Congenital self-healing Langerhans cell histiocytosis vs benign cephalic histiocytosis: A comprehensive literature review of pediatric cutaneous histiocytoses

Introduction

The Histiocytosis Working Group created a system to categorize histiocytic disorders into 3 main groups: Langerhans cell histiocytosis (LCH), non-Langerhans cell histiocytosis (non-LCH), and malignant histiocytosis. This classification is based on identifying Langerhans cell antigens and the distinct clinical characteristics of each category. LCH features specialized dendritic cells called Langerhans cells. Non-LCH encompasses various disorders lacking specific antigens, while malignant histiocytosis involves aggressive, often cancerous, histiocytic cell proliferation.¹

LCH is a rare disorder marked by the abnormal proliferation of Langerhans cells. The condition is characterized by the accumulation of these cells in various tissues and organs, leading to a wide range of clinical manifestations. Despite extensive research, the exact cause and pathogenesis of LCH remain poorly understood, making it a challenging disease to diagnose and treat.²

Congenital self-healing Langerhans cell histiocytosis (CSHLCH), also referred to as congenital self-healing reticulohistiocytosis or Hashimoto-Pritzker disease, is a rare neonatal condition marked by the presence of skin lesions at birth or shortly thereafter. This condition is notable for its lack of systemic involvement, distinguishing it from other forms of LCH. The cutaneous lesions associated with this disease are typically self-limiting, resolving spontaneously within a period of weeks to months without requiring medical intervention. Despite its rarity, early recognition of this benign condition is important to avoid unnecessary treatment or invasive diagnostic procedures.^3,4

Benign cephalic histiocytosis (BCH) is a rare, self-limiting non-LCH disorder that primarily presents in infancy, typically within the first year of life. Clinically, BCH is characterized by the appearance of small erythematous to yellow-brown maculopapular lesions. These lesions are often grouped and may be slightly raised, predominantly affecting the head and neck regions of affected infants and young children. The etiology of BCH remains unclear, and it is considered a benign condition with no systemic involvement. Histopathological examination reveals dermal infiltration by histiocytes without Birbeck granules, distinguishing it from LCH.⁵ Importantly, BCH follows a self-resolving course, with spontaneous regression of skin lesions typically occurring within months to a few years after onset. No treatment is generally required, and the prognosis is excellent, with no long-term sequelae reported.^5,6

LCH, CSHLCH, and benign cephalic histiocytosis are categorized as nonmalignant histiocytic disorders, particularly those linked to the dendritic cell-histiocyte lineage. Despite their shared histiocytic origin, LCH arises from Langerhans cells, whereas BCH originates from non-Langerhans cells. These conditions predominantly affect infants and young children, with the skin being a common site of manifestation. While they share overlapping features, they differ significantly in cellular origin, clinical presentation, and prognosis.^2,3,5,7

This report highlights 2 exceedingly rare cases of cutaneous histiocytoses observed in pediatric patients. Both cases presented distinct cutaneous manifestations, prompting a detailed diagnostic workup, including histopathological examination and immunohistochemical analysis, to confirm the diagnosis. A comprehensive review of the literature was conducted to delineate evidence-based strategies for management. Treatment approaches for cutaneous histiocytoses remain largely individualized, with options ranging from observation for spontaneously resolving lesions to systemic therapies for more aggressive forms. Early recognition and tailored therapeutic strategies are critical in mitigating potential complications and improving quality of life in affected patients.

Case 1

A term male infant was born with a congenital lesion on the anterior aspect of the left leg. The lesion exhibited a raised, firm, erythematous border and central yellowish discoloration, with a size of 15 × 20 mm. This prompted the attending neonatologist to initiate systemic antibiotics on the first day of life. The lesion exhibited a rapid progression to a deep ulcer with yellow-brown exudation. Over the course of several days, the lesion underwent a transformation into necrotic tissue, accompanied by scaling at the periphery (Fig 1, A and B). The Tzanck smear, Gram stain, potassium hydroxide preparation, and bacterial and fungal culture of the lesion were all negative. Physical examination, in addition to laboratory investigations including Toxoplasmosis, Rubella, Cytomegalovirus, and Herpes Simplex Virus (TORCH) serology, metabolic panels, and imaging studies including skeletal surveys and computed tomography scans, was reported as normal. At 12 days of age, the newborn underwent skin biopsy, which histopathology revealed infiltration of the subcutaneous tissue by relatively monomorphic histiocytes lacking pleomorphism with grooved nuclei and amphophilic or eosinophilic cytoplasm with an increased mitotic index, admixed with neutrophils and a few giant cells arranged in nodular structures. Areas of necrosis and eosinophilic infiltration were also noted. The diagnosis was consistent with LCH. Immunohistochemistry showed diffuse positive staining for CD 68, S-100, and CD1a and patchy staining for Langerin (CD 207), confirming the diagnosis (Fig 2).

Fig 1.

Skin lesion of the neonate with congenital self-healing Langerhans cell histiocytosis. A, At birth. B, At 5 days. C, At 12 days. D, After biopsy. E, At 2 months. F, At 4 months.

Fig 2.

A, Aggregations of Langerhans cells admixed with intervening adipocytes (hematoxylin and eosin ×200). B, Langerhans cells with amphophilic cytoplasm and grooved nuclei admixed with a few lymphocytes (hematoxylin and eosin ×400). C, Diffuse strong staining with CD1a (IHC×200). D, Positive staining with Langerin in infiltrated Langerhans cells (IHC×200).

Furthermore, the biopsy specimen was subjected to testing for BRAF V600E mutations, which yielded a negative result. The patient was managed with a watch-and-wait strategy, with no intervention. The lesion began to heal and regressed spontaneously within a few months (Fig 1, C-F). Consequently, in the absence of any systemic disease and considering the natural history of the lesion, he was diagnosed with CSHLCH.

Case 2

A 3-month-old male infant, born to a mother diagnosed with non-Hodgkin's lymphoma during pregnancy, was referred to a pediatric clinic because of multiple small yellowish to pink papules forming a solitary raised oval wheal-like plaque with a warty surface on his lower back. The infant was otherwise healthy, and his physical examination was unremarkable. The lesion exhibited a gradual growth pattern, subsequently evolving into a collection of vesicles that ruptured at the age of 5 months, resulting in the formation of a 4 × 2 cm plaque with an umbilicated center (Fig 3). At this time, the infant underwent a punch biopsy.

Fig 3.

Skin lesion of the infant with benign cephalic histiocytosis. A, At diagnosis at 3 months of age. B-D, Spontaneous improvement of the lesion in 5 months.

Histological evaluation of the tissue sample revealed an uninvolved epidermis, accompanied by a diffuse interstitial infiltration of medium-sized oval and spindle-shaped histiocytes with abundant pale eosinophilic cytoplasm, indistinct cell borders, and round to oval nuclei without atypia or mitotic activity.

These cells were characterized by a diffusely positive CD68 expression and a negative S-100, CD1a, Langerin, and CD117 expression profile on immunohistochemistry analysis. Furthermore, a scattered distribution of lymphocytes and eosinophils among the histiocytes was observed (Fig 4). The patient was diagnosed with BCH, a non-Langerhans cell histiocytic disorder, based on clinical, histopathological, and immunohistochemical findings. The lesion regressed spontaneously within 4-5 months without any intervention, leaving a faint scar.

Fig 4.

A, Skin tissue with marked histiocytic infiltration in the dermis (hematoxylin and eosin ×100). B, Histiocytes with pink cytoplasm and vesicular nuclei infiltrated between collagen bundles (hematoxylin and eosin ×400). C, Negative staining with CD1a in histiocytes (IHC×200). D, Negative staining with Langerin in histiocytes (IHC×200).

Discussion

CSHLCH and BCH are among the unique histiocytic disorders of early infancy.^3,5 Since 1987, significant advances have improved the understanding of cellular origin, molecular pathology, and clinical features of histiocytic disorders. According to the revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages, histiocytic disorders have been categorized into 5 groups: (L) Langerhans-related, (C) cutaneous and mucocutaneous, (M) malignant, (R) Rosai-Dorfman disease, and (H) hemophagocytic lymphohistiocytosis and macrophage activation syndrome.⁷ In accordance with the aforementioned classification system, LCH is categorized within group L (Langerhans-related), whereas BCH is assigned to group C (cutaneous and mucocutaneous histiocytoses).⁷ The distinguishing characteristics of the 2 entities are delineated in Table I.

Table I.

Differentiation between CSHLCH and BCH

Feature	CSHLCH	BCH
Incidence	Unknown	Unknown
Age at onset	At birth or neonatal period, mostly before 7 mo	Mean at 7 mo, with 50% diagnosed before 6 mo
Sex	Male	Male
Location of lesions	Generalized	Most commonly on cheeks and forehead
Histopathology	Langerhans cells in epidermis and dermis with Birbeck granules	Pleomorphic epithelioid histiocytes within the upper and mid-dermis
Immunohistochemistry	Positivity for CD1a, CD207, CD68, and S-100	Positivity for CD68, CD163, Factor XIIIa, and S-100
Prognosis	Spontaneous regression	Spontaneous regression
Treatment	Self-healing, cobimetinib was recently suggested	Self-healing, topical rapamycin was recently suggested

BCH, Benign cephalic histiocytosis; CSHLCH, congenital self-healing Langerhans cell histiocytosis.

LCH cells are positive for S-100 and CD1a markers and characteristically show rod-shaped inclusions known as Birbeck granules in the cytoplasm on electron microscopy.⁸ LCH has a reported incidence of about 2-9 cases per million children per year and is most commonly found in young children.⁹ LCH of the cutaneous type is usually associated with the involvement of other organs, but isolated cutaneous disease accounts for 2% of all cases.¹⁰

The incidence of congenital or neonatal LCH has been documented as 1-2 cases per 1,000,000 newborns. A retrospective study of patients enrolled in the DAL HX-83, DAL HX-90, and the International LCH-I and LCH-II clinical trials revealed that 61 out of 1069 patients with LCH (6%) were first presented in the neonatal period. Of these patients, the majority (59%) developed multisystem LCH.^11,12

CSHLCH, first described by Hashimoto and Pritzker in 1973, is a rare variant of LCH that differs from other forms of LCH in its benign, spontaneously involuting nature and presentation at birth or early infancy.¹³

CSHLCH typically presents as a reddish-brown papule, nodule, or pustule with a button-like central erosion. Rare variants may be presented as hemorrhagic bullae, urticarial plaques with positive Darier's sign, “blueberry muffin” lesions, or molluscum-like papules, which usually resolve by 3 months of age.12, 13, 14

The most common presentation of the cutaneous lesions is that of multiple lesions ⁴; however, the presence of a solitary skin lesion has also been documented.^15,16 A single report details 7 cases of CSHLCH, of which 71.4% exhibited solitary lesions. All lesions demonstrated regression within a mean period of 2.5 months, with a range of 1 to 4 months. No relapses were observed, except in 2 cases where follow-up was incomplete.¹⁷ Nevertheless, there have been documented cases of cutaneous lesions associated with ophthalmic and pulmonary involvement.18, 19, 20 In addition, it is important to note that not all cases of CSHLCH will undergo spontaneous regression.

There have been reports of recurrence and multiorgan involvement following resolution of lesions of CSHLCH. Four cases of widespread CSHLCH at birth have been reported in which skin lesions are resolved spontaneously. However, 1 patient experienced a cutaneous relapse at 3 months of age, and another developed a bony relapse requiring systemic therapy at 6 months of age.²¹ Therefore, due to the unpredictable and variable course of CSHLCH in infancy, long-term follow-up of this rare benign disorder is recommended.

In our case, the cutaneous lesion was solitary, the neonate appeared healthy, and there were no indications of bacterial, fungal, or viral infections. It is essential to differentiate this presentation from other vesiculobullous conditions in newborns, such as congenital varicella zoster, intrauterine herpes simplex virus infection, congenital candidiasis, and impetigo neonatorum.

Somatic mutations in BRAF V600E, which lead to the continuous activation of the RAS-RAF-MEK-ERK-MAP kinase pathway, represent the most frequent genetic abnormality found in 19% to 55% of pediatric LCH.^22,23 A study conducted in India discovered that patients with the BRAF V600E mutation exhibited more extensive disease and inferior survival outcomes in comparison to those who did not possess the mutation. This finding serves to emphasize the role of the BRAF V600E mutation as a marker of poor prognosis and a crucial indicator for predicting disease progression and relapse.^23,24 A report from Japan describes 2 cases of CSHLCH in which no BRAF mutation was identified in the skin lesions.

Interestingly, the lesions spontaneously resolved within a few months without any form of medical intervention.²⁵ In the literature, 5 cases of CSHLCH with multiple skin lesions have been documented that were found to have BRAF V600E mutation detected by RT-PCR; however, they exhibited no signs of systemic disease or recurrence of skin lesions by 10 months of age.26, 27, 28 Additionally, cases of CSHLCH with wild-type BRAF have also been reported.⁹ In our case, no mutation in BRAF V600E was detected.

CSHLCH typically does not require active intervention due to its self-limiting nature. Regular outpatient follow-up is advised to counsel caregivers regarding its benign prognosis. In cases of persistent cutaneous lesions, therapeutic options include the use of topical corticosteroids, tacrolimus, mechlorethamine, or surgical excision for localized refractory lesions.²⁹

In the second case, BCH was diagnosed with a solitary skin lesion on the lower back. BCH, an extremely rare diagnosis of unknown etiology, is a non-LCH disorder that presents itself as a self-healing eruption.

This condition was first characterized by Gianotti et al in 1971.³⁰ BCH commonly manifests as asymptomatic, multiple, small, asymmetric, round or oval raised papules with an orange-red to yellow-brown hue. The lesions are primarily distributed on the face, neck, and shoulders, usually presenting within the first 3 years of life.^5,31

As of 2022, a total of 72 cases of BCH have been reported in the literature, with 23 demonstrating extrafacial involvement. Interestingly, only 1 case was exclusively confined to extrafacial regions, although it is presented with multiple lesions.³² Our presented case was the first documented instance in literature to manifest as a solitary extrafacial lesion.

To date, the literature has not provided a description of systemic involvement in BCH. However, there have been 2 documented cases of diabetes insipidus and diabetes mellitus in association with BCH, attributable to the infiltration of the pituitary stalk.^33,34

BCH generally has an excellent prognosis, as the condition resolves on its own within months to years³¹; however, in rare instances, there is a rare potential for progression to generalized eruptive histiocytosis.⁵

In the present study, both cases exhibited a self-limiting course with spontaneous regression, thus demonstrating that intervention is not necessary for such cases. The surveillance of the patients was focused on monitoring and reassuring the family, highlighting the favorable prognosis of these conditions.

Conflicts of interest

None disclosed.