A 28-year-old man presented with insidious onset of intense right shoulder pain of one month's duration.
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Figure 1: Plain AP radiograph of the right shoulder.
Figure 2: Tc99 bone scan.
Figure 3: Axial T1-weighted MRI of the right shoulder.
Figure 4: Axial T2-weighted MRI of the right shoulder.
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Answer to Radiologic Case Study
Langerhans Cell Histiocytosis
A 28-year-old man presented several times to the emergency department with intense pain in his right shoulder that worsened during night, affecting his sleep. Initially, his symptoms were unexplained and no simple shoulder radiographs or other examinations were performed. Each time, the patient was discharged after an intramuscular injection of a strong opioid analgesic. One month after the initiation of the symptoms, radiographic examination of the right shoulder revealed a small lytic area in the scapula, just behind the scapular neck (Figure 1). Palpation of the posterior shoulder at this level was extremely painful.
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Figure 1: A lytic area (*) in the scapula is shown on a plain AP radiograph of the right shoulder. Figure 2: Tc99 bone scan reveals increased uptake of the radionuclide in the scapular neck posteriorly. Figure 3: Axial T1-weighted MRI shows the bone lesion and the cortical lysis in the scapular neck. Figure 4: Axial T2-weighted MRI demonstrates the bone marrow edema and the expansion of the lesion beyond the bone, in the borders of infraspinatus muscle.
A Tc99 bone scan revealed increased concentration of the radionuclide in the affected area of the right scapula (Figure 2) and magnetic resonance imaging (MRI) showed cortical lysis, and bone marrow edema that extended beyond the bony scapula posteriorly into the infraspinatus muscle (Figures 3-6).
Peripheral blood testing was negative (normal blood cell count, normal erythrocyte sedimentation rate [ESR], no shift on the protein electrophoresis diagram, normal calcium and parathyroid hormone) as was urine examination (no Bence Jones proteins, etc). Echo of the abdomen demonstrated splenomegaly (14 cm). An open biopsy was performed under general anesthesia with intralesional removal of the pathologic tissue from the bone and muscular tissue. The histological examination of the sample tissue from the biopsy established the diagnosis of Langerhans cell histiocytosis. The patient was referred to the hematology department for further evaluation.
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Figure 5: Sagittal oblique T1-weighted MRI. Figure 6: Sagittal oblique T2-weighted MRI. Both figures illustrate similarly as figures 3 and 4 the lesion in the scapula.
Langerhans cell histiocytosis, previously named histiocytosis X, refers to a group of disorders with a wide spectrum of clinical manifestations, characterized by the proliferation and tissue infiltration of specific, bone marrow-derived, dendritic (Langerhans) cells. Langerhans cell histiocytosis includes diseases that formerly had been described as disparate diagnoses: eosinophilic granuloma, Letterer-Siwe disease, Hand-Schuller-Christian syndrome, and Hashimoto-Pritzker disease and has varying clinical picture; treatment approaches; and prognosis.1 The function of Langerhans cells led some authors to believe that an immune dysfunction is responsible for the disease. In fact the pathogenesis and etiology remains unknown and enigmatic. Langerhans cell histiocytosis is classified as a reactive disorder or neoplastic process or a clonal proliferative disorder. Recently a viral infection has been suggested as a possible inciting agent but without evidenced confirmation.2
Langerhans cell histiocytosis is a rare disease with an estimated annual incidence ranging from 2 to 5 cases per million people per year and a higher incidence in men.3 It affects predominantly children and infants, with more than 50% of cases diagnosed between the ages of 1 and 15, but occasionally occurs in adulthood.4
The clinical presentation of Langerhans cell histiocytosis depends on the tissue and system involved, such as bone, lungs, pituitary gland, skin/mucous membrane, lymph nodes, liver, spleen, or bone marrow.
Bone lesion is the most common manifestation of Langerhans cell histiocytosis and may be solitary (more frequently) or multiple, involving any bone, with the skull being the most common site, followed by the long bones of lower extremities, ribs, pelvis, vertebra, and mandible.2 The scapula is a rare location of Langerhans cell histiocytosis H. Patients usually are asymptomatic for a long time from the onset of the disease but pain with or without adjacent soft tissue swelling and localized tenderness may occur with the progress of the disorder and bone erosion. These lesions are lytic and mainly are found in older children and young adults. Additional symptoms are correlated with the bone involved. Skull lesions can be associated with neurologic manifestations, mandible lesions with loose teeth, while destruction of the temporal, the mastoid process or orbital wall can cause otitis media, mastoiditis or proptosis respectively. Osteolytic lesions of the long bones predispose them to pathologic fractures; however, this is rare. In the spine, the lytic process may result in vertebral body compression and collapse (vertebra plana). The flat bones are affected more often in patients aged >20 years, while in younger patients any bone may be affected.2,4,5
Skin is a frequent location of Langerhans cell histiocytosis and often the cutaneous lesions are the first sign of the disease. The clinical picture varies; usually it is about a seborrhea-like brown to red papule with vesiculation and superficial ulceration. Sometimes this is the sole manifestation of the disease (usually jn infants) and may regress spontaneously.2,5
Hepatosplenomegaly in the patient suffering from Langerhans cell histiocytosis may indicate these organs are affected by the disease, but the enlarged nodes in the porta hepaticus or Kupffer cell hypertrophy could be the cause.
Lymph nodes involvement in Langerhans cell histiocytosis may occur in 3 variants: unifocal; lesion, accompanying bone; or cutaneous lesions or part of the disseminated disease.
Lungs may be affected either as part of a systematic Langerhans cell histiocytosis or as a solitary pulmonary Langerhans cell histiocytosis (mainly in adult smokers). Patients may be asymptomatic according to plain radiographs, or they may present with cough, dyspnea, tachypnea, pneumothorax.2
Diabetes insipidous is the most significant endocrinopathy and develops more often in patients with bone disease localized on the skull.
Central nervous system and gastrointestinal tract also may be involved but acute signs of these systems are rare and often are underestimated.5
After a thorough initial clinical assessment of symptoms and signs, a baseline diagnostic evaluation follows. This includes complete blood cell count, reticulocyte count, ESR, direct and indirect Coombs levels, immunoglubin levels and coagulation tests. If anemia, leukopenia, or thrombocytopenia are noted, a bone marrow aspiration is required. Liver function tests also are performed and if abnormal a biopsy should be performed to exclude cirrhosis. Moreover urine osmolarity measuring after overnight water deprivation is useful to detect a diabetes insipidous.
Plain radiographs are the mainstay in initial assessment of bone lesions of Langerhans cell histiocytosis, whose appearance may be variable. When first seen, a permeative pattern of destruction with poorly defined margins may be found and mimic the radiographic appearance of infection or sarcoma (Ewing or osteosarcoma).5 Later in the progress of the disease healing may occur giving a radiographic image of trabeculation of lytic areas and sclerosis. Specifically, skull lesions (developed in the diploic space) appear as lytic with sharp borders and a punched-out appearance; occasionally a residual bone fragment, referred as button sequestrum, can be found, resembling osteomyelitis. In long bones, lesions (usually diaphyseal) are lytic, with ill-defined or sclerotic margins, endosteal scalloping, cortical thinning and erosion, intracortical tunnelling and medullary cavity expansion. In the spine, where involvement of the vertebra body is mainly found, the common finding is a vertebra plana.5-7
Following identification of a bone lesion on plain radiographs, further evaluation of the whole skeleton is indicated. Different authors have suggested either conventional skeletal survey or scintigraphy as being superior in the primary detection of bone lesions, with a variety of rates for false-positive and false-negative results for both investigations. Substantially, the two modalities are complementary and have a significant role for the initial assessment of bone Langerhans cell histiocytosis, while either can be used for follow-up.6,8,9
Computed tomography (CT) scans help with demonstrating the extension of cortical destruction and may be particularly useful in osseous lesions in areas with complex anatomy, such as the mastoids, temporal bones, pelvis, and spine.6
Magnetic resonance imaging is helpful in depicting bone marrow edema and surrounding soft tissue structures. Osseous lesions of Langerhans cell histiocytosis demonstrate decreased signal intensity on T1-weighted and hyperintense signal on T2-weighted and STIR sequences. The lesion may enhance after the administration of gadolinium. Despite its high sensitivity, MRI findings are not specific, often leading to an overestimation of the lesion appearance, and overlapping with both infection and malignancy.5,6
Both CT and MRI have a role when following lesions that are in the healing process, when planning radiation therapy, and for the purpose of biopsy localization.
Computed tomography, MRI, and radionuclide study are complementary examinations to plain radiographs, all of them being important for the diagnosis and follow-up of Langerhans cell histiocytosis bone lesions; however, a histopathologic confirmation is still needed.
Diagnosis requires confirmation by biopsy of the involved tissue/system, to identify the pathologic Langerhans cells. These cells, with conventional histological techniques, present a moderate amount of homogenous, pink, granular cytoplasm and distinct cell margins.2 Variable numbers of eosinophils, osteoclast-like giant histocytes, T lymphocytes and macrophages often are found (Figure 7).
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Figure 7: Large cells with irregular nuclei and abundant pink cytoplasm, and giant multinucleated cells infiltrated by numerous eosinophils and lymphocytes (hematoxylin-eosin, original magnification ×200 ). Figure 8: Positivity of large cells in CD1a immunohistochemical staining (original magnification ×200). Figure 9: Positive S-100 immunohistochemistry (original magnification ×400 ).
Because these morphological characteristics are not distinct, special electron microscopy and immunohistochemical studies may be necessary. Demonstration by electron microscopy of rod-shaped or tennis racket-shaped Birbeck granules in the cytoplasma of Langerhans cells remains the gold standard for identifying these cells. Moreover, Langerhans cells express a variety of surface antigens. The positivity of CD1a, S-100 protein and Langerin/CD207 in immunohistochemical stains as well as the idendification of Birbeck granules (in electron microscopy) are the most useful markers for Langerhans cells10 (Figures 8 and 9).
Based on clinical criteria, histopathology, and immunohistochemical techniques, The Histiocyte Society has published confidence levels for the diagnosis of Langerhans cell histiocytosis. To make a definitive diagnosis, identification of Birbeck granules and/or CD1a antigens is required. A designated diagnosis includes light morphologic features in combination with positive S-100 and peanut agglutinin stains. When only light morphologic characteristics are present, a presumptive diagnosis is set.1,10
Treatment and Prognosis
Solitary bone lesions in patients with Langerhans cell histiocytosis may be asymptomatic and tend to resolve spontaneously over a period of months or years. The current consensus favors minimal treatment, involving only biopsy (necessary to confirm the diagnosis) and surgical curettage, when the lesion is readily accessible; this procedure may initiate healing. In case of intense pain, unacceptable deformity, or high potential for fracture, additional treatment should be considered. Local radiation therapy in low doses, alone or after surgical excision, also has been used for unifocal bone Langerhans cell histiocytosis with good results, usually when other treatment modalities have failed. Alternatively local injection of corticosteroids has been reported to relieve pain and accelerate healing.2,4,6
Multifocal bone lesions or recurrence can be treated with curettage, corticosteroids infiltration, or observation only as spontaneous healing often occurs. Occasionally chemotherapy can be used.6
Disseminated Langerhans cell histiocytosis is treated with a variety of systemic chemotherapeutic agents, most commonly vinblastin with or without corticosteroids.
Langerhans cell histiocytosis is essentially a benign, often self-limited disease and patients with unifocal bone lesions generally have an excellent prognosis.7 Prognosis for the extensive type of Langerhans cell histiocytosis depends on the initial clinical picture, the age of onset and the progression rate of the disease. Poor prognostic factors, associated with increased morbidity and mortality, are considered the dysfunction of critical organs rather than their involvement, and age <2 years at presentation.11
- Writing Group of the Histiocyte Society (Chu T, DAngio GJ, Favara B, Ladisch S, Nesbit M, Pritchard J). Histiocytosis syndromes in children. Lancet. 1987; 1:208-209.
- Egeler RM, DAngio GJ. Langerhans cell histiocytosis. J Pediatr. 1995; 127:1-11.
- Raney RB, DAngio GJ. Langerhans cell histiocytosis (histiocytosis X): experience at the Childrens Hospital of Philadelphia, 1970-1984. Med Pediatr Oncol. 1989; 17:20-28.
- Howarth DM, Gilchrist GS, Mullan BP, et al. Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. Cancer. 1999; 85:2278-2290.
- Kilborn TN, Teh J, Goodman TR. Paediatric Manifestations of Langerhans Cell Histiocytosis: a Review of the Clinical and Radiological Findings. Clin Radiol. 2003; 58:269-278.
- Azouz EM, Saigal G, Rodriguez MM, Podda A. Langerhans cell histiocytosis: pathology, imaging and treatment of skeletal involvement. Pediatr Radiol. 2005; 35:103-115.
- Meyer JS, Harty MP, Mahboubi S. Langerhans cell histiocytosis: presentation and evolution of radiologic findings with clinical correlation. Radiographics. 1995; 15:1135-1146.
- Van Nieuwenhuyse JP, Clapuyt P, Malghem J, et al. Radiographic skeletal survey and radionuclide bone scan in Langerhans cell histiocytosis of bone. Pediatr Radiol. 1996; 26:734-738.
- Dogan AS, Conway JJ, Miller JH, Grier D, Bhattathiry MM, Mitchell CS. Detection of bone lesions in Langerhans cell histiocytosis: complementary roles of scintigraphy and conventional radiography. J Pediatr Hematol Oncol. 1996; 18:51-58.
- Favara BE, Feller AC, Pauli M, et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol. 1997; 29:157-166
- Egeler RM, Nesbit ME Jr. Langerhans cell histiocytosis and other disorders of monocyte-histiocyte lineage. Crit Rev Oncol Hematol. 1995; 18:9-35.
Drs Kontakis, Christoforakis, and Katonis are from the Department of Orthopedics and Traumatology, University of Crete, Greece.
Correspondence should be addressed to: George M. Kontakis, MD, 1 Pindarou Str, 71305 Heraklion, Crete, Greece.