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DOI: 10.1111/jdv.13044

REVIEW ARTICLE

Paediatric cutaneous lymphomas: a review and comparison with adult counterparts W. Kempf,1,2,* D. V. Kazakov,1,3 I. E. Belousova,4 C. Mitteldorf,5 K. Kerl2 €rich, Switzerland Kempf und Pfaltz, Histologische Diagnostik, Zu €rich, Zu €rich, Switzerland Department of Dermatology, University Hospital Zu 3 Department of Pathology, Medical Faculty in Pilsen, Charles University in Prague, Prague, Czech Republic 4 Department of Dermatology, Medical Military Academy, Saint-Petersburg, Russia 5 Department of Dermatology, HELIOS-Klinikum, Hildesheim, Germany *Correspondence: W. Kempf. E-mail: [email protected] 1 2

Abstract Primary cutaneous lymphomas (CL) in children is rare. Only a few studies focused specifically on paediatric CL and therefore little is known whether primary CL in children are similar to or different from their adult counterparts with respect to the clinicopathological presentation, behaviour and prognosis. An extensive literature search using PubMed/MEDLINE from January 1995 through July 2014 was undertaken for articles reporting cases of paediatric CL. In addition, we identified 31 children with CL in our institutions. Mycosis fungoides and lymphomatoid papulosis are the two most prevalent lymphoma forms in children. A few entities of cutaneous lymphomas such as zary syndrome have not been reported so far in chilcutaneous diffuse large B-cell lymphoma leg type, and Se dren. Other lymphoma entities such as hydroa vacciniforme-like lymphoma are mostly seen in certain geographic areas (Asia, Central and South America). In the paediatric population, low-malignant indolent forms such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle centre lymphoma are very rare, whereas the more aggressive forms of B-cell lymphomas, precursor lymphoblastic lymphomas, and blastic plasmacytoid dendritic cell neoplasm are the most common forms in children, mostly involving the skin secondarily. Most paediatric lymphomas have similar clinicopathological features and course as their adults counterparts, particularly in the group of cutaneous T-cell lymphomas. The spectrum of cutaneous B-cell lymphomas in children significantly differs from the one in adults. Diagnostic work-up and treatment of paediatric patients with lymphomas are best achieved in close collaboration with paediatric haematopathologists and oncologists. Received: 21 October 2014; Accepted: 16 January 2015

Conflict of interest The authors state no conflict of interest

Introduction Primary cutaneous lymphomas (CL) comprise a heterogeneous group of entities with a wide variety of clinical, histopathological and immunophenotypic features as well as diverse biological behaviour.1,2 In general, most CL commonly affect adult and elderly patients, whereas CL arising in childhood is rare.3 The incidence rate of all cutaneous T-cell lymphoma (CTCL) in the US was calculated to be approximately 0.1 in age group 0–9 years and 0.3 in age group 10–19 years per million personyears, whereas similar data are missing for cutaneous B-cell lymphomas (CBCL).4 Very few studies focused specifically on the clinicopathological manifestations of paediatric CL and therefore little is known whether primary CL in children is similar to or different from their adult counterparts with respect to the clinicopathological presentation, behaviour and prognosis.5,6

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This study combines the previously published material that was extensively reviewed and our own experience with a series of primary CL in children.

Materials and methods An extensive literature search using PubMed/MEDLINE from January 1995 through July 2014 was undertaken for articles published in English and reporting cases of paediatric cutaneous lymphoma. The search keys were (‘lymphoma, cutaneous’[MeSH Term] OR (‘skin lymphoma’[All Fields] AND ‘child’[All Fields] OR ‘pediatric’[All Fields] OR (‘plasmablastic’[All Fields] AND ‘lymphoma’[All Fields]) OR ‘children’[All Fields]). The reference lists of each retrieved article were scrutinized for additional reports, and these articles were retrieved and reviewed. In addition, large series of particular cutaneous

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lymphomas were reviewed to identify paediatric cases included there. Editorials, reviews without additional cases, and non-published abstracts were excluded. The literature review was restricted to cases classified according to the REAL classification and later schemes such as the EORTC, the consensus WHOEORTC classifications and the current WHO classification (4th edition, 2008). The institutional and referral files of the authors in three institutions were searched for cases of paediatric CL (defined as age 18 years or younger) over a period from 1993 to 2013. The cases were retrieved and reviewed together with clinical information and follow-up (when available) by two of us (WK and DVK). Some cases lacked the essential clinical information and were excluded. Nine of the included cases have been subjects of five previous publications.7–10 We did not include cases of Hodgkin lymphoma, myelomonocytic leukaemia or chronic lymphocytic leukaemia with secondary cutaneous involvement.

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Results and Discussion In the literature, two series specifically focusing on the frequency of cutaneous lymphomas in children were identified. The spectrum of entities, number of patients and gender ratio are summarized in Table 1 together with 31 cases of our series.5,11 Differences in the epidemiology of CL entities among different studies are due to differences in the definition of “children”, i.e. the age of included patients, but also due to geographic differences). In the following part the features of CL in children are described in an entity-based manner and the clinicopathological features of CL in children compared to their adult counterparts based on the literature and the findings in our series of 31 patients. Cutaneous T-cell lymphomas

Mycosis fungoides (MF) is the most common form of primary CL in adults and is among the most prevalent CL in children as well.5,11 MF is usually a disease of the elderly, but a thorough

Table 1 Frequency and demographics of cases of paediatric cutaneous lymphoproliferative disorders in large series Entities

Frequency and demographics in 69 cases reported by Fink-Puches et al.

Frequency and demographics in 51 cases reported by Boccara et al.

Frequency and demographics in 31 cases from Zurich, Pilsen and Saint-Petersburg

Mycosis fungoides

24 (34.7%) (M = 12; F = 12; MA = 17)

5 (9.8%) (M = 4; F = 1; MA = 13.1)

12 (38.7%) (M = 8; F = 4; MA = 12.5)

CD30+ anaplastic large cell lymphoma

13 (18.8%) (M = 7; F = 6; MA = 14)

0

3 (9.7%) (M = 1; F = 2; MA = 15.6)

Lymphomatoid papulosis

11 (15.9%) (M = 5; F = 6; MA = 12)

24 (47%) (M = 24; F = 0; MA = 7.8)

10 (32.6%) (M = 6; F = 4; MA = 11.4)

Small to medium pleomorphic T-cell lymphoma

2 (2.9%) (M = 1; F = 1; MA = 18)

0

1 (3.2%) (F = 1; 11 yo)

Subcutaneous panniculitis-like T-cell lymphoma

1 (1.5%) (F = 1; 20 yo)

1 (1.9%) (M = 1; 1 yo)

0

c/d T-cell lymphoma

0

1 (1.9%) (F = 1; 13 yo)

0

Marginal zone B-cell lymphoma

7 (10.1%) (M = 2; F = 5; MA = 17)

0

3 (9.7%) (M = 1; F = 2; MA = 14.7)

Follicle center cell lymphoma

1 (1.5%) (F = 1; 20 yo)

0

0

B-lymphoblastic lymphoma

6 (8.7%) (M = 5; F = 1; MA = 5.5)

6 (11.8%)*

2 (6.5%) (M = 1; F = 1; MA = 5.5)

T-lymphoblastic lymphoma

0

1 (1.9%)*

0

Acute leukaemia

2 (2.9%)† (M = 0; F = 2; MA = 10.5)

7‡ (M = 3; F = 4; MA 2 mo)

Not searched for

Hodgkin disease (secondary)

1 (1.5%) (M = 1; 20 yo)

0

Not searched for

T/NK-cell lymphoma, nasal type

1 (1.5%) (F = 1; 15 yo)

1 (1.9%) (F = 1; MA = 15)

0

Epstein–Barr virus-related lymphoproliferative disorders

0

5 (9.8%) (M = 2; F = 3; MA = 6.5)

0

F, female; M, male; MA, Median age in years (unless otherwise specified). *B-lymphoblastic leukaemia and T-lymphoblastic leukaemia are lumped together allowing no identification of a male–to-female ratio and age for each group. †Both cases represented secondary cutaneous involvement by acute myeloid leukaemia. ‡Six of the seven cases were classified as monoblastic leukaemia (with five of them being congenital), whereas the remaining cases was unclassifiable.

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history taken from adult patients may reveal the onset of symptoms during childhood or adolescence.12 The incidence of MF starting at an early age has been estimated to range from 0.5% to 7%.13–16 but some geographic variability or differences in the inclusion criteria obviously exists.17 For example, in a series of MF from Kuwait, children and adolescent MF patients (younger than 18 years) comprised 16.6% of a total of MF cases diagnosed over 19 years (36 of 223) representing an unusual high number.17 With regard to the gender ratio, some studies identified a prevalence of males similar to adult disease, whereas in others a striking female predominance was observed.18 Juvenile MF may show the classic presentation with erythematous patches and plaques and epidermotropism of lymphocytes (Fig. 1), but in addition various atypical clinical variants have been reported, including hyperpigmented, ichthyosiform, follicular, poikilodermic, solitary and intraoral18–22 (Fig. 2). The hypopigmented form appears to be overrepresented in childhood/ adolescent MF as observed in a series of 15 cases of hypopigmented MF with 10 patients being younger than 20 years of age.23 Hypopigmented MF is often associated with a cytotoxic phenotype characterized by expression of CD8 and TIA-1.23 Diagnosis of hypopigmented MF may be challenging and therefore delayed. Rarely, juvenile MF patients manifested a combination of two atypical disease variants. Some atypical variants of MF are vanishingly rare in children, with just a few or even single reports. For example, of the 35 cases of MF involving the oral mucosa reported by 2003, only one child developed cutaneous disease (poikilodermic lesions) at the age of 6 months and oral involvement occurred 8 years later.20 In a recent series of 15 cases of solitary (unilesional) MF with a review of the previously reported 128 cases of this disease variant, there were only two patients younger than 18 years.22 In our series, there was a single case of a 6 –year-old girl with unilesional MF on the abdomen (Fig. 3). Juvenile-onset MF may be associated with lymphomatoid papulosis (LyP) (up to 18% in one series) or be accompanied by eruptions resembling pityriasis lichenoides. In the latter case, distinction from so-called pityriasis-like MF may be difficult.24 Various histopathological and phenotypic variants have been reported in adults (for review see ref. 25 and 26). The phenotype, however, is not linked to biological behaviour. In particular CD8+ MF cases do have an indolent behaviour neither in adults nor in children.23 In our series, there was a patient with coexpression CD8 and CD56 by tumour cells, but with an indolent disease course.27 There is some controversy on the classification of juvenile cases of alopecia mucinosa/follicular mucinosis as MF (Fig. 4). In adults, alopecia mucinosa/follicular mucinosis is thought to represent a lymphoma, but a recent study of 31 children has questioned this concept.28 Interestingly, 12 cases in that study fulfilled the International Society of Cutaneous Lymphomas diagnostic criteria for early MF but in all cases cutaneous lesions

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(a)

(b)

Figure 1 Mycosis fungoides. A 16-year-old boy with multiple patches on the back (a), with histology showing marked epidermotropism of small convoluted lymphocytes forming intraepidermal collections (Pautrier microabscesses) (b).

resolved and none persisted or recurred. In a series on paediatric follicular mucinosis, most patients responded to topical treatment with steroids or retinoids or phototherapy and experienced a benign course. Molecular analysis showed that only two cases of 11 cases were clonal. The authors proposed that histopathological diagnosis of follicular mucinosis should not be equated with follicular MF.29 In the most recent study of 50 juvenile MF

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(a)

(b) (b)

Figure 3 Unilesional mycosis fungoides. Showing histologically a dense infiltrate composed of small cerebriform lymphocytes with focal epidermotropism (a), a 6-year-old girl with a solitary plaque (b).

Figure 2 Mycosis fungoides. A 12-year-old boy with multiple slightly hyperpigmented patches (a, b).

cases; however, follicular MF was the second most common variant.30 The authors employed inclusion criteria based on the WHO-EORTC classification but admitted that some of their cases might have represented so-called cutaneous T-cell dyscrasia rather than early follicular MF. Further studies on children with alopecia mucinosa/follicular mucinosis with long-term follow-up are warranted to validate this observation, as in adults follicular MF shows a more aggressive behaviour and a worse prognosis than classical MF.31 A majority of juvenile-onset MF patients presents with stage IA and IB disease and therefore has an excellent prognosis with survival rate similar to that seen in the general population.30,32–34 Progression to plaque-stage, tumour-stage disease or

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erythroderma and death due to lymphoma was observed in a small subset of cases.12,15 The factors that predict tumour progression in young MF patients have not been established. Pagetoid reticulosis (Worringer-Kolopp disease) represents a unilesional subtype of MF. The original description by Worringer and Kolopp in 1939 involved a paediatric case. However, later studies demonstrated a relative paucity of the disease among children and some series dedicated to the disease did not include children at all.35,36 The clinicopathological presentation of paediatric and adult cases seems to be similar. The patients usually present with a solitary asymptomatic, sharply circumscribed patch or plaque, often having polycyclic borders and involving the distal extremities. There is a male predilection. Histopathologically, the epidermis, especially the lower part is infiltrated by small- to medium-sized atypical lymphocytes, whereas the dermal component of the infiltrate is rather sparse.37,38

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(a)

(b)

(c) Figure 4 Mycosis fungoides accompanied by follicular mucinosis in a 14-year-old boy. Apart from lesions on the trunk, the patients had patches on his face and arms, some of which were hypopigmented (a). Histological appearances of follicular mucinosis on haematoxylin and eosin stained (b) and alcian blue (c) stained sections.

Granulomatous slack skin (GSS) is a very rare MF subtype characterized by the slow development of cutis laxa-like changes in the major skin folds, i.e. axillae and groins, and histologically by an infiltrate of clonal small T cells and scattered large multinucleated giant cells with emperipolesis and elastophagocytosis.39 Extracutaneous involvement is rare, but in half of the patients second lymphomas, particularly Hodgkin lymphoma, can occur.40 GSS has been reported in children only rarely, but in some cases of adult disease the history indicated the onset in childhood.41–43 We were able to identify five paediatric cases published in the literature.41,43–46 The clinicopathological presentation is identical to the adult counterpart but documented progression to CD30+ large cell lymphoma in the cases with longer follow-up suggests that paediatric GSS may be more aggressive. An unusual case was reported by Tronnier and coworkers with GSS preceded by follicular MF with alopecic areas in the scalp and numerous infundibular cysts involving the mons pubis.47 Histopathologically crystalline and doubly retractile material of an unknown origin were present within some of multinucleated giant cells in the GSS lesions.47 Sezary syndrome (SS) is a rare and aggressive form of CTCL accounting for 3% of all cutaneous lymphomas.48 With regard to paediatric cases, progression of MF to erythroderma has been reported but bona fide cases of SS in childhood have not been reported. Primary cutaneous CD30+ lymphoproliferative disorders (CD30+ LPD) are the second most common form (20–25%) of CTCL, comprising primary cutaneous CD30+ anaplastic large cell lymphoma (PCALCL), lymphomatoid papulosis (LyP) and borderline lesions. Cutaneous CD30+ LPD were the second (n = 13; 19%) and the third (n = 11; 16%) most common CL types, respectively, in a series of 69 paediatric CL after MF being the most common form.5 In another series of 51 children with

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age 15 years and younger, CD30+ LPD was the most common disorder (n = 24), all represented by LyP and with no case of CD30+ ALCL (Table 1). Of the 487 paediatric patients registered within the Anaplastic Large Cell Lymphoma-99 trial, 33 cases presented with a skin limited CD30+ LPD.49 In our series, LyP was the second most common form (10 of 31 cases) after MF. Primary cutaneous CD30+ anaplastic large cell lymphoma (PCALCL) most commonly presents with a solitary, large, often ulcerated nodule or localized tumours and shows nodular cohesive infiltrates of large pleomorphic, anaplastic or immunoblastlike tumour cells, of which, by definition, more than 75% express CD30.50 PC-ALCL can occur also in children. Paediatric cases of ALCL appear to have similar clinicopathological features to their adult counterpart including the excellent prognosis. Like in adult cases, some cases show overlapping features of ALCL and LyP. Rare cases with unusual histological variants including the small cell-type ALCL, so-called inflammatory-type with numerous neutrophils and eosinophils, lesions accompanied by marked follicular mucinosis, angiocentric/angiodestructive growth or containing neoplastic cells reminiscent of rhabdomyoblasts or showing erythrophagocytosis.5,8,51–55 In addition to the most common phenotypes (CD4+ CD8 or CD4 CD8+), unusual and rare cases of PCALCL expressing CD56 have been observed.56 PCALCL usually lacks expression of ALK-1 and t (2;5). Thus, particularly in ALK+ ALCL cases, secondary cutaneous involvement should be considered. Interestingly, Oschlies et al.49 reported a series of six children with ALK-positive ALCL limited to the skin with complete remission and excellent prognosis. Further studies are, however, needed to clarify the biology of the ALK-positive PCALCL. Lymphomatoid papulosis is a chronic recurrent eruption characterized by a typical waning and waxing course of self-healing

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papules and nodules. LyP most commonly affect people in the fifth decade, but can occur also in children. Bekkenk et al.57 found that 12 of 118 (10%) patients with LyP were younger than 20 years of age at the time of diagnosis with a median age of 12 years of age (range 4–19 years of age). The youngest patient with LyP reported so far in the literature is an 11-month-old boy.58 In a recent study on 25 children with LyP, the median age at diagnosis was 7.5 years.59 In our series of 10 children with LyP, the median age at diagnosis was 11.4 years (with an age range from 6 to 18 years) and a male preponderance with a male to female ratio of 1.5 : 1. One third of children with LyP show association with atopy.59 In most cases, LyP manifested clinically and histologically similar to LyP in adults.60 Compared to LyP in adults, three unusual patterns were identified in children suffering from LyP: First, after initial outbreak, dwindling outbreaks (both in frequency and number of lesions) until the eruption ceased completely; second, LyP localized to one area for years before generalizing, and third, presentation with hundreds of lesions. In some cases, LyP runs a protracted course over years.61 Pruritus is a common feature in paediatric LyP and was observed in 40% of the patients.59,62 Five histopathological subtypes of LyP have been delineated: LyP type A (so-called histiocytic), type B (mycosis fungoideslike), type C (anaplastic large cell lymphoma-like), type D (cytotoxic epidermotropic) and E (angioinvasive), and a sixth type F has been considered (for review see ref. 63) (Fig. 5). The reports of children affected by LyP were mostly of the three-first types A to C which may be explained by the fact that LyP type D and E have been described only very recently.62,64–66 In our series of LyP biopsies in children comprised the histological types A, C and E with the latter found in two of our patients. Due to the presence of eosinophils in paediatric LyP and common pruritus, bite reaction is also a differential diagnostic consideration.8,67 Phenotypically, LyP with expression of CD8+ by the atypical

Figure 5 Large pleomorphic cells in lymphomatoid papulosis.

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CD30+ lymphocytes seems to be more common in children than in adults.65 Saggini et al.68 stressed that the cytotoxic epidermotropic variant of LyP (type D) may be histopathologically indistinguishable from primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, and may be the source of pitfalls in the diagnosis and classification. Luckily, cases of primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma in children are extremely rare, if existent at all (see below). An important differential diagnostic consideration is pityriasis lichenoides et varioliformis acuta (PLEVA) which can express CD8 and CD30.69 Remarkably, almost a third of children with LyP presented with pityriasis lichenoides chronica before onset of their disease11 LyP may persist lifelong, but complete remission can occur at any time and can be observed in nearly half of the patients.60 Despite LyP is not associated with mortality, patients with LyP are at risk to develop a second lymphoma, particulary MF, Hodgkin lymphoma and ALCL, before occurrence of LyP or during disease course. The frequency of second lymphomas in LyP patients ranges from 10 to 62% (for details see 63). In the series by Miquel et al.59, none of the 25 children developed a second lymphoma. Zirbel et al., however, reported that two previously reported patients with childhood-onset of LyP had lymphoma as adults. One patient in our series presented with so-called agminated LyP and later developed MF (patch stage). As consequence, children with LyP should have lifelong followup to identify putatively arising associated malignant lymphomas as early as possible. Subcutaneous panniculitis-like T-cell lymphoma

According to the current WHO classification, the term subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is reserved for cases with expression of the a/b chain of the T-cell receptor by the neoplastic cells.70 The disease manifests as subcutaneous nodules resembling panniculitis, and up to 50% of the patients present with systemic symptoms and/or laboratory abnormalities, including cytopenia and elevated liver enzymes. In approximately 15% of cases, hemophagocytic syndrome occurs and such cases follow a more aggressive course. Histopathologically, the appearances are those of lobular panniculitis with the infiltration of the subcutaneous fat by variably sized atypical lymphocytes displaying most commonly a CD4 , CD8+, CD56 phenotype and expression of betaF1 as the diagnostically most important and defining feature.71 Paediatric cases of SPTCL are rare with approximately 40 cases reported to date. The only case series specifically focusing on SPTCL in childhood and early adulthood is a recent study of 16 cases.72 In another study on SPTCL conducted by the EORTC group, both adult and paediatric patients were included in the cohort of 63 patients, with 12 individuals (19%) being 20 years of age or younger.71 In addition, there are case reports on SPTCL in children.73–76 Based on the data in the literature paediatric

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SPTCL shows no gender predilection and mostly occurs around puberty (12–16 years). The youngest patient is a 4-month infant.74 In addition, one patient with congenital HIV infection was documented. In a minority of cases, the disease was accompanied by haemophagocytic syndrome with a more aggressive course and death. Most cases were treated with the CHOP regime (cyclophosphamide, doxorubicin, vincristine and prednisolone). Of note, lack of a demonstrable clonal T-cell population was seen in almost two-thirds (six of 17) cases in the series of Huppmann et al.72 With regard to the good prognosis of SPTCL, a wait-and-see strategy or systemic steroids can be considered as therapeutic first-line approach for this lymphoma.1,2 Cyclosporine A and bexarotene maybe alternative therapeutic options.77 Extranodal NK/T-cell lymphoma, nasal-type, hydroa vacciniforme-like lymphoma and related conditions

Extranodal NK/T-cell lymphoma, nasal type, is a rare but aggressive lymphoma variant associated with the Epstein–Barr virus (EBV).78 A common late clinical complication is hemophagocytic syndrome which is often associated with a rapidly fatal outcome. The lymphoma is much more common in Asians than in patients of European or North American background.79–81 EBV-positive lymphoproliferative disorders of childhood comprise an important group of disorders listed in the WHO classification, of which hydroa vacciniforme-like lymphoma is the most common entity representing a cutaneous natural killer cell (NK)/T-cell lymphoma mainly affecting children from Central and South America and Asia.80 As its name implies, the disease clinically resembles hydroa vacciniforme (HV), a photosensitivity disorder of unknown aetiology characterized by papulovesicular eruption on sun-exposed sites, often with seasonal activity, with no laboratory abnormalities and resolving in the adult life.82 In contrast to HV, HV-like lymphoma is not induced by sun and the lesions can occur in both sun-exposed and covered body areas and are usually more severe, with facial swelling and ulceration. Although spontaneous improvement may temporally occur, the lesions eventually progress and are accompanied by other features such as fever, wasting, lymphadenopathy, hepatosplenomegaly and laboratory abnormalities. The prognosis is generally poor. Increased numbers of EBV-encoded RNA (EBER)-positive in the lesional cells, abnormal antibody titres to EBV and hypersensitivity to mosquito bites in these patients altogether suggest that the disease may represent a form of chronic active EBV infection and thereby related to hypersensitivity to mosquito bites, which represents an EBV-related disease restricted to Asia and Mexico.80,83–91 Histopathologically, there is a dense lymphoid infiltrate involving the whole dermis and often extending into the subcutaneous tissue or skeletal muscle. Angiocentric/angiodestructive features can be seen. The infiltrate is predominantly composed of small- to medium-sized lymphocytes. Epidermal changes include epidermotropism, keratinocyte

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necrosis and vesiculation.92 A recent series demonstrated a variation in the immunophenotype of the EBV-positive neoplastic cells similar to what is seen in extranodal NK/T-cell lymphomas of the nasal type.80 While most cases exhibited a NK-cell phenotype, there are also cases with EBER-positive cells expressing CD8+ beta F1 or the c/d phenotype.93 No correlation of a particular immunophenotype and the clinical outcome was noted, but a higher mortality was associated with late onset of disease, thrombocytopenia and T-cell infection. In addition, the mode of treatment appears to be a factor influencing the outcome. In a series of 12 Bolivian patients, most died of disease, which contrasts to the outcome in a series of 20 Mexican children, most of them undergoing radiotherapy in combination with immunomodulators and immunosuppressive therapy.92,94 Cutaneous peripheral T-cell lymphoma, unspecified/not otherwise specified (PTL- NOS) represents a phenotypically and prognostically heterogenous group of cutaneous T-cell lymphomas (CTCL) that do not fit into any of well-defined CTCL subtypes.95 Among PTL, NOS, three entities have been delineated based on their characteristic clinicopathological, immunophenotypic and prognostic features: • Cutaneous CD4+ small/medium-sized T-cell lymphoma (CD4+ SMTL) • Cutaneous CD8+ aggressive epidermotropic cytotoxic Tcell lymphoma • Cutaneous c/d+ T-cell lymphoma Primary cutaneous CD4-positive small/medium T-cell lymphoma (CD4+ SMTL) represents a provisional entity in both the 4th edition of WHO classification and the WHO-EORTC classification. Its relationship of CD4+ SMTL to nodular T-cell pseudolymphoma is still a matter of discussion (for review see Kempf et al.96). In a majority of cases, the disease manifests as a non-ulcerated nodule (up to 3 cm) arising on the head and neck area, especially on the face without preceding patches and plaques97 Histopathologically, the dense nodular non-epidermotropic infiltrate is predominantly composed of small- and mediumsized lymphocytes with slight to moderate nuclear pleomorphism (Fig. 6).98 Paediatric cases of CD4+ SMTL are rare, with only a single short case series of four patients being described and three isolated case reports included in a large series on the disease.98–101 In addition, paediatric patients were included in large series of Beltraminelli et al., but the number of children in that series was not specified by the authors.97 Based on these data, there is a male preponderance. The age at diagnoses ranged from 3 to 16 months, with all but one case presenting with a solitary nodule. The disease exhibits the same excellent prognosis in children as in adults, especially when presenting with a solitary lesion. Surgical excision or radiotherapy is the first-line treatment in adults. Tumour regression after biopsy may occur. The only child with multiple papules, nodules and tumours involving the

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(a)

(b)

Figure 6 (a) Primary cutaneous CD4positive small/medium T-cell lymphoma in a child. A dense multinodular infiltrate in the reticular dermis (b) composed of small- to medium-sized pleomorphic lymphocytes.

scalp, trunk and groin was reported by Baum et al.99 The lesions were excised and the patient had no recurrences at 129-month follow-up.99 This contrasts to the impaired prognosis of multifocal CD4+ SMTL in adults. Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (CD8+ AECTCL) usually affects elderly patients with a male predominance (male-to-female ratio 2 : 1). It clinically manifests as generalized, rapidly progressing patches and plaques, often with a haemorrhagic crusts. The disease runs an aggressive course with a tendency to systemic spread to extracutaneous sites. The histopathological hallmark of the lymphoma is a marked epidermotropism of small medium-sized irregular lymphocytes expressing CD8 and often accompanied by necrotic keratinocytes.102 The disease is exceedingly rare, if existent at all, in the paediatric population. A recent review identified 50 reported cases of CD8+ AECTCL identified only a single patient (a 19-year-old female) reported originally by Wang et al.103,104 The patient had a rather unusual presentation for primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma, namely, widespread pyoderma gangrenosum-like lesions. She partly responded to four cycles of CHOP but died 22 months later.104 Apart from this case, Kikuchi et al. documented primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma in a 6-year-old girl, presenting with unusual features including hypersensitivity to mosquito bites, peripheral lymph node involvement by CD8+ cells and large (up to 10 cm) cutaneous necrotic lesions.105 Primary cutaneous c/d+ T-cell lymphoma (CGD-TCL) is a rare malignancy characterized by a clonal proliferation of mature activated c/d T cells thought to derive from local organ-specific c/d T-cell populations.106,107 The disease is rare with approximately 100 cases reported to date. The authors of a recent large series comprising 53 cases of this lymphoma type challenged the concept of cutaneous c/d+ T-cell lymphoma as a distinct entity and demonstrated its complexity and heterogeneity, highlighting the overlapping features with other lymphoma entities.108 Observations of cases with indo-

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lent behaviour have been reported by others.109–114 Paediatric cases of CGD-TCL are very rare. For example, no single paediatric case was included in the series of Guitart et al.108 Some children with CGD-TCL were included in a particular series but it is difficult, if possible at all, to extract conclusive informations.107 Two 10-year-old children were included in the series reported by Marzano of panniculitis-like lymphoma with cytophagic histiocytic panniculitis and died within 1 year.115

Cutaneous B-cell lymphomas Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is defined as an indolent B-cell lymphoma composed of small B lymphocytes, centrocyte-like cells, lymphoplasmacytoid cells and plasma cells and often numerous reactive T cells.7,116 Presentation with solitary or multifocal skin lesions is frequent, including violaceous papules, plaques or nodules preferentially involving the trunk or extremities (especially the arms)117 (Fig. 7). We found 20 published cases of paediatric PCMZL and recently have published three cases, with a detailed review.5,7,118– 125 Based on the 23 cases, it can be summarized that paediatric PCMZL mostly arises in teenagers and shows no gender predilection, presents in an approximately one third of cases with lesions involving more than one anatomical site and persistent disease occurs in a minority of instances. Association with Borrelia burgdorferi is rare. Paediatric PCMZL follows the indolent course and excellent prognosis similar to its adult counterpart.7 Primary cutaneous follicle centre lymphoma (PCFCL) is predominantly composed of centrocyte-like differentiated tumour cells with cleaved nuclei2 (Fig. 8). Three growth patterns are encountered, including follicular, follicular and diffuse, and diffuse. The disease has a characteristic clinical presentation with solitary or grouped plaques and tumours, mainly involving the scalp/forehead or the trunk.126,127 The neoplastic cells in primary express B-cell markers, bcl-6 (germinal centre cell marker), but do not express bcl-2 and demonstrate no t14;18 translocation in most cases, which contrasts to nodal follicular lymphoma.128

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Figure 7 Marginal zone lymphoma presenting as a grouped papules [details in (7)].

PCFCL in children appears to be vanishingly rare, with only three paediatric cases reported, to the best of our knowledge. In the above-mentioned series of Fink-Puches et al.5, the authors identified a 20-year-old woman with PCFCL who was alive with lymphoma 13 months after diagnosis. Ghislanzoni et al. reported an unusual case of a 16-year-old boy in whom the neoplasm occurred on the nose and the left nasolabial fold, extended onto the left cheek, and involved the left maxillary sinus and the soft palate.129 Polychemotherapy was administered and the patient was disease free after 41 months. This case was unusual as PCFCL rarely involve the nose, and only occasionally disseminates to extracutaneous sites.129 Rarity of PCFCL in paediatric population is highlighted by the study of Amitay-Laish et al.118 who identified a single individual with PCFCL among 90 paediatric patients with primary CBCL who was a 17-year-old woman

(a)

with an annular plaque on the scalp. There were unusual histopathological features including a heavy dermal lymphocytic infiltrate containing spindle cells with myxomatous changes in the stroma and expression of CD30 by the spindled cells that otherwise demonstrated the immunoprofile consistent with PCFCL. The patient was treated with excision and electron beam therapy and was alive with no evidence of disease at 25 months.118,130 Primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type, is a rare and aggressive variant of CBCL most commonly presenting with skin lesions on the (lower) legs in elderly patients.131 Our review of the literature did not disclose any paediatric case of primary cutaneous DLBCL, leg type. This would be important to keep in mind while diagnosing B-cell childhood pseudolymphoma in particular sites such as the nipple and scrotum where lesions often manifest atypical features including confluent sheets of centroblasts imitating DLBCL.132,133 Plasmablastic lymphoma is a rare variant of diffuse large B-cell lymphoma mostly arising in the oral cavity of HIV-infected patients or posttransplant patients. The skin is rarely involved.134,135 An association of EBV with this lymphoma type has been established. In adult patients, the disease is characterized by an aggressive course, with mean survival 6 months. HIV patients appear to have a more favourable prognosis compared with posttransplant patients.136,137.Reports of paediatric cases of plasmablastic lymphoma are scarce and rare patients were obviously reported by different groups twice.138–141 Both types have been reported, including HIV-positive and -negative cases, patients after organ transplantation, lesions confined to the skin at presentation and occurrence in unusual sites (vulva).142–144 Among other lymphomas of large B cells, neither primary cutaneous T-cell/histiocyte-rich large B-cell lymphoma nor primary intravascular B-cell lymphoma has been reported in children, to the best of our knowledge.

(b)

Figure 8 Follicular centre cell lymphoma. At scanning magnification bottom heavy infiltrate can be recognized (a). Note centroblasts and centrocytes in the infiltrate (b).

JEADV 2015, 29, 1696–1709

© 2015 European Academy of Dermatology and Venereology

Cutaneous lymphomas in children

Precursor lymphoblastic lymphomas/leukaemias and related conditions Lymphoblastic lymphoma/leukaemia (LBL) is a neoplasm of immature B cells committed to the B- or T-cell lineage and account for approximately 2% of all nodal and extranodal lymphoproliferative disorders. LBL are postulated to arise from precursor B cells in the bone marrow or thymic T cells at varying stages of differentiation respectively. The skin is infrequently involved in both B-lymphoblastic lymphoma/leukaemia and very rarely in T-lymphoblastic lymphoma/leukaemia.145,146 About 80% of precursor B-cell neoplasms present as acute leukaemias, with bone marrow and peripheral blood involvement. By definition, the term “lymphoma” is used in cases exhibiting a bulky lesion in the mediastinum (or elsewhere), with no or minimal evidence of peripheral blood and bone marrow involvement, with a threshold of

Paediatric cutaneous lymphomas: a review and comparison with adult counterparts.

Primary cutaneous lymphomas (CL) in children is rare. Only a few studies focused specifically on paediatric CL and therefore little is known whether p...
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