FINAL DIAGNOSIS: ADULT LANGERHANS CELL HISTIOCYTOSIS
Langerhans Cell Histiocytosis (LCH) is a non-neoplastic proliferation of Langerhans cells with variable clinical course. In 1868 Paul Langerhans decided to use gold chloride techniques to stain skin tissue and discovered "non-pigmentary dendritic cells" in the epidermis that he regarded as intraepidermal receptors for extracutaneous signals of the nervous system. He reported his findings in a paper entitled "On the nerves of the human skin" 1, 6. One century later, Birbeck described the pentalaminar cross-striated granules known as "Birbeck-granules" 1, 5. LCH is characterized by a proliferation of CD1a+ dendritic cells, but the etiology remains unknown. In selected cases, EBV has been described as the trigger and smoking has been associated with isolated pulmonary LCH.
The incidence of LCH in adults is approximately 1-2 cases per million, with a mean age of diagnosis 35+/- 14 years 1. LCH is regarded as a pediatric disease, but as many as 30% of cases can present in adults 2. The presenting symptoms depend on the organ involvement. Local pain is the most common symptom (34%), followed by weight loss (11%) and fever (10%) 1, 3. Bone lesions are most often seen in the axial skeleton as skull (51%), the jaw (30%) and patients might present with complaints of loosing their teeth 1. If the lesion is in the appendicular skeleton; is more likely to be in long bones, but still long tubular bones (17%), vertebrae (13%), pelvis (13%) and ribs (6%) are less frequently seen. One study of 211 adult patients and 330 pediatric patients with LCH showed that rib involvement was present in 25% of adults compared to 8% of children. In this same study, the most common radiographic feature was cortical destruction in 50% of pediatric and 53% of adult cases 2. The WHO of Tumors of Soft Tissue and Bones 4 states "In adults, the rib is the most frequent site of involvement". Pituitary gland involvement leads to diabetes insipidus, and patients can present with polyuria and polydipsia. Skin manifestations were the second most common form of extraskeletal LCH in one study with eczema, seborrhea-like rash, "hemorrhagic macular rash" (these patients had also thrombocytopenia), ulcers in female genitalia and perianal regions 5. Pulmonary involvement can be isolated or systemic, presenting with cough, dyspnea and chest pain. Pulmonary LCH has been associated with increase risk for carcinomas and associated with lymphomas 1.
The clinical classification of LCH includes a localized (single-system disease) and disseminated (multi-system disease) forms 1, 5. Twenty to thirty percent of adult patients with LCH present with isolated pulmonary involvement. Another classification includes three different clinical entities which affect mostly children 3 - 5:
The diagnosis of LCH is done by biopsy of the organ lesions, most commonly of bone, lungs and skin 1. Histologic features show a destructive lesion composed of clusters, loose meshwork and/or dispersed mononuclear cells with indented nuclei sharing morphology of Langerhans cells. The lesion is infiltrated by aggregates of lymphocytes and large number of eosinophils, which classically form pseudoabscesses. Mitotic activity is variable and it can be as high as 10 mitoses per 10 HPF, but no atypical forms should be present. Destruction of bony trabeculae with trapped lamellar bone is seen in approximately 29% of cases. Necrotic bony trabeculae are uncommon and usually are associated with tumor necrosis. The histologic differential diagnosis of LCH involving bone includes malignant lymphoma, osteomyelitis, and sinus histiocytosis with massive lymphadenopahty (Rosai-Dorfman Disease) 5. Perhaps the most challenging one is differential with osteomyelitis and some believe the entrapped bony trabeculae on LCH can help in the distinction, but others have seen entrapped necrotic bone in osteomyelitis. LCH requires demonstration by immunohistochemistry of CD1a antigen. They are also positive with S100, CD31, CD68, PLAP (placental alkaline phosphatase) 1, 4, 5. Careful interpretation of S100 and CD1a is needed, since cells derived in peripheral blood, paracortical reticulum interdigitating cells, and activated macrophages can also be positive for these markers 5.
The minimum workup for staging of patients with LCH includes a bone scan, skeletal X-ray of bone lesions, a chest X-ray and abdominal ultrasound 1, 5. Extensive work-up should exclude silent locations before categorizing the patient as isolated lung LCH 1.
The treatment for adult LCH cases depends on organ involvement and clinical course. The options include watchful waiting, local treatment, immunomodulation, irradiation, chemotherapy and liver, lung allogeneic stem cell transplantation in advance disease stages 1. When pain relief is the main concern, the procedure of transcutaneous fluoroscopic guided biopsy and corticosteroid injection allows combined diagnosis and treatment 2-3. Patients with limited disease have excellent prognosis. In contrast, multifocal involvement needs systemic therapy and has a worse prognosis. Counseling on smoking cessation is crucial. Most patients have good prognosis with an indolent course but may progress to end-stage pulmonary fibrosis and honeycomb lung 1, 2.
Contributed by Rosemary Recavarren, MD and Roy A. Frye, MD, PhD