Lymphomatoid Papulosis

Are You Confident of the Diagnosis?

• What you should be alert for in the history

Lymphomatoid papulosis (LyP) is characterized by a chronic relapsing course with grouped or disseminated papulonodular lesions involving the trunk and/or extremities. The duration of the disease may vary from less than 1 year to several decades. The eruption is generally asymptomatic. However, some patients complain of a mild itching. Each individual lesion evolves rapidly and regresses within a few weeks or months, usually over 3 to 12 weeks. The lesions heal with occasional secondary scarring.

The interval between relapses is variable. Some patients never experience complete remission and suffer from a constant appearance of new lesions. Waxing and waning of recurrent papulonodular lesions is a hallmark of LyP. Ask the patient about such a specific nature of the eruption.

LyP has been found to be associated with additional lymphomatous neoplasms that may precede, concur or develop after the onset of the eruption. It is therefore important to inquire about a previous history of lymphoma, particularly mycosis fungoides (MF), primary cutaneous or nodal anaplastic large cell lymphoma (ALCL), or Hodgkin`s lymphoma. Ask for the presence of B symptoms.

• Characteristic findings on physical examination

The characteristic findings on physical examinations are reddish to reddish-brown papular, papulonodular or small nodular lesions (usually up to 1cm) in different stages of evolution. Central necrosis leading to ulceration and hemorrhagic crusting is common (Figure 1). Occasionally collarette-like scales are observed (Figure 2). This polymorphous eruption is usually generalized, located predominantly on the trunk and limbs (Figure 3). Rarely the lesions affect other areas, such as face, palms and soles, or may be localized to just one anatomic area.

Figure 1.

Figure 2.

Figure 3.

The number of lesions may vary from a few to many. Hypo- or hyperpigmented superficial atrophic scars are occasionally observed. Look carefully for the possible presence of patches and plaques suggestive of MF, which is the most frequently associated lymphoma. Check for the presence of any enlarged peripheral lymph nodes (cervical, clavicular, axillary or inguinal).

• Expected results of diagnostic studies

Histologic examination, including immunohistochemical staining, is the next step in the diagnostic work-up. It is better to obtain a biopsy (at least 4mm in diameter) from a fully developed lesion to capture the characteristic findings of LyP. The histologic features of LyP are variable with 3 main subtypes: type A, the most common; type B, the least common; and type C.

Type A is characterized by a a wedge-shaped diffuse dermal infiltrate containing scattered or clustered medium-sized to large pleomorphic or anaplastic lymphoid cells that are positive for CD30 (Figure 4). These cells are admixed with many inflammatory cells, including small lymphocytes, histiocytes, eosinophils and neutrophils. The CD30+ lymphocytes are positive for CD3+, with usually a CD4+/ CD8- phenotype (Figure 5).

Figure 4.

Figure 5.

Type B is characterized by features that are indistinguishable from early stage MF. There is an epidermotropic infiltrate of small atypical lymphocytes with a lymphocytic infiltrate in the upper dermis. The infiltrate is usually negative for CD30.

Type C is characterized by histopathologic and immunohistochemical features that are indistinguishable from those of primary cutaneous anaplastic large cell lymphoma (PCALCL). There are cohesive sheets of CD30+ large atypical lymphocytes with only a few admixed reactive inflammatory cells. These CD30+ cells are CD4+ in most cases and are negative for epithelial membrane antigen (EMA) and anaplastic large cell lymphoma kinase (ALK).

Some LyP lsions may show combined histologic features of the different variants in the same specimen. If you obtain more than one biopsy, be aware that different histopathologic variants can be observed in different lesions in the same individual.

Once a histopathologic report is received, it is crucial to make a clinicopathologic correlation to reach the correct diagnosis and to avoid overdiagnosis of either MF or PCALCL. Clonal rearrangement of T-cell receptor genes done by PCR is found in up to 80% of the specimens. Usually, it is not mandatory to check for the presence of clonality to reach the correct diagnosis.

Recommended laboratory studies include complete blood count with differential, blood chemistry including LDH.

There are no published guidelines about radiologic examinations recommended for patients with LyP and normal physical examination and laboratory blood tests. However, to rule out the presence of a concurrent lymphoma, it is reasonable to order at least chest x-ray and abdominal ultrasound (US). A bone marrow biopsy is not indicated.

Certainly, when lymphoma is suspected, additional imaging studies should be performed, such as computed tomography (CT) of chest, abdomen, pelvis and inguinal areas or positron-emission tomography (PET)/CT. Lymph node biopsy should be done if an enlarged lymph node is detected.

• Diagnosis confirmation

The diagnosis of LyP is based on the correlation of the clinical and the histopathologic findings. The most frequent clinical differential diagnosis of LyP is pityriasis lichenoides et varioliformis acuta (PLEVA). Patients with PLEVA usually are younger, have a papular eruption and do not develop nodular lesions. In addition, usually there are more lesions in PLEVA than in LyP. The histopathologic findings are different in PLEVA.

Small recurrent LYP lesions may be misdiagnosed clinically as a persistent arthropod bite reaction or folliculitis. Histopathologic differentiation is generally not difficult. However, in rare cases of arthropod bites the histopathologic features may simulate LyP with the presence of scattered CD30+ T cells in a mixed inflammatory infiltrate.

The rare papular variant of MF can be difficult to differentiate from LyP type B, given the identical histopathologic findings in both entities. However, the papules of MF do not tend to wax and wane and do not present with ulceration, as in the case of LyP.

The most challenging differential diagnosis is PCALCL. The combination of waxing and waning papulonodular eruption with histopathologic findings of PCALCL is diagnostic for LyP type C. However, in patients presenting with a short history of papulonodular eruption, it may be almost impossible to differentiate between multifocal PCALCL and LyP type C. In such cases, the presence of lesions above 2cm in diameter favors the diagnosis of PCALCL.

The term “borderline case ” has been coined to describe patients in whom, despite careful clinicopathologic correlation, a definite distinction between PCALCL and LyP could not be established. The follow-up will usually disclose the exact nature of the eruption.

Who is at Risk for Developing this Disease?

Ask the patient about previous history of lymphoma, particularly mycosis fungoides, anaplastic large cell lymphoma (primary cutaneous or nodal) and Hodgkin’s lymphoma. There is apparently a male predominance. LyP can affect any age, although it is rare among children. The peak incidence is around 40 years. There are no known precipitating factors, such as infections, use of drugs or trauma. The appearance of LyP in immunosuppressed patients after solid organ or bone marrow allograft has rarely been reported.

What is the Cause of the Disease?

• Etiology

• Pathophysiology

Both the etiology and the pathogenesis of LyP are unknown.

LyP belongs to the group of primary cutaneous CD30+ lymphoproliferative disorders. This group consists of a spectrum of diseases, ranging from the clinically indolent LyP to the more aggressive PCALCL.

The fact that there is an overlap in the clinical and histopathologic features with lymphoma, the detection of dominant clone in the lesion, and the increased risk to develop lymphoma (MF, ALCL, or Hodgkin’s lymphoma), which is sometimes clonally related to the associated LyP—all these led many investigators to regard LyP as a low-grade cutaneous T-cell lymphoma. In fact, LyP is recognized by the recent WHO–EORTC as a nosologic entity within the primary cutaneous T-cell lymphomas. Nevertheless, whether LyP represents an indolent lymphoma or a reactive clonal process is still debatable.

CD30 is an activation marker expressed by large lymphocytes of several lymphomas. These include LyP and ALCL (primary cutaneous, nodal including secondary cutaneous), MF with large-cell transformation, and Hodgkin’s lymphoma. CD30 may also be expressed in the skin by normal activated lymphocytes in infectious diseases (viral, including herpes simplex and HIV, parasitic and bacterial) and in inflammatory dermatoses such as atopic dermatitis.

CD30 (formerly termed Ki-1 antigen) is a TNF-like cell surface receptor that interacts with CD30 ligand. CD30 activation can result in either proliferation or apoptosis, depending on the downstream effector molecules available. The exact pathogenic role of CD30 in LyP is still unclear. Several viral infections have been implicated in the pathogenesis of CD30+ lymphoproliferative disorders, such as herpes virus including Epstein-Barr virus, but without any clear evidence.

Systemic Implications and Complications

LyP in general is not associated with systemic illness. However, patients are at high risk of developing lymphoma. Lymphoma is associated with up to 25% of patients with LyP. The most common lymphoma is MF. Because LyP-associated lymphomas may occur before, concurrent with or after onset of LyP, life-long follow-up is required in all patients with LyP including those with childhood-onset disease. No clinical risk factors for the development of these associated lymphomas have been identified. Likewise, the distinction between the different histopathologic variants of LyP has no prognostic implications.

Treatment Options

Table I. Treatment options for LyP