Letterer-siwe disease presenting as a retro auricular swelling-a diagnostic dilemma

Abstract

Langerhans cell histiocytosis (LCH) is a rare disorder involving clonal proliferation of cells in mononuclear phagocyte system. Clinical forms of LCH are Letterer-Siwe disease, Hand-Schuller-Christian disease, eosinophilic granuloma. LCH involves skeleton in 80% of cases. One and half year old male child presented with a left retroauricular swelling 2 × 3 cm in size for 2 months and intermittent fever for 15 days. FNAC and excisional biopsy showed admixture of Langerhans cells. Immunohistochemistry showed CD1a-positive Langerhans cells. MRI of brain was suggestive of bi-temporal mastoid osteolytic lesion. Final diagnosis was acute disseminated form of LCH-Letterer-Siwe disease. Child was treated with chemoradiotherapy and followed up for 8 months.

Keywords: Langerhans cell histiocytosis, Hand-Schuller-Christian disease, eosinophilic granuloma, CD1a-positive

Introduction

Histiocytic disorder constitute heterogeneous group of disease characterized by accumulation of reactive or neoplastic histiocytes in various tissues. The disease spectrum results from clonal accumulation and proliferation of cells resembling the epidermal dendritic cells called “Langerhans cells”, hence it is sometimes called “Dendritic cell histiocytosis”. Langerhans cell histiocytosis (LCH) is clinically divided into unifocal, multifocal unisystem, multifocal multisystem. Three basic clinical forms of LCH are Letterer-Siwe disease (acute or subacute disseminated form), Hand-Schuller-Christian disease (disseminated chronic form) and eosinophilic granuloma (localized chronic form). These all are characterized by accumulation of proliferating Langerhans cells, which have surface markers and ultrastructural features similar to cutaneous Langerhans cells and variably admixed with eosinophils. LCH usually affects children between 1 and 15 years old, peak incidence is between 5 and 10 years of age. Incidence of children less than 10 years is 1 in 2,00,000. It is most prevalent in Caucasians, and affects males twice as often as females. LCH is usually a sporadic and nonhereditary condition but familial in limited cases.

Case Report

A 1½-year-old male child weighing 10 kg product of nonconsanguineous marriage, born after a full-term normal vaginal delivery with a birth weight of 2.8 kg, was referred to our institute with chief complaint of retroauricular swelling for 2 months and fever for 15 days. The child was apparently normal 2 months back, when he developed a left retroauricular swelling which gradually increased in size not associated with any ear discharge, or pain or itching, followed by the child developing fever, intermittent in nature, ranging from 99 to 101°F not associated with chills and rigor. The child was misdiagnosed outside as a lymph node swelling due to some infective etiology and treated with oral antibiotics for 5 days before he reported to our hospital. 

Distension of abdomen started along with fever and this increased gradually. Urine frequency was normal. Appetite decreased over a period of 2 months. On examination, he was conscious, irritable, febrile (100 °F) and respiratory rate was 28/min, regular. Pulse was 110/min, regular, normovolumic, all peripheral pulses palpable with blood pressure 90/54 mmHg in right upper arm in supine position. Bilateral anterior cervical and postauricular lymph nodes were palpable. There was no cyanosis, edema and jugular venous pressure was not raised. On local examination, the swelling was 2.5 × 3 cm in size, soft, nontender, nonfluctuant, mobile with normal overlying skin and no punctum. A healed lesion was present over the parietal region of left scalp. No other punctum or abnormal bony prominence, rash, seborrheic areas were present over scalp. Abdominal examinations revealed hepatomegaly (liver span of 12 cm).

Liver was firm with smooth margin and nontender. Spleen was enlarged 4 cm below left costal margin and firm. Shifting dullness and fluid thrill were absent. Normal bowel sounds were heard. All other systems revealed no clinical abnormality. Fundoscopy was within normal limits.

Diagnostic Work-up

Complete blood cell (CBC) examination revealed hemoglobin - 10.3 g/dL, total leukocyte count (TLC) - 12,200/mm3, TPC - 5.42 lacs/mm3, absolute eosinophil count - 440/mm3, erythrocyte sedimentation rate (ESR) - 38 mm/1st hour (modified Westergren method), peripheral smear examination revealed microcytic hypochromic blood picture. No hemoparasites were found. Liver function tests (LFTs) showed serum bilirubin total 0.3 mg/dL, direct 0.2 mg/dL with mild raised serum glutamic-oxaloacetic transaminase (SGOT) - 61 U/L, serum glutamic-pyruvic transaminase (SGPT) - 72 U/L and alkaline phosphatase (ALP) - 371 U/L. Urine examination revealed trace albumin, 20-25 pus cells, 2-3 epithelial cells; bacterial content was present. Urine culture revealed insignificant bacteriurea. Stool examination revealed normal finding. 

A thorough radiological evaluation was performed. Digital X-ray of skull revealed multiple osteolytic lesions. Ultrasonography (USG) of whole abdomen and pelvis showed hepatomegaly (liver span 12.6 cm) with irregular multiple hypoechoic distal shadowing lesions in both lobes, coarse echo-texture with periportal cuffing, intrahepatic biliary radicals showed diffuse irregular thickening of walls, enlarged spleen.

MRI of brain revealed bi-temporal mastoid osteolytic lesions with soft tissue mass extending to both labyrinths with involvement of both middle ears and both ossicular chains, tegmen were tympani eroded but no obvious extracranial extension feature suggestive of LCH. Magnetic resonance cholangiopancreatography (MRCP) (3D) showed hepatomegaly with periportal infiltrates. Dilated proximal and peripheral segmental intrahepatic biliary radicles with intraluminal sludge/infiltrates suggestive of hepatic involvement in LCH were seen. Fine-needle aspiration cytology (FNAC) of the retroauricular swelling showed high cellularity, numerous large histiocytes, multinucleated giant cell and inflammatory cells. Histiocytes were large, vesicular, folded/indented nuclei having prominent nucleoli. Among inflammatory cells predominant eosinophils, many binucleated and multinucleated cells seen scattered among histiocytes. Cytomorphological feature suggestive of eosinophilic granuloma was made as a presumptive diagnosis. An excisional biopsy from retroauricular swelling revealed a cellular lesion with polymorphic appearance having few lymphoid follicles with variable areas of fibrosis. Mixture of Langerhans cells, histiocytes, lymphocytes and eosinophils with few plasma cells and neutrophils, numerous multinucleate giant cells were found. Predominantly Langerhans cells having eosinophilic cytoplasm and elongated nuclei in lobulated pattern were demarcated. Immunohistochemically, the Langerhans cell were CD1a-positive; hence, a final diagnosis of LCH was made. Bone-marrow aspiration from right posterior superior iliac spine showed normal hematopoiesis, mild eosinophilia (eosinophils and metamyelocytes together constitutes 16% of marrow nucleated cells), M:E - 6:1 without any neoplastic Langerhans cells.

Treatment

For localized disease or single bony lesion-curettage, bisphosphonate, low dose local radiation therapy. Multisystem disease is treated with chemotherapy, combining vinblastine, prednisolone, 6- mercaptopurine. Children are treated for total duration of 12 months.

From all above findings, a final diagnosis of acute disseminated form of LCH-Letterer-Siwe disease was made. It has been categorized into high-risk group as there was multiple systemic involvement of bone, lymph node and liver. The patient was on treatment with chemotherapy with prednisolone 40 mg/m2/day × 5 days, 3 weeks cycle: 6-mercaptopurine 50 mg/m2/day × 12 months, vinblastine 6 mg/m2 × 3 weeks and methotrexate 20 mg/m2 orally weekly × 12 months. He was followed up for 8 months without any disease progression except for nonhealing ulcer over the biopsy site of left retroauricular area.

Discussion

Childhood histiocytosis is a diverse group of disorders, which through rare but may be severe in their clinical expression. Generic term “histiocyte” refers to several types of cells and these cells have an important role in the immune system acting as scavengers and most importantly Langerhans cells act as antigen presenting cells. Alfred Hand was the first to report a case of histiocytosis in 1893. In 1941, Farber described his condition when reporting the overlap among diseases that would later be termed “histiocytosis X” by Lichtenstein in 1953. Letterer-Siwe syndrome was used to describe an acute disseminated multisystem disease process of the reticuloendothelial system that typically affected children younger than 3 years of age. International Histiocyte Society in 1987 established a classification of histiocytoses into three groups: (1) LCH; (2) histiocytoses of mononuclear phagocytes other than Langerhans cell and (3) malignant histiocytic disorders. But such classification is not recommended by the World Health Organization (WHO).

LCH is a rare nonmalignant disease characterized by clonal proliferation of pathologic cells with characteristics of Langerhans cells in single/multiple sites and an unpredictable course. It is a sporadic and nonhereditary condition. The clinical presentation is heterogeneous, ranging from single system to multisystem involvement. Hallmark of LCH in all forms of disease is characteristic electron microscopic finding of Langerhans cells. Birbeck granule, a tennis racket shaped bi-lamellar granule, when seen in the cytoplasm of lesional cells in LCH is diagnostic of the disease. Birbeck granules express CD-207. Definitive diagnosis of LCH can be established by demonstrating CD1a-positivity of lesional cells. The lesion may contain Langerhans granule containing cells, lymphocytes, granulocytes, monocytes and eosinophils.

Pathogenesis is not well-established. Langerhans cells are thought to arise from epidermal Langerhans cells in response to some external hyperinflammatory stimulus or cell autonomous stimulus or as a result of activation of a cell autonomous genetic event. These activated Langerhans cells undergo transcriptional reprogramming which subsequently causes epithelial-mesenchymal cell transformation (EMT). Activation and EMT are necessary for the spread and invasion of these cells to the particular site. Accumulation of Langerhans cells along with other inflammatory cells create cytokine cascade through autocrine and paracrine amplification of cell signals resulting in development of LCH through recruitment, maturation and proliferation of Langerhans cells.

The clinical course of LCH varies depending on the extent and number of organs involved as well as the age of the patient at the time of the diagnosis. Most common involvement is of skeleton (80%). Bony lesions can be single or multiple affecting skull bones, long bones, vertebrae, mastoid and mandibles. Lesions may be painless or present with pain and local swelling. In flat and long bones, osteolytic lesions with sharp borders and no evidence of reactive new bone formation are seen until the lesions begin to heal. Vertebral collapse, spinal cord compression, pathological fracture, chronically draining infected ear are the common clinical manifestations. Free floating teeth due to destruction in mandible and maxilla appear on radiograph. Skin involvement occurs in 50% of cases leading to scaly, papular, seborrheic dermatitis of scalp, axilla, posterior auricular, diaper region and sometimes involves back, palm and soles. Localized or disseminated lymphadenopathy is found in approximately 33% of cases. 

Hepatosplenomegaly occurs in 20% of cases. Liver involvement may lead to sclerosing cholangitis and cirrhosis. Otitis media is present in 30-40% of patients, deafness may follow destructive lesion of the middle ear. Pulmonary infiltrates are found on radiograph in 10-15% cases. The lesions may range from diffuse fibrosis and disseminated nodular infiltrates to diffuse cystic changes. Bilateral involvement of retro-orbital area may lead to exophthalmos. Bone-marrow involvement leads to anemia and thrombocytopenia. Pituitary and hypothalamic involvement leads to growth retardation, diabetes insipidus and panhypopituitarism. Central nervous system manifestation may be ataxia, dysarthria and other neurological symptoms. Systemic manifestations are fever, weight loss, malaise, irritability and failure to thrive.

Conclusion 

Langerhans cell histiocytosis has diverse spectrum of clinical manifestations. A differential diagnosis of LCH in pediatric age group when the child presents with lymph node swelling hepatosplenomegaly should not be neglected from the beginning. The prognosis depends chiefly upon the involvement of multiple organ system, organ dysfunction and the patients response to chemotherapy during the initial 6 weeks of treatment. Even after getting therapy for more than 8 months our patient was still surviving but not in remission phase. In view of bad prognosis of Letterer-Siwe disease, an early diagnosis by fine-needle aspiration biopsy with a thorough radiological investigation should be emphasized. Clinicians should have an eagle’s eye vision to differentiate a benign and an extremely rare but emergency situation. 

Suggested Reading

1. Hoover KB, Rosenthal DI, Mankin H. Langerhans cell histiocytosis. Skeletal Radiol. 2007;36(2):95-104.
2. Chevrant-Breton J, Jambon N, Danrigal A, Kernec J, de Labarthe B, Ferrand B. Letterer-Siwe’s disease in the adult: a report of two cases. Ann DermatolVenereol. 1978;105(3):309-11.
3. Stefanato CM, Andersen WK, Calonje E, Swain FA, Borghi S, Massone L, et al. Langerhans cell histiocytosis in the elderly: a report of three cases. J Am AcadDermatol. 1998;39(2 Pt 2):375-8.
4. Chevrant-Breton J. Adult Letterer-Siwe’s disease: review of literature. Ann DermatolVenereol. 1978;105:301-5.
5. Vollum DI. Letterer-Siwe disease in the adult. ClinExpDermatol. 1979;4(4):395-406.