one prominent nucleolus and resemble Reed-Sternberg cells when binucleate, as in HD; subtype A is the most common histologic variant and accounts for 75% of all LyP specimens
• Subtype B - This is characterized by smaller (8-15 µm) atypical cells with hyperchromatic cerebriform nuclei resembling the atypical lymphocytes in mycosis fungoides (MF); CD30⁺ large cells are rare, but epidermotropism is more common in this variant; some authorities feel that this subtype may be better classified as a papular variant of MF
• Subtype C (diffuse large cell type) - This is characterized by sheets of CD30⁺ anaplastic large cells indistinguishable from those of ALCL, except for the minimal subcutaneous invasion; although these lesions resolve spontaneously and are therefore classified as LyP, some authorities view this histologic variant as borderline anaplastic large cell lymphoma (ALCL) or perhaps pcALCL^[37]
• Subtype D (epidermotropic CD8 variant) - This 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^[38]
• Subtype E (angioinvasive) - This is characterized by an angiodestructive infiltrate of small-to-medium atypical lymphocytes with CD30⁺ and often CD8⁺ staining^[39]
• LyP with chromosomal rearrangements of the DUSP22-IRF4 locus on 6p25.3^[36]

Uncommonly, patients may have more than one histologic subtype of LyP.

Immunophenotyping and molecular findings

Although CD30 (Ki-1) expression is characteristic, other diseases can be CD30⁺ as well; thus, CD30 positivity alone is insufficient. The atypical lymphocyte is predominantly a CD4⁺ helper/inducer T cell with human leukocyte antigen (HLA)-DR and interleukin (IL)-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^–.

Tumor cells in LyP 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 LyP is now considered a distinct clinical entity.

Clonality in LyP is controversial. Not all cases of LyP 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 LyP 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 LyP comprises a mixture of polyclonal large atypical cells (CD30⁺) and smaller monoclonal T cells (CD30^–). The (2;5)(p23;q35) translocation is not detected.

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Approach Considerations

Typical treatment for lymphomatoid papulosis (LyP) is a combination of topical corticosteroids, methotrexate (MTX) and phototherapy (ultraviolet [UV]-A and UV-B). There is, however, insufficient evidence to prove that early treatment prevents the development of a second malignancy or affects the course of the disease. Thus, in view of the mild and self-limiting nature of the disease, an active surveillance strategy can be the first-line treatment.^[40]  MTX remains the treatment of choice for LyP.

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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 reduce the possibility of progression to Hodgkin disease (HD), anaplastic large cell lymphoma (ALCL), or mycosis fungoides (MF).

Low-dose weekly MTX^{[41, 42, 43, 44]} is a safe and effective treatment for suppressing LyP.^{[45, 46]}  Some patients may require higher weekly doses. Recurrence of disease several weeks after discontinuance of methotrexate is common.

Oral psoralen plus UV-A (PUVA) phototherapy also effectively treats and suppresses the disease.

One report described successful use of PUVA-bath photochemotherapy to treat recalcitrant LyP in a pediatric patient.^[47] Another report described successful treatment of a pediatric patient with full-body narrowband UV-B light and targeted photodynamic therapy with 20% aminolevulinic acid.^[48]

A few reports also have found that topical carmustine, topical nitrogen mustard, topical MTX, topical imiquimod cream,^[49] intralesional interferon, low-dose cyclophosphamide, chlorambucil, medium-dose UV-A1 therapy, excimer laser therapy,^[50] photodynamic therapy,^[51] and dapsone helped disease suppression.

Various other agents, most of which target CD30 (eg, anti-CD30 monoclonal antibodies and conjugated antibodies [brentuximab vedotin] and chimeric antigen receptor T-cell [CAR-T] therapy), are under investigation for the treatment of LyP.^[40]

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Consultations

Consultation with a dermatologist is recommended for evaluating clinical findings and obtaining skin biopsy specimens of appropriate lesions. Ideally, the dermatologist should have substantial 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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Long-Term Monitoring

Patients with 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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Methotrexate (Jylamvo, Otrexup, Rasuvo)

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Clinical Context: 

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Methoxsalen (8MOP, Oxsoralen, Oxsoralen Ultra)

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Clinical Context: 

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