Lymphomatoid Papulosis in Children a Retrospective Cohort Study of 35 Cases

STUDY Lymphomatoid Papulosis in Children A Retrospective Cohort Study of 35 Cases

Tamar Nijsten, MD; Clara Curiel-Lewandrowski, MD; Marshall E. Kadin, MD

Background: Lymphomatoid papulosis (LyP) is a rare of follow-up was 9.0 years. All included patients were con- entity, considered to be part of the spectrum of the CD30+ firmed by histologic examination. cutaneous lymphoproliferative disorders. About 10% to 20% of the adult LyP patients will develop an associated Results: The age distribution was significantly differ- lymphoid malignancy. Only a few cases of LyP have been ent, with boys having an earlier onset of LyP (P=.03). described in children, and the risk of associated lym- Of the 35 LyP patients, 3 (9%) developed a malignant phoid malignancies in these patients is not known. lymphoma; all were diagnosed as having non-Hodgkin lymphoma. Compared with the general population, pa- Objectives: To study the association between child- tients with childhood-onset LyP have a significantly in- hood onset of LyP and other malignancies and to deter- creased risk of developing non-Hodgkin lymphoma (rela- mine the clinical characteristics in this subgroup of pa- tive risk, 226.2; 95% confidence interval, 73.4-697.0). tients. More than two thirds of the patients reported being atopic, which is significantly more than the expected preva- Design: Retrospective cohort study. lence of atopy (relative risk, 3.1; 95% confidence interval, 2.2-4.3). Setting: Referral center at a university hospital. Retro- spective registry for patients with LyP of childhood on- Conclusions: Lymphomatoid papulosis presents simi- set (Յ18 years). larly in children and adults, including the risk of lymphoid malignancies. Therefore, all LyP patients should Patients: Thirty-five patients with childhood-onset LyP be closely monitored throughout their lives. (19 boys and 16 girls) were interviewed by telephone using a standardized questionnaire. The median duration Arch Dermatol. 2004;140:306-312

YMPHOMATOID PAPULOSIS semble Hodgkin disease (HD) (type A), (LyP) was described by Mac- mycosis fungoides (type B), or anaplastic aulay1 in 1968 as “a clini- large-cell lymphoma (type C) (Figure 1).3 From the Department cally benign condition with The eruption is in general not asso- of Dermatology (Drs Nijsten the histopathology of a ma- ciated with systemic illness.3 However, and Curiel-Lewandrowski), lignant lymphoma.” It is a rare skin dis- about 5% to 20% of adult LyP patients will the Division of L + ease within the spectrum of the CD30 cu- develop a malignant lymphoma, most Hematology/Oncology, taneous lymphoproliferative disorders.2 commonly mycosis fungoides, HD, and cu- Cutaneous Oncology Program + (Dr Curiel-Lewandrowski), and The cause of LyP is unknown. There is no taneous and systemic CD30 anaplastic the Department of Pathology sex predilection, and LyP can affect indi- large cell non-Hodgkin lymphomas 18-22 (Dr Kadin), Beth Israel viduals of any age, although it has been re- (NHLs). The overall 5-year survival of Deaconess Medical Center, ported only rarely in children.3-17 The clini- LyP patients is excellent (100%).18,19 To our Harvard Medical School, cal presentation and histopathological knowledge, the possible association of Boston, Mass. features of LyP in children are compa- childhood onset of LyP and lymphoid ma- Drs Curiel-Lewandrowski and rable to those in adults, with recurrent lignancies has not been systematically as- Nijsten equally contributed to crops of reddish brown papules and/or sessed. this article. Dr Nijsten is now nodules primarily involving the trunk and We, therefore, established a retro- with the Department of 3,4 Dermatology, University extremities. Typically, recurrent epi- spective registry for LyP with childhood Hospital Antwerp, Edegem, sodes of LyP lesions will last an average onset at the Beth Israel Deaconess Medi- Belgium. The authors have no of 2 to 8 weeks, followed by spontaneous cal Center, with the primary objective of relevant financial interest in resolution with frequent secondary scar- evaluating the long-term risk of develop- this article. ring. The histologic types of LyP can re- ing lymphoid malignancies in childhood

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 cases of LyP. We also sought to identify genetic and en- vironmental risk factors for the development of LyP. The A present study details the demographic variables, the clinical characteristics, and the risk of associated malignancies of the 35 enrolled patients with childhood LyP.

METHODS

First, patients with LyP with an onset at 18 years or younger were selected from the files of the Cutaneous Oncology Clinic at Beth Israel Deaconess Medical Center and the con- sultation files of 1 of us (M.E.K.) between September 1, 1980, and June 1, 2002. The diagnosis of LyP was confirmed by a pathology report of a certified pathologist or dermato- pathologist. We attempted to locate the patients via their medical rec- ords, referring physicians, and/or recent e-mail addresses. When a telephone number was obtained and permission granted, the patient or the legal guardian (if the patient was Ͻ18 years at the time of the interview) was interviewed. The questionnaire B was standardized and conducted by 2 of us (T.N. and C.C.-L.). Participants were asked more than 50 questions concerning demographic variables, personal and familial medical history, disease characteristics, use of treatment, and clinical response to each treatment used on a scale from 1 (ineffective) to 10 (highly effective). We defined a therapy being effective as the 4 most extreme ratings on the 10-point scale. Participants were considered to be atopic when they reported ever being diagnosed by a physician as having atopic dermatitis, allergic rhinitis, seasonal allergy, and/or asthma. A written informed con- sent, and corresponding assent, if applicable, for patients younger than 16 years was obtained. The relative risk (RR) and 95% confidence intervals (CIs) of NHL in childhood LyP cases were calculated using the expected number of NHL cases in persons younger than 45 years from the Surveillance, Epidemiology, and End Results data.23 The RR and 95% CI of atopy were calculated using the expected numbers for persons 45 years or younger with asthma, Figure 1. Erythematous and violaceous papules with evidence of central rhinitis, and/or conjunctivitis from the Surveillance, Epidemi- necrosis involving the face (A) and posterior lower extremities (B) ology, and End Results registry; and for the risk estimate of white of a 13-year-old boy with lymphomatoid papulosis. children developing LyP compared with nonwhite children, we used the population census data for children 18 years and younger. was significantly different (P=.03), with boys having an We used the Mann-Whitney test to determine the statis- earlier onset of LyP (median, 5.50 years; 75th percen- tical significance in the distribution of continuous variables, tile, 13.3 years; and 25th percentile, 3.0 years) com- and the ␹2 test or the Fisher exact test to determine the statis- pared with girls (median, 12.0 years; 75th percentile, 16.0 tical significance in the distribution of categorical variables. years; and 25th percentile, 6.0 years) (Figure 2). Ex- PՅ.05 was considered significant, and all statistical tests were cept for one patient with Asian ancestry, all other pa- 2 sided. All statistical analyses were performed with Stata 7.0 tients were white, which is more than expected com- (Stata Corp, College Station, Tex) and Crunch, version 4 pared with the general population among individuals (Crunch Software Corp, Oakland, Calif). younger than 19 years (RR, 1.60; 95% CI, 1.26-2.04). The median duration of follow-up was 9.0 years (75th per- RESULTS centile, 17.5 years; and 25th percentile, 2.5 years). Fe- male patients were significantly more likely to report a Of the 48 patients with childhood-onset LyP, we were longer follow-up (P=.04). able to contact 35 (73%) in the spring of 2002. Of those Of the 35 LyP patients, 3 (9%) developed an NHL contacted, all agreed to participate in the registry. We in- (Table 2). Patients with childhood-onset LyP have a terviewed the parents of the affected individuals, except significantly increased risk (RR, 226.2; 95% CI, 73.4- for 3 participants whom we interviewed personally. The 697.0) of developing NHL compared with the general results are summarized in Table 1. population 44 years or younger in the United States. Of the 35 patients, 19 were male and 16 were fe- We did not detect significant associations between the male; the median age at onset of LyP was 8.0 years (75th development of NHL and sex, age at onset of LyP, percentile, 14.0 years; and 25th percentile, 4.0 years). The duration of follow-up, maximum number of lesions at age at the interview ranged from 2 to 52 years (median, one point in time, positive family history of lymphoid 16.0 years; 75th percentile, 27.0 years; and 25th percen- malignancies, or active disease at the interview (data tile, 9.5 years). The distribution of the age at onset of LyP not shown). The time relation between the onset of

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Minimum/Maximum Patient No./ Type of LyP No. of Skin Distribution of Active Response Follow-up, Sex/Age, y* Allergy Lesions† Lesions Ever LyP Lesions Scarring LyP‡ to Sunlight Therapy§ y

1/M/14 Atopic Papules 0/Ͼ100 Extremities Some Active Improved TS(5), Ab(1), UV-B(1), 21⁄2 dermatitis/ RA(1), and penicillin methotrexate(9) 2/M/5 None Papules 0/50-99 Extremities Some Inactive None TS(1) and UV-B(7) 81⁄2 3/F/7 None Papules/nodules 0/Ͻ10 Trunk/face Always Active None None 21⁄2 4/M/3 Seasonal Papules/nodules 1-9/Ͼ100 Extremities Some Active Improved TS(1) and Ab(1) 1⁄2 5/F/16 None Papules 1-9/Ͼ100 Generalized Never Active Improved TS(3) and UV-B(9) 2 6/F/15 Asthma Papules/nodules 0/Ͻ10 Arms Always Active Improved TS(2), Ab(1), UV-B(8), 11⁄2 and Protopic(1) 7/F/12 None Papules/nodules/ 1-9/10-49 Extremities/face Some Active Improved TS(4), methotrexate(7), 40 plaques and CT(1) 8/F/17 Urticaria Papules 0/100 Generalized Some Active Improved TS(1), Ab(1), PUVA(10), 23 and prednisone(9) 9/M/5࿣ None Papules 0/10-49 Legs Some Active Improved TS(5) 2 10/M/0.9 None Papules 10-49/Ͼ100 Extremities/face Never Active Improved TS(1) 2 11/F/9࿣ Seasonal Papules/nodules 1-9/50-99 Generalized Some Active Improved TS(5), Ab(1), and 2 UV-B(7) 12/F/4 Atopic Papules 0/10-49 Generalized Never Active NA TS(2) and Ab(2) 1⁄2 dermatitis 13/F/0.8 Asthma Papules/nodules 0/Ͻ10 Generalized Some Inactive None Ab(1) 4 14/F/5 None Papules 1-9/10-49 Legs Never Active Improved TS(8) and Ab(2) 21 15/M/8 None Papules/nodules 0/Ͻ10 Trunk/legs Always Inactive None TS(1), prednisone(5), 3 and IL corticosteroids(1) 16/M/8 Cefaclor Nodules 0/Ͻ10 Extremities Always Inactive Improved TS(10) 31⁄2 17/F/18 None Papules 1-9/10-49 Extremities Always Active Improved TS(1), Ab(1), UV-B(8), 18 Tazorac(7), and Elidel(5) 18/F/12¶ Seasonal Papules 1-9/50-99 Trunk Never Active Improved TS(1), RT(7), and CT(1) 9 19/F/8 Seasonal Papules/nodules 0/Ͻ10 Extremities/face Some Inactive Improved TS(5) 25 20/M/13 Asthma Papules/nodules/ 1-9/Ͼ100 Arms/trunk/face Most Active Improved TS(9) and Ab(9) 31⁄2 plaques 21/F/15¶ Seasonal Nodules 0/10-49 Extremities Some Inactive Worse TS(1), Elidel(1), and IL 171⁄2 corticosteroids(1) 22/M/3 None Papules/nodules/ 1-9/Ͼ100 Generalized Some Active None TS(8) and Ab(8) 2 plaques 23/M/14 Seasonal/atopic Papules 0/Ͼ100 Extremities Some Inactive None Ab(9) 4 dermatitis 24/F/1 None Papules/nodules/ 0/50-99 Extremities/face Some Inactive None TS(5) and Ab(6) 9 plaques 25/M/6 Cefaclor Papules/nodules 10-49/Ͼ100 Extremities Some Active Improved TS(1) 11⁄2 26/M/14࿣ Seasonal Papules/nodules 1-9/50-99 Generalized Most Active Improved TS(6) 41⁄2 27/M/16 Seasonal Papules/nodules 0/10-49 Extremities Some Inactive Improved TS(2) and UV-B(5) 17 28/M/1.5 Seasonal Papules/nodules 1-9/Ͻ10 Legs Some Active None None 121⁄2 29/M/5.5 Dust mite Papules 0/10-49 Generalized Some Inactive NA TS(1) and Ab(1) 81⁄2 30/F/15 Seasonal Papules/nodules/ 0/Ͻ10 Generalized Most Inactive None TS(3) 17 plaques 31/F/18 Seasonal Papules 0/10-49 Extremities Never Inactive NA TS(2) and Ab(5) 9 32/M/2 Seasonal Papules 1-10/50-100 Generalized Some Active Improved TS(1) and Ab(1) 1⁄4 33/M/14 None Papules/nodules 1-10/Ͻ10 Generalized Some Active None TS(1) and Ab(8) 13 34/M/6.5 None Papules 0/Ͻ10 Trunk Always Inactive NA Ab(1) and SE(5) 8 35/M/12¶ None Nodules 0/Ͻ10 Generalized Some Inactive NA Ab(7) and SE(10) 2

Abbreviations: Ab, antibiotic; CT, chemotherapy; IL, interleukin; LyP, lymphomatoid papulosis; NA, data not applicable; PUVA, psoralen−UV-A; RA, oral retinoid; RT, radiation therapy; SE, surgical excision; TS, topical corticosteroid. *At LyP onset. †Papules were 5 mm or smaller; nodules, larger than 5 mm. ‡Active indicates LyP lesions were present at the interview. §Numbers in parentheses indicate the effectiveness of the therapy, rated by the patient, on a scale from 1 to 10 (10 indicates very effective). The generic name for Protopic is tacrolimus ointment; for Tazorac, tazarotene gel; and for Elidel, pimecrolimus. ࿣Familial history of hematologic malignancies. ¶This patient had an associated lymphoma.

LyP and the development of NHL varied from simulta- tients. Three patients reported a family history of hema- neous up to more than 15 years after the onset of LyP tologic malignancies in a first- or second-degree relative (Table 2). No other cancers were reported in the 35 pa- (Table 1).

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 At some point, almost all patients developed 4 papular lesions; about half of those also reported hav- Girls ing had nodules as well (Table 1). Four patients devel- Boys oped plaquelike lesions of LyP. Only 6 subjects (17%) 3 indicated that none of the LyP lesions left residual scars. About half of the patients reported at least 1 epi- 2 sode with 50 or more LyP lesions. Of the 35 patients, No. of Persons 15 reported never experiencing complete remission, 1 with a minimum number of active lesions of 1 or more since the onset of the disease. Neither clinical appear- 0 ance nor the maximum number of LyP lesions corre- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 lated significantly with ever having complete clear- Age at Onset of LyP, y ance, activity of disease, or malignant transformation Figure 2. The distribution of age at onset of lymphomatoid papulosis (LyP) (data not shown). in boys and girls. Most patients (31 of 35) had skin lesions that re- solved spontaneously within 1 to 3 months. Four patients observed the same lesion for 6 months or more. ago). In both patients, LyP lesions reoccurred a few Six individuals categorized the average duration of epi- months after completion of the chemotherapy regimen. sodes of LyP as less than a month; 14, between 1 and 3 The use of photo(chemo)therapy and/or methotrexate was months; and 11, more than 3 months. About a third of not significantly associated with extensive (maximum the patients (13 of 35) reported that the average dura- number of lesions, Ͼ50), active, or scarring disease tion between episodes of LyP lasted 3 months or less, and (P=.26, .43, and Ͼ.99, respectively). Reporting the use 12 reported intervals of longer than 3 months. Of the 35 of 3 or more different treatments was significantly asso- patients, 3 (patients 7, 23, and 35) reported a single epi- ciated with an increased age of onset (P=.001), but not sode of LyP. When asked whether the disease had changed with duration of follow-up or maximum number of le- in time, 10 patients (29%) indicated that the disease was sions (P=.24 and .52, respectively). stable; 23 (66%), the frequency of episodes decreased; 1 At the interview, more than two thirds of the par- (3%), the frequency of episodes increased; and 1 (3%), ticipants reported having atopic dermatitis, seasonal al- the disease went into complete remission (percentages lergies (rhinitis and/or conjunctivitis), and/or asthma di- do not total 100 because of rounding). Of the 35 pa- agnosed by a physician. Atopy was associated with tients, 14 (40%) reported pruritus in association with the increasing age at the interview (P=.01). Compared with LyP lesions. About two thirds of the patients (21 of 35) the general US population 45 years or younger, patients reported having active disease at the interview. Patients with childhood LyP are significantly more likely to be with a short follow-up were significantly more likely to diagnosed as having atopy (RR, 3.1; 95% CI, 2.2-4.3). Four have active disease (P=.04). Except for persons report- persons reported cutaneous drug reactions induced by ing 50 or more LyP lesions (P=.05), none of the clinical antibiotics (Table 1). characteristics was significantly associated with a likeli- The subjects participating in the study are being clini- hood of having active disease at the interview (data not cally managed by dermatologists (n=17), oncologists shown). However, the risk of having active disease in pa- (n=8), or a dermatologist and an oncologist (n=5). Five tients with 50 or more lesions decreased significantly in participants are no longer being observed by a physi- time compared with patients who had fewer than 50 le- cian for LyP. sions (P=.009) (Figure 3). Ten years after the onset of LyP, 14 (40%) patients had active disease. COMMENT The pathology slides corresponding to 11 patients were reviewed by 1 of us (M.E.K.). The following sub- Compared with adult LyP, childhood LyP has not been types of LyP were identified: 5 type A, 2 type B, and 1 well described because of its rarity.3-17 The risk of asso- type C; 3 simultaneous features of LyP type A/B (n=2) ciated lymphoid malignancies in pediatric patients is not and A/C (n=1) were observed in the same patient. known. In this case series, 3 patients developed NHL. The Sun exposure seemed to be beneficial in most indi- observed incidence of NHL in patients with childhood- viduals (19 of 35 patients), except for patient 21, who onset LyP is more than 200 times the expected inci- reported worsening of her LyP after intense sun expo- dence of NHL in a comparable population without child- sure. Except for 2 patients, all participants received therapy hood-onset LyP. None of the participants have been for LyP (Table 1). The most commonly reported treat- seriously ill or have died of extracutaneous disease. Com- ments included topical corticosteroids (n=29), antibi- pared with adults with LyP, the risk of developing he- otics (n=19), and phototherapy (n=8). Topical cortico- matologic malignancies is similar (about 10%).18-22 We steroids and antibiotics were significantly less likely to observed only NHL and no other lymphomas associated be effective compared with photo(chemo)therapy, pri- with LyP. However, another 6-year-old patient referred marily UV-B, which was rated as effective by all but one to 1 of us (M.E.K.), not included in the study for lack of patient (P=.01). Low-dose methotrexate showed good follow-up, developed HD, nodular sclerosing type, and results in 2 patients. Two patients received chemo- LyP (M.E.K., unpublished data, 1995). In this patient, therapy (patient 18 for her NHL and patient 7, who was the HD went into remission after chemotherapy, but LyP initially misdiagnosed as having a lymphoma Ͼ25 years persisted for 21⁄2 years after treatment. The period in which

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Table 2. Characteristics of Patients With Childhood Onset of LyP Who Developed a Lymphoma*

Patient Age at Onset Interval Between LyP Histologic Active No. of LyP/Lymphoma and Lymphoma Type of LyP Type of Lymphoma/Stage/IH Treatment of Lymphoma LyP† 18 12/13 y 3 mo A NHL CD30+ CT/BMTX Yes

(systemic/nodal)/IE-IB/positive for Ki-1, LCA, UCHL-1, L26, B1, B4, ␬, and ␭ and negative for T1, T3, T4, and T8 21 15/32 y 17 y A Primary cutaneous CD30+ stage Spontaneous regression No ALCL/positive for CD30, CD43, LCA, and CD3 35 12/12 y 0 mo Unknown Primary cutaneous CD30+ stage Spontaneous regression No ALCL/positive for CD30, LCA, and CD3 and negative for Leu M1, EMA, c-kit, and Alk-1

Abbreviations: ALCL, anaplastic large cell lymphoma; BMTX, bone marrow transplantation; CT, chemotherapy; EMA, endomysial antibody; IH, immunohistochemistry; LCA, leukocyte common antigen; LyP, lymphomatoid papulosis; NHL, non-Hodgkin lymphoma. *All 3 patients were white; the lymphoma was in remission in all 3 patients. †Active disease at the interview.

minimized patients’ recall bias. The validity of self- 1.0 Patients With <50 Lesions reported atopy is reasonable.24 However, the signifi- Patients With ≥50 Lesions 0.8 cance of the association between atopy and LyP may be All Patients overestimated, because the estimate of expected preva- 0.6 lence of atopy in the general population (Surveillance, Epidemiology, and End Results data) did not include 0.4 atopic dermatitis. Excluding the 2 patients who

0.2 reported atopic dermatitis alone did not substantially Risk of Having Active LyP change the risk estimate (RR, 2.9; 95% CI, 2.0-4.2). We 0 compared the prevalence of atopy in our population 1 2 3 4 5 6 7 8 9 10 with that in the general population 44 years or younger Follow-up, y because all but one subject belonged in that category at Figure 3. The absolute risk of having active lymphomatoid papulosis (LyP) the interview. The risk would further increase if we in time for all persons, for those with fewer than 50 lesions, and for those compared our cohort with those younger than 18 years with 50 or more lesions. in the general population (RR, 3.9; 95% CI, 2.7-5.6). Although all ascertained cases were confirmed by associated malignancies have been described is compa- pathology reports, we were unable to classify the LyP rable between adult- and childhood-onset LyP, ranging cases into the 3 histologic subtypes because we could from weeks to decades.18-22 Of our 3 patients with asso- not obtain every diagnostic skin biopsy result. The ciated malignancies, 2 reported the onset of LyP and the appearance and distribution of histologic subtypes do lymphomas in the same calendar year. not seem to differ between adults and children.3 Lym- The strength of this study includes the many pa- phomatoid papulosis type A was observed on pathologi- tients assessed and the substantial follow-up, with a me- cal examination in 2 patients who developed an associ- dian of almost 10 years. This case series exceeds by far ated NHL in this cohort. In adults, LyP type A has also previous observations and the largest existing registry of been observed in association with lymphoid malignan- 10 children with LyP by the Dutch Cutaneous Lym- cies.19,25,26 phoma Working Group.3,4 Moreover, to our knowledge, The clinical characteristics of LyP in children do not we are the first to report childhood cases of LyP associ- seem to differ substantially compared with those in adults.18 ated with lymphoid malignancies. All included patients Although LyP is a chronic disease, the risk of having ac- in this registry have histologically proved diagnoses of tive disease decreases significantly in time, especially for LyP and NHL. We obtained detailed information about patients affected by more lesions, for which we do not have the patient variables, the clinical characteristics and course an explanation. More than three quarters of the patients of LyP, and the use of treatment. did not perceive changes in the frequency or duration of It is not likely that a selection bias substantially con- the episodes or in the appearance of the lesions during the founded our observations because all contacted pa- follow-up period (data not shown). tients participated in the study. An observational bias may Because cases were ascertained at a tertiary derma- have affected the high risk of NHL in those with child- tologic clinic and white persons are more likely to have hood LyP because these patients are more likely to be access to specialized medical care, the increased risk of closely monitored than children in the population with- white children developing LyP is probably overesti- out LyP. The resultant potential bias might have led to a mated. modest overestimate of the associated risk of lymphoid Although the sample size is limited, the increased malignancies. By using clear standardized questions, we risk of atopy in patients with childhood LyP is notable.

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Other lymphoproliferative diseases, such as HD and my- term use of this drug should be carefully balanced against cosis fungoides, are possibly associated with atopy.27,28 the risk of using it in a pediatric population. An atopic history seemed to have a protective effect in In summary, our study shows that LyP in children patients with HD.27 This may be because of an increased does not differ from LyP in adults, including the in- proportion of activated T helper (TH) 2–type T cells in creased risk of lymphoid malignancies. No clinical fea- patients with atopic disease, which is linked to an in- tures could be identified to predict an increased risk for creased expression of CD30, a member of the tumor ne- developing malignancies. Therefore, all patients should crosis factor/nerve growth factor receptor superfam- be carefully monitored throughout their lives. Further 29 ily. CD30 is preferentially expressed by TH2 cells and studies to investigate potential causative factors are war- is consistently expressed by the large atypical cells in pa- ranted. tients with LyP.30,31 The natural ligand for CD30 (CD153) is expressed at higher levels in regressing than non- Accepted for publication June 11, 2003. regressing skin lesions, and this may explain the unique This study was supported by a grant from the Fund for clinically benign behavior of LyP and CD30+ cutaneous Scientific Research–Flanders, Brussels, Belgium (Dr Nijsten). anaplastic large cell lymphomas.32,33 It is also possible that We thank Warren L. Macaulay, MD, for his pioneer a high expression of CD30 contributes to the abnormal description of the first case of LyP and transfer of the ini- proliferation of atypical cells in patients with LyP, as it tial registry data to one of us; Reed Drews, MD, for provid- does in Hodgkin or Reed-Sternberg cells in patients with ing the clinical images; and Robert S. Stern, MD, for his sup- HD.34 In vitro studies35-37 have given conflicting results port of this project and assistance in the statistical analysis. on the effect of CD30 activation in patients with lym- Corresponding author and reprints: Clara Curiel- phoproliferative disorders. It is possible that the differ- Lewandrowski, MD, Department of Dermatology, Beth Is- ent effects (proliferation vs cell death) are determined by rael Deaconess Medical Center, 330 Brookline Ave, Bos- the strength of the signal activating CD30, just as the dif- ton, MA 02215 (e-mail: [email protected]). ferentiation of healthy T lymphocytes toward TH1vsTH2 is determined by the strength of the signal activating the REFERENCES T-lymphocyte receptor.38 The exact role of CD30 in pa-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 18. Bekkenk MW, Franc¸oise AM, Geelen J, et al. Primary and secondary cutaneous 28. Tuyp E, Burgoyne A, Aitchison T, MacKie R. A case-control study of possible CD30+ lymphoproliferative disorders: a report from the Dutch Cutaneous Lym- causative factors in mycosis fungoides. Arch Dermatol. 1987;123:196-200. phoma Group on the long-term follow-up data of 219 patients and guidelines 29. Leonard C, Tormey V, Faul J, Burke CM, Poulter LW. Allergen-induced CD30 ex- for diagnosis and treatment. Blood. 2000;95:3653-3661. pression on T cells of atopic asthmatics. Clin Exp Allergy. 1997;27:780-786. 19. Beljaards RC, Willemze R. The prognosis of patients with lymphomatoid papu- 30. Del Prete G, De Carili M, Almerigogna F, et al. Preferential expression of CD30 losis associated with malignant lymphomas. Br J Dermatol. 1992;126:596-602. by CD4+ T cells producing Th2-type cytokines. FASEB J. 1995;9:81-86. 20. Christensen HK, Thomsen K, Vejlsgaard GL. Lymphomatoid papulosis: a fol- 31. Kadin ME, Nasu K, Sako D, Said J, Vonderheid EC. Lymphomatoid papulosis: a low-up study of 41 patients. Semin Dermatol. 1994;13:197-201. cutaneous proliferation of activated helper T cells expressing Hodgkin’s disease- 21. Cabanillas F, Armitage J, Pugh WC, Weisenburger D, Duvic M. Lymphomatoid associated antigens. Am J Pathol. 1985;119:315-325. papulosis: a T-cell dyscrasia with a propensity to transform into malignant lym- 32. Mori M, Manuelli C, Pimpinelli N, et al. CD30-CD30 ligand interaction in primary phoma. Ann Intern Med. 1995;122:210-217. cutaneous CD30+ T-cell lymphomas: a clue to the pathophysiology of clinical re- 22. Wang HH, Myers T, Lach LJ, Hseih CC, Kadin ME. Increased risk of lymphoid gression. Blood. 1999;94:3077-3083. and nonlymphoid malignancies in patients with lymphomatoid papulosis. Can- 33. Beljaards RC, Kaudewitz P, Berti E, et al. Primary cutaneous large cell lympho- cer. 1999;86:1240-1245. mas: definition of a new type of cutaneous lymphoma with a favorable progno- 23. Public Health Service, US Department of Health and Human Services. SEER Can- sis: a European multicenter study of 47 patients. Cancer. 1993;71:2097-2104. cer Statistics Review, 1973-1999. Bethesda, Md: US Dept of Health and Human 34. Horie R, Watanabe T, Morishita Y, et al. Ligand-independent signaling by over- Services, National Cancer Institute; 2001. NIH publication 97-2789. expressed CD30 drives NF-␬B activation in Hodgkin–Reed-Sternberg cells. On- 24. Kilpelainen M, Terho EO, Helenius H, Koskenvuo M. Validation of a new ques- cogene. 2002;21:2493-2503. tionnaire on asthma, allergic rhinitis and conjunctivitis in young adults. Allergy. 35. Gruss HJ, Boiani N, Williams DE, Armitage RH, Smith CA, Goodwin RG. Pleio- 2001;56:377-384. tropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell 25. Basarab T, Fraser-Andrews EA, Orchard G, Whittaker S, Russel-Jones R. Lym- lines. Blood. 1994;83:2045-2056. phomatoid papulosis in association with mycosis fungoides: a study of 15 cases. 36. Mir SS, Richter BW, Duckett CS. Differential effects of CD30 activation in ana- Br J Dermatol. 1998;139:630-638. plastic large cell lymphoma and Hodgkin’s disease. Blood. 2000;96:4307-4312. 26. Chott A, Vonderheid EC, Olbricht S, Miao NN, Balk SP, Kadin ME. The dominant 37. Levi E, Wang Z, Petrogiannis-Haliotis T, et al. Distinct effects of CD30 and Fas T cell clone is present in multiple regressing skin lesions and associated T cell signaling in cutaneous anaplastic lymphoma: a possible mechanism for disease lymphomas of patients with lymphomatoid papulosis. J Invest Dermatol. 1996; progression. J Invest Dermatol. 2000;115:1034-1040. 106:696-700. 38. Brogdon JL, Leitenberg D, Bottomly K. The potency of TCR signaling differen- 27. Amlot PL, Slaney J, Brown R. Atopy: a favourable prognostic factor for survival tially regulates NFAT c/p activation and early IL-4 transcription in naı¨ve CD4+ T in Hodgkin’s disease. Br J Cancer. 1983;48:209-215. cells. J Immunol. 2002;168:3825-3832.

News and Notes

he 25th Symposium of the International Soci- T ety of Dermatopathology will be held in Lisbon, Portugal, September 16-18, 2004, under the patronage of the International Society of Dermatopathology and the Portuguese Society of Dermatology and Venereolgy. Sci- entific Committee: L. Cerroni, O. Sangueza, H. Kutzner, L. Requena, E. Vale, L. Almeida. The preliminary program is presented on www.intsocdermpath.org or www .mundiconvenius.pt. For further information, contact: MUNDICONVENIUS, Rua do Embaixador, 13-2°, 1300-215, Lisboa, Portugal; phone: ++351213649498; fax: ++351213649523; e-mail: saudade_leitao @mundiconvenius.pt.

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