Pediatric Mycosis Fungoides Mimicking Benign Dermatoses: A Report of a Rare Case

Introduction

Primary cutaneous lymphomas (PCL) are a multifaceted spectrum of cutaneous T cell lymphoma (CTCL) and cutaneous B cell lymphomas (CBCL). It is the second most prevalent extra-nodal non-Hodgkin lymphoma site after the gastrointestinal tract, with an estimated annual incidence of 1: 100 000 [1,2]. Mycosis fungoides (MF) is a rare subset of CTCL that primarily affects adults, and its occurrence in children is exceedingly rare [3–5]. It was first described by Jean Alibert in the 18th century, who initially described the early patch-stage symptoms in patients with classic MF [6]. Mycosis fungoides (MF) accounts for 3.9% of all non-Hodgkin lymphoma cases and accounts for over 50% of all CTCL cases [2,7]. In Europe and the United States, there are 6 cases of MF per 1 000 000 people annually, typically affecting adults 50–60 years old, with a male-to-female ratio between 1.6 and 2 [3]. Only 4–5% of MF cases occur in children, with usual age at onset of 6–8 years old [3–5]. The disease is more common among Blacks than Whites or Asians. Among the cutaneous lymphomas, nearly two-thirds are of the T cell type. The most common immunophenotype is CD4-positive [8].

Diagnosis of MF, either in children or adults, is made through clinical assessment, blood investigations, histopathology examination, and radiological imaging, or lymph node biopsy in later stages [8]. The diagnosis of pediatric MF is challenging due to its resemblance to benign skin conditions such as pityriasis alba, pityriasis versicolor, eczema, psoriasis, photo-dermatitis, and atopy eczema [9]. This can lead to delayed diagnosis, with a median of definitive diagnoses made 5 years after onset [9].

The causes of MF are still unknown, and the clinical stages progress slowly over years or even decades, starting from the patch stage and advancing to the plaque stage with greater infiltration, and ultimately to the tumor stage [10]. Cutaneous tumors in MF can resemble those in other cutaneous lymphomas, and as the disease progresses from patch to plaque to tumor stage, the likelihood of lymph node or visceral involvement increases, reflecting a greater risk of dissemination to lymph nodes and organs in later stages [8,11]. Children mostly exhibit the early patch stages of MF [3]. The tumor-node-metastasis-blood (TNMB) classification system is used to stage CTCL, with various atypical variants of pediatric MF identified [2,3].

Based on the European Organisation for Research and Treatment of Cancer (EORTC), histopathological adult MF variants include classical, folliculotropic, pagetoid reticulosis, granulomatous MF, and Sézary syndrome [2,11], but in children, hypopigmented MF is usually the most prevalent type [9]. A 2023 study showed an increased prevalence of the folliculotropic variant in children [5]. Other variants in pediatric MF include classic, poikilodermatous, hyperpigmented, pityriasis lichenoid-like, and unilesional MF [3,12,13].

Management is based on the stages, with an individualized approach. For early stages, topical treatment such as corticosteroids, nitrogen mustards, bexarotene, imiquimod, and skin-directed treatment such as psoralen-ultraviolet A (PUVA) or narrow-band ultraviolet B (NBUVB) therapy is recommended [2]. For the advanced stage, combination therapy of skin-directed therapy, localized radiation, and systemic treatment (eg, methotrexate, bexarotene, targeted immunotherapy, polychemotherapy) is recommended [2,5]. This case report describes the clinical and histopathological features of a rare case of pediatric MF that mimicked common benign skin conditions in a 7-year-old Malaysian boy.

Case Report

A 7-year-old boy presented at a primary care clinic with progressive and evolving skin lesions spanning 12 months. Initially, they started as pruritic, erythematous patches on the bilateral cheeks and extensor surface of the forearms. He had been doing well, without concurrent systemic manifestations. After 6 months, certain areas evolved into dark hyperpigmented patches on the cheeks and upper limbs. New erythematous rashes emerged on the bilateral upper and lower limbs, primarily in sun-protected regions. The pruritus intensified as the number of rashes increased, although systemic symptoms remained absent. By 12 months, most of the rashes had transitioned into hypopigmented, dry, and scaly patches, spreading to encompass the bilateral upper and lower limbs, abdomen, back, and buttocks. Notably, thickened and lichenified plaques appeared over the elbows and buttocks, with escalating pruritus and minimal pain noted at excoriated sites on the buttocks and elbows due to excessive friction. Throughout this progression, he remained devoid of systemic problems.

Over the 12 months, his parents sought medical attention for the child at more than 10 distinct primary care facilities, where he received diagnoses of either eczema or pityriasis versicolor. Treatment regimens entailed the administration of various topical corticosteroids and aqueous cream, yet yielded no discernible improvement. Notably, the patient had no comorbidi-ties, was not on any systemic medication, and had no history of food or drug allergies. Furthermore, there was no personal or familial background of atopy, and he never experienced contact dermatitis prior to this episode. The patient was born at full term via spontaneous vaginal delivery, and had been well until the onset of these symptoms.

Upon physical examination, he exhibited age-appropriate growth and development. Skin inspection revealed multiple dry, scaly, and hypopigmented patches of varying sizes scattered bilaterally across his cheeks, the extensor area of the upper and lower limbs, abdomen, and back. Observations revealed thick lichenified eczematous plaques with multiple papules and intervening excoriations between his buttocks and bilateral elbows. The overall skin lesion accounted for approximately 10% of his total body surface area (Figures 1–3). Remarkably, his palms, soles, scalp, nails, mucosal surfaces, and genitalia were spared from these manifestations.

Systemic examinations did not reveal lymphadenopathy over the cervical, axillary, and inguinal areas. Mucosal areas, including the lips, buccal cavity, and genital regions, showed no lesions or signs of inflammation. The cardiovascular system examination revealed normal heart sound and the apex was not displaced; the respiratory system was normal with equal breath sound bilaterally; the abdominal system had no hepatosplenomegaly, no abdominal masses, or tenderness; and the musculoskeletal system had no joint involvement, swelling, tenderness, or restricted movement suggesting systemic disease. Furthermore, examination of hair and nails did not reveal any remarkable findings.

These findings led to the diagnosis of eczema and initiation of treatment with an emollient aqueous cream, 1% hydrocortisone cream, and oral loratadine. However, considering the absence of a personal and family history of atopy, the atypical distribution of extensive eczematous skin involvement, and prior inadequate responses to topical therapies, a referral to the Dermatology team was made for further evaluation and management.

He was seen in the Dermatology clinic 2 weeks after the referral, and a similar diagnosis was given: eczema, with differential diagnoses of pityriasis alba and pityriasis versicolor. He was prescribed aqueous cream and more potent steroids (topical clobetasone butyrate 0.05% cream once daily for his face and betamethasone valerate cream 1: 4 twice a day for the rest of the body). However, at the 1-month follow-up visit, his condition had progressed. The lesions remained itchy and had spread more widely, especially on the face. There were more thickened hypopigmented patches and papules over the face, front, back, and bilateral lower limbs and buttocks, with collarette scales. There were no palpable lymph nodes or hepatosplenomegaly. Woods’ lamp examination showed negative results for tinea corporis, pityriasis versicolor, erythrasma, and vitiligo. Thus, he was scheduled for a skin and fungal culture biopsy to confirm the diagnosis, with the suspicion of MF or pityriasis versicolor.

The first skin biopsy histopathological examination (HPE) revealed focal basilar tagging with mild enlarged atypical lymphocyte epidermotropism with focal clusters of lymphocyte exocytosis, exhibiting hyperchromatic and irregular nuclear membrane with perinuclear halos and perivascular infiltrates seen. Few mitotic figures are seen. Immunohistochemistry (IHC) showed predominant positive CD3+, and positive CD2+ and CD5+ expression, with reduced expression of CD4, CD7, and CD8 at the epidermis level (Figures 4–6). Melanocytes were present at the base. The dermis showed mild to moderate perivascular inflammation with scattered mast cells. These features suggested an early or patch stage of MF. His tissue for fungus culture from the skin biopsy was negative.

He was then referred to a pediatric dermatologist for further expert opinion. Given his clinical skin examination findings and HPE, he was diagnosed with pityriasis lichenoides chronica (PLC), which can also present with similar skin lesions and is more common than MF. This diagnosis was also considered, given that MF is an exceedingly rare condition in the pediatric population. The HPE findings in this patient were quite challenging as they showed hyperkeratosis and parakeratosis with predominant CD3+ expression upon IHC, which can also be found in PLC; however, in PLC there should be no epidermotropism and atypical lymphocytes at the epidermis level. The patient was prescribed syrup erythromycin 300 mg twice a day for 6 weeks, topical aqueous cream for the face, and continued application of topical betamethasone valerate cream 1: 4 twice a day for the papules and hypopigmented areas.

The patient underwent another review after 6 weeks. He now had worsening, more generalized, and more thickening of skin lesions, with a similar character as before. A repeated biopsy was done to confirm the diagnosis, and blood investigations including full blood count (FBC), renal profile (RP), liver function test (LFT), erythrocyte sediment rate (ESR), and electrolytes, which were performed to rule out any systemic involvement, and a peripheral blood film (PBF) was taken as well to rule out any Sézary cell or hematological lymphoma features.

His FBC revealed hypochromic microcytic anemia. His PBF revealed mild hypochromic microcytic anemia with mild anisopoikilocytosis, likely secondary to iron deficiency anemia, as he was noted to be a picky eater. Target cells and pencil cells were present and there was no evidence of Sézary cells in his PBF. There were no other significant abnormalities or blast cells in the PBF. His liver function test, renal profile, calcium, and magnesium revealed normal values.

His second skin biopsy showed that the epidermis has a few scattered atypical lymphocyte exocytoses with slightly enlarged, irregular nuclear membranes and perinuclear halos. No obvious lymphocyte abscess or basal vacuole was seen. The dermis showed mild to moderate perivascular inflammation with scattered mast cells. The immunohistochemistry showed CD3+ expression and slightly reduced CD2+, CD5+, and CD7+ expression. CD4+ expression was equivocal. A clinicopathological conference between the pediatric dermatologist, dermatologists, and pathologists was held to discuss this case, as there was a high suspicion of MF. It was concluded that he had CTCL, specifically, the hypopigmented patch stage of MF with the TNMB classification system of T1bN0M0B0, based on his clinical presentation and histopathology findings (Table 1).

Following the diagnosis, he was prescribed phototherapy using narrow-band ultraviolet B (NBUVB) twice a week for treatment of MF. After 3 months of treatment, the rashes on his face improved, and those on his upper chest and upper limb remained but thinned. He was also regularly monitored long-term for any systemic involvement of lymphoma and disease progression, with investigations such as PBF for monitoring of Sézary cells, renal profile, and liver function test. His iron studies revealed iron deficiency anemia. He was prescribed syrup ferric ammonium citrate (FAC) 120 mg once daily and folic acid 5 mg once daily and he was also advised to consume a high-iron diet. After treatment for 3 months, his hemoglobin normalized.

The final diagnosis of MF was made 4 months after the initial presentation in the Dermatology Department, which is 16 months after visiting multiple primary care and dermatology clinics, and following referral to a pediatric dermatologist, with 2 skin biopsies performed in total.

Discussion

Pediatric MF is a rare dermatological condition. This case report illustrates the challenge in making a diagnosis as the initial presentation of pruritic, erythematous skin lesions, which then evolved to hypopigmented, dry, and scaly patches resembling benign dermatoses such as eczema and pityriasis versicolor, leading the attending physicians give this diagnosis at different points in time [4,13,14]. This is consistent with other reported cases of pediatric MF [4,13,14]. Hence, a comprehensive differential diagnosis is crucial for hypopigmented skin conditions, highlighting the importance of thorough clinical evaluation and history taking. The prolonged duration of symptoms with poor response to standard treatments for such benign conditions were key features in moving forward to establishing the correct diagnosis.

In adults, MF typically presents with the classical type and Sézary syndrome, characterized by systemic involvement, including erythroderma, lymphadenopathy, and malignant T cells in the skin, lymph nodes, and peripheral blood. This results in more advanced staging and a poorer prognosis [2,3,11]. Our patient presented with a patch stage of hypopigmented MF, the most predominant variant in childhood, especially in darker-skinned patients, which is in line with the literature [9,13]. In differentiating our patient with MF from other hypopigmented and scaly dermatoses such as pityriasis alba, pityriasis versicolor, psoriasis, eczema, and pityriasis lichenoides chronica, each diagnosis has some distinguishing features clinically and from histopathological examination (HPE) that should be considered. In this case, the patient had fulfilled more than 4 points for diagnosis of early MF based on the International Society for Cutaneous Lymphomas (ISCL) Task Force: persistent and progressive patches at non-sun-exposed locations with variations in size and shapes, and HPE classical findings of superficial lymphoid infiltrate, epidermotropism and lymphoid atypia [15].

Conducting FBC, RP, LFT, ESR, and PBF is essential [11,12]. These tests help assess systemic involvement, which is crucial for staging and management. FBC monitors blood cell counts, which is vital for tracking disease progression. RP evaluates renal function, as renal involvement can occur, while LFT is important for detecting liver infiltration [11,12]. Elevated ESR suggests inflammation, prompting further investigation. PBF detects abnormal Sézary cells, indicating advanced disease or transformation to Sézary syndrome, which was absent in this patient [6,11,13].

Together, these tests provide a comprehensive evaluation, guide treatment decisions, and monitor disease activity in CTCL.

Skin biopsy is vital in diagnosing pediatric MF [6,11,12]. Our patient had undergone 2 biopsies, and previous studies show an average of 3 biopsies are done to diagnose pediatric MF and to validate the diagnosis [16]. A repeat biopsy was performed in this case to validate the diagnosis, given the rarity of the condition in children, especially in Malaysia. This emphasizes the importance of thorough and confirmatory investigations in rare diagnoses. Our patient was diagnosed earlier, at 16 months, compared to the typical median of 5 years to achieve diagnosis [9,17]. This underscores the need for early skin biopsies in pediatric patients with resistant or evolving lesions.

Histologically, hypopigmented MF cannot be differentiated from the classic MF variant, as both reveal features such as epidermotropism, with or without Pautrier microabscesses, and lymphocytic infiltrates at the epidermal level [18]. These findings align with our biopsy results, which revealed superficial lymphoid infiltrate, atypical lymphocyte exocytosis, and irregular nuclear features within the epidermis and upper dermis (epidermotropism). Pautrier microabscesses were absent [2]. Prior case reports indicate that most hypopigmented MF variants demonstrate IHC of CD8+ expression [5,16]. However, a diverse array of CD markers was also found [19]. For classic MF, there is predominantly CD4+ expression with CD3+, CD2+, CD5+, and reduced CD7 and CD8 expression [18]. In our case, IHC staining revealed predominant positive CD3+ expression, positive CD2+, and CD5+, and reduced CD4, CD8, and CD7 expression [2]. The histopathology findings and their correlation with immunohistochemistry features for this patient is summarized in Table 2. Demonstrating T cell receptor (TCR) clonality proves the neoplastic nature of T cells but is costly and not available in Malaysia. Therefore, IHC findings should be interpreted alongside clinicopathology data [8].

Treatment for pediatric MF differs from adult cases due to the early diagnostic stage (stages IA, IB, and IIA) and lower tendency to progression [20]. Phototherapy is a common first-line treatment, with psoralen-ultraviolet A (PUVA) therapy showing longer remission durations but with potential adverse effects, while narrow-band ultraviolet B (NBUVB) shows shorter remission requiring more sessions but with fewer adverse effects [2,19,21,22]. Topical corticosteroids are also used, often in combination with other therapies such as bexarotene, nitrogen mustard, vitamin D analogs, carmustine, and pimecrolimus [20,23,24]. Our patient was treated with phototherapy with NBUVB, which is the recommended approach for early-stage MF, and he responded well to this treatment, similar to previous cases in the literature [19,22].

Early-stage pediatric MF has a good prognosis, with survival rates comparable to the general population [25–27]. The survival rate varies based on the extent of skin involvement and disease stage, with advanced cases having a poorer prognosis. According to a recent study, the 10-year disease survival rate is 97% for all patients with stage 1a MF (10% patch/plaque skin surface). The rate drops to 83% in stage 1b (more than 10% skin surface), then to 68% for patients with stage II (tumor), and it drops to 20% for stage III (lymph node involvement). Patients in stage IV (large T cell lymphoma, visceral involvement, and effaced lymph nodes) often have an aggressive clinical course and frequently die due to infections or systemic complications [17,25–27]. Our patient presented with hypopigmented MF in stage 1b, and based on a previous study on pediatric MF, the prognosis of the hypopigmented MF variant is good, with a 10-year disease survival rate of 96% [28]. Long-term follow-up is essential to ensure treatment safety and efficacy and monitoring of disease progression in pediatric MF [21].

From a primary care point of view, timely referral, monitoring, and recognition of red flags by the primary care physician were crucial in identifying lesions indicative of a rare skin condition, which can potentially progress to systemic lymphoma [25]. Collaboration among primary care physicians, dermatologists, pediatric dermatologists, and pathologists was vital in concluding the diagnosis, especially after 1 year and 4 months of misdiagnoses and treatment.

A limitation of this case report is the lack of TCR genetic testing at our center, which limits the confirmation of the neoplastic nature of the infiltrate, particularly in the early stages with nonspecific findings. This case highlights the need to understand variations in presentation for children compared to adults, and increased awareness and education for primary care physicians on atypical manifestations of rare conditions like MF is recommended.

Conclusions

Pediatric MF is a rare CTCL that can present with features resembling common benign skin conditions, thus becoming a diagnostic challenge. Due to the low incidence of pediatric MF in Malaysia, primary care physicians as the first point of care in the community should have a high index of suspicion for any common skin problems that do not respond to standard treatments, and should consider rarer disorders like MF. This case report highlights the need to closely monitor unresolved hypopigmented lesions to avoid inappropriate treatments and prevent potentially serious disease progression. Timely diagnosis and skin biopsy are essential for effective management and better patient outcomes.