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CMSXXX10.1177/1203475417716366Journal of Cutaneous Medicine and SurgeryAbuHilal et al

Original Article

Journal of Cutaneous Medicine and Surgery

Associated Hematolymphoid 1­–6


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DOI: 10.1177/1203475417716366
https://doi.org/10.1177/1203475417716366

Lymphomatoid Papulosis: jcms.sagepub.com

A Canadian Retrospective Study

Mohanad AbuHilal1, Scott Walsh1, and Neil Shear1

Abstract
Background: Lymphomatoid papulosis is one of the primary cutaneous CD30+ T-cell lymphoproliferative disorders.
Although considered a benign disease, lymphomatoid papulosis has been associated potentially with an increased risk of
secondary hematolymphoid malignancies.
Objective: The aim of this study was to assess the clinical characteristics and histologic subtypes of lymphomatoid papulosis,
identify the prevalence and types of secondary hematolymphoid malignancies, and determine the potential risk factors for
development of these hematolymphoid malignancies.
Methods and Materials: A retrospective chart review was performed for all histologically confirmed cases of lymphomatoid
papulosis between 1991 and 2016.
Results: Seventy patients with lymphomatoid papulosis were identified. Thirty patients (43%) experienced a secondary
hematolymphoid malignancy. Twenty-four (80%) of the hematolymphoid malignancies occurred after the onset of
lymphomatoid papulosis. Older age at diagnosis of lymphomatoid papulosis, male sex, histology type B, and the presence of
T-cell receptor gene rearrangement are associated with higher risk of developing hematolymphoid malignancy.
Conclusion: Lymphomatoid papulosis is associated with increased risk of developing secondary hematolymphoid
malignancies, particularly mycosis fungoides and cutaneous anaplastic large cell lymphoma.

Keywords
CD30+ lymphoproliferative disorders, cutaneous T-cell lymphoma, lymphomatoid papulosis, mycosis fungoides, secondary
hematolymphoid malignancy

Lymphomatoid papulosis (LyP) is one of the primary cutane- lymphocytes, and histiocytes. Type A resembles the histol-
ous CD30+ T-cell lymphoproliferative disorders. LyP and ogy of Hodgkin disease (HD). Type B resembles the histol-
cutaneous anaplastic large cell lymphoma (C-ALCL) are ogy observed with patch-stage mycosis fungoides (MF)
grouped within the indolent primary cutaneous T-cell lym- where lesions show an epidermotropic infiltrate of small- to
phomas (CTCLs) in the modified World Health Organization– medium-sized lymphocytes with variable CD30 expression.
European Organization for Research and Treatment of Type C resembles the histology of C-ALCL with dermal foci
Cancer (WHO-EORTC) classification.1,2 and clusters of large anaplastic-like CD30+ cells with a rela-
Clinically, LyP is characterised by recurrent crops of self- tively scant inflammatory background. Type D displays epi-
healing papulonodular and papulonecrotic skin lesions. dermotropic infiltrates of CD30+ small- to medium-sized
These lesions typically self-regress and often heal with hypo- lymphoid cells that express the CD8+ cytotoxic phenotype.
or hyperpigmented, depressed varioliform scars. LyP occurs Type E is characterised by an angioinvasive and angiode-
in all age groups, with a peak incidence in the fifth decade. structive infiltrate of small to medium CD30+ atypical
Men are more frequently affected than women.3 lymphoid cells also with a CD8+ phenotype. Type F is rare
The histological findings of LyP are variable and depend
on the age of the lesion as well as the histopathologic sub- 1
Division of Dermatology, University of Toronto, Toronto, ON, Canada
type. Several histopathologic subtypes have been described
Corresponding Author:
for LyP. Type A is the most common subtype and accounts
Mohanad AbuHilal, Division of Dermatology, Sunnybrook Health Sciences
for around 60% to 70% of cases. It is characterised by a Center and University of Toronto, 2075 Bayview Ave,
wedge-shaped infiltrate of large pleomorphic atypical Suite M1-700, Toronto, ON M4N 3M5, Canada.
CD30+ cells and numerous neutrophils, eosinophils, small Email: derm.moe@gmail.com
2 Journal of Cutaneous Medicine and Surgery 00(0)

and is characterised by folliculotropic infiltrates of CD30+ Table 1.  Demographics and Clinical and Histologic
atypical lymphoid cells. Different lesions of LyP in the same Characteristics of 70 Patients With Lymphomatoid Papulosis.
patient may exhibit more than one of the above histologic Characteristic Mean, Range
patterns.4
An association between LyP and the development of other Age, mean (range), y 50.7 (20-90)
hematolymphoid malignancies (HLMs) has been reported. Age at diagnosis of LyP, 43.5 (18-87)
In this study, we assess the demographics, clinical character- mean (range), y
Sex, % (n) (n = 70)
istics, and histologic subtypes of LyP in a large cohort of
 Male 54 (38)
patients and determine the types and prevalence of associ-
 Female 46 (32)
ated secondary HLMs.5-7
Ethnicity, % (n) (n = 70)
 White 51 (36)
Methods and Materials   Middle Eastern 14 (10)
 Asian 11 (8)
The study was approved by the institutional review boards at
 Hispanic 9 (6)
Sunnybrook Health Sciences Centre, Women’s College
  African American 6 (4)
Hospital, and the University of Toronto. A retrospective chart
 Others 9 (6)
review was conducted for medical records and databases of
Presence of itch, % (n) (n = 70)
all patients with a histopathological diagnosis of LyP at the  Yes 51 (36)
dermatology and hematology clinics at Sunnybrook Health  No 49 (34)
Sciences Centre and the phototherapy clinics at Women’s Presence of pain, % (n) (n = 70)
College Hospital from January 1991 to July 2016. Data col-  Yes 16 (11)
lected included sex, ethnicity, age at onset of LyP, age at  No 84 (59)
diagnosis, number of lesions, presence of itch or pain, histo- Severity, % (n) (n = 64)
pathologic subtypes, lactate dehydrogenase (LDH) level at   20 lesions or less 47 (30)
presentation, T-cell receptor (TCR) gene rearrangement from   More than 20 lesions 53 (34)
biopsy specimens, treatments received, presence and type of Histologic subtype, % (n) (n = 70)
secondary HLM, and the onset of HLM in relation to LyP  A 50 (34)
onset.  B 18 (12)
Statistical analyses were performed using SPSS version  C 16 (11)
23 (SPSS, Inc, an IBM Company, Chicago, Illinois). Fisher  D 4 (3)
exact test and contingency tables were used to assess cate-  E 1 (1)
gorical data and to calculate the odds ratio (OR). A 2-sided P  F 1 (1)
value less than .05 was considered statistically significant for  A/B 3 (2)
all tests performed.  A/C 6 (4)
 B/C 1 (1)
  Subtype not available 1 (1)
Results Association of HLM, % (n) (n = 70)
  Not associated with HLM 57 (40)
Demographics, Clinical Characteristics, and
  Associated with HLM 43 (30)
Histological Types
HLM, hematolymphoid malignancy; LyP, lymphomatoid papulosis.
Seventy patients with histopathologically confirmed LyP
were identified. Table 1 summarises the demographic and
clinical characteristics of these patients. Mean follow-up pathology: 2 patients (3%) had both types A and B, 4 patients
time was 86.5 months (range, 21-300 months). Thirty-eight (6%) had both types A and C, and 1 patient (1%) had both
patients (54%) were male, and 32 patients (46%) were types B and C.
female. The mean age of the patients was 50.7 years (range,
20-90 years). The mean age at time of LyP diagnosis was Associated Hematolymphoid Malignancies and
43.5 years (range, 18-87 years). Pruritus and pain were pres-
Risk Factors
ent in 36 patients (52%) and 11 patients (16%), respectively.
The histopathologic subtype was reported for 69 patients. Type Thirty cases (43%) were found to have a secondary HLM. Of
A was the most common, being present in 34 patients (50%). these, 6 HLMs (20%) had onset prior to the diagnosis of LyP
The remainder included 12 patients (18%) with type B, 11 while 24 HLMs (80%) were diagnosed after the diagnosis of
patients (16%) with type C, 3 patients (5%) with type D, 1 LyP (Figure 1). The associated HLMs were as follows: 18
patient (1%) with type E, and 1 patient (1%) with type F. patients (60%) with classic MF, 3 patients with folliculo-
Seven patients had a mixture of more than 1 subtype on tropic MF (10%), 4 patients (13%) with C-ALCL, 2 patients
AbuHilal et al 3

methotrexate therapy given was 12.5 mg/wk. Twenty-two of


37 patients (59%) treated with methotrexate achieved com-
plete clinical response. Mean dose of mycophenolate therapy
given was 1250 mg/d for MMF and 720 mg/d for MPS. Ten
of 12 patients (83%) treated with MMF or MPS achieved
complete clinical response (Table 4). Treatment for LyP did
not alter the risk for development of a secondary HLM. No
specific treatment modality, including methotrexate and
mycophenolate, was found to be a risk factor for develop-
ment of a secondary HLM.

Prognosis and Survival


None of the LyP patients in our study died over follow-up
periods extending to 25 years. All patients who developed
MF or one of its variants before or after the onset of LyP had
Figure 1.  Number, percentage, and distribution of 70 patients no progression of their MF beyond the original stage at the
with lymphomatoid papulosis (LyP). time of diagnosis.

(7%) with HD, 2 patients (7%) with chronic lymphocytic


leukemia (CLL), and 1 patient (3%) with a non-Hodgkin
Discussion
lymphoma (NHL). Of the 18 patients with classic MF, 11 The clinical characteristics of patients with LyP in our study
patients (61%) were stage 1A, 6 patients (33%) were stage were similar to other studies. In agreement with the majority
1B, and 1 patient (6%) was stage 2A (Table 2). The mean of the published literature, there was a slight male predomi-
time from LyP diagnosis to development of secondary HLM nance in our cohort with a male to female ratio of 1.19:1.5,7-10
was 45 months (range, 10-180 months). The mean age at time of diagnosis for the 70 patients was
Male sex (OR, 3.16; 95% confidence interval [CI], 1.16- 43.5 years, which is close to the mean age reported in several
8.59; P = .03) and older age at diagnosis of LyP (OR, 1.08; previous studies.7,9,11 The frequency of the LyP histologic
95% CI, 1.03-1.12; P = .0002, respectively) were associ- subtypes in our study is also consistent with that reported in
ated with increased risk of developing HLMs. Data on TCR the medical literature, with type A being most common, fol-
gene rearrangement were available for 45 patients (64%). lowed by types B and C, respectively.5,7-9,11,12
Patients with TCR gene rearrangement were 4.5 more likely Several studies have suggested an association between
to have a secondary HLM (95% CI, 1.26-16.63; P = .03). LyP and the development of secondary HLMs. In these stud-
White ethnicity, presence of itch or pain, severity of lesions ies, the prevalence of secondary HLMs has ranged from
(less or more than 20 lesions), and serum LDH levels (nor- 9.4% to 61%.5-8,10,11 The prevalence of associated HLMs in
mal or high) were not associated with development of a our patients was 43%, confirming that patients with LyP
secondary HLM (Table 3). Histologic subtype B was sig- have a high risk of developing these diseases. A possible rea-
nificantly associated with higher frequency of HLM com- son for the high percentage of secondary HLMs in this study
pared with other histologic types combined (OR, 5.14; 95% could be referral bias because our patient population reflects
CI, 1.27-3.26; P = .024). None of the other histologic sub- referrals to large university-based advanced dermatology
types was associated with a higher risk of developing HLM clinics and to a specialised cutaneous lymphoma clinic.
(Table 3). Our cohort was consistent with previous studies, with MF
being the most common associated HLM accounting for
Treatment 60% of cases.3,7-9,11-13 C-ALCL was the second most com-
mon associated HLM, accounting for 10% of all malignan-
Treatments used for LyP (over a mean time of 7 years) were cies. The most common stage of MF associated with LyP was
topical corticosteroids (n = 66, 94%), ultraviolet-B (UVB) stage 1A. Prior studies have reported that LyP-associated
(n = 25, 36%), psoralen with ultraviolet-A (PUVA) (n = 22, HLM, particularly MF, more commonly precedes the diag-
31%), methotrexate (n = 37, 53%), mycophenolate mofetil nosis of LyP or is diagnosed simultaneously.6-8 However, our
(MMF) or mycophenolate sodium (MPS) (n = 12, 17%), oral data showed that 80% of the malignancies occurred after the
doxycycline (n = 4, 6%), and oral isotretinoin (n = 1, 1%). onset of LyP, with a mean time of 45 months.
Five of 25 patients (20%) treated with UVB and 7 of 22 Different risk factors have been associated with the devel-
patients (32%) treated with PUVA achieved complete clini- opment of secondary HLMs in different studies. Male sex
cal response defined by complete disappearance of lesions and histology types B and C were found to be risk factors in
and not having new lesions while on treatment. Mean dose of the largest study of 180 patients by Wieser et al.5 Male sex
4 Journal of Cutaneous Medicine and Surgery 00(0)

Table 2.  Thirty cases of Hematolymphoid Malignancies Reported in 70 Patients With Lymphomatoid Papulosis.

Hematolymphoid Malignancy Before Diagnosis of LyP (n = 6), n After Diagnosis of LyP (n = 24), n All (n = 30), % (n)
MF (all stages) 5 13 60 (18)
C-ALCL 0 4 13 (4)
Folliculotropic MF 1 2 10 (3)
HD 0 2 7 (2)
CLL 0 2 7 (2)
NHL 0 1 3 (1)
Total 6 24 30

C-ALCL, cutaneous anaplastic large-cell lymphoma; CLL, chronic lymphocytic leukemia; HD, Hodgkin disease; LyP, lymphomatoid papulosis; MF, mycosis
fungoides; NHL, non-Hodgkin lymphoma.

Table 3.  Risk Factors for the Development of Secondary Hematolymphoid Malignancies in Patients With Lymphomatoid Papulosis.

Factor n HML Present, % OR 95% CI P Value


Age at diagnosis
  Continuous (18-87) 70 43 1.08 1.03-1.12 .0002
Sex 70  
 Male 38 55 3.16 1.16-8.59 .03
 Female 32 28 1
Ethnicity 70  
 White 36 50 1.8 0.7-4.7 .24
 Nonwhite 34 35 1
Histological subtype 70 30  
  A (vs others) 34 41 0.93 0.36-2.43 1
  B (vs others) 12 75 5.14 1.27-3.26 .02
  C (vs others) 11 36 0.75 0.37-1.95 .75
  D, E, and F (vs others) 5 20 0.30 0.03-2.85 .38
  Mixed (vs others) 7 29 0.49 0.09-2.69 .46
  Subtype not available 1 0 NA NA NA
LyP severity 64  
  <20 lesions 30 53 2.12 0.8-5.58 .15
  20 lesions or more 34 41 1
LDH level 60  
 Normal 54 44 0.75 0.09-5.7 1
 High 4 50 1
TCR gene rearrangement 45  
 Positive 17 71 4.58 1.26-16.63 .03
 Negative 28 26 1
Pain 70  
 Present 11 45 1.13 0.31-4.1 1
 Absent 59 42 1
Itch 70  
 Present 36 44 1.14 0.44-2.94 .81
 Absent 34 41 1

CI, confidence interval; HLM, hematolymphoid malignancy; LDH, lactate dehydrogenase; LyP, lymphomatoid papulosis; NA, not applicable; OR, odds ratio;
TCR, T-cell receptor.

was also predictive of lymphoma development by Kunishige development. TCR gene rearrangement and older age at time
et al.13 Histopathologic subtypes B and C were also predic- of LyP diagnosis were also risk factors in a recently pub-
tors for development of HLM in a small study of 24 patients.11 lished French study.6 In our study, male sex, older age at
De Souza and her colleagues7 suggested that mixed histology onset of LyP, histology type B, and presence of TCR gene
and clonality were significantly associated with HLM rearrangement were associated with development of HLMs.
AbuHilal et al 5

Table 4.  Treatment Modalities Used for Lymphomatoid rearrangement are associated with a higher risk of develop-
Papulosis. ing HLM. The study also confirms the good prognosis and
Complete Response, favourable outcome of LyP, even when associated with
Treatment Modality n (%) n (%) HLM. Limitations of our study include a relatively small
number of patients and potential referral bias from a univer-
Topical corticosteroids 66 (94) NA sity-based tertiary referral centre focusing on cutaneous lym-
UVB 25 (36) 5 (20) phomas. Long-term follow-up of patients with LyP is
PUVA 22 (31) 7 (32)
important for the early detection of potential secondary
Systemic methotrexate 37 (53) 22 (59)
HLMs. Larger and prospective studies are needed to confirm
Mycophenolate mofetil or 12 (17) 10 (83)
mycophenolate sodium
the association of LyP with HLMs and the associated risk
Oral doxycycline 4 (6) NA factors.
Oral isotretinoin 1 (1) NA
Declaration of Conflicting Interests
NA, not applicable; PUVA, psoralen with ultraviolet-A; UVB, ultraviolet-B.
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
White ethnicity, presence or absence of itch or pain, number
of lesions (less or more than 20), and elevated serum LDH
levels at the time of diagnosis were not significantly associ- Funding
ated with increased risk of secondary HLMs. The author(s) received no financial support for the research, author-
Several treatment modalities are commonly used for treat- ship, and/or publication of this article.
ment of LyP, but methotrexate and PUVA are considered the
most widely accepted and effective treatments.14-16 Treatment References
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