Mycosis fungoides in children and adolescents

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Mycosis fungoides in children and adolescents Expert Rev. Dermatol. 8(3), 309–320 (2013)

Arti Nanda* and Hejab Al-Ajmi Pediatric Dermatology Unit, As’ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait *Author for correspondence: [email protected]

Mycosis fungoides (MF) is a low-grade lymphoproliferative disorder that is histologically characterized by an epidermotropic proliferation of small or medium-sized atypical T lymphocytes with cerebriform nuclei and is primarily a disease of the elderly. It is rare in children and adolescents; in large series of MF published in the literature, only a small percentage of patients were observed to have onset of MF below adolescence. It was believed that a younger age of onset of MF may herald a poorer prognosis. Recently, with improved knowledge of the basic nature of the disease and refined diagnostic facilities, a few series of MF among children and adolescence have appeared and have drawn more awareness to the behavior of MF in this age group. This review summarizes the clinicoepidemiological features, treatment and prognosis of MF among children and adolescents based on the current literature. Keywords: adolescents • children • clinicoepidemiological features • mycosis fungoides • prognosis • treatment

Mycosis fungoides in children & adolescents: an overview

Cutaneous lymphomas comprise a heterogeneous group of lymphoproliferative disorders with skin involvement and are classified as a subgroup of non-Hodgkin’s lymphoma. The term ‘primary cutaneous lymphoma’ refers to cutaneous T-cell lymphomas and cutaneous B-cell lymphomas that, at the time of diagnosis, are present only on the skin without extracutaneous involvement [1] . Classification of primary cutaneous lymphomas has been proposed by the WHO and European Organization for Research and Treatment of Cancer (WHO–EORTC) [1] that applies to both adults and children. Cutaneous lymphomas are rare in children and adolescents and are mostly of T-cell lineage, and among them the most common is mycosis fungoides (MF). Other cutaneous T-cell lymphomas and cutaneous B-cell lymphomas in children are published as isolated case reports or very small case series. This article will review the recent literature on MF in children and adolescents. Historically, Alibert reported the first case of MF in 1806 [2] and Bazin later defined the three cutaneous phases of the disease (patch, plaque and tumor stage) [3] . In its classical form, MF shows a progressive, indolent course with an evolution from patches to plaques and eventually tumors over several years [1] . It commonly affects middle-aged and older adults 50 years of www.expert-reviews.com

10.1586/EDM.13.29

age or above. MF is rare in children and adolescents, and it was commonly believed that an onset of the disease at a younger age determined an aggressive course. In the earlier large series, approximately 0.5–5% of patients were reported to have onset of MF below 20 years of age [4,5] . However, recently with more awareness of the disease and better diagnostic facilities, an increased number of MF cases occurring in children and adolescents have been reported in the literature [6–14] . It is now generally believed that the behavior of MF among children and adolescents does not differ from that in adults. Despite the growing awareness of MF among children and adolescents, the data of MF in this age group is still lacking for many parts of the world. The present review focuses on the clinicoepidemiological features, management options and prognosis of MF in children and adolescents based on the recent literature [4–14] . Epidemiology

Children and adolescents constitute around 0.4–16.6% of total MF cases, with a higher prevalence reported among Asians [13–15] than from the west [4–8] . In most of the earlier series from the west, approximately 4–5% of patients were reported to have onset of disease before the age of 20 years, and in approximately 0 .4–2.7% of patients the diagnosis was settled by the age of 18 years [4–8] . A report from Singapore [15]

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Figure 1. Patch-stage mycosis fungoides showing erythematous scaly patches in the groin and lower abdomen.

describes 11% of juvenile-onset MF patients diagnosed by the age of 20 years. One of the largest series of MF in children and adolescents published to date is among Arabs, reporting 36 cases diagnosed by the age of 18 years who were observed to constitute 16.6% of the total MF patients [13] . In a recent report from Turkey, 5.4% of patients were diagnosed by the age of 18 years [14] . The age-adjusted annual incidence of MF among Arab children and adolescents was reported to be 0.29 cases/100,000 population/year [13] compared with the overall annual incidence rate of MF among Arabs of 0.66 cases/100,000/year [16] . The figures of age-adjusted annual incidence rate of MF among children and adolescents are not available among other ethnic groups. The overall annual incidence of MF from the USA is 0.41 cases/100,000 population/year [17] . Given an overall proportion of juvenile-onset cases of around

5%, the annual incidence rate among children and adolescents seems to be much less than that reported among Arabs [13,16] ; however, this needs to be confirmed. Whether a higher prevalence of MF reported among Asian children and adolescents in the recent reports is related to more awareness of the disease with improved facilities to diagnose these cases or to ethnic and geographic variations needs to be determined [13–15] . Table 1 compares the clinicoepidemiological features of MF among children and adolescents described in large series (including at least ten patients) to date [6,8–14] . Table 2 includes the salient features of MF among children and adolescents reported in the large series [6–14] . Most of the series show a trend towards male dominance (Table 1) , with a male to female ratio of 1.25:1 among Arab children and adolescents to a highest of 3.6:1 among Koreans [8,9,11,13,14] , whereas an equal sex predisposition (1:1) was reported from the USA, Austria and Canada [6,10,12] . Overall, males were observed to outnumber females by a 1.6:1 ratio (Table 2) . The median age at diagnosis of MF in different series has ranged from 10 to 19 years and median duration of disease before the diagnosis was settled was observed to range from 1 to 7.5 years [6,8–11,13,14] . There have been reports of infantile-onset MF with confirmation of diagnosis by the age 2 years [6,18] . Clinicopathological characteristics

In its classical form, the disease evolves through three stages – the patch, plaque and tumor stage [1,2,19–22] . Histologically, MF is characterized by the proliferation of small cerebriform lymphocytes showing epidermotropism. However, MF has a plethora of clinicopathological manifestations, some of which differ substantially from the classical form and are referred to as ‘atypical’ forms of MF [1,21] . Although children and adolescents show classical presentation of MF, the rare variants are more often described among them compared with adult-onset disease [6–8,11–15] . One of the plausible explanations for this could be that the lesions of classic MF in the early stages mimic common inflammatory dermato ses including eczema, psoriasis and so on, and a skin biopsy in children for such lesions is usually not performed until they show an atypical behavior [11] , whereas atypical variants of MF draw an early attention of the physicians. Whether higher prevalence of atypical variants of MF among children and adolescents is related to the younger age of onset or an over-representation due to the lack of confirmation of classical cases in children being missed for common inflammatory dermatoses needs to be confirmed. Classical MF

Figure 2. Erythematous, mildly scaly plaques of mycosis fungoides on the thighs.

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The lesions may start as nonspecific scaly patches (Figure 1) resembling various inflammatory dermatoses including chronic eczema, parapsoriasis, tinea corporis, psoriasis, and so on, or may present as more distinctive irregular well-circumscribed scaly patches varying in size from 2–3 to 10–15 cm. The lesions present as a few patches, or in other instances, may be seen as numerous, widely distributed lesions [1,19–21] . It usually takes several years until the patches progress into plaques (Figures 2 – 4) and tumors, which may then ulcerate [21] . Histologically, in the patch stage, the classical Expert Rev. Dermatol. 8(3), (2013)

Mycosis fungoides in children & adolescents

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Table 1. Clinicoepidemiological features of mycosis fungoides among children and adolescents reported in the literature. Clinical features Patients studied (n)

Country (reference n) USA [6]

UK [8]

Israel [9]

Austria [10]

Korea [11]

Canada [12]† Kuwait [13]

Turkey [14]

24

34

10

24

23

22

36

20

4

NA

NA

NA

NA

16.6

5.4

Prevalence among total MF 4.3 cases of all ages (%)

Sex distribution M

12 (50%) 24 (71%) 6 (60%)

12 (50%)

18 (78%)

(52.5%)

20 (56%)

12 (60%)

F

12 (50%) 10 (29%) 4 (40%)

12 (50%)

5 (22%)

(47.5%)

16 (44%)

8 (40%)

M:F

1:1

2.4:1

1.5:1

1:1

3.6:1

1:1

1.25:1

1.5:1

Range

1.8–56

6–61

3.8–17.5

3–20

4–19

NA

5–18

2–18

Mean

21

19

15

15.5

11

9.9 ± 3.8

13

9

Median

19

16

14

17

10

NA

13

10

NA

0.09–10

NA

0.25–10

0–6

Age at diagnosis (years)

Duration of disease before diagnosis (years) Range

0–43

0–46

0.3–14.5

Mean

10

9.8

6

2.7

4

2

Median

7.5

5

5

2

3

1

27 (75%)

12 (60%)

Morphological types Patch stage

19 (79%) 21 (62%) 6 (60%)

NA

16 (70%)

11

Plaque stage

5 (21%)

11 (32%) 1 (10%)

2 (9%)

5

9 (25%)

4 (20%)

Both

0

1 (3%)

3 (30%)

5 (22%)

6

0

4 (20%)

Not specified

0

1 (3%)

0

0

0

0

0

Hypopigmented

5 (21%)

9 (26%) ‡

7 (70%) ‡

3 (13%)

5 (22%)

15 (59%) ‡

23 (64%) ‡

9 (45%) ‡

Poikilodermatous

2 (8%)

9 (26%)

0

0

1 (4%)

1

0

0

PPD-like

0

0

0

0

0

0

0

6 (30%)

PLC-like

0

0

0

0

4 (17%)

0

4 (11%)

0

PR

0

0

0

1 (4%)

0

0

0

0

Folliculotropic

0

3 (9%)

0

1 (4%)

0

0

2 (6%)

0

Unilesional

0

0

2 (20%)

0

0

0

1 (3%)

4 (20%)

Ichthyosis-like

0

0

0

0

2 (9%)

0

0

0

ILVEN-like

0

0

0

0

1 (4%)

0

0

0

Atypical variants

TNM staging

§

Stage IA

9 (37.5%) 17 (50%) 6 (60%)

13 (54%)

12 (52%)

6 (30%)

6 (17%)

12 (60%)

Stage IB

12 (50%) 16 (47%) 4 (40%)

10 (42%)

11 (48%)

13 (65%)

27 (75%)

7 (35%)

Stage IIA

3 (12.5%) 1 (3%)

0

1 (4%)

0

1 (5%)

3 (8%)

1 (5%)

Stage IIB

0

0

0

0

0

0

0

Stage III

0

0

0

0

0

0

0

Stage IV

0

0

0

0

0

0

0

A report from the International CRCL housed at the Hospital for Sick Children (Toronto, ON, Canada) and included patients from eight centers (Canada – one; USA – six; Australia – one). ‡ Includes all the patients showing hypopigmented lesions with or without other lesions. § Staging performed in 20 patients. CRCL: Childhood Registry for Cutaneous Lymphomas; F: Female; ILVEN: Inflammatory linear verrucous epidermal nevus; M: Male; MF: Mycosis fungoides; NA: Not available; PLC: Pityriasis lichenoides chronica; PPD: Pigmented purpuric dermatosis; PR: Pagetoid reticulosis; TNM: Tumor, Node, Metastasis. †

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Table 2. Salient features of mycosis fungoides among children and adolescents† concluded from major studies. Characteristics

Values

Prevalence among total MF cases

Sex distribution

4–16.6%

‡

§

M

104 (61%)

F

67 (39%)

M:F

1.6:1

Age at diagnosis (years)

§

Range

1.8–56

Mean

14.8

Median

14

Duration of disease before diagnosis (years)

§

Range

0–43

Mean

5.75

Median

3.9

Morphological types

¶

Patch stage

112 (66%)

Plaque stage

37 (22%)

Both

19 (11%)

Not specified

1 (0.6%)

Figure 3. Psoriasiform plaque of mycosis fungoides on the calf.

Hypopigmented

76 (39%)

Poikilodermatous

13 (7%)

Pigmented purpura-like

6 (3%)

Pityriasis lichenoides-like

5 (2.6%)

Pagetoid reticulosis

1 (0.6%)

Folliculotropic

6 (3%)

Ichthyosis-like

2 (1%)

haloed cells or in a linear fashion (Figure 5) [1,22,23] . In the plaque stage, epidermotropism is more pronounced (Figures 6 & 7) . The presence of an intraepidermal collection of atypical lymphocytes (Pautrier’s microabscesses) (Figures 6 & 7) is a highly characteristic feature, but may not be observed in all cases [1,22,23] . As the disease progresses to tumor stage, the atypical lymphocytic infiltrate becomes more diffuse with loss of epidermotropism. In addition, blast cells with prominent nuclei may be seen. Progression may be accompanied by transformation into a diffuse large-cell lymphoma. Immunophenotypically, the atypical lymphocytes in MF show a mature CD3 +, CD4 +, CD45RO +, CD8- phenotype [1] . Transformation to large-cell lymphoma can be either CD30 positive or negative, and is often associated with a poor prognosis [1,24] . Loss of pan-T-cell antigens such as CD2, CD3 and CD7 may be noticed with disease progression and is an important adjunct in the diagnosis of MF [25] . Expression of cytotoxic proteins (TIA-1, granzyme B) by the neoplastic cells has been reported in some patients, but is a more common feature of blast transformation [23] . Clonal T-cell receptor gene rearrangements may be detected in many cases [23] .

Atypical variants

ILVEN-like

TNM staging

1 (0.6%) #

Stage IA

75 (44%)

Stage IB

87 (51%)

Stage IIA

9 (5%)

n = 193. ‡ Prevalence not available for all studies. § Calculated from 171 cases. ¶ Calculated from 169 patients. # Calculated from 191 patients. F: Female; ILVEN: Inflammatory linear verrucous epidermal nevus; M: Male; MF: Mycosis fungoides; TNM: Tumor, Node, Metastasis. Data taken from [6,8–14]. †

lesions of MF show superficial lichenoid infiltrates consisting mainly of lymphocytes and histioc ytes admixed with few atypical lymphocytes with small-to-medium-sized, highly indented (cerebriform) hyperchromatic nuclei. The atypical lymphocytes are mainly confined to the epidermis (epidermotropism) as single 312

Atypical MF variants

Various atypical presentations of MF include hypopigmented, hyperpigmented, pityriasis lichenoides-like, folliculotropic, bullous, granulomatous, ichthyosiform, granulomatous slack skin, pagetoid reticulosis, pigmented purpura-like, unilesional and Expert Rev. Dermatol. 8(3), (2013)


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papular variant [20,21,26] . Among them, hypopigmented MF, poikilodermatous, pityriasis lichenoides-like, folliculotropic, unilesional and pigmented purpura-like presentation are often reported among children and adolescents. Hypopigmented MF

This is a common variant of MF reported in patients with a dark complexion. It is reported in all age groups but is more prevalent among younger patients [16] . There have been several isolated reports and small series on hypopigmented MF among children and adolescents published in the literature [7,15,27–36] . Although it is more prevalent among patients of colored races, the cases have been reported among caucasians as well [28,30–33] . Among the major series of MF reported in children and adolescents [6,8–14] , the prevalence of MF was observed to range between 13% in Austria [10] and 70% in Israel [9] . A prevalence of 64 and 45% of hypopigmented MF was reported in Kuwait [13] and Turkey [14] , respectively. The lesions present as hypopigmented to depigmented, mildly scaly macules of different sizes (Figures 8 & 9) . The hypopigmented macules may be a sole manifestation or may be admixed with other types of MF lesions. In many instances, hypopigmented MF lesions are clinically misinterpreted as pityriasis versicolor, pityriasis alba, vitiligo, leprosy or postinflammatory hypopigmentation. The histological features as well as clinical course and prognosis of hypopigmented MF are similar to those of the classical patch-stage disease. Recent studies have shown that neoplastic cells in hypopigmented MF often express a CD8 + T-cell phenotype [30] . In response to treatment, perifollicular pigmentation may be observed. The pathogenesis of hypopigmented MF is still unclear. Hypomelanosis may be due to the cytotoxic effect of T-suppressor lymphocytes on melanocytes. The peculiar clinical changes might result from a decreased transfer of melanosomes from melanocytes to keratinocytes and melanocyte degeneration, as evidenced by electron microscopic studies [37,38] . However, these changes are not peculiar to hypopigmented MF and are also seen in various other disorders with acquired hypopigmentation.

Figure 4. Psoriasiform plaques of mycosis fungoides on the soles.

Pigmented purpura-like MF

This is a rare variant of MF and patients with this clinically variant present with persistent pigmented purpuric lesions (Figure 11) [42] . Histologically, there is usually a lichenoid band-like infiltrate composed mainly of cerebriform lymphocytes accompanied by substantial numbers of siderophages, extravasated erythrocytes and some histiocytes [21,43] . The majority of atypical lymphocytes are CD4 +, but some express CD8. Pigmented purpura (PP)-like MF was reported earlier in children and adolescents as isolated case reports [42,44,45] . Among children and adolescents from Turkey, 30% of patients (six out of 20) patients were observed to have the PP-like variant of MF (Table 1) [14] . None of the other series on juvenile-onset MF had cases of PP-like MF (Table 1) . Whether

Poikilodermatous MF

Poikilodermatous MF is considered a clinical variant of MF [20,21] that is characterized by patches or plaques with areas of hypopigmentation and hyperpigmentation, atrophy and telangiectasia, and has recently been defined as an important clinical feature that is relatively specific for early MF [39] . Although more often described in adults, poikilodermatous MF is seen among younger patients as well [40] . Histology is compatible with early patch or plaque stages of MF with additional features of epidermal atrophy, hydropic degeneration, interface dermatitis, pigment incontinence and telangiectatic vessels (Figure 10) [40,41] . It shows a predominant CD8 + and CD4 - atypical lymphocyte phenotype and carries an overall favorable prognosis [40] . Among children and adolescents, poikilodermatous MF was observed to represent 4–26% of the patients in different series (Table 1) [6,8,11] , with a higher prevalence reported among patients from the UK [8] . www.expert-reviews.com

Figure 5. Photomicrograph showing superficial dermal and perivascular lymphocytic infiltrate with a collection of atypical lymphocytes along the basal cells and within the dermis (hematoxylin and eosin staining; magnification ×40).

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Figure 6. Photomicrograph showing dense upper dermal and perifollicular lichenoid infiltrate with marked epidermotropism of atypical lymphocytes within the epidermis as single cells and in collection (Pautrier microabscesses).

a high prevalence of PP-like MF in Turkey is related to an ethnic variation or some of these cases are missed in this age group and not included in the reports from elsewhere needs to be confirmed [6,8–13] . Atypical presentation and course of pigmented purpuric

Figure 7. Photomicrograph showing mild epidermal hyperplasia and epidermotropism with an intraepidermal collection of atypical lymphocytes as single cells and Pautrier microabscesses.

dermatosis should raise suspicion of MF and the patient should be closely monitored. Pityriasis lichenoides-like MF

Pityriasis lichenoides is a papulosquamous disorder of unknown origin that is known to affect both adults and children, and is traditionally divided into acute and chronic forms [46,47] . The exact pathogenesis is unclear and is considered to be a clonal lymphoproliferative disorder that represents a hypersensitivity reaction to an infective agent [46–48] . There have been isolated reports in children and adolescents of pityriasis lichenoides being associated with, presenting as or evolving to MF (Figure 12) [49–51] . In total, 11% of children and adolescents from Kuwait and 17% from Korea were observed to have pityriasis lichenoides-like MF [11,13] . Folliculotropic MF

Folliculotropic MF, also known as pilotropic or follicular MF, is a rare variant of MF characterized by the presence of folliculotropic infiltrate of atypical lymphocytes often sparing the epidermis with or without associated follicular mucinosis [1,52] . Lesions can evolve at any site with preferential involvement of the head and neck. Folliculotropic MF occurs commonly in adults and may occasionally affect children and adults [1,8,10,13,53] . Patients may present with follicular papules, acneiform lesions, indurated plaques and sometimes tumors. Lesions are often associated with alopecia. Immunophenotypically, it is indistinguishable from classical MF; the most significant feature is follicular and perifollicular localization of neoplastic infiltrate, which makes them less accessible to skin-targeted therapies with an overall poor 5-year survival. Unilesional MF Figure 8. Widespread lesions of hypopigmented mycosis fungoides in a child.

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Unilesional MF refers to the occurrence of solitary lesions of MF that are clinically and histologically indistinguishable from classical MF [54,55] . Although a rare presentation, cases have been Expert Rev. Dermatol. 8(3), (2013)


reported among children and adolescents [9,13,14,53,56,57] . It differs clinically and histologically from pagetoid reticulosis (Woringer– Kolopp disease), a rare variant of MF [1,53,54,57–59] . The current WHO–EORTC classification defines pagetoid reticulosis as “a variant of mycosis fungoides characterized by the presence of localized patches or plaques with an intraepidermal proliferation of neoplastic T cells.” There is usually a relative paucity of dermal infiltrate and the immunophenotype of neoplastic T cells is variable. Unilesional MF, in contrast, has diverse clinical presentations [9,13,14,53–57] , including a psoriasiform plaque, an indurated plaque, an eczematous lesion, a poikilodermatous patch, a hypopigmented macule, or folliculotropic plaque or nodule. Histologically and immunophenotypically, it cannot be distinguished from classical MF. Unilesional MF appears to run an indolent course; however, there have been isolated reports of unilesional MF cases progressing to tumor stage from folliculotropic plaques or to CD30 + large-cell transformation from patch-stage MF in adults [60,61] . Erythrodermic MF and Sézary syndrome appear to be very rare among children and adolescents. In the major series of MF among children and adolescents, no cases of erythrodermic MF or Sézary syndrome were observed. There have been isolated reports of other rare presentations of MF among children and adolescents including erythrodermic follicular mucinosis with features of Sézary syndrome [62] , granulomatous slack skin [63] , ichthyosislike MF [11] and MF mimicking inflammatory linear verrucous epidermal nevus [11,64] . Pathophysiology

The exact etiopathogenesis of MF is still not clear. Various factors including genetic, ethnic, infectious (including the role of retroviruses), drugs and occupational factors have all been discussed [65] . It has been proposed that a persistent antigenic exposure and stimulation associated with some immunological imbalance in the host may lead to the development of a malignant clone of T lymphocytes in pre-existing benign lymphocytes [66,67] . The override of apoptotic control is suspected to contribute to the pathogenesis [68] . Fas is a transmembrane protein that mediates apoptosis, and defective Fas signaling has been suggested as a possible causative agent in MF pathogenesis in early lesions [68] . Chromosomal loss at 10q and abnormalities of cell cycle control genes and well-defined tumor suppressor genes such as p15, p16 and p53 may also contribute to disease pathogenesis, progression and treatment resistance [24,69] . Familial clustering, together with the detection of certain class II alleles with MF, supports that genetic factors play a role in MF [70,71] . Whether the early age of onset of MF and a higher prevalence of juvenile MF in certain ethnic groups is related to certain environmental, ethnic or genetic factors has not been settled.

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Box 1. Skin-directed therapies indicated for early stages (stage IA, IB and IIA) of mycosis fungoides. Topical modalities • Emollients • Potent topical steroids • Mechlorethamine • Carmustine • Bexarotene • Calcipotriol • Pimecrolimus Radiotherapy • Local radiotherapy • Total electron beam radiations Phototherapy • BB-UVB • NB-UVB • PUVA (topical/systemic) • UVA1 • Photodynamic therapy Systemic • Acitretin • Bexarotene • Methotrexate • Re-PUVA • IFN-α BB-UVB: Broadband-UVB; NB-UVB: Narrowband-UVB; PUVA: Psoralens + UVA; Re-PUVA: retinoids + PUVA.

of MF are more often seen among children and adolescents than among adult-onset disease. Clinical suspicion is a key factor leading to diagnosis, and MF should be suspected whenever atypical behavior of a common dermatosis is noticed. The diagnosis of MF depends on a combination of clinical and pathological examinations [1] . In several instances, a close follow-up and several skin

Diagnosis & clinical staging

The same diagnostic standards are adopted for MF in children and adolescents as for the adult-onset disease. MF is a great imitator, and in its early stages the diagnosis may be missed for benign inflammatory dermatoses. Moreover, atypical variants www.expert-reviews.com

Figure 9. Multiple hypopigmented, mildly scaly macules of mycosis fungoides on the thighs.

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Treatment & prognosis

Since most MF patients among children and adolescents in the series reported to date had early stages (stage IA–IIA) of disease, skin-directed treatment modalities were the mainstay of treatment [8,9,11,12,14,15] . No consensus statement or guidelines on the selection of a treatment modality are available for treating MF patients with juvenile-onset disease. Box 1 lists various treatment modalities that have been used for early stages of MF among children and adolescents [8,9,11,12,14,15,34,74–76] . Selection of treatment modalities depends upon clinical staging, extent of skin lesions, type of lesions, availability of treatment, experience of the treating physician with various modalities, or other relevant factors including cost–effectiveness, patient tolerance or side effects related Figure 10. Photomicrograph showing epidermal atrophy, vacuolar degeneration to a therapy. Topical steroids and emollients of basal cells, pigment incontinence in the upper dermis, dilation of capillaries, may help in early patches or should be used and lichenoid infiltrate with the presence of atypical haloed lymphocytes along as adjuncts to other lines of treatment. the basal cells and within the dermis. Phototherapy including broadband UVB, biopsies may be required before the diagnosis can be established. narrowband UVB, psoralens with UVA and UVA1 have been In doubtful cases, immunophenotyping and analysis of clonal widely used with a favorable response in most patients. Systemic gene rearrangements serve as adjuncts [1] . A diagnostic algorithm retinoids (acitretin, bexarotene) may be of help in resistant cases has been proposed to diagnose early MF cases in order to ensure or those that show progression while on treatment. Methotrexate, timely treatment and better prognosis [39] . Once diagnosed, clin- IFN-α and total electron beam therapy are other alternatives in ical staging is mandatory to decide the appropriate treatment resistant cases with widespread lesions. More advanced disease and determine the prognosis [72] . All the cases of MF reported will benefit from combination treatments including drug therapy, among children and adolescents in the large series to date had phototherapy and radiotherapy. In practice, combined treatments early stages (stage IA–IIA) of disease, with more than 90% of may reduce adverse events and improve response rates [77] . patients belonging to stage I disease (Tables 1 & 2) [6,8–14] . There Contrary to earlier beliefs that an early onset of MF determines have been only isolated reports on advanced stages of MF in this a poor prognosis [4,5] , the overall prognosis of MF among children age group [62,73] . and adolescents seems to be broadly comparable to adult-onset

Figure 11. Pigmented purpura-like patches of mycosis fungoides on both legs.

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Figure 12. Pityriasis lichenoides-like mycosis fungoides in a child.

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disease. Some also believe that children have a better prognosis compared with adults. Most of the series of MF among children and adolescents [10–12,15] , except for that reported by Wain et al. [8] , did not observe a progression of MF to advanced stages of disease. Over a follow-up period of 1–45 years (median: 6 years), Wain et al. observed progression to advanced stages in 15% of their patients, with a disease-specific survival of 93 and 95% at 5 and 10 years, respectively [8] . However, more series of juvenile-onset MF with a longer follow-up are required to determine a true prognosis of the disease. A close surveillance of juvenile-onset cases throughout life is indicated for disease progression or development of secondary neoplasia [5,78] . Expert commentary

Recently, several reports on MF among children and adolescents have appeared in the literature, highlighting that MF is not as rare in this age group as previously thought. However, data on MF among children and adolescents are still lacking from many parts of the world. An overall incidence of MF among the general population has been estimated to be 0.5 cases/100,000 population/year. Apart from a study among Arabs from Kuwait [13] , the age-adjusted prevalence rate of MF among children and adolescents is not available. Among total MF cases reported in a given population, children have been reported to constitute 4–16.6% of total MF patients [6,8,13–15] , with a higher prevalence noticed among Asians [13,15] . Although children show classical presentation of MF as described in adults, there is now enough literature to support that the atypical variants including hypopigmented MF, poikilodermatous MF and pityriasis lichenoides-like MF are more often encountered in this age group than in adults [6–15] . Whether more representation of atypical variants in the younger age group is related to age of onset, ethnic variations or underdiagnosis of classical MF cases being missed with common inflammatory dermatoses and not biopsied needs to be settled. Unfortunately, there are no protocols or guidelines available for treating MF in children and adolescents. Since most of the patients in this age group have early stages of disease (stage IA, IB and IIB), skin-directed therapies have been the mainstay of treatment [8,9,11,12,14,15] . Contrary to an earlier belief, none of the series of MF

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among children and adolescents have confirmed that early onset of MF determines a poorer prognosis. Comparable to adults, the disease also runs an indolent course in younger patients. In fact, from the literature available to date, children seem to have a better prognosis [8,9,11,12,14,15] ; however, no consensus can be drawn at this stage. Whether children and adolescents with MF have a better treatment response and a better prognosis than adults can only be decided after having more data of MF in this age group with controlled treatment trials and a long-term prospective follow-up from different parts of the world. Five-year view

With the current existing knowledge of MF among children and adolescents, it is anticipated to: • Have more series describing the clinical characteristics, treatment and prognosis of MF in this age group from different parts of the world; • Have data on the age-adjusted incidence of MF among children and adolescents among different ethnic groups; • Hear about molecular research activities related to MF in this age group to have a better insight into the pathophysiology of MF; • Have guidelines on treatment of MF in children and adolescents by WHO–EORTC and other lymphoma working groups to determine a better prognosis.

Acknowledgements

We acknowledge with thanks our consultant dermatopathologist for providing us with the photomicrographs. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma that often affects middle-aged individuals. It is rare in children and adolescents, and in the large series published on MF among the general population, only 0.5–5% of patients were reported to have an onset of disease before adolescence. • The diagnosis of MF in children and adolescents is often delayed due to a low index of suspicion in this age group. • With more awareness of the disease and improved diagnostic standards, a number of series of MF have appeared among children and adolescents from different parts of the world, highlighting that the disease is not as rare as it was thought to be, with a prevalence rate of 4–16.6% among total MF cases. • Data are still lacking from many parts of the world and the figures on the age-adjusted prevalence rate of MF among children and adolescents in a given population are not available. • Children and adolescents appear to manifest more often with atypical variants than those with adult-onset disease. • Contrary to the earlier belief that an early onset of MF determines a poor prognosis, the available literature supports that, like in adults, the disease also runs an indolent course among children and adolescents and probably carries a better prognosis. • No guidelines on the treatment of MF among children and adolescents are available as yet.


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