Table of Content

Archive

Autumn 2019, Vol. 27 No. 3

Hong Kong J. Dermatol. Venereol. (2019) 27, 107-119


Original Article

Lymphomatoid papulosis: a case series in Hong Kong

淋巴瘤樣丘疹病:香港的病例系列之一

HF Cheng 鄭學輝, SC Ng 吳順展, MMT Ng 吳孟婷

Abstract

Background: Lymphomatoid papulosis is considered a clinically benign disease with an alarming cytomorphology. Its association with lymphoma is well recognised. This study serves to review the latest local data and provide a better understanding. Objective: We report a case series of lymphomatoid papulosis in Hong Kong, focusing on its clinical and histopathological features. The association with second lymphoma was also studied. Methodology: The biopsy histopathology and immunohistochemical findings, together with clinical records of patients diagnosed with lymphomatoid papulosis were retrieved from 2010 to 2018. The findings were then reviewed and compared with the published data. Results: Ten patients and 14 biopsy-confirmed cases of lymphomatoid papulosis were identified. The majority were of type A and CD30 positivity was noted in all cases. Although the disease ran a relapsing course, there were no mortalities. Only one patient developed mycosis fungoides. Conclusion: Findings of this local series are in line with published data. Clinicopathological correlation is important in managing patients with lymphomatoid papulosis. Life-long follow-up is recommended due to its chronic recurrent course and risk of development of lymphoma.

背景:淋巴瘤樣丘疹病被認為是臨床上良性的疾病,但有著令人擔憂的細胞形態學表現。它與淋巴瘤的相關聯是無可置疑的。本研究旨在回顧最新的本地數據以提供更好的理解。目的:我們報告了一系列香港的淋巴瘤樣丘疹病個案,重點是其臨床和組織病理學特徵。還研究了與繼後的淋巴瘤的相關聯。方法:我們檢索了2010年到2018年的活檢組織病理學和免疫組化結果,以及淋巴瘤樣丘疹病患者的臨床記錄。然後對以上結果進行了回顧,並與公佈的數據進行了比較。結果:確定了10名患者的14例活檢確診的淋巴瘤樣丘疹病病例。大多數是A型,並且所有病例都是分化簇30陽性。雖然病情反覆,但沒有死亡個案。只有一名患者患上了蕈狀肉芽腫。結論:此本地系列結果與已公佈數據一致。臨床病理學相關性對於治療淋巴瘤樣丘疹病患者實為重要。因此病的慢性復發病情和淋巴癌的潛在發生風險,故建議終身覆診跟進。

Keywords: CD30, histopathology, immunohistochemistry, lymphomatoid, papulosis

關鍵詞: 分化簇30、組織病理學、免疫組織化學染色法、淋巴瘤樣、丘疹病

Introduction

Lymphomatoid papulosis is considered to be a benign cutaneous lymphoproliferative disorder.1 It takes on a chronic, relapsing and remitting course, with a predilection for the trunk and limbs. Clinically, lesions consists of papules and nodules with or without surface erosion. A number of histopathological subtypes have been reported in the literature, each resembles different cutaneous lymphoproliferative disorders.2

The association with lymphoma becomes a major reason for life-long surveillance. According to published studies, the estimated risk of lymphoma development is about 10% to 20%3-6 As the prevalence in general population is low, local data is scarce and is limited to three case reports.7-9

This series aims to summarise the clinical and pathological features of cases collected in the past eight years in order to bridge the gap and facilitate a better understanding of this entity.

Methodology

The study was an eight-year retrospective analysis from 2010 to 2018. Computer records of skin biopsy with a histopathological diagnosis of lymphomatoid papulosis were retrieved from the database of division of Histopathology and Cytopathology, Public Health Laboratory Centre, Department of Health. Both histopathology and immunohistochemical stains performed on formalin-fixed, paraffin-embedded tissue were reviewed.

The corresponding hand-written clinical records of the patients from the respective requesting locations under Social Hygiene Service, Department of Health were then retrieved. These locations included Yung Fung She Dermatological Clinic, Wan Chai Male Social Hygiene Clinic, Sai Ying Pun Dermatological Clinic, Yaumatei Dermatological Clinic, Fanling Integrated Treatment Centre and Cheung Sha Wan Dermatological Clinic. The demographic data, clinical features, pre-biopsy differential diagnosis, biopsy findings, treatment offered and clinical outcome were studied together with the pathological findings. Histopathology and immunohistochemistry of cutaneous lymphoma, being diagnosed in conjunction with lymphomatoid papulosis, were also reviewed.

Results

Demographic features
There was a total of ten patients in the series, all of whom were Chinese. They were all referred by physicians working in either public or private sectors. The patient demographic and clinical features are summarised in Table 1. The age of patients ranged from 12 to 89 (mean age was 40.5 years, median age 34 years). There were five male and five female patients respectively. One (10%) of the patients (patient 6) had a history of thyroidectomy and cholecystectomy for benign diseases. Another patient had a history of Becker's naevus (patient 7). One of the patients suffered from lymphoma which was treated with radiotherapy (patient 9). However, the clinical history and treatment details in relation to that lymphoma diagnosis could not be traced. There was no significant past medical history in the remaining patients.

Table 1 Clinical features of patients diagnosed with lymphomatoid papulosis
Patient number Demographic data at the time of the diagnosis Past medical history Morphology of the lesions and the anatomical distribution Clinical differential diagnosis Treatment / clinical outcome Subsequent course of action
1 Female/12 Unremarkable Papulo-necrotic lesions, T&L LyP, PN, PNT, vasculitis Topical steroid / information unavailable Referred oncology, lost to FU
2 Female/31 Unremarkable Papules, L Pseudo-lymphoma, granulomatous dermatitis, histiocytosis, PLC, LE, LP, LyP Topical steroid / persistence of lesions FU
3 Female/44 Unremarkable Nodules, breast region Information unavailable Not yet treated / information unavailable Lost to FU 4/52 after first visit
4 Male/18 Dermatitis for 3 years, given oral anti-fungal therapy but no clinical response Papules with scabs, T&L LyP, PLC, dermatitis Topical steroid & phototherapy / in remission after 8 weeks of phototherapy Lost to FU after 8 weeks of phototherapy
5 Male/31 Unremarkable Papules and pustules, thigh and buttock LyP, lymphocytoma cutis, PLEVA, arthropod bite reaction, papular eczema Topical steroid / wax-and-wane clinical course Normal CT and BM biopsy; FU
6 Female/65 Thyroidectomy, cholecystectomy Erythematous papules or nodules, T&L Eczema, PLEVA, PLC, arthropod bite reaction Topical steroid / in remission Normal CT and BM biopsy, referred oncology; FU
7 Male/26 Becker's naevus Papulosquamous eruption and PIH, T&L Guttate psoriasis, LP, LyP, papular eczema Topical steroid / in remission Lost to FU 16 months after the first visit
8 Male/37 Unremarkable Papules over chest and arms; poikiloderma over thigh CTCL, LyP, poikiloderma vasculare atrophicans Topical steroid & phototherapy / both diseases are in remission FU
9 Male/52 Seborrhoeic dermatitis, history of lymphoma with RT given Papules over occiput, axillae and forearms, thigh and trunk Psoriasis, eczema, LE Topical steroid / wax-and-wane clinical course Lost to FU
10 Female/89 Known history of lymphomatoid papulosis Painful papules and nodules, face, T&L Boil, LyP, CTCL Topical steroid / wax-and-wane clinical course FU
T&L: trunk and limbs, L: limbs, LyP: lymphomatoid papulosis, PN: prurigo nodularis, PNT: papulonecrotic tuberculid, PLC: pityriasis lichenoides chronica, PLEVA: pityriasis lichenoides et varioliformis acuta, LP: lichen planus, CTCL: cutaneous T-cell lymphoma, LE: lupus erythematosus, CT: computer tomography scan, BM: bone marrow, FU: active follow-up and medical care

Site of lesions
The trunk and limbs were the most commonly affected sites. One (10%) patient (patient 3) presented with lesions over the breast region. In addition to the lesions over trunk and limbs, one patient (patient 9) had lesions over axillary and occipital scalp regions. Another patient (patient 10) had facial lesions. None of the cases presented with mucosal lesions.

Symptomatology
Except for one patient (10%) who reported pain as the presenting complaint in addition to skin lesions, the other nine patients were asymptomatic. There was no systemic upset.

Lesion morphology
Eight (80%) patients presented with papulonecrotic lesions. One patient (patient 7) presented with a papulosquamous eruption. Only one patient (patient 3) presented with nodular, tumefactive lesions over her breast region.

Pre-biopsy clinical differential diagnoses
The differential diagnoses included prurigo nodularis, papulonecrotic tuberculid, pityriasis lichenoides chronica/pityriasis lichenoides et varioliformis acuta, arthropod bite reaction, guttate psoriasis, papular eczema, psoriasis, lichen planus, cutaneous lupus erythematosus, vasculitis, pseudo-lymphoma, granulomatous dermatitis, and boils. Lymphomatoid papulosis was considered in seven out of ten patients (patient 1, 2, 4, 5, 7, 8 and 10).

Time of presentation and diagnosis
The time interval between onset of the skin lesions and first clinical consultation visit at our service ranged from two to ten months. The histopathological diagnosis of lymphomatoid papulosis was obtained within a short period of time (all cases apart from patient 6 and 8 received a skin biopsy in less than four months). The mean duration time between the clinical suspicion of lymphomatoid papulosis and histopathological diagnosis was 3.7 months (range: one to eleven months).

Histopathology subtypes and immunohistochemistry
Within the series, two patients had more than one skin biopsy done (patient 6 had four skin biopsies and patient 10 had two skin biopsies done during the study period), amounting to a total of fourteen biopsy cases.

Thirteen of the cases were diagnosed lymphomatoid papulosis type A. Except the second biopsy of patient 6 and the first biopsy of patient 10, the haematoxylin and eosin sections of the remaining eleven cases showed superficial perivascular and interstitial inflammatory infiltration. A wedge-shaped pattern and surface erosion were not consistently present. There was no vasculitis or necrotising granulomatous inflammation. On high power magnification, atypical large lymphoid cells with enlarged convoluted nuclei (resembling the mononuclear variant of Reed-Sternberg cells) were identified amongst a mixed lymphoid background. Immunohistochemistry revealed a presence of CD30-positive large atypical lymphoid cells, highlighted in the background of mixed lymphoid infiltrates which were CD30-negative. The characteristic cytoplasmic membranous and peri-nuclear Golgi apparatus staining pattern was consistently demonstrated by the CD30 immunohistochemical marker (Figure 1).

Figure 1 (Patient 9) Type A Lymphomatoid papulosis. (a) The clinical lesion featured a scaly erythematous papule with a well-defined border. (b) Low power appearance showing superficial and deep perivascular infiltration into the adjacent dermis, forming expansile nodular clusters. The epidermis is otherwise unremarkable. H&E stain, 40x. (c) High power appearance shows a heterogeneous population in which discohesive atypical large cells are found admixed with small lymphoid cells in the background. The tumour cells showed enlarged irregular to convoluted hyperchromatic nuclei and presence of nucleoli. H&E stain, 600x. (d) The CD30 stain, featuring a diffusely strong membranous and Golgi apparatus positivity.

The second biopsy of patient 6 had atypical lymphoid infiltrates centered at the dermo-subcutis junction, with septal fibrous expansion and rare foci of lobular panniculitis at the edge of the fat lobules. The vasculature at the level of subcutis showed no granuloma, vasculitis, angiocentric lymphoid aggregation or tissue infarction. There was no rimming of adipocytes by the large atypical lymphoid cells. The CD30 immunohistochemical stain indicated the presence of atypical large lymphoid cells in a characteristic pattern, supporting a diagnosis of type A lymphomatoid papulosis (Figure 2).

Figure 2 (Patient 6) Type A Lymphomatoid papulosis at the level of dermo-subcutis junction. (a) The clinical lesion featured an erythematous papule with scale crust atop. (b) Low power appearance showing a predominantly bottom-heavy infiltrates involving the dermo-subcutis junction, with expansion of fibrous septa. The epidermis showed mild psoriasiform epidermal hyperplasia. H&E stain, 50x. (c) Another low power view showing an expansion of fibrous tracts along the edge of the panniculus, compatible with septal panniculitis. There was no granuloma or vasculitis. H&E stain, 50x. (d) High power view showing a heterogeneous lymphoid infiltrates with an obvious presence of atypical large lymphoid cells close to the subcutis fat lobules. The tumour cells showed enlarged irregular to convoluted hyperchromatic nuclei and nucleoli. H&E stain, 400x. (e) The epithelial membrane antigen stain. Only the epidermis and eccrine sweat gland lobules are stained up. The lymphoid infiltrates were negative, excluding a possibility of metastatic carcinoma. (f) The CD30 stain, featuring a diffusely strong membranous and Golgi apparatus positivity, supporting a diagnosis of lymphomatoid papulosis.

In addition to the superficial perivascular inflammatory infiltrates, the first biopsy of patient 10 showed foci of deep dermal lymphoid aggregates admixed with localised collection of interstitial mucin. The atypical lymphoid infiltrates did not demonstrate folliculocentricity. There was no evidence to suggest myxoid soft tissue neoplasm or metastatic mucinous tumour. The final diagnosis was lymphomatoid papulosis type A. CD30 staining was positive for the atypical large lymphoid cells (Figure 3).

Figure 3 (Patient 10) Type A Lymphomatoid papulosis. (a) The clinical lesion was those of an erythematous papule with minimal surface scaling. (b) Low power appearance showing a localised collection of deep dermal lymphoid aggregate within a conspicuous myxoid stroma. There was no suggestion of it being part of a hair follicle. H&E stain, 50x. (c) High power appearance showing loose individual tumour cells with enlarged irregular hyperchromatic nuclei and prominent nucleoli. The background lymphoid infiltrate is neutrophil-rich. The stromal mucin is present. H&E stain, 400x. (d) The CD30 stain, featuring a diffusely strong membranous and Golgi apparatus positivity.

One biopsy (patient 3) displayed features of type C lymphomatoid papulosis. There were diffuse dense clusters of monotonous anaplastic tumour cells occupying and expanding the entire dermis. These contained enlarged irregular hyperchromatic nuclei in a wreath-like arrangement, resembling the cells found in systemic nodal anaplastic large cell lymphoma. Mitotic activity was brisk. Immunohistochemically the atypical large lymphoid cells were negative for anaplastic lymphoma kinase and cytokeratin MNF116, but strongly and diffusely positive for CD30. The final diagnosis was type C lymphomatoid papulosis (Figure 4).

Figure 4 (Patient 3) Type C Lymphomatoid papulosis. (a) The clinical lesion was those of a nodular tumour. (b) Low power appearance showing a massive dermal tumoural infiltration. H&E stain, 40x. (c) High power appearance showing sheets of tumour cells with enlarged irregular hyperchromatic nuclei. Mitosis is easily discerned. H&E stain, 200x. (d) The CD30 stain, featuring a diffusely strong membranous and Golgi apparatus positivity. (e) The cytokeratin stain MNF116 was negative in these tumour cells, excluding poorly differentiated carcinoma. (f) The anaplastic lymphoma kinase (ALK) stain was negative in these tumour cells.

Association with second lymphoma
Mycosis Fungoides was diagnosed concurrently with lymphomatoid papulosis in one patient (patient 8, n=1, 10%). Information as to when the lymphoma initially developed was not available. In this patient, papules of lymphomatoid papulosis were found over the right anterior chest wall and both arms. Macular erythema and poikiloderma were present over the ankle and thigh regions, with features of mycosis fungoides on histopathology. There was no large cell transformation. Immunohistochemically, the neoplastic lymphocytes were T-cell in origin, with positive CD3, CD2 and CD5 cytoplasmic membranous staining and partial loss of CD7 expression (Figure 5).

Figure 5 (Patient 8) Mycosis Fungoides. (a) The clinical lesion was those of an erythematous papulo-squamous eruption without tumour nodule formation. (b) Low power appearance showing a lichenoid infiltration over papillary dermis. The epidermis showed attenuation of rete ridges and otherwise unremarkable orthokeratosis. The reticular dermis was unremarkable. H&E stain, 50x. (c) Medium power view showed superficial perivascular lymphocytic infiltration, and lichenoid band like infiltrates of small lymphocytes in addition. There were foci of lymphocyte exocytosis into the epidermis. There was no vasculitis or granuloma. H&E stain, 100x. (d) High power appearance showing a focus of lymphocyte exocytosis, coupled with mild spongiosis. The intra-epidermal lymphocytes demonstrated a more pronounced nuclear atypia. H&E stain, 400x. (e) The CD2 stain. (f) The CD3 stain. (g) The CD5 stain. (h) The CD7 stain. (i) The CD30 stain.

The information regarding the histopathological subtype and association with lymphoma development is summarised in Table 2.

Table 2 The relationships between lymphomatoid papulosis and lymphoma
Patient Clinical differential diagnosis Chronological association with lymphoma (if applicable) Histologic subtype of LyP Treatment outcome of the LyP Treatment outcome of the lymphoma The Latest status of lymphomatoid papulosis*
1 LyP, PN, PNT, vasculitis Not applicable A Information unavailable Not applicable Lost to FU, information unavailable
2 Pseudo-lymphoma, granulomatous dermatitis, PLC, LE, LP, LyP, histiocytosis Not applicable A Persistence of lesions despite topical steroid Not applicable Persistence of lesions
3 Information unavailable Not applicable C Information unavailable Not applicable Lost to FU, information unavailable
4 LyP, PLC, dermatitis Not applicable A In remission after 8 weeks of phototherapy Not applicable Lost to FU after the phototherapy, information unavailable
5 LyP, lymphocytoma cutis, PLEVA, arthropod bite reaction, papular eczema Not applicable A Wax-and-wane clinical course despite topical steroid Not applicable Recurrence noticed as at the last clinic visit
6 Eczema, PLEVA, PLC, arthropod bite reaction Not applicable A In remission after topical steroid Not applicable In remission
7 Guttate psoriasis, LP, LyP, papular eczema Not applicable A In remission after topical steroid Not applicable Lost to FU 16 months after the first visit
8 CTCL LyP, poikiloderma vasculare atrophicans Concurrent development of Mycosis Fungoides A In remission after topical steroid and phototherapy Topical steroid, phototherapy, in remission In remission
9 Psoriasis, eczema, LE Not applicable A Wax-and-wane clinical course despite topical steroid Not applicable Lost to FU
10 Boil, LyP, CTCL Not applicable A Wax-and-wane clinical course despite topical steroid Not applicable In remission as at the last clinic visit
LyP: lymphomatoid papulosis, PN: prurigo nodularis, PNT: papulonecrotic tuberculid, PLC: pityriasis lichenoides chronica, PLEVA: pityriasis lichenoides et varioliformis acuta, LP: lichen planus, CTCL: cutaneous T-cell lymphoma, LE: lupus erythematosus, FU: follow-up.
*The information is the most update at the time of writing up this article.

Workup, treatment offered and the therapeutic outcome
Only two patients (patient 5 and 6, 20%, n=2) underwent staging with computer tomography scan and bone marrow biopsy. Two other patients (patient 1 and 6, 20%, n=2) were referred to clinical oncology department for further assessment.

Essentially there were two principal treatment modalities offered in this series. Out of the nine patients receiving topical corticosteroid therapy (patient 1, 2, 4, 5, 6, 7, 8, 9 and 10, 90%, n=9), only one of them noticed persistent skin lesions (patient 2, 10%, n=1) despite treatment. Three others (patient 5, 9 and 10, 30%, n=3) showed episodic recurrences. Four of them (patient 4, 6, 7, 8, 40%, n=4) were in remission. Two patients (patient 4 and 8, 20%, n=2) received phototherapy in addition to the topical corticosteroid therapy. Patient 8 developed concomitant mycosis fungoides, which was well controlled by phototherapy. At the time of writing, five patients (patient 2, 5, 6, 8 and 10, 50%, n=5) were still receiving follow-up care in our service. The other five patients were lost to follow-up. Those who still remained under follow-up care were either in complete remission or in episodic recurrences.

Discussion

Historical perspective
The term lymphomatoid papulosis was first coined by Macaulay in 1968.10 The alarmingly malignant cytomorphology, in stark contrast with its random regression and recurrences, has been baffling clinicians for years as to their genuine nature. Based on the histopathological findings, the biological behaviour and risk of lymphoma development cannot be predicted.

The evolving Lymphoma classification systems
Prior to the era of Revised European American Lymphoma (REAL) Classification in 1994, the understanding and clinical management of cutaneous lymphomas were derived from knowledge of the systemic nodal lymphomas, of which the diagnosis were solely morphology-based.11 With gradual accumulation of clinical experience, survival data and knowledge gained from immunohistochemistry, clinicians and scientists realised that cutaneous lymphomas are biologically distinct from the morphologically similar systemic nodal counterparts. The first endeavour addressing such differences was made by a group of European scientists in 1997, the effort of which was later known as European Organization for Research and Treatment of Cancer (EORTC) cutaneous lymphoma classification system.12 Under EORTC classification, lymphomatoid papulosis was accepted as a distinct clinicopathological entity, strictly defined by some very specific clinical, histopathological and immunohistochemical criteria. Subsequent refinements had led to World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification system in 2005, with consensus criteria that appeals to practitioners in haematologic oncology, dermatology and pathology.13 The latest revised 4th edition of WHO classification of lymphoid tumours in 201714,15 embraces similar sets of criteria, with addition of newer histological subtypes and novel molecular signature.16 Despite the discovery of various entity subtypes, the prognosis of lymphomatoid papulosis has still been regarded as excellent.1

Histopathological subtypes and issues relating to misdiagnosis
Amongst all the limited reaction patterns observed, type A lymphomatoid papulosis was still the commonest entity subtype to encounter in this series. This finding parallels the current understanding. The significance of mucin deposition as observed in one of the cases remains uncertain. The major differential diagnosis to exclude here would be follicular mucinosis secondary to cutaneous T cell lymphoma.17 The histopathological features were not supportive of such proposition.

There are three commonly described subtypes of lymphomatoid papulosis type A (which resembles Hodgkin's lymphoma histologically and accounts for the majority of the cases encountered worldwide), type B (which resembles mycosis fungoides histologically, CD30 immunohistochemistry will invariably give a negative result) and type C (which resembles anaplastic large cell lymphoma, either the primary cutaneous or systemic nodal primary).2,18 The so-called type D looks remarkably similar to type B except for its dual CD30 and CD8 positivity on immunohistochemistry.2,19 Primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T-cell lymphoma is the major differential diagnosis.18,20,21 Type E lymphomatoid papulosis presents with ulcer or eschar, histologically there is infarction of skin tissue secondary to angio-centric vascular destruction by the lymphoid infiltrates.2,22 The morphology closely resembles those of extra-nodal NK/T-cell lymphoma, nasal type or primary cutaneous γδ lymphoma.18 Folliculocentric pattern of infiltration, if present, will make it distinctive enough to be named as type F lymphomatoid papulosis.23 A novel subtype involving a translocation at locus DUSP22-IRF4 rearrangement at chromosome 6p25.3 has been described recently. Histopathologically, there is a combination of pagetoid reticulosis-like intra-epidermal lymphocytosis and a nodular dermal infiltrate of CD30-positive lymphoid cells.24 Despite the worrying cytomorphology, all these reported novel subtypes carry no diagnostic, prognostic or therapeutic implications.11 Each individual subtypes themselves are not associated with increased mortality.1 In our series, there was no documented anaplastic large cell lymphoma development within the lesions of lymphomatoid papulosis.

The utility of CD30 immunohistochemistry
Our study observed that a positive CD30 staining in a characteristic pattern, coupled with an appropriate clinical history, assists in the diagnosis of lymphomatoid papulosis. There are other inflammatory and neoplastic conditions in which CD30 immuno-staining will be positive - insect bite reaction, herpes simplex viral infection, molluscum contagiosum, lymphomatoid drug eruption, atopic dermatitis and pityriasis lichenoides et varioliformis acuta, to name but a few.2,21,25-28 Anaplastic large cell lymphoma, Hodgkin's lymphoma, and transformed mycosis fungoides are also known to express CD30 marker. Non-lymphoid neoplasms, notably embryonal carcinoma of gonads, inflammatory myofibroblastic tumour, and some cases of angiosarcoma could invariably express CD30 to a certain extent.29 In dermatopathology, one has to rule out reactive dermatological conditions and proceed to staging investigations to exclude systemic nodal lymphoma before concluding the case as bona fide lymphomatoid papulosis.

The clinicopathological approach
The range of presumptive clinical diagnoses seen in our case series reflects the possible morphological spectrum of lymphomatoid papulosis at different stages of development. An accurate diagnosis demands both on sharp clinical acumen and a sound working knowledge of histopathology. Therefore, close collaboration between clinicians and pathologists cannot be over-emphasised.30 Distinguishing between type C lymphomatoid papulosis and anaplastic large cell lymphoma adequately illustrates the importance of such practice.30 De Souza et al had concluded that careful interpretation and correlation with clinical data may allow for a more specific and precise clinical diagnosis. Sometimes, it may even lead to revision of the final diagnosis.27,30 Committing a wrong diagnosis will inevitably subject patients to unnecessary investigations and treatment.

The risk of lymphoma development
The relationship between lymphomatoid papulosis and lymphoma development has long been recognised.31 Our study observed a 10% incidence rate, which is in accordance with majority of the published series. The apparently low lymphoma incidence may partly be contributed by the difficulty encountered in diagnosing lymphomatoid papulosis. The resultant low incidence of lymphoma may therefore be an under-representation of the true incidence. A larger scale, long-term prospective study might help to address the deficiency of our study and clarify the real situation.

Mechanisms of lymphomagenesis remains unclear. Contributing risk factors may include Asian ethnicity,32 presence of different histological subtypes within the same lesion,33 male gender,34,35 histological subtype B and C,34 advanced age and presence of T-cell clone.33,35,36 Fernández-de-Misa et al concluded that mycosis fungoides development was unrelated to histological subtype or T-cell clonality, contrary to the previously held beliefs.6 The differences may be attributed to factors geographic or demographic, selection or referral bias, or the wide-ranging follow-up intervals. Owing to the rarity of lymphoma development in this series, it is deemed impossible to determine which risk factors were responsible. It is accepted that all the available treatment options, regardless of their effectiveness in inducing disease remission, cannot prevent lymphoma from developing.34 Based on the available evidence and findings in this study, life-long surveillance is still recommended.

Various treatment options and data from clinical trials
In this study, the overall survival of lymphomatoid papulosis was excellent. It can be argued that there were a number of cases who defaulted is indirect evidence of the benign course of the condition. So far there are no universally agreed or evidence-based treatment options. The short-term benefits of intervention must be carefully balanced against the side effects of the treatment.37 Newly published multi-centre study found that phototherapy alone will result in a longer disease-free survival when compared to other modalities of treatment.6 In complicated cases, oral methotrexate or phototherapy may offer rapid disease control, but sustained clinical response is rarely achieved upon discontinuation of medical treatment.38 Newland et al concluded that while methotrexate is well-tolerated, safe and efficacious to use in lymphomatoid papulosis; relapse is inevitable upon cessation of the drug.39 Brentuximab vedotin, a monoclonal anti-CD30 antibody, is licensed for use in classical Hodgkin's lymphoma and relapsed systemic anaplastic large cell lymphoma.40 The drug works by inducing cell-cycle arrest and apoptosis. Its efficacy and safety profile in the management of lymphomatoid papulosis are yet to be defined, but the data generated from a number of clinical trials are promising.40 It should be noted that in the vast majority of the lymphomatoid papulosis cases, different treatment options do not seem to alter the natural history.33,37,38 Given the indolent clinical behaviour, expectant management is the first-line approach.38

Short-comings of this study
As this was a retrospective study on a rare disease entity, the sample size was limited. Also, as not all of the biopsy cases were subject to T-cell receptor gene rearrangement assay, subgroup analysis of the molecular data was rendered infeasible and therefore omitted. Phototherapy was offered to two patients, one of whom developed concurrent mycosis fungoides at the time of diagnosis, while the other was lost to follow-up. As a result, the therapeutic efficacy of phototherapy could not be adequately evaluated. It was also impossible to assess efficacy or safety profile of methotrexate or CD30-antagonist in our local population as they were not offered.

Conclusion

Despite a small sample size and all the limitations of the study design, this case series provided updated local data on lymphomatoid papulosis. Although rare and benign, the disease deserves attention owing to its bewildering diagnostic possibilities and associated management implications. The majority of the findings in this series were in-line with the currently published data. The long-term excellent outcome sheds light on how these patients should be managed. Follow-up and regular examination is still required in view of the possibility of disease recurrence and potential lymphoma development. Larger scale studies are called for in future.

References

1. Kempf W, Kerl K, Mitteldorf C. Cutaneous CD30-positive T-cell lymphoproliferative disorders-clinical and histopathologic features, differential diagnosis, and treatment. Semin Cutan Med Surg 2018;37:24-9.

2. Kempf W. Cutaneous CD30-Positive Lymphoproliferative Disorders. Surg Pathol Clin 2014;7:203-28.

3. Weinman VF, Ackerman AB. Lymphomatoid papulosis. A critical review and new findings. Am J Dermatopathol 1981;3:129-63.

4. Wang HH, Myers T, Lach LJ, Hsieh CC, Kadin ME. Increased risk of lymphoid and nonlymphoid malignancies in patients with lymphomatoid papulosis. Cancer 1999;86:1240-5.

5. Kunishige JH, McDonald H, Alvarez G, Johnson M, Prieto V, Duvic M. Lymphomatoid papulosis and associated lymphomas: a retrospective case series of 84 patients. Clin Exp Dermatol 2009;34:576-81.

6. Fernández-de-Misa R, Hernández-Machín B, Servitje O, Valentí-Medina F, Maroñas-Jiménez L, Ortiz-Romero PL et al. First-line treatment in lymphomatoid papulosis: a retrospective multicentre study. Clin Exp Dermatol 2018;43:137-43.

7. Cheng SY. Case 1: A Boy with Lymphomatoid Papulosis or Lymphoma? HK Dermatol Venereol Bull 1998;6:16-9.

8. Cheng S, Lam WY. A woman with recurrent self healing erythematous patches on arms and trunk. Hong Kong J Dermatol Venereol 2006;14,146-9.

9. Chan JC, Trendell-Smith N, Yeung CK. A middle-aged man with self-healing papulonecrotic lesions over the trunk and proximal limbs. Hong Kong J Dermatol Venereol 2011;19,30-4.

10. Macaulay WL. Lymphomatoid papulosis. A continuing self-healing eruption, clinically benign-istologically malignant. Arch Dermatol 1968;97:23-30.

11. Cerroni L. Past, present and future of cutaneous lymphomas. Semin Diagn Pathol 2017;34:3-14.

12. Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 1997;90:354-71.

13. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-85.

14. Xavier Júnior JCC, Ocanha-Xavier JP. Cutaneous T-cell lymphomas in the revised 4th edition of World Health Organization classification of tumors of hematopoietic and lymphoid tissues (2017). An Bras Dermatol 2018;93:871-3.

15. Sundram U. Cutaneous Lymphoproliferative Disorders: What's New in the Revised 4th Edition of the World Health Organization (WHO) Classification of Lymphoid Neoplasms. Adv Anat Pathol 2019;26:93-113.

16. Karai LJ, Kadin ME, Hsi ED, Sluzevich JC, Ketterling RP, Knudson RA, et al. Chromosomal rearrangements of 6p25.3 define a new subtype of lymphomatoid papulosis. Am J Surg Pathol 2013;37:1173-81.

17. Dore E, Swick BL, Link BK, Ghahramani GK, Liu V. Follicular lymphomatoid papulosis with follicular mucinosis: a clinicopathologic study of 3 cases with literature review and conceptual reappraisal. J Cutan Pathol 2017;44:360-6.

18. Kempf W, Kazakov DV, Kerl K. Cutaneous lymphomas: an update. Part 1: T-cell and natural killer/t-cell lymphomas. and related conditions. Am J Dermatopathol 2014;36:105-23.

19. Cardoso J, Duhra P, Thway Y, Calonje E. Lymphomatoid papulosis type D: a newly described variant easily confused with cutaneous aggressive CD8-positive cytotoxic T-cell lymphoma. Am J Dermatopathol 2012;34:762-5.

20. McQuitty E, Curry JL, Tetzlaff MT, Prieto VG, Duvic M, Torres-Cabala C. The differential diagnosis of CD8-positive ("type D") lymphomatoid papulosis. J Cutan Pathol 2014;41:88-100.

21. Guitart J, Martinez-Escala ME, Subtil A, Duvic M, Pulitzer MP, Olsen EA, et al. Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas. Mod Pathol 2017;30:761-72.

22. Kiavash K, Abner SM, Malone JC. New variant lymphomatoid papulosis type E preceding and coexisting with mycosis fungoides - a case report and review of the literature. J Cutan Pathol 2015;42:1018-23.

23. Ross NA, Truong H, Keller MS, Mulholland JK, Lee JB, Sahu J. Follicular Lymphomatoid Papulosis: An Eosinophilic-Rich Follicular Subtype Masquerading as Folliculitis Clinically and Histologically. Am J Dermatopathol 2016;38:e1-10.

24. Karai LJ, Kadin ME, Hsi ED, Sluzevich JC, Ketterling RP, Knudson RA. Chromosomal rearrangements of 6p25.3 define a new subtype of lymphomatoid papulosis. Am J Surg Pathol 2013;37:1173-81.

25. Kempf W. A new era for cutaneous CD30-positive T-cell lymphoproliferative disorders. Semin Diagn Pathol 2017;34:22-35.

26. Willemze R, Meijer CJ. Classification of cutaneous T-cell lymphoma: from Alibert to WHO-EORTC. J Cutan Pathol 2006;33 Suppl 1:18-26.

27. Werner B, Massone C, Kerl H, Cerroni L. Large CD30-positive cells in benign, atypical lymphoid infiltrates of the skin. J Cutan Pathol 2008;35:1100-7.

28. Kempf W, Kazakov DV, Palmedo G, Fraitag S, Schaerer L, Kutzner H. Pityriasis lichenoides et varioliformis acuta with numerous CD30(+) cells: a variant mimicking lymphomatoid papulosis and other cutaneous lymphomas. A clinicopathologic, immunohistochemical, and molecular biological study of 13 cases. Am J Surg Pathol 2012;36:1021-9.

29. Berger GK, Gee K, Votruba C, McBride A, Anwer F. Potential application and prevalence of the CD30 (Ki-1) antigen among solid tumors: A focus review of the literature. Crit Rev Oncol Hematol 2017;113:8-17.

30. De Souza A, Carter JB, Harris NL, Ferry JA, Duncan LM. Contribution of longitudinal follow up and clinical pathological correlation in the diagnosis CD30-positive skin infiltrates. J Cutan Pathol 2015;42:452-8.

31. Wang HH, Lach L, Kadin ME. Epidemiology of lymphomatoid papulosis. Cancer 1992;70:2951-7.

32. Gan EY, Tang MB, Tan SH. Lymphomatoid papulosis: is a second lymphoma commoner among East Asians? Clin Exp Dermatol 2012;37:118-21.

33. de Souza A, el-Azhary RA, Camilleri MJ, Wada DA, Appert DL, Gibson LE. In search of prognostic indicators for lymphomatoid papulosis: a retrospective study of 123 patients. J Am Acad Dermatol 2012; 66:928-37.

34. Wieser I, Oh CW, Talpur R, Duvic M. Lymphomatoid papulosis: Treatment response and associated lymphomas in a study of 180 patients. J Am Acad Dermatol 2016;74:59-67.

35. AbuHilal M, Walsh S, Shear N. Associated Hematolymphoid Malignancies in Patients With Lymphomatoid Papulosis: A Canadian Retrospective Study. J Cutan Med Surg 2017;21:507-12.

36. Cordel N, Tressières B, D'Incan M, Machet L, Grange F, Estève É, et al. French Study Group on Cutaneous Lymphoma. Frequency and Risk Factors for Associated Lymphomas in Patients With Lymphomatoid Papulosis. Oncologist 2016;21:76-83.

37. Bekkenk MW, Geelen FA, van Voorst Vader PC, Heule F, Geerts ML, van Vloten WA, et al. Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood 2000;95:3653-61.

38. Kempf W, Pfaltz K, Vermeer MH, Cozzio A, Ortiz-Romero PL, Bagot M, et al. EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood 2011;118:4024-35.

39. Newland KM, McCormack CJ, Twigger R, Buelens O, Hughes CF, Lade S, et al. The efficacy of methotrexate for lymphomatoid papulosis. J Am Acad Dermatol 2015;72:1088-90.

40. Ansell SM. Brentuximab vedotin. Blood 2014;124:3197-200.