Insights into etiology and management of a case of Langerhans cell histiocytosis manifesting as perianal lesions: a case report

Abstract

Background

Langerhans cell histiocytosis is a rare disorder characterized by abnormal proliferation of Langerhans cells, primarily affecting children and occasionally adults. Etiology remains enigmatic, with genetic and environmental factors implicated. Diagnosis relies on histopathology and clinical manifestations, often necessitating a multidisciplinary approach.

Case presentation

We report a unique case of Langerhans cell histiocytosis with perianal lesions as initial manifestations in a 41-year-old Chinese deaf male patient with a history of perianal abscess. Examination revealed erosion and plaque-like changes in the mucosa around the anus. Histopathology and immunohistochemistry confirmed Langerhans cell histiocytosis, and a whole-body positron emission tomography-computed tomography scan revealed no other organ involvement, indicating monosystemic disease. Then, 3 months post-treatment, the patient declined a repeated magnetic resonance imaging scan during outpatient follow-up owing to no significant discomfort reported, which resulted in loss to follow-up and discontinuation of treatment.

Conclusion

This case suggests that perianal lesions may be a manifestation of Langerhans cell histiocytosis, and underscores the importance of whole-body positron emission tomography-computed tomography scanning for follow-up in instances of pure skin involvement.

Background

Langerhans cell histiocytosis (LCH) is a rare disease characterized by abnormal proliferation and involvement of Langerhans cells. It can affect various organs throughout the body, with the most common sites being the skeleton and skin. This condition typically occurs in children aged 1–3 years, presenting with a complex and diverse range of clinical manifestations ranging from mild, asymptomatic single-organ involvement to aggressive multisystem involvement [1]. Skin involvement in LCH is common, particularly among infants, often manifesting as seborrheic dermatitis. In adults, it may present as refractory eczema in specific regions. Isolated skin involvement can be definitively diagnosed through histopathological and immunohistochemical examination. However, when the disease occurs in adults, with solitary lesions and slow progression, it is prone to misdiagnosis, leading to delayed diagnosis and treatment. Although LCH can affect multiple parts of the body, perianal skin lesions as the initial manifestation are uncommon [2]. This article reports a case of adult Langerhans cell histiocytosis with perianal skin lesions as the initial presentation and aims to discuss the clinical features, pathological diagnosis, treatment, and prognosis of adult LCH with perianal skin lesions as the initial manifestation.

Case presentation

Patient information

A 41-year-old Chinese male patient presented with a 1-year history of dry stool, which progressed to rectal bleeding for 1 month. He had undergone perianal abscess surgery in 2009. Colonoscopy revealed circumferential mucosal erosion and granular or nodular protrusions covered with fragile, white tissue, suggestive of perianal mucosal changes (Fig. 1).

Fig. 1

Langerhans cell histiocytosis clinical spectrum. A Colonoscopy revealed annular mucosal erosion and granular or noduar elevation at the anus (as shown by the black arrow); B enhanced magnetic resonance imaging scan demonstrated a round-shaped hyperintensity on fat-suppressed T2-weighted imaging within the anal canal (indicated by the black arrow)

The patient appeared well, with no enlarged lymph nodes. He had hearing impairment and a history of pulmonary tuberculosis. Anorectal examination revealed circumferential mucosal erosion and hard, tender granular or nodular protrusions mainly on the right side, extending proximally from the anus to 3 cm of the anal canal. The diagnosis was an anal canal mass, and further tests are needed to confirm its nature. The doctor recommended imaging and biopsy to gather more information. Fortunately, all routine blood, urine, stool, liver, and kidney function tests came back normal. A magnetic resonance imaging (MRI) scan showed some changes owing to a previous surgery, as well as a missing part of the back wall of the internal sphincter. In addition, there is a round area near the sphincter gap that appears bright on the scan and has enhanced walls. This area extends into the skin tissue around the left side of the anus, measuring about 3.1 cm in length and, additionally, shows enhanced walls. (Fig. 1).

Histopathological examination

Histopathological examination of the anal skin lesion revealed two specimens: 0.7 cm × 0.4 cm × 0.3 cm and 1.1 cm × 0.5 cm × 0.3 cm, with a slightly tough, grayish-white texture. Microscopically, there was hyperkeratosis, parakeratosis, epidermal hyperplasia, and downward extension of epidermal ridges, along with focal epidermal erosion. A diffuse proliferation of histiocytic-like cells was evident in the dermis and subcutaneous tissue, with pale cytoplasm, nuclear grooves, and numerous eosinophilic granulocyte infiltrates. Immunohistochemically, the tumor immunophenotype was Langerin⁺, CD1α⁺, S-100⁺, CD4⁺, CD8⁺, CD20⁺ (B cell), CD3⁺ (T cell ), BRAF V600E⁺(1), CK⁻, HMB45⁻, and Ki67⁺ (15%), additionally, the expression of CD4 is more than that of CD8. These findings supported a diagnosis of Langerhans cell histiocytosis (LCH). A positron emission tomography-computed tomography (PET/CT) scan excluded involvement of other organs, confirming monosystemic LCH. (Fig. 2).

Fig. 2

Langerhans cell histiocytosis lesion histology. Images demonstrate typical histology of LCH lesion obtained from perianal skin lesion biopsy, with pathologic histiocytes and inflammatory infiltrate. A–C Hematoxylin and eosin stain demonstrates histiocytes with pale cytoplasm, reniform nuclei, epiphenomenon presence, and nuclear atypia. Immunohistochemistry positive for D Langerin, E CD1a, F S100a, and G Braf V600E

Treatment and prognosis

The deaf patient, with limited family support, had not undergone systematic treatment, relying solely on symptomatic measures to improve diet, bowel habits, and constipation relief with laxatives. He was advised to follow-up closely with the colorectal surgery department. Then 3 months later, during the outpatient follow-up, the patient was requested to undergo a repeat magnetic resonance imaging (MRI) scan, but declined, stating that he did not experience any significant discomfort. Subsequently, the patient was lost to follow-up and did not resume treatment.

Discussion

Langerhans cell histiocytosis (LCH) is a neoplastic disorder resulting from abnormal proliferation of immature dendritic cells. Classified as an inflammatory myeloid neoplasm in the 2017 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, LCH is part of the L-group of histiocytosis, alongside Erdheim–Chester disease (ECD) [3]. Clinically, LCH displays significant variation, often leading to delayed diagnosis. It can manifest as a systemic disease with high mortality rates among infants and young children or as a typically nonfatal chronic disease affecting children and adults. Any organ can be affected, although it is more common in children and relatively rare in adults, with an annual incidence rate of 5 per 1,000,000 in children and 1–2 per million in adults [4]. In addition, males are disproportionately affected.

Common sites of LCH involvement include bone, skin, lung, thyroid, and the nervous system. Skin involvement typically occurs on the scalp, trunk, skin folds, and mucosal sites, presenting as seborrheic eczema in infants and refractory eczema in the genital region in adults [5]. Rarely, the disease may solely affect the anal genital region, although anogenital lesions are often just one manifestation among various sites. Initial manifestations of anogenital lesions in LCH often present as skin nodules, ulcers, or swellings in the perianal area, leading to patient discomfort, pain, and an increased risk of local infection. These symptoms may be misdiagnosed as other common perianal conditions owing to their similarity, such as hemorrhoids, anal fistulas, extramammary Paget’s disease, and skin Crohn’s disease [6]. In this case, the patient had a history of perianal abscess surgery in 2009 and presented with no obvious involvement of other organs, leading to an initial misdiagnosis of perianal inflammatory disease. However, subsequent histopathological examination confirmed the diagnosis of LCH. For adult patients with perianal skin lesions suspected of LCH, a detailed history, physical examination, biopsy, and histopathological examination are crucial for accurate diagnosis. Additional auxiliary examinations, such as imaging studies and blood tests, aid in assessing disease severity and extent.

The pathological hallmarks of LCH are abnormal proliferation and infiltration of Langerhans cells [3]. In our case, the tumor cells primarily infiltrated the upper dermis, exhibiting uniform morphology with lightly stained, kidney-shaped vacuolar nuclei, longitudinal grooves, and eosinophilic cytoplasm. Nucleoli were nonprominent, and mitosis was evident. Eosinophils were abundant, displaying epidermotropic features. Immunohistochemically, the tumor cells expressed Langerin⁺, CD1α⁺, S-100⁺, CD4⁺, and CD8⁺, and the expression of CD4 was greater than that of CD8. Oda T et al. [7] reported that electron microscopy revealed Birbeck granules within histiocytes, which was further confirmed by immunohistochemical and enzyme histochemical techniques. Unfortunately, we did not allocate tissues for electron microscope analysis. Expression of Langerin (most specific markers) and CD1α is imperative for the diagnosis of LCH, along with strong positivity for monocyte-macrophage histiocytic markers, such as CD68 and factor XIIIa, and reduced expression of CD45 and CD4 [8]. Our findings are in congruence with existing literature reports, reinforcing the consistency and reliability of our observations.

The etiology and pathogenesis of LCH remain enigmatic. Current hypotheses suggest LCH as a reactive proliferative disorder linked to immune dysfunction, though specific etiologies remain elusive. Abnormal Langerhan cell (LC) counts have been documented in various inflammatory dermatoses. Xiao Chunying et al. [9] reviewed studies indicating abnormal epidermal LC counts, maturation, and activation states in psoriasis patients. These aberrant LCs can mediate T cell activation, contributing to psoriasis pathogenesis. Our patient had a history of perianal abscess, and the study revealed the presence of both CD4 and CD8 expression in tumor tissue, with CD4 > CD8, indicating that inflammation or antigen stimulation may lead to LC abnormalities. Skin lesion inflammation can impact LC numbers, and perianal inflammatory diseases may cause aberrant LC activation and maturation. Abnormal clonal proliferation of LCs can precipitate LCH development. We postulate that persistent inflammation may play a role in myeloid tumor development.

We observed weak BRAF V600E expression in tumor cells, suggesting a central role for the Raf oncogenic pathway in LCH pathogenesis, thereby classifying LCH as a neoplastic disease. Previous studies by Badalian-Very et al. [10] reported BRAF V600E mutations in ~ 60% of patients with LCH. Our findings align with these reports and further suggest ethnic differences in BRAF V600E mutation frequencies, with lower rates in Asian countries compared with North American and European countries [11]. Other genetic mutations, including MAP2K1, KRAS, ARAF, ERBB3, NRAS, PTPN11, NF1, and CBL are also involved in LCH pathogenesis, primarily affecting the mitogen-activated protein kinase (MAPK) pathway [12, 13]. Additionally, activating mutations of the phosphatidylinositol 3‑kinase (PI3K) signaling pathway and c-KIT mutations have been implicated [12, 14].

In adult LCH treatment, individualized plans tailored to the patients’ conditions are crucial. Localized modalities, such as topical medications, laser therapy, or surgery, manage perianal lesions. Systemic approaches, such as chemotherapy or radiation, are needed for severe cases [16]. Chemotherapy resistance in BRAF V600E-mutated LCH highlights immunotherapy’s potential [15, 16]. Recently, a unique skin-limited LCH subtype (SS-S) was recognized [17]. In Japan, BRAF + MEK inhibitor treatment, approved for BRAF V600E-mutated histiocytosis, is a novel treatment paradigm implemented clinically for this patient subset [16].

The prognosis of adult LCH varies individually, being influenced by disease severity, treatment methods, and the patient’s overall health [18]. The earlier the age of onset, the greater the involvement of high-risk organs by the pathology, and the more numerous the lesion foci, the poorer the prognosis for the patient. Treatment plans should be tailored on the basis of the extent of involvement and risk stratification. For patients presenting with perianal skin lesions suggestive of LCH, the cure rate can reach above 80% with an appropriate treatment regimen; however, there is a recurrence risk for 30–50% of these patients [19]. Therefore, long-term follow-up is crucial for the standardized management of patients. Conducting PET/CT scans at 3 months and within 1 year after treatment to assess disease prognosis aids in the research on treatment and prognosis evaluation of this disease, thereby enhancing patients’ quality of life and extending their survival duration [16].

Conclusion

Our report underscores the importance of considering LCH in the differential diagnosis of refractory eczema and similar perianal conditions, even in atypical manifestations. Prompt identification and treatment are crucial for disease management and patient outcomes. In addition, the value of whole-body PET/CT scanning in the diagnosis and follow-up of patients with LCH is emphasized, particularly in cases involving pure skin involvement. We advocate for further research into adult LCH manifestations, especially perianal lesions, to enhance understanding of diagnosis, therapy, and prevention. This holds potential for novel insights and treatment approaches for this rare condition.

Learning point

• We report an adult LCH case initially manifesting as perianal skin lesions, highlighting the need to consider LCH in refractory eczema and similar perianal skin conditions.

• This case report underscores the significance of recognizing persistent inflammation as a potential presenting feature of LCH, especially in atypical cases.

• It emphasizes the value of whole-body PET/CT scanning in the diagnosis and follow-up of patients with LCH, particularly in cases involving pure skin involvement.