Primary cutaneous T‐cell lymphomas in childhood and adolescence

Primary cutaneous lymphomas are extranodal non‐Hodgkin lymphomas of T‐ or B‐ cell origin, that predominantly affect older patients but have been reported in all age groups and as early as in the first years of life. Diagnosis of cutaneous lymphomas is challenging and requires high clinical suspicion and close collaboration between dermatologists, pediatric oncologists and pathologists. Skin involvement of non‐Hodgkin lymphomas in children or adolescents can either be primary cutaneous or secondary due to an underlying nodal lymphoma. The most common primary cutaneous lymphomas encountered in children are of T‐cell origin, with mycosis fungoides being the most prevalent cutaneous T‐cell lymphoma, followed by CD30+ lymphoproliferative disorders. While cutaneous lymphomas share clinicopathologic characteristics between juvenile and adult forms, there are important differences in terms of clinical presentation, diagnosis and treatment. The hypopigmented variant of mycosis fungoides seems to be overrepresented in the pediatric age group. Prognosis and treatment of mycosis fungoides are stage dependent. The majority of children present with early‐stage disease and respond well to topical corticosteroids and phototherapy.


Epidemiology and clinical presentation
Mycosis fungoides represents the most common form of PCL both in adults and children with an estimated age-adjusted incidence rate of 4.1 per 1,000,000 person-years (age-adjusted to the 2000 US standard population) [4,7]. The prevalence of juvenile MF varies geographically and accounts for approximately 5 % of all MF cases in US-and European studies and up to 17 % in an Arabic cohort [8,9].
The mean age at diagnosis for juvenile MF is 11.0 years. MF is more commonly diagnosed in boys than in girls, with a ratio of 1.4:1 (Table 1). MF is staged according to the International Society for Cutaneous Lymphomas (ISCL) and European Organization for Research and Treatment of Cancer (EORTC) classification of MF and SS (Tables 2, 3) [25].
Juvenile MF is diagnosed in early disease stages in more than 95 % (Table 1) of children with either limited patches or plaques involving < 10 % body surface area (BSA) (IA) or generalized patches/plaques > 10 % BSA (IB). However children with advanced disease stages and disease progression leading to a fatal outcome have been reported as well [10,16].
MF has many faces and often resembles benign inflammatory skin diseases [26], thus resulting in a median diagnostic delay of three years [27]. A large single center study of childhood MF published by Heng and coworkers found that only 41.3 % of all patients were diagnosed before skin biopsy [23]. Knowledge of the different clinical presentations of juvenile MF may help to differentiate the disease from benign inflammatory or autoimmune diseases ( Figure 1) [26].
While most adult MF patients present with erythematous patches or plaques on sun protected areas of the body, most pediatric MF patients don't have a classic presentation [9]. The majority of children with MF present with atypical variants, with hypopigmented MF being the most prevalent from, seen in over 60 % of all juvenile cases (Table 1) [8,22,23]. This MF variant seems to be overrepresented in young patients, compared to older patients were it accounts for less than 10 % of all MF variants and is generally more prevalent in skin of color [22]. Other forms include hyperpigmented MF, folliculotropic MF (FMF), poikilodermatous MF, unilesional MF and overlapping variants with a combination of features (e.g., hypo-and hyperpigmented patches, hypopigmented and erythematous patches and plaques) [8,17,21,22].
Despite the vast variety of MF presentations, only FMF, Pagetoid reticulosis and granulomatous slack skin (GSS) are recognized as different disease variants by the current EORTC-WHO classification for PCL, due to their different clinical and pathophysiological behavior [2].

Hypopigmented MF
Children and adolescents with this MF variant have hypopigmented patches or plaques. Hypopigmented MF has been the most prevalent form of pediatric MF encountered in the review performed (Table 1). Differential diagnoses include vitiligo, postinflammatory hypopigmentation and pityriasis alba ( Figure 1). Castano et al. studied 35 cases of pediatric hypopigmented MF and found that up to three Juvenile MF is diagnosed in early disease stages in more than 95 % of children with either limited patches or plaques involving < 10 % body surface area.
The majority of children with MF present with atypical variants, with hypopigmented MF being the most prevalent from.
The prevalence of juvenile MF varies geographically and accounts for approximately 5 % of all MF cases in US-and European studies.     biopsies were needed to establish a correct diagnosis [22]. Children with hypopigmented MF patches and plaques tend to have darker skin types (Fitzpatrick IV-VI) [19,20,22,23,28], prompting the question whether this variant is truly more prevalent in skin of color or whether it is underdiagnosed in patients with fair skin. It is also possible to have hypopigmented lesions along with classic erythematous MF lesions [22]. This is important, because while most patients (both adults and children) with hypopigmented MF have an excellent prognosis, studies have shown that children with both hypopigmented and classic MF patch lesions may experience progressive disease to plaque and tumor stage MF [22,28].
Children with hypopigmented MF patches and plaques tend to have darker skin types.  Biopsies from hypopigmented MF lesions show epidermotropism of small-to-medium-sized lymphocytes (comparably with classic MF patch lesions). Immunohistochemically, CD7 staining is reduced and the atypical lymphocytes are CD8 + compared to classic MF where the malignant cells are predominantly CD4 + [22].

Folliculotropic MF
Clinically, FMF presents with indurated patches and plaques often on hair bearing body parts including the face, eyebrows and scalp, along with acneiform lesions and alopecia [29][30][31].
In children, FMF features are often more subtle, compared to adult patients and present as grouped follicular papules and patches with associated hair loss on the trunk, arms and legs [24]. Differential diagnoses include pityriasis rubra pilaris, keratosis pilaris and alopecia mucinosa (    variant, accounting for 36 % of all patients [24]. Interestingly, the majority of FMF cases in their cohort had a combination of hypopigmented and typical FMF lesions [24]. Histopathologically, FMF is characterized by neoplastic lymphocytes infiltrating the hair follicles [32]. The interfollicular epidermis is usually spared and Pautrier's microabscesses are infrequently seen, in contrast to classic MF [33]. Due to the deep perifollicular infiltrates seen pathologically in FMF, this variant was previously thought to be an independent prognostic indicator for poor outcome. However, newer studies have shown that FMF patients can be subdivided into two clinical groups, an early indolent group of patients with follicle-based patches, flat plaques, keratosis pilaris like and acneiform lesions and an advanced stage group of patients having thick follicle-based infiltrated plaques and tumors. The latter group is less responsive to therapies and carries a worse prognosis [29-31, 34, 35]. The majority of children with FMF have early stage disease and respond well to bath or systemic psoralen and ultraviolet A (PUVA) [31,36].
The differentiation of FMF from primary follicular mucinosis is difficult and is subject of debate. Follicular mucinosis describes the presence of mucin deposits around hair follicles, a pathologic description that is often present in FMF biopsies [37,38]. In adults, primary follicular mucinosis presents clinically with diffuse cutaneous lesions and is considered a variant of MF. In children, primary idiopathic follicular mucinosis commonly appears as localized patches with follicular papules often involving the head and neck and either resolves spontaneously or respond well to topical steroids or phototherapy. Prognosis is usually excellent [37].

Pagetoid reticulosis
Pagetoid reticulosis is rare, both in adults and in children. It is recognized as different variant of MF by the EORTC-WHO classification for PCL [2]. Woringer and Kolopp reported the first case of Pagetoid reticulosis in 1939 in a 13-year-old boy. Since this original case, less than ten pediatric patients with pagetoid reticulosis have been published in the literature [4,[39][40][41][42][43]. Pagetoid reticulosis presents clinically as a solitary, erythematous slowly progressive plaque on the distal extremities (usually hands and feet). Histologically, a hyperplastic epidermis with epidermotropism and small to medium sized nests of pagetoid cells may be the evident finding [39]. Immunohistochemistry of the reported pediatric cases has shown a CD3 + , CD4and CD8 + phenotype [39][40][41][42][43]. Treatment modalities include surgery of the solitary lesions [41], radiotherapy [42,43] and less common, photodynamic therapy [40]. The overall prognosis of pagetoid reticulosis is excellent and complete remissions have been achieved with the above-mentioned treatments.

Granulomatous slack skin
Granulomatous slack skin is a rare distinct disease variant of MF that is characterized by the presence of slowly developing pendulous bulky skin folds, located in the flexural areas [2]. Histologically large multinucleated giant cells (immunophenotypically expressing CD68) emperipolesis and loss of elastic tissue are evident [44,45]. Treatments among others include PUVA, radiotherapy, interferon alpha and surgery, but treatment outcomes are often disappointing [46]. It is important to note, that patients with GSS may also have or develop associated other malignant lymphomas. So far, only few cases of pediatric GSS have been reported in the literature [46,47]. Patients with GSS may also have or develop associated other malignant lymphomas.
In 1997 Moreno-Giménez et al. described the case of an 11-year-old boy with GSS who was initially successfully treated with systemic corticosteroids and surgical excision of the localized bulky groin lesions [47]. Ten years later the same group published the follow-up data of their initial report. The child experienced several relapses over a course of ten years and died at the age of 20, despite treatment escalation with chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) [48].

Work-up and staging
Every child with a clinical suspicion for MF/Sézary-Syndrom (SS) should undergo a complete physical examination including the documentation of the extent of BSA and determination of the morphology of skin lesions (patch/plaques/tumors) [49]. Photo documentation may be helpful to document the disease course and response to therapy. In addition, palpation of regional lymph nodes and organs should be performed to rule out lymphadenopathy or organomegaly [50]. A skin biopsy of a representative lesion (in some cases several biopsies are needed) should be performed including immunohistochemistry and TCR gene rearrangement studies. Initial blood work-up should include CBC with differential, liver function tests, LDH, creatinine, electrolytes, and C-reactive protein. Although extremely rare in the pediatric population, but if erythrodermic MF or SS are suspected, blood work-up needs to be extended (TCR gene rearrangement studies and Sézary cell count/flow cytometry) [9,50]. Radiographic imaging should be performed based on the TNMB stage. For diseases with limited skin involvement (IA, IB) chest x-ray and ultrasonography of the abdomen and regional lymph nodes are usually sufficient [9,50]. Whole-body imaging is recommended to rule out lymphadenopathy and potential visceral involvement in children staged ≥ IIB. Excisional lymph node biopsy should be performed in those patients with a radiographic node > 1.5 cm [9,50].
Patients should be staged according to the TNMB staging of MF and SS (Tables 2, 3) [25].

Therapy and prognosis
The treatment modality depends on the disease stage. Table 1 summarizes 17 studies with a total of 366 childhood MF cases, encountered in the English literature (single case reports or studies reporting less than 5 cases where not included). The majority of juvenile MF patients (95 %) had early-stage disease and were therefore treated with skin directed therapies. The most used treatment modality included narrowband-UVB (NB-UVB) alone or in combination with topical steroids. PUVA was used as second line treatment in some cases or first line therapy for FMF. Topical or oral retinoids were only used occasionally. Only 5 % of children had advanced stage MF, in these cases multiple agents were used, including topical nitrogen mustard, radiotherapy and stem cell transplantation. Novel systemic treatment modalities including the antibody-drug conjugate, brentuximab vedotin and the anti-chemokine receptor 4 monoclonal antibody, mogamulizumab have recently been approved for the treatment of advanced staged MF [51,52]. Efficacy data of brentuximab vedotin in the pediatric population exist for the treatment of relapsed or refractory Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma but are still scarce for pediatric MF [53].
Most children with early-stage disease responded well to phototherapy, but relapses were not uncommon prompting reintroduction of therapy. Laws and A skin biopsy of a representative lesion should be performed.
Patients should be staged according to the TNMB staging of MF and SS.
The treatment modality depends on the disease stage.
Most children with early-stage disease responded well to phototherapy, but relapses were not uncommon.
The most used treatment modality included narrowband-UVB alone or in combination with topical steroids.
co-workers published their long-term follow-up data of 28 children receiving phototherapy and found that patients receiving PUVA had fewer relapses compared to those who received NB-UVB [19]. Long term follow-up of pediatric MF patients is recommended to allow early detection of relapses and timely reintroduction of therapy. Prognosis of childhood MF is generally excellent, since most juvenile MF patients have early-stage disease. It is however noteworthy that advanced MF cases with disease progression leading to death have been reported in children as well (1 % of cases included in summary Table 1). For most cases published in the literature follow-up is limited, hampering our ability to predict the intermediate and long-term prognosis. Considering the longer life expectancy of juvenile patients, rigorous long-term follow-up exams -ideally at dedicated centers -are recommended to allow for early detection of disease progression.
One example is a 14-years old patient with granulomatous MF that we have published in 2016, who has initially responded well to phototherapy at six-month follow-up but unfortunately showed disease progression one year after our report was published [54,55].

Epidemiology and clinical presentation
Lymphomatoid papulosis (LyP) is a chronic disorder that is characterized by a waxing and waning disease course, i.e. it is typically self-regressing [56,57]. LyP is considered a rare disease and children and adolescents account for only 4-10 % of LyP cases [56,58]. On the other hand, LyP represents the second most common form of CTCL in children [5]. We previously published a systematic review on LyP in children and adolescents aged 0-18 years where 251 patients were identified from the literature including seven own cases [59]. The mean age at diagnosis was 9.3 years (although the reported age at onset of symptoms was on average approximately one year earlier) and the youngest patient was only 11 months old. Comparable to the adult form, LyP is slightly more prevalent in boys than girls 1 : 1.4 [59]. The lesions can be found on any part of the body and are typically erythematous papules or nodules and only rarely pustules, plaques, papulovesicles or tumors ( Figure 2) [59]. The diagnosis of LyP is often delayed and differential diagnoses include scabies, arthropod bites, pityriasis lichenoides, and hydroa vacciniforme [59]. Whether LyP should be considered a benign or malignant disease still remains subject of debate: While the long-term prognosis of LyP remains excellent with a 5-year overall survival close to 100 %, between 10-30 % of patients will develop a secondary non-Hodgkin lymphoma over the course of their disease [56-58, 60, 61]. In our systematic review, associated lymphomas were reported in 5.6 % of the children and adolescents [59].

Histopathology
Lymphomatoid papulosis is categorized as a CD30 + LPD [56]. CD30 is a cell surface marker that can be found on T and B lymphocytes but was first identified on Reed-Sternberg cells in Hodgkin lymphoma by Stein and coworkers [62]. CD30 can also be expressed in certain viral infections, germ-cell tumors, and arthropod bites [63]. In our systematic review, 96.3 % of the reported biopsies in children showed CD30 expression [59]. Since the initial description of LyP, five major histopathological subtypes (types A to E) have been described [57,[64][65][66]. Recently, Lymphomatoid papulosis is typically self-regressing.
Lymphomatoid papulosis is slightly more prevalent in boys than girls.
The long-term prognosis of LyP remains excellent.
additional subtypes have been identified and reported: "type F" representing follicular LyP, LyP with a γ/δ phenotype, and 6p25.3 rearrangement [57,[67][68][69]. The majority of pediatric cases are classified as subtype A (79.1 %) or C (11.9 %) [59]. The high percentage of subtype A may be an overestimation, taking into consideration that over the years the histopathologic classification of LyP has been refined [59]. It is important to note, that the more recently published and rarer subtypes have also been reported in children [59,65,70].

Diagnostic work-up
Given the clinical and histopathological heterogeneity and overlap with other lesions/diseases, the diagnosis of LyP is always a correlation of the clinical appearance, clinical course and histologic, immunophenotypic, and cytogenetic features [71]. Particularly in cases where the diagnosis is equivocal, it is recommended to refer the patient to a dedicated center with expertise for the diagnostic work-up to permit a short line of communication between clinician and histopathologist as one may not be able to establish the diagnosis without the other.

Therapy and prognosis
In view of the self-limiting disease course and the excellent overall prognosis, risks and benefits of therapeutic interventions should be carefully weighted in children.
While the majority of children are given one medication (most often topical corticosteroids), our systematic review has identified cases with up to five different modalities including chemotherapy, bexarotene, methotrexate and radiation [59]. An early referral and timely diagnostic confirmation of LyP likely prevents unnecessary treatment regimens. Ideally, LyP is managed by a dedicated CTCL expert as overtreatment should be avoided due to the self-regressing nature of the disease. In many instances topical corticosteroids are sufficient for a symptomatic disease The majority of pediatric cases are classified as subtype A. control as treatment does not appear to have an effect on the overall disease course [58,59]. Other treatment modalities should be reserved for those patients with a high symptom burden and frequent relapses. Due to the association with lymphomas long-term follow up by a dermatologist experienced in CTCL is warranted as pediatric cases have been reported, where associated lymphomas developed up to 17 years after the initial diagnosis of LyP [59].

Epidemiology and clinical presentation
Primary cutaneous anaplastic large cell lymphomas (cALCL) are defined as anaplastic large cell lymphomas (ALCL) in the absence of systemic disease as confirmed by the initial staging workup [72]. In children primary cALCL account for 11 % of all cutaneous LPDs [5]. Patients typically present with a large solitary red to brown cutaneous nodule or tumor that may ulcerate with time [57]. Multifocal disease with lesions involving more than one body region or by a lesional area larger than 15×15 cm is present in up to 20 % [1,57,73]. The nodules or tumors regress in up to 50 %, but typically do not resolve completely [74]. Fink-Puches and colleagues published 13 cases of children and adolescents with cALCL diagnosed at a median age of 14 (range, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] years with equal distribution between boys and girls [4]. Cases have been reported even in the neonatal period [75]. The clinicopathological features in children appear to be similar to those in adults [4,5].
McQuitty and coworkers studied the differentiation of CD8 + cALCL from LyP type D in 27 patients. The authors found that the presence of ulceration, epidermotropism with small lymphocytes and marked density of CD30 + large atypical cells extending to the subcutaneous tissue may be indicators that favor a diagnosis of cALCL [80].

Diagnostic work-up
Following the clinical examination and confirmatory biopsy, systemic ALCL should be excluded. The German guidelines for CTCLs recommend full-body imaging and lymph node sonography and state that a PET-CT may be considered [50]. Given the rarity of cALCL, no specific recommendations are available for children.
Due to the association with lymphomas long-term follow up by a dermatologist experienced in CTCL is warranted.
Primary cutaneous anaplastic large cell lymphomas are defined as anaplastic large cell lymphomas in the absence of systemic disease.
Histologically cALCL can have overlapping features with LyP -especially subtypes C and D.

Treatment and Prognosis
In the general population, the treatment of choice for solitary primary cALCL lesions is typically surgical excision. When multiple lesions are present, low-dose electron beam radiation can be considered. In some patients adjuvant radiation might be recommended, especially when the surgical margins are not clear [57,73,81]. Specific treatment recommendations for children are scarce. Surgical excision has been reported with good response rates [75]. In the series of Fink-Puches and colleagues the overall prognosis in children was good. At a median follow-up of 9.5 months (range, 4-84 months), 50 % were disease free and no disease-related deaths were observed [4].

Epstein-Barr virus-positive lymphoproliferative disorders in childhood
Epstein-Barr virus (EBV)-positive LPD in childhood comprise hydroa vacciniforme-like LPD (HV-like LPD) and hypersensitivity reactions to mosquito bites, which are now included in the 2018 update of the WHO-EORTC classification for PCL [2].
Hydroa vacciniforme-like LPD and hypersensitivity reactions to mosquito bites are skin manifestations of chronic EBV infections, predominantly affecting children and adolescents in Central American, South American and certain Asian regions [2,[82][83][84].
Children affected by these primary cutaneous LPD may progress to systemic EBV-positive T-or natural killer-cell lymphoma [2].
Clinically, HV-like LPD are characterized by blisters, ulcers, crusts and sometimes disfiguring scar formation, along with edema affecting sun-exposed body parts, such as the face and the extremities [82,83]. Histologically, atypical smallto medium-sized T-lymphocytes infiltrating the epidermis, dermis and subcutis, sometimes showing an angiotropic pattern, are seen on skin biopsies. In addition to the skin manifestation, systemic symptoms including fatigue, fever, lymphadenopathy and hepatosplenomegaly may be seen [82,85]. Skin lesions may follow a waxing and waning course [84]. Prognosis of reported cases with available long-term follow-up data was dismal, with many children not responding to chemotherapy or radiotherapy and dying of sepsis or liver failure in the course of their disease [82,84]. Differential diagnoses include other CTCL, especially cutaneous nasal natural killer (NK)/Tcell lymphoma, MF and subcutaneous panniculitis-like T-cell lymphoma [82].
Children with hypersensitivity reactions to mosquito bites present with ulcerative and necrotic lesions at the site of the mosquito bite and may have the same systemic symptoms as patients with HV-like LPD [2].   7. Which of the following statements is correct with regards to lymphomatoid papulosis (LyP) in children and adolescents? a) By definition LyP is a CD4+ lymphoproliferative disorder. b) LyP is typically observed in children and adolescents (0-18 years) and only rarely affects people older than 18 years. c) The diagnosis of LyP is often delayed and common misdiagnoses include scabies, arthropod bites, pityriasis lichenoides, and hydroa vacciniforme. d) The clinical examination is unreliable, and the diagnosis is exclusively established by histopathologic work-up. e) Due to the disease course, the initial treatment modality should be systemic in children and adolescents.
8. Which of the following statements is true with regards to disease course, prognosis and follow-up of lymphomatoid papulosis in children and adolescents? a) LyP is a chronic disorder that is characterized by a waxing and waning disease course. b) LyP typically presents as a large solitary nodule or tumor that typically ulcerates over time. c) LyP has a poor overall prognosis with a dismal 5-year overall survival rate. d) LyP in adults is associated with other lymphomas, but this does not apply to pediatric patients with LyP. e) LyP should be treated by a Dermatologist experienced in CTCL, but once the lesions disappear the patient can be discharged and does not need follow-up.