Imaging in Eosinophilic Granuloma of the Skeleton 

Updated: Jun 14, 2018
  • Author: Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR; Chief Editor: Felix S Chew, MD, MBA, MEd  more...
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Practice Essentials

Eosinophilic granuloma (EG) is a rare, benign tumorlike disorder characterized by clonal proliferation of antigen-presenting mononuclear cells of dendritic origin known as Langerhans cells. It is the most common variant of Langerhans-cell histiocytosis (LCH). Any organ or system of the human body can be affected, but 80% of cases are skeletal and account for less than 1% of all bone tumors. [1]   Children between 1 and 15 years of age make up more than 50% of cases of LCH, with peak incidence in children younger than 3 years. [2]   

Eosinophilic granuloma is characterized by single or multiple skeletal lesions, but solitary lesions are more common than multiple lones. When multiple lesions occur, the new osseous lesions appear within 1-2 years, and the condition is still classified as eosinophilic granuloma. Any bone can be involved; the more common sites include the skull, mandible, spine, ribs, and long bones (see the images below). [3, 4, 5] Pathologic fractures may ensue. [3, 6, 7]  

The other two variants of LCH, Letterer-Siwe disease and Hand-Schuller-Christian disease, are multisystem syndromes, with the manifestations ranging from isolated bone lesions to multisystem disease. [1]

Chest radiograph in a 30-year-old woman who presen Chest radiograph in a 30-year-old woman who presented with shortness of breath and a palpable swelling over the right parietal region. The radiograph shows an interstitial lung pattern with a honeycomb appearance in the upper zones (see the next image).
Lateral skull radiograph in a 30-year-old woman wi Lateral skull radiograph in a 30-year-old woman with shortness of breath and a palpable swelling over the right parietal region shows 2 purely lytic lesions in the frontoparietal region of the skull. The larger parietal lesion has beveled edges, suggestive of an eosinophilic granuloma. Biopsy results confirmed the diagnosis of eosinophilic granuloma.
Transaxial nonenhanced computed tomography scans o Transaxial nonenhanced computed tomography scans of the skull in a 28-year-old woman who presented with a palpable swelling over the calvarium. Scanogram of the patient's skull shows a geographic lytic lesion within the parieto-occipital region. Transaxial scan through the vertex, examined in a bone window, shows an expanding lytic lesion within the diploic space (see the next image).
Transaxial nonenhanced computed tomography scans t Transaxial nonenhanced computed tomography scans through the vertex in a 28-year-old woman with a palpable swelling over the calvarium, examined in a brain window. Images show destruction of both the outer and inner tables of skull; however, no brain involvement is noted.

Because patients with EG may present with multiple bone lesions at a single site (single-system multifocal bone), differentiation must be made from other variants of LCH with bone lesions affecting other organ systems (multisystem, including bone). [2]  Radiologists need to be aware that additional eosinophilic granuloma of bone, occurring as long as 4 years after initial diagnosis, should be interpreted as a localized form of LCH. This differentiation is important, because decreased mortality has been found in high-risk multisystem LCH patients who had bone involvement, suggesting that those with bone LCH may have more indolent disease. [8]

Lung involvement occurs in 20% of patients with eosinophilic granuloma and in an older group (age, 20-40 yr), with a strong association with smoking. Diffuse pulmonary infiltrates may be a manifestation of a covert osseous disease. In 50-75% of patients, the disease is monostotic. Skull involvement is seen in 50% of patients. [9] Rarely, the growing epiphysis is involved with eosinophilic granuloma; in most such cases, transphyseal extension can be demonstrated, both by the radiologic findings and by the histopathologic results. [10]

Eosinophilic granuloma may masquerade as an aggressive periodontitis [11] ; therefore, eosinophilic granuloma should be considered when an expanding lytic jaw lesion is encountered.

Preferred examination

A skeletal survey, skull series (or low-dose whole bone CT), and chest radiograph (AP and lateral) are the first radiographic examinations to be done. CT of specific areas of the skeleton are indicated when mastoid, orbital, scapular, vertebral, or pelvic lesions are found by plain radiographs. MRI may detect additional osseous or extraosseous lesions. A skeletal scintigram (bone scan) alone does not suffice. [12, 13, 14]

A wide variety of bone lesions may mimic eosinophilic granuloma; these include infections, traumatic lesions, and neoplasms. A false-negative diagnosis of eosinophilic granuloma is exceptional when plain radiographic findings are used, although difficulty may be encountered with lesions in areas with more complex anatomy, such as the posterior elements of the vertebral bodies. In these cases, conventional tomography or CT scanning may be useful. With radionuclide scanning, the false-negative rate is 30%.

Differential diagnosis

The differential diagnosis of eosinophilic granuloma includes aneurysmal bone cyst, bone infarct and bone metastases, thoracic eosinophilic granuloma, and fibrous dysplasia, as well as acute pyogenic, chronic, and variant osteosarcoma.

When the skull is involved, the following conditions should be considered: venous lake; meningocele, encephalocele, and cranium bifidum; arachnoid granulation; parietal foramen; epidermoid cyst; hemangioma; cholesteatoma; fibrous dysplasia; metastasis; surgical defect; and osteomyelitis.

The presence of vertebra plana should prompt consideration of causes such as fracture, hemangioma, osteomyelitis, metastasis, lymphoma, leukemia, plasmacytoma, chordoma, aneurysmal bone cyst, and Ewing sarcoma. Although eosinophilic granuloma is the most common cause of vertebra plana, it is distinguished by isolated spinal disease, the lack of constitutional symptoms, and minimal laboratory abnormalities. Cervical spine eosinophilic granuloma more often manifests with osteolytic lesions, rather than vertebra plana. [1]

When the long bones are affected, Ewing sarcoma, chronic osteomyelitis, Brodie abscess, and chondroblastoma should be considered.

Other interstitial lung diseases should be taken into consideration with pulmonary involvement.

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Radiography

Plain radiography remains the mainstay of diagnosis in patients with eosinophilic granuloma, although a specific diagnosis cannot always be made without bone biopsy, because children and adolescents are not spared skeletal neoplasms. In descending order of frequency, sites involved with monostotic osseous disease include the calvarium, mandible, ribs, long bones of the upper extremity, pelvis, and vertebrae (see the following images).

Chest radiograph in a 30-year-old woman who presen Chest radiograph in a 30-year-old woman who presented with shortness of breath and a palpable swelling over the right parietal region. The radiograph shows an interstitial lung pattern with a honeycomb appearance in the upper zones (see the next image).
Lateral skull radiograph in a 30-year-old woman wi Lateral skull radiograph in a 30-year-old woman with shortness of breath and a palpable swelling over the right parietal region shows 2 purely lytic lesions in the frontoparietal region of the skull. The larger parietal lesion has beveled edges, suggestive of an eosinophilic granuloma. Biopsy results confirmed the diagnosis of eosinophilic granuloma.
Anteroposterior radiograph of the mandible (left i Anteroposterior radiograph of the mandible (left image) in a 10-year-old boy who presented with swelling of the left mandible. A lytic expanding lesion is seen within the ramus of the left mandible. An oblique view of the mandible (right image) shows floating teeth within the lytic bone lesion (see the angiogram).
Plain radiograph of the pelvis in a 10-year-old gi Plain radiograph of the pelvis in a 10-year-old girl shows a lytic lesion of eosinophilic granuloma within the left ileum. Biopsy results confirmed the diagnosis of eosinophilic granuloma.
Chest radiograph in a 9-year-old boy who presented Chest radiograph in a 9-year-old boy who presented with mid dorsal pain. Note the collapsed vertebra and paraspinal soft-tissue mass.
Anteroposterior radiograph of the dorsal spine in Anteroposterior radiograph of the dorsal spine in a 9-year-old boy with mid dorsal pain. These results confirm the chest radiographic findings.

When tubular bones are involved in eosinophilic granuloma, diaphyseal and metaphyseal localization is more frequent than epiphyseal localization. Epiphyseal lesions may cross the open physeal plate.

The skull is affected in one half of patients, [5, 9] including the diploic space of the parietal and temporal bones. Skull lesions are lytic, with a beveled edge or sharp and serrated margins and the absence of sclerosis in calvarial lesions. A hole-within-a-hole appearance may occur as a result of uneven erosion of the inner and outer tables of the skull. In addition, sclerosis may occur around orbital lesions, and marginal sclerosis may occur during the healing phase in up to 50% of patients with a calvarial lesion. A button sequestrum is seen because a central bone opacity within a lytic lesion is an unusual presentation.

A soft-tissue mass may be obvious overlying the skull defect; this mass is often clinically palpable. A soft tissue mass is also occasionally seen with orbital lesions, with or without underlying bone erosion.

Mandibular lesions may be associated with gingival and soft-tissue swelling and floating teeth (see the image below).

Anteroposterior radiograph of the mandible (left i Anteroposterior radiograph of the mandible (left image) in a 10-year-old boy who presented with swelling of the left mandible. A lytic expanding lesion is seen within the ramus of the left mandible. An oblique view of the mandible (right image) shows floating teeth within the lytic bone lesion (see the angiogram).

The ribs show lytic expansile lesions, which may be associated with pathologic fractures. The scapulae and pelvis show destructive lesions; periosteal elevation is minimal, and some lesions show sclerotic margins, particularly lesions occurring in the supra-acetabular regions.

Long bones below the knees and distal to the elbows are rarely involved. Lesions are lytic, round or oval, and expansile, with ill-defined or sclerotic margins. The medullary cavity may be expanded and may be associated with cortical thinning, intracortical tunneling, and erosion of the cortex, as well as an adjacent soft-tissue mass. Laminated periosteal new bone formation is common around the involved segment of bone, but spread across growth plates is unusual. Tubular long bone lesions may appear rapidly over 3 weeks.

Vertebral destruction may lead to flattening of the vertebral body, which is termed vertebra plana, a finding that is much more common in children than in adults and that is more common in the dorsal spine. [15, 16, 17] An associated paraspinal mass may occasionally occur. Associated kyphosis has not been described, but scoliosis can occur. Eosinophilic granuloma can produce expansile lytic lesions of the vertebral bodies and the posterior vertebral elements. However, involvement of the second cervical vertebra is extremely rare; it may cause atlantoaxial instability. [18]

Lung involvement is seen in as many as 20% of patients and an older subset (ie, aged 20-40 yr), with an incidence of 0.05-0.50 per 100,000 patients annually. Plain radiographic findings may demonstrate an alveolar pattern in an early stage, which may be followed by nodular shadows (3-10 mm) and/or a reticulonodular pattern with a predilection for the apices. Eventually, fibrosis and a honeycomb lung may ensue. Recurrent pneumothoraces occur in 20% of patients. Hilar lymphadenopathy and pleural effusions are rare.

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Computed Tomography

CT scanning is considerably better than plain radiography and conventional tomography in depicting an intracranial extension of eosinophilic granuloma. CT scans may be particularly useful in osseous lesions in areas with complex anatomy, such as the mastoids, atlantoaxial joints, and posterior elements of the vertebral bodies. Also, soft-tissue components are better depicted with CT scanning than with other imaging modalities. The destruction of the mastoid, petrous ridge, tegmen tympani, and lateral sinus plate and the destruction of the inner and external ear are depicted elegantly on CT scans (see the images below). CT scans may demonstrate an isoattenuating and homogeneously enhancing mass in the hypothalamus/pituitary gland. [13]  CT scan appearances of eosinophilic granuloma are nonspecific, and a variety of inflammatory and neoplastic processes may mimic this condition.

Transaxial nonenhanced computed tomography scans o Transaxial nonenhanced computed tomography scans of the skull in a 28-year-old woman who presented with a palpable swelling over the calvarium. Scanogram of the patient's skull shows a geographic lytic lesion within the parieto-occipital region. Transaxial scan through the vertex, examined in a bone window, shows an expanding lytic lesion within the diploic space (see the next image).
Transaxial nonenhanced computed tomography scans t Transaxial nonenhanced computed tomography scans through the vertex in a 28-year-old woman with a palpable swelling over the calvarium, examined in a brain window. Images show destruction of both the outer and inner tables of skull; however, no brain involvement is noted.

CT of long bones with LCH indicate thick diaphysis and thin cortical bone. Round or ovoid radiolucent areas suggested osteolytic, cystic, or expansile bone destruction.Cross-sectional scanning of CT show lytic and periosteal reaction, medullary bone destruction and cortical bone destruction. [2]

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Magnetic Resonance Imaging

The value of using MRI for patients with eosinophilic granuloma lies in the sensitivity of this modality; its specificity is low. However, the cost of the procedure and the procedural problems encountered in imaging young children confer no advantages over plain radiography.

The soft-tissue component around the osseous lesion has poor definition and shows signal inhomogeneity; the appearance may mimic that of a malignant tumor, infection, or stress fracture.On spin-echo MRIs, osseous lesions of eosinophilic granuloma reveal decreased signal intensity on T1-weighted images and high signal intensity on T2-weighted sequences. The lesion may enhance after the administration of a gadolinium-based contrast agent (see the following image). [12]

T1-weighted nonenhanced sagittal magnetic resonanc T1-weighted nonenhanced sagittal magnetic resonance image through the spine in a 9-year-old boy with mid dorsal pain shows the vertebra plana. Note the preserved disk spaces. Biopsy results confirmed the diagnosis of eosinophilic granuloma.

Gadolinium-based contrast agents have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see Nephrogenic Systemic Fibrosis. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape.

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Ultrasonography

Conventional radiography, CT, and radionuclide imaging usually diagnose these lesions. Ultrasound of the skull with guided core biopsy has previously been reported in 3 cases with excellent results. [19] Viewing of the frontal bone solitary eosinophilic granuloma with ultrasound has been found instructive and useful.

(See the images below.)

T1-weighted nonenhanced sagittal magnetic resonanc T1-weighted nonenhanced sagittal magnetic resonance image through the spine in a 9-year-old boy with mid dorsal pain shows the vertebra plana. Note the preserved disk spaces. Biopsy results confirmed the diagnosis of eosinophilic granuloma.
CT image of a 4-year-old boy with long-standing (1 CT image of a 4-year-old boy with long-standing (1 y) gradually increasing swelling over the forehead (left to the midline). Courtesy of Ravi Devidas Kadasne, MBBS, MD, Specialist in Radiology, Emirates International Hospital, UAE.

Compare the vascularity of an eosinophilic granuloma in the first image below, where only stretching of the vessels is noted on the angiography. Doppler interrogation in the second image below show internal vascularity not previously shown.

External carotid angiogram in a 10-year-old boy wi External carotid angiogram in a 10-year-old boy with swelling of the left mandible shows an avascular mass within the mandible, with stretching of the vessels around the lytic lesion. Biopsy results confirmed the diagnosis of eosinophilic granuloma.
CT image of a 4-year-old boy with long-standing (1 CT image of a 4-year-old boy with long-standing (1 y) gradually increasing swelling over the forehead (left to the midline). Courtesy of Ravi Devidas Kadasne, MBBS, MD, Specialist in Radiology, Emirates International Hospital, UAE.
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Nuclear Imaging

Radiographic examination and radionuclide bone imaging are complementary techniques in detecting bone lesions in bone marrow disorders, including eosinophilic granuloma. Scintigraphy is more useful in cases of unifocal eosinophilic granuloma than in cases of multifocal disease, in which radiography is superior. Negative radionuclide findings occur in 35% of patients with known eosinophilic granuloma in whom plain radiographic findings are positive.

Eosinophilic granuloma shows a variety of activity patterns on radionuclide bone scintigrams obtained by using technetium-99m (99mTc) diphosphonate. The bone lesions may be hot, cold, or cold with an area of increased surrounding reparative-ring activity. Areas of increased activity vary in intensity. In the lower limbs, eosinophilic granuloma lesions tend to appear more elongated and diffuse than bone metastasis. Recurrences are identified more readily with fewer false-negative findings (see the image below).

Radionuclide bone scans in a 28-year-old woman wit Radionuclide bone scans in a 28-year-old woman with a palpable swelling over the calvarium show a solitary lesion within the skull and a photon-deficient mass surrounded by a rim of intense activity. Biopsy results confirmed the diagnosis of eosinophilic granuloma.

Bone lesions in all types of Langerhans cell histiocytosis are not gallium-67 (67Ga) citrate–avid, but 67Ga imaging may be helpful for detection of nonosseous lesions. Hence, it is useful in the initial assessment and serial follow-up imaging of patients with Langerhans cell histiocytosis. Thallous chloride-201 (201Tl) uptake detected on single-photon emission CT (SPECT) scans has been reported in a patient with skull eosinophilic granuloma, which was photon deficient on a 99mTc methylene diphosphonate uptake study. [20]

Fluorodeoxyglucose (FDG) positron-emission tomography (PET) scanning is more sensitive than gallium scanning and may also be used when evaluating patients for LCH. [21]   FDG-PET scanning has poor sensitivity for spinal lesions but is able to identify LCH in tissues, including lymph nodes, spleen, and lung. Obert and colleagues demonstrated that serial FDG-PET-CT scans may be useful for evaluating treatment responses, particularly in cases with bone LCH involvement. [22]

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Angiography

In most instances, angiography has little or no role in the investigation of eosinophilic granuloma. Eosinophilic granuloma shows no neovascularity, and angiography therefore is usually not performed. Rarely, angiography may be performed in patients in whom staging is required before surgical intervention and to exclude other vascular lesions that can mimic eosinophilic granuloma, such as hemangioma and aneurysmal bone cyst. (See the following image.)

External carotid angiogram in a 10-year-old boy wi External carotid angiogram in a 10-year-old boy with swelling of the left mandible shows an avascular mass within the mandible, with stretching of the vessels around the lytic lesion. Biopsy results confirmed the diagnosis of eosinophilic granuloma.

 

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