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Mycosis fungoides in pediatric population: comprehensive review on epidemiology, clinical presentation, and management

Mycosis fungoides (MF) is the most common type of cutaneous T‐cell lymphoma. However, it is rare in pediatric population. Most of the cases of pediatric MF present with hypopigmented patches and/or various other forms, which may often mimic common childhood dermatoses, thereby causing a delay in the diagnosis. There are no established treatment guidelines for pediatric MF. As the progression of childhood MF is extremely rare and it has an indolent course, it is usually diagnosed at an early stage (IA, IB, IIA), and hence phototherapy with a response rate of >80% is a well‐established effective treatment in children. However, as recurrences are frequently seen on stopping the therapies, a maintenance regimen and long‐term follow‐up is equally important. This article reviews the epidemiological factors, clinical presentations, diagnosis, and various treatment modalities used in pediatric MF. We analyzed and compared the data of almost 616 childhood MF cases from various studies undertaken from 1988 to 2021.


Introduction
Primary cutaneous lymphomas are a heterogenous group of non-Hodgkin extranodal lymphomas arising from either T-or Blymphocytes. Cutaneous T-cell lymphomas (CTCL) are the most common, and the incidence increases with age with an average age of 50 years at diagnosis. 1 However, they are rare in pediatric population. Mycosis fungoides (MF), the most frequent type of CTCL, accounts for 38.7-65% of all primary cutaneous Age MF can affect any age group, but the average age at disease diagnosis is 50-60 years. 8 Pediatric age group represents a rare subset with most of the cases having onset between 6-8 years of age 7,9 and diagnosed at a mean age of 9-11 years 10 illustrating a delay in diagnosis of approximately 1-5 years for many patients, however, may at times be up to 14-24 years in rare cases. 11,12 The delay in diagnosis of pediatric MF may be due to avoidance of skin biopsy in children in addition to resemblance of MF lesions to various benign dermatoses in childhood like pityriasis alba, eczema, psoriasis, and vitiligo. 13 Hence, MF was aptly called the "great imitator" by Zackheim et al. 14

Sex
Slight male preponderance is seen in childhood MF, however, many studies reported a ratio between males and females close to 1 : 1 15 as compared to 2 : 1 seen in adults. 4,11,16,17 Only few studies showed an increased incidence in female children with one of them reporting a ratio as high as 1 : 9 (M : F). 18,19 Genetics Several human leukocyte antigen (HLA) alleles have been associated with MF in adult population, namely HLA-DQB1 and HLA-DRB1, however, no statistically significant association was found between pediatric MF and any of these HLA alleles except HLA-B*73, the biological significance of which remains questionable due to its low frequency. 20 Certain rare cases of familial MF have higher frequency of HLA-DQB1*03 as compared to controls (66.7% vs. 33%, respectively), which may support an association of this allele with the familial form of MF. 21

Clinical presentation
The classical presentation of MF in adults is gradually progressive asymptomatic scaly erythematous patches and plaques usually in the sun protected areas, which may progress to nodules/tumors over a period of several years. 29 MF is typically characterized by a course in three stages: erythema/patch, plaque, and tumor stage. As children mainly show early forms of MF, patch stage is primarily observed. Most of the studies report hypopigmented MF as the predominant variant accounting for almost 55-100% of the cases. 11,15,20,[30][31][32][33] Other common variants reported are the classical MF, which may account for 15-40% of the cases, 4,9,10,34,35 folliculotropic variant (3-36%), 4,9,11,34 and poikilodermatous MF (5-26%). 16,36 There are few uncommon variants which have been reported in children including pityriasis lichenoides chronica-like (PLC)   MF, unilesional MF, pigmented purpuric dermatosis-like MF,  granulomatous MF, ichthyosiform MF, hyperpigmented and   intraoral presentation, inflammatory linear verrucous epidermal nevus-like MF, and pagetoid reticulosis, which may at times be difficult to diagnose at the initial presentation. 20,[37][38][39][40][41][42][43][44] Few rare cases of familial MF and MF post organ transplant have also been reported 21,45,46 (Table 1). Mycosis fungoides with largecell transformation in children is extremely rare and hence lacks a standardized therapeutic regimen. It is defined when the lymphoid infiltrate has more than 25% large cells with nuclei more than four times the normal size. It may present with erythematous patches, plaques, tumors, or nodules and has an aggressive course. 47,48 Hypopigmented MF in childhood The hypopigmented variant of MF in childhood is overrepresented and involves usually the trunk and extremities with lesions predominantly located on the sun protected sites. However, any site may be involved, and pruritus is a variable feature. 49 It may be diagnosed late as it resembles many benign dermatoses in childhood like pityriasis alba, atopic dermatitis, tinea versicolor, post-inflammatory hypopigmentation, or other conditions like vitiligo, leprosy, sarcoidosis, hypopigmented parapsoriasis en plaque, and progressive macular hypomelanosis. 48,50 Among Fitzpatrick skin type IV to VI, hypopigmented MF is more commonly seen in children, and it usually presents at a younger age as compared to children with other variants of MF. 8,30,51 Stage The majority of childhood MF cases are diagnosed at an early stage (IA, IB, IIA) 4,15,31,34 while advanced disease like stage IIB and beyond is rare and carries a poor prognosis 11,30 as they may end up reaching after a significant delay to the dermatologist or may be treated initially with some other close differential diagnosis as reported in one of the studies by Dulmage et al.

Diagnosis
In children, poor response to treatment with the persistence of hypopigmented, papulosquamous, and purpuric lesions should raise a suspicion with MF as a differential diagnosis. 30 (Table 2).

Histopathology in hypopigmented MF
Along with epidermotropism, it shows minimal dermal involvement or fibroplasia of the reticular dermis. 53 Juvenile-onset MF generally has a comparably good prognosis and responds well to treatment; however, due to the potential long-term therapy in children, the treatments need to be chosen with care. 15 Recurrences are frequently seen on discontinuing therapies, which signifies the importance of maintenance therapy and a long-term follow up. 4 (Table 3). The studies which did not report the specific number of cases who received either NBUVB or PUVA were not included. 26,34 Topical therapy It forms an integral part as an adjuvant or in few cases as the sole agent in the management of childhood MF. TCS are the most commonly used agents. TCS used alone in very early disease gave an average overall response of almost 50%. 4,6 Recent studies involving topical bexarotene used as monotherapy in one patient and along with NBUVB and TCS in other achieved complete remission. 63 Topical nitrogen mustard used in MF in 203 adults and children achieved an overall response rate of 83%. 65 The rest of the topical agents are almost always used in conjunction with other therapies. Many newer agents like mogamulizumab, alemtuzumab, immune checkpoint inhibitors, histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, belinostat, and resminostat), pralatrexate, forodesine, denileukin diftitox, duvelisib, lenalidomide, and everolimus may be available, however, these are usually reserved for trials, advanced and refractory cases, and data for use in pediatric MF is lacking. They may form a part of future therapies in pediatric cases once sufficient data is available for each of these agents. 66

Prognosis
In general, the prognosis of MF is stage dependent as the extent of skin involvement and presence or absence of extracutaneous disease are the main prognostic factors for the course of the disease. The overall prognosis in pediatric MF is good.
Progression to advanced-stage MF during childhood seldom occurs (~3.3%). 9 Survival rates at 5 and 10 years follow-up are 95% and 93%, respectively. The hypopigmented and poikilodermatous variant appears to have a better prognosis. CD8 + T cell immunophenotype is also associated with a better prognosis compared to adult-onset MF. 36,63,64 Conclusion Mycosis fungoides in the pediatric population is an uncommon disease. Diagnosis, and hence treatment, is usually delayed as it may mimic various common childhood dermatoses. As the majority of the patients has an early-stage disease (IA, IB, IIA) and favorable prognosis, phototherapy as first-line treatment is an effective treatment option for pediatric MF. Juvenile MF patients respond well to conventional therapy. Long-term follow-up and safety considerations of long-term treatment are needed in children. Due to a lack of standard treatment guidelines, there is a need to perform large scale studies to formulate effective and various patient tailored treatment regimens for the management of pediatric MF.