Beyond cutaneous xanthogranulomas: Recognising the existence of mixed histiocytosis

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A 25-year-old man presented with asymptomatic, minimally elevated, smooth yellowish-brown papules over his bilateral cheeks for 4 months [Figure 1]. He also had skin-coloured papules over his lower eyelid margins, forming a beaded appearance. There were no other cutaneous lesions. For the same duration, he had an occasionally tender bony swelling over the left mandible. There were no other bony complaints; however, there was a history of recovered spastic paraplegia secondary to radiologically diagnosed Pott’s spine 3 years ago. He had polydipsia and polyuria for 4 years with no other symptoms of hormonal deficiencies. He had no history of fever, fatigue, or neurological, ocular, or respiratory complaints. With a provisional diagnosis of Erdheim-Chester disease (ECD) type non-Langerhans cell histiocytosis (NLCH), he was subjected to further workup. Skin biopsy from xanthomatous papules showed dense dermal infiltrates of lymphocytes, many histiocytes, neutrophils, eosinophils with Touton giant cells, and plasma cells consistent with NLCH [Figure 2a]. Surprisingly, bone biopsy showed sheets of large, round-to-oval tumour cells with nuclear grooves, abundant eosinophilic cytoplasm, minimal pleomorphism, and dense eosinophilic stromal infiltrate [Figure 2b]. The tumour cells were immunopositive for CD1a, Langerin, and CD163 and immunonegative for BRAFV600E [Figure 3a and 3b]. The features were consistent with Langerhans cell histiocytosis (LCH). Magnetic resonance imaging (MRI) and computed tomography (CT) revealed multiple expansile lytic lesions with peripheral soft tissue extension in the skull, vertebrae, ribs, pubic bone, and mandible [Figure 3c]. Aspirate from a small paravertebral collection also showed a mixed cell inflammatory infiltrate and a few Langerhans cells. Acid-fast bacilli (AFB) stain and Xpert MTB/RIF (Mycobacterium tuberculosis/ Rifampicin resistance) assay (Cephid) were negative from the aspirate. He was also diagnosed with diabetes insipidus. Recognising the coexistence of both Langerhans and NLCH, a final diagnosis of mixed histiocytosis was made, a rare but known entity. Due to multisystem involvement, he was referred to medical oncology, where he was started on chemotherapy (prednisolone + vinblastine).

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Figure 1:

Smooth barely elevated yellowish- brown papules over cheeks, skin-coloured papules over lower eyelid margins leading to a beaded appearance.

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Figure 2a:

Biopsy from xanthomatous papules showing dense dermal infiltrates of lymphocytes, histiocytes, neutrophils, eosinophils, Touton giant cells (arrow), and plasma cells consistent with non-Langerhans cell histiocytosis (Haematoxylin and eosin, 40x).

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Figure 2b:

Biopsy left mandible showing sheets and clusters of pale staining histiocytes. The background shows numerous eosionophils. (Haematoxylin and eosin, 40x)

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Figure 3a:

Immunohistochemistry of bone biopsy showing tumour cells positive for CD1a (IHC, 40x).

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Figure 3b:

Immunohistochemistry of bone biopsy showing tumour cells positive for Langerin (IHC, 40x).

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Figure 3c:

Lytic expansile lesion in the left mandible on MRI.

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LCH is rare in adults, with an incidence of 1-2 per million.¹ Skeletal lesions of LCH usually affect the skull, femur, mandible, pelvis, and spine. Spinal involvement is observed in 6.5% to 25% of cases. Spinal LCH is often initially misdiagnosed as Pott’s spine, as in our patient.² Our patient was provisionally suspected to have Erdheim-Chester disease, an aggressive variant of NLCH, to explain the bony and pituitary involvement. Mixed histiocytosis is a rare occurrence, with ECD-LCH being the most reported phenotype in 10-15% of ECD patients. In a systematic review of 105 mixed histiocytosis cases by Arturo Bonometti, the most frequent NLCH diagnosis was ECD (60%), followed by xanthogranuloma and Rosai Dorfman disease (19% each).³ Most patients had multisystem involvement, including the bone, skin, and central nervous system. They can present with neurological symptoms or isolated diabetes insipidus, like in our patient. Skin lesions vary from xanthelasma-like lesions to erythematous papules and patches. Other features include lung involvement and association with haematologic diseases. BRAFV600E mutation is more common in ECD-LCH overlap than ECD alone, making targeted treatment with BRAF (v-Raf murine sarcoma viral oncogene homolog B) and/or MEK (mitogen-activated extracellular kinase) inhibitors a better therapeutic option than conventional chemotherapy for these patients.¹ Our patient lacked the BRAF mutation, hence was treated with a conventional chemotherapy regimen. Median age at presentation for mixed histiocytosis is 40 years, and no significant difference in survival has been reported between patients with ECD alone and those with ECD-LCH overlap, with a 5-year mortality around 35%. Older age, coexisting haematologic conditions, and treatment failure predict a poor prognosis; while lytic bone lesions, as in our case, indicate a better outcome.¹

This case was particularly intriguing, as skin involvement in the form of a few xanthogranulomas, albeit mild, led to the final diagnosis of mixed histiocytosis, a rare entity. In a systematic review of 105 cases of mixed histiocytosis, bone and skin involvement (63% and 53% respectively) were the most reported, with both osteolytic and osteosclerotic bony lesions observed. Diabetes insipidus, noted in our case, was a recurring manifestation in 35.2% of patients in the review. Although the BRAFV600E mutation was present in 70% of the tested patients, our patient tested negative.³ In this patient, spinal involvement by LCH mimicked Pott’s spine, leading to three years of anti-tubercular therapy and surgical intervention. Raising awareness about such atypical presentations of adult-onset LCH is crucial to avoid delays in diagnosis and treatment. In cases of mixed histiocytosis, bony lesions may result from LCH, non-LCH, or a combination of both, which can even coexist in the same biopsy. Therefore, a bone biopsy is essential to identify the underlying cause of bony involvement.