CD30 signaling is known to have an effect on the growth and survival of lymphoid cells. CD30 transcription is controlled by a genetically determined polymorphic promoter. In a study published in 2005, colleagues from Western Australia and I analyzed CD30 promoter microsatellite alleles in 32 unrelated Caucasian patients diagnosed with LyP alone or LyP plus lymphoma, as well as 8 unrelated Caucasian patients with CD30+ primary cutaneous ALCL. Controls were 57 Caucasian healthy volunteers and patients with nonlymphoid malignancies. Patients and controls were gender-matched. We determined that two allelic forms of the CD30 promoter microsatellite repressive element, designated 30M377 and 30M362, are associated with the development of lymphomatoid papulosis and CD30+ lymphomas in lymphomatoid papulosis patients, respectively. These findings suggest that allele-specific differences in the control of CD30 transcription may affect the pathogenesis of the spectrum of CD30+ cutaneous lymphoproliferative disorders.[8]
In a study from Beth Israel Deaconess Medical Center and Harvard, we reported 35 cases of LyP beginning in childhood.[9] These patients had a significantly higher prevalence of atopy (relative risk [RR] = 3.1; 95% confidence interval [CI] = 2.2–4.3). Compared with the general population, patients with childhood-onset LyP had a significantly increased risk of developing non-Hodgkin lymphoma (RR = 226.2; 95% CI = 73.4–697.0). Fletcher and coauthors also reported an association of CD30+ PCLPD with atopic eczema beginning in childhood.[10] Three patients had primary cutaneous ALCL, of whom two developed systemic disease and one died. A fourth patient developed LyP type A, which resolved after withdrawal of cyclosporine therapy. We conclude that LyP presents similarly in children and adults, including the risk to develop lymphoma, and that all patients should be closely monitored for the development of lymphoma throughout their lives.
The interferon regulatory factor-4 (IFR4) gene is overexpressed in multiple myeloma and some B-cell lymphomas. IFR4 translocations occur in multiple myeloma and some B-cell lymphomas. Recently, recurrent translocations involving the IFR4 locus have been reported in 8 of 14 primary cutaneous ALCLs, indicating a role for IFR4 in the pathogenesis of primary cutaneous ALCL.[11]
Association of LyP With Malignant Lymphoma and Non-lymphoid Malignancies
A major concern of LyP patients, and parents of children with LyP, is whether the affected individual will develop a malignant lymphoma. Many individual or small series of cases have been reported, but there are few reports of large numbers of affected patients. In one series, including a review of the literature, 50 patients with LyP-associated lymphomas were evaluated.[12] Three main types of LyP-associated lymphomas were distinguished: cases associated with mycosis fungoides (19/50), Hodgkin disease (12/50), and CD30+ large-cell lymphoma (16/50). Mycosis fungoides and Hodgkin disease could develop before, after, or concurrent with LyP, but CD30+ large-cell lymphoma always developed in patients with existing LyP, often showing a slow progression from regressing LyP lesions to persistent skin tumors.
LyP patients with mycosis fungoides, Hodgkin disease, and CD30+ large-cell lymphoma limited to the skin generally had a favorable prognosis.[12] The prognosis of LyP patients developing a systemic CD30+ large-cell lymphoma was generally poor. Few LyP patients develop Hodgkin disease followed by a systemic CD30+ large-cell lymphoma, which also is associated with a poor prognosis. In a subsequent review of 118 LyP patients in the Netherlands, 23 (19%) developed malignant lymphoma—11 developed mycosis fungoides; 10, CD30+ ALCL; and 2, Hodgkin lymphoma.[3]
The relationship between LyP (a T-cell disorder) and Hodgkin disease (primarily a B-cell disorder) is poorly understood. I am aware of patients who had LyP lesions before or after Hodgkin disease. When the Hodgkin disease was treated with chemotherapy, the LyP lesions often disappeared temporarily, only to reappear shortly thereafter. In rare cases, a clonal relationship between the CD30+ cells in LyP and Hodgkin disease was shown by DNA sequencing. A clonal relationship between LyP, mycosis fungoides, and ALCL is firmly established.[13,14]
In a case-control study of 57 patients with biopsy-proven LyP and 67 individually matched controls, we found a significantly increased frequency of prior or co-existing lymphoproliferative disorders, an increased frequency of non-lymphoid malignancies, and exposure to radiation therapy.[15] Among patients with LyP, 3 had a history of Hodgkin disease, 3 had non-Hodgkin lymphoma, and 10 had mycosis fungoides; none of the control subjects reported such histories. Prospective study of this group of patients over an 8-year period (1988–1996) revealed that 6 LyP patients (10.5%) and 1 control (1.5%) developed nonlymphoid malignancies. Two patients and no controls developed lymphoid malignancies. The expected numbers of nonlymphoid and lymphoid malignancies in the LyP group, based on Surveillance, Epidemiology and End Results (SEER) data, were 1.93 and 0.15, respectively, yielding a relative risk of 3.11 (95% CI = 1.26–6.47) for nonlymphoid malignancies and 13.33 (2.44–44.05) for malignant lymphoma among LyP patients. There was no significant difference between observed and expected numbers of malignancies in the control group. These results confirm that LyP patients are at increased risk of developing lymphoid malignancies but for the first time revealed that they also have an increased risk of non-lymphoid malignancies.[16]
The prognosis of LyP patients developing a systemic CD30+ large-cell lymphoma is generally poor. In two such cases, we found that progression of LyP to systemic ALCL was associated with mutations of receptors for the lymphocyte growth inhibitor, transforming growth factor–beta, allowing unregulated growth of the CD30+ cells.[17,18]
Treatment
Control of LyP lesions does not appear to affect the risk of developing lymphoma. Most patients with few or infrequent papules do not require therapy. For patients with extensive papules, nodules, and/or scarring lesions, particularly on the face, hands, or legs, which are cosmetically disturbing, the most effective therapies are low-dose oral methotrexate or psoralen plus ultraviolet A or ultraviolet B (PUVA/UVB). Methotrexate is effective in controlling lesions in approximately 90% of patients and induces a permanent remission in up to 20% of patients.[19]
Vonderheid treated 45 patients with relatively severe LyP, CD30+ primary cutaneous ALCL, and interface/borderline lesions with oral methotrexate.[19] During induction, patients received 10 to 60 mg/wk (median = 20 mg/wk). Clinical improvement usually occurred quickly, typically at doses of 15 to 20 mg weekly, and satisfactory long-term control was achieved in 39 patients (87%) with maintenance doses given at 10- to 14-day intervals (range = 7–28 days). Responding patients were usually free of active lesions within 4 weeks of receiving the first dose. After methotrexate was discontinued, 10 patients remained free of CD30+ lesions for more than 24 months to more than 227 months (median = > 127 months. The median total duration of methotrexate therapy for all patients exceeded 39 months (range = 2–205 months). Adverse effects were generally mild and transient, and included fatigue (47%), nausea (22%), weight loss (13%), diarrhea or gastrointestinal cramping (10%), increased serum hepatic transaminase levels (27%), anemia (11%), or leukopenia (9%). Early hepatic fibrosis was found in 5 of 10 patients, all of whom had been treated for more than 3 years (range = 38–111 months).
