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.
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).
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.
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?
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.
Table I. Treatment options for LyP
|Medical Teatment||Surgical procedures||Physical Modalities|
|Topical corticosteroids||Excision of a lesion||PUVA|
|MTX||NBUVB, UVA1,BBUVB, UVA+UVBbath-PUVA|
|Topical:imiquimodbexarotenenitrogen mustardSystemic:retinoidsantibiotics: tetracyclines, erythromycinacyclovirIFN-alpha||Targeted phototherapyPhotodynamic therapyRadiation|
Optimal Therapeutic Approach for this Disease
Explain that there is no curative treatment for LyP. In general, none of the therapies have been shown to alter the chronic natural course of the disease. Only a few patients achieve sustained complete remission following discontinuation of treatment. Currently, there is no evidence that treatment prevents LyP-associated second lymphomas. Therefore, the short-term benefit of any treatment should be balanced carefully against the potential side effects.
All the recommendations for treatment are based only on retrospective studies on small series of patients (most of them are not fully detailed) as well as on the personal experience of experts in the field. Treatment options are summarized in Table I.
Taken together, non-interventional strategy is a legitimate first-line approach. In general, PUVA and MTX are the best-documented and probably the most effective treatment for LyP.
Determine the extent of the eruption and its effect on the patient’s quality of life.
In patients with relatively few lesions who require treatment, topical potent to superpotent steroids (clobetasol 0.05% or equivalent), especially in early evolving lesions, are the first-line treatment. Topical steroids occasionally accelerate regression, however, they will not prevent the appearance of new lesions. For a particularly disturbing lesion, topical steroid with occlusion or intralesional steroid can be tried. Anecdotal reports with very few patients on other topical therapies for LyP have appeared in the literature including topical bexarotene and imiquimod.
Phototherapy is a second-line treatment. Most patients will respond to oral PUVA within a few weeks; some will achieve complete remission. Alternatively, therapy with other types of phototherapy can be tried: NBUVB, UVA1, BBUVB, combination of UVA and UVB (NB or BB), or bath-PUVA.
Phototherapy in general is contraindicated in patients with known systemic lupus erythematosus or photosensitive dermatoses. Caution should be exercised in those with a history of multiple non-melanoma skin cancer and melanoma and intake of photosensitizing medications. PUVA should be used with caution in the presence of liver disease. Maintenance therapy is usually not justified in this group of patients.
In patients with widespread disease who require therapy, phototherapy or low-dose MTX are the first-line recommended therapies, depending on the comorbidities and the availability of therapy. To achieve sustained control, maintenance therapy is justified in such cases.
MTX is administered in a low-dose regimen, ordinarily at doses of up to 25 to 30 mg once a week in a single oral dose. Most of the patients will respond to 15 to 20mg once a week, and usually within 4 weeks. Once the disease is adequately controlled, ie, complete remission or reduction in the number, size, and life cycle time of the lesions, the dose should be reduced to the lowest possible amount of drug needed to achieve adequate control. Alternatively, you may try to increase the interval between doses (usually 10- to 14-day intervals) to minimize the risk of toxicity, while still seeking to suppress the development of new lesions.
Once MTX is stopped, the disease usually but not invariably recurs. To reduce the side effects, oral folic acid should be supplemented to patients treated with MTX at doses of 1 to 5 mg daily, except for the day of MTX administration.
Contraindications to MTX are pregnancy, alcoholism, liver disease, significant anemia, leukopenia, thrombocytopenia. Caution should be exercised in patients with abnormalities in renal function, obesity, diabetes mellitus, and active infection. Hepatotoxic drugs and drugs that interfere with renal secretion of MTX should be avoided.
Alternatives to phototherapy and MTX
Consider the following options:
– Systemic retinoids: In practice, although the literature is limited, many recommend oral bexarotene as monotherapy for LyP.
– Because of the similarity between LyP and PLEVA, some authors reported on the effectiveness of antibiotics in LyP. Oral tetracycline HCL 2 g/day (500 mg 4 times daily) is given until control of the disease and then the dosage is reduced to 1 g/day. Alternatively, oral minocycline 100 mg once a day can be tried. (If tetracyclines are contraindicated, oral erythromycin can be administered, but the likelihood of response is very low.)
– Topical nitrogen mustard, interferon alpha in subcutaneous administration, oral acyclovir, oral retinoids other than bexarotene—all have been mentioned in anecdotal reports.
All the aforementioned therapies can be combined with topical steroids to the most disturbing lesions.
Explain the natural history of LyP. Explain that LyP is a marker for increased risk for development of lymphoma either in the skin or in other tissues. Stress that the eruption itself is not dangerous. Stress that none of the therapies are curative and after discontinuation, LyP usually relapses. Explain that none of the therapies are known to prevent the development of associated lymphomas.
Stress that life-long follow-up is mandatory in all patients since lymphoma can develop even after many years. This will include periodic physical examination of the skin and lymph nodes as well as blood tests. Explain that repeated biopsies are not indicated unless there is a suspicion for the development of cutaneous lymphoma.
Tell the patients that the risk of any treatment must be carefully weighed against the potential benefit and that usually therapy is not mandatory.
Explain the pros and cons of maintenance therapy with phototherapy, i.e., the suppression of LyP versus the potential for skin aging and non-melanoma skin cancer after long-term therapy. In case of PUVA, mention also melanoma as a potential late side effect.
Explain that complete blood count and liver function tests should be closely monitored in patients treated with MTX, and the risk for liver fibrosis and cirrhosis after long-term therapy with the drug. Stress that the risk of liver disease is correlated with high cumulative doses. Therefore, once control is achieved the doses will be reduced or the intervals between doses will be increased.
Unusual Clinical Scenarios to Consider in Patient Management
Childhood LyP: The risk/benefit ratio is of particular importance in the management of childhood LyP. Excluding oral PUVA, other types of phototherapy such as NBUVB are the first-line therapies when treatment is mandatory. PUVA-bath is a promising option for LyP in children with quite a good safety profile. If antibiotics are considered, erythromycin 30 to 50 mg/kg/day is recommended in young children, since tetracyclines are contraindicated. MTX and oral PUVA should be considered only in severe recalcitrant cases.
Localized/regional LyP, or treatment-resistant lesions: Targeted phototherapy or photodynamic therapy are reasonable options for such lesions.
A single treatment-resistant lesion: Excision or radiotherapy are possible options. If such a lesion is either larger than 2cm in diameter or is long-lasting, histopathologic evaluation of the lesion is indicated to rule out the possibility of PCALCL.
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