The clinical presentation of patients with eosinophilic granuloma can include symptoms that are related to changes in the bony structures, such as pain and swelling at the site of its development. In some cases, a palpable mass can be detected during physical examination, but the condition may have an asymptomatic course as well. Depending on the location of the lesion, various findings may be observed, such as neurological deficits in the setting of EG developing in the spine and otorrhea sometimes accompanied with hearing loss when the petrous bone is involved [16] [18]. Additional features, such as exophthalmos and loose teeth have also been reported in patients with EG [16].

• Swelling

  On examination, he had spastic paraplegia in addition to painful swelling on the back. A myelogram showed a block just below the T2 vertebra. [ncbi.nlm.nih.gov]

  The presence of a post-aural swelling may hence be mistaken for a mastoid abscess. [jpgmonline.com]

  They may include pain, swelling, or even pathological fractures. [consultant360.com]

• Hodgkin Lymphoma

  […] to collapse; - note that non Hodgkin lymphoma of the spine may cause a compression fracture may give the appearance of vertebra plana; - always consider osteomyelitis of spine : - Biopsy: - may be required for diagnosis unless the radiographic picture [wheelessonline.com]

  The differential diagnosis includes osteomyelitis, non hodgkin's lymphoma, and hodgkin's disease. [streetdirectory.com]

  The presence of eosinophils with histiocytes can mimic Hodgkin's lymphoma, but the identification of Reed Sternberg cells should be mandatory for the diagnosis of this disease. [jcytol.org]

  Case presentation A 16-year-old male patient, without any relevant aspects in his medical history except a Non-Hodgkin lymphoma of his father, which is currently being treated, and a breast cancer of his mother, also in treatment. [head-face-med.biomedcentral.com]

• Fracture

  Delayed swelling after skull fractures is an uncommon complication following head trauma in children. [ncbi.nlm.nih.gov]

• Otalgia

  The initial symptoms of eosinophilic granuloma include otalgia, otorrhea, hearing impairment, and postauricular swelling. [3] Hearing loss, if present, is usually conductive type. [indianjotol.org]

  It may present as otorrhoea, polyp in the external canal, otalgia or post-auricular swelling. [jpgmonline.com]

The diagnostic workup of patients with suspected EG should comprise imaging studies and biopsy of the lesion. Plain radiography should be conducted as an initial diagnostic method, which can reveal nonspecific changes in the bony parenchyma, while CT, MRI or bone scintigraphy can identify the main diagnostic feature - lytic lesions [3] [5], as well as the potential presence of extra-skeletal lesions and make an initial distinction between different forms of Langerhans-cell histiocytosis [19]. Moreover, other causes, such as primary bone tumors and infections, may be excluded. Sometimes, EG may present with multiple lesions (most commonly in the lungs and the GI tract). In these cases a biopsy, either percutaneous or open, is necessary to make a definite diagnosis [2] [20]. Eosinophilic granuloma will show the typical presence of Langerhans cells together with abundant eosinophils that completely replace normal bone tissue. Once the diagnosis is made, adequate treatment can be initiated.

• Granulomatous Tissue

  Though erosion. of the labyrinth has been reported [2], [10] such involvement is rare, suggesting that the bony labyrinth is extremely resistant to invasion by the granulomatous tissue. [jpgmonline.com]

When eosinophilic granuloma presents as a solitary lesion, which is in most cases, surgical excision is recommended. Recurrence rates of about 10% have been observed following excision of solitary lesions [21]. Curettage of the lesion, as well as autologous iliac bone graft repair is performed in the setting of EG and the procedure is associated with a good prognosis [22] [23] Apart from surgical treatment, agents that have shown significant benefit include corticosteroids and NSAIDs, but chemotherapy and radiation have also been used, as EG seems to be very sensitive to radiation therapy [24]. Indomethacin, belonging to the group of NSAIDs, has shown significant effiicacy against this condition, primarily due to its inhibition of inflammatory cytokines, such as interleukin 1 (IL-1) and prostaglandins, which have been shown to be involved in the pathogenesis of this condition [5] [25]. A similar mechanism was proposed for corticosteroids and their use in EG is well-documented [4] [22]. Chemotherapy as well as corticosteroids is preferred in cases where multifocal involvement is noted. In general, EG has a good response to treatment and full remission is achieved in a substantial number of patients. Smoking cessation has been reported as an effective therapeutic modality in some cases [10] [11] [12].

In comparison to other forms of Langerhans-cell histiocytosis, eosinophilic granuloma has a very good prognosis, due to its solitary lesions and the very rare presence of a polyostotic form of the disease. Overall survival rates for this condition are estimated to be 95%, with only a minority of patients progressing to forms of the disease that affect several systems, such as the lungs, liver and other organs [17]. Much poorer outcomes have been reported for Letterer-Siwe disease and Hand-Schüller-Christian disease, in which progression to systemic disease with reduced therapeutic efficacy is more commonly observed.

Although distinct histological features have been established in this benign form of Langerhans-cell histiocytosis, the exact cause remains unknown [7]. Langerhans cell, which is derived from the bone marrow and performs important functions as an antigen-presenting cell with the expression of major histocompatibility complex (MHC) class II, usually resides in the skin and lymphatic system [8]. However, this cell, with its characteristic features, is recognized inside the lesion, together with numerous eosinophils and other inflammatory infiltrates. The reason for the appearance of these cells is still poorly understood. Infectious causes have been suggested in connection with this phenomenon, including viral pathogens, but further evidence is necessary to confirm this theory [9]. Smoking was also suggested by several studies as a factor in the pathogenesis [10], as several patients markedly improved after cessation of cigarette smoking [10] [11] [12], but the underlying mechanism is yet to be determined [10].

Eosinophilic granuloma,as well as other forms of Langerhans-cell histiocytosis, are rarely encountered in medical practice. Incidence rates of around 1 in 5,000,000 children were established in certain studies [13]. The median age of diagnosis has been reported to be around 4 years [14], which implies that EG is most commonly identified in young children, adolescents, and young adults. A significant predilection toward male gender has been reported. Incidence rates have been found to be higher amongst people of Northern European ancestry [15]. Smoking is considered to be a significant risk factor for EG presenting with pulmonary lesions [2].

Eosinophilic granuloma is usually a solitary lesion that develops in the skeletal system. It is characterized by proliferation of histiocytes - a term that describes dendritic cells and macrophages. Dendritic cells, as well as macrophages, originate in the bone marrow and are important constituents of the innate immune response, as their primary function is antigen presentation. Their usual location is the skin, thymus, and lungs and they circulate through the body via the lymphatic system. They contain MHC class II molecules, which serve to stimulate lymphocytes, specifically T-regulatory cells in lymph nodes, which is a major step in mounting an adequate immune response against certain pathogens [8].

EG occurs as a result of the extensive proliferation of histiocytes and eventual formation of Langerhans cells, a large elongated (often described as racquet-shaped) histiocyte containing Birbeck granules inside its basophilic cytoplasm [16]. Eosinophils are, in this variant of histiocytosis, abundantly present around this abnormally developed cell. As Langerhans cells proliferate, they cause osteolysis seen in virtually all EG patients due to the effects of interleukin-1 (IL-1), a potent inhibitor of bone formation, and prostaglandin E2 (PGE2), which was shown to induce resorption in vitro [5]. The end-result is the appearance of characteristic osteolytic lesions on imaging studies, one of the first signs and hallmarks of EG [3] [5] [6].

Avoiding cigarette smoking can be considered a preventive strategy, as cessation of smoking has been observed to cause regression of pulmonary, and skeletal lesions [2] [10] [11] [12].

Eosinophilic granuloma (EG) is one of the forms of Langerhans-cell histiocytosis, a condition in which proliferation of histiocytes within the skeletal system and potentially other organs occurs. Since its initial discovery in the 1940s [1], awareness about this bone lesion has significantly increased, but the exact cause of this lesion remains unknown. Its classification into a neoplastic or non-neoplastic disorder is still a topic of discussion. EG is most commonly observed in children and adolescents, with a significant predilection for male gender although reasons for it are unknown. This benign monostotic solitary lesion most frequently develops within bony structures, primarily the skull, while the ribs, pelvis, vertebrae and the mandible are also reported sites. EG is distinguished from other forms of Langerhans-cell histiocytosis - Letterer-Siwe disease and Hand-Schüller-Christian disease by its solitary appearance exclusively in the skeletal system, while multifocal lesions in other organs such as the lungs, central nervous system, liver, and thymus suggest the development of the other variants of histiocytosis. However, multifocal variants of EG have been reported [2], and the term "polyostotic" is used to describe multiple lesions in the skeletal system. Clinical presentation of patients with EG may be asymptomatic, but in most cases, symptoms such as local pain and swelling, as well as the development of pathological fractures may occur. Depending on the site of the lesion, symptoms such as otorrhea and hearing loss may be present if the temporal bone is involved. The initial diagnosis of EG can be difficult to make, but the use of various imaging studies, including plain radiography, computed tomography (CT), magnetic resonance imaging (MRI) or scintigraphy can clearly indicate the presence of a soft-tissue mass and the characteristic osteolytic lesions seen in this condition [3] [5] [6]. A definite diagnosis is made with either a percutaneous or open biopsy. Microscopic examination of the lesion can confirm the diagnosis, which will reveal the presence of Langerhans cells together with eosinophils and neutrophils, which completely disrupt the bony parenchyma. Treatment principles include corticosteroids, chemotherapy, radiation, surgery, or administration of non-steroidal anti-inflammatory drugs (NSAIDs), with all treatment forms being very effective against this disease. EG carries a good prognosis for the vast majority of patients, unlike other forms of Langerhans-cell histiocytosis, with survival rates of more than 95%, and only a small number of patients progressing to severe forms of the disease. It may spontaneously regress, depending on the site and number of lesions, but it may recur as well, which is why long-term monitoring of patients diagnosed with this condition should be conducted.

Eosinophilic granuloma is one of the variants of Langerhans-cell histiocytosis, which is a group of diseases characterized by abnormal proliferation of certain cell types of the immune system that develop in the bone marrow. It is important to distinguish between the three forms of this disease (the other two being Letterer-Siwe disease and Hand-Schüller-Christian disease) because they have a slightly different presentation, but more importantly, they carry a significantly worse prognosis compared to eosinophilic granuloma. Usually, in EG, a single mass develops within the skeletal system, most commonly in the skull, while the ribs, the pelvic bones, long bones and the spine are also sites where this benign lesion can occur. In rare cases, more than one mass may be found, most commonly in other parts of the skeletal system, lungs and the gastrointestinal tract. The exact cause of this condition remains unknown. Eosinophilic granuloma is most commonly diagnosed in young children and adolescents and for some reason, it is much more frequently encountered in males. This condition is considered to be rare and is estimated to occur in approximately 1 in 5,000,000 children. Symptoms include pain and swelling at the site where this mass develops. The mass can sometimes be palpated during physical examination. Many patients though do not experience symptoms of the disease and are diagnosed incidentally. The overall survival rate of patients with this condition is over 95%. Significant improvement is achieved with various forms of therapy, although recurrences, as well as progression to severe disease have also been documented. So it is important to make a definite diagnosis as soon as possible. A thorough diagnostic workup should be performed, which primarily includes various imaging studies, such as X-rays, computed tomography scan, magnetic resonance imaging, or scintigraphy, which can detect the presence of a mass causing tissue damage in the skeletal system. The term "lytic lesion" is used to describe the finding of bone destruction caused by the mass. To make a solid diagnosis, biopsy should be performed, with microscopic evaluation of the obtained sample. It will reveal the presence of Langerhans cells - large, elongated cells, together with numerous eosinophils that disrupt normal bone structure. Treatment principles include surgery in case only one mass is identified, while chemotherapy, radiation, corticosteroids and non-steroidal anti-inflammatory drugs such as indomethacin have all been effective in leading patients to complete remission and recovery. Recurrences, as well as progression to severe multiorgan disease has been observed in all three forms of Langerhans-cell histiocytosis, including eosinophilic granuloma, which is why long-term patient monitoring is necessary, even after successful treatment.

1. Lichtenstein L, Jeffe HL. Eosinophilic granuloma of bone: With report of a case. Am J Pathol. 1940;16:595–604.
2. Kaul R, Gupta N, Gupta S, Gupta M. Eosinophilic granuloma of skull bone. J Cytol. 2009;26(4):156-157.
3. Karagoz Guzey F, Bas NS, Emel E, Alatas I, Kebudi R. Polyostotic monosystemic calvarial and spinal langerhans' cell histiocytosis treated by surgery and chemotherapy. Pediatr Neurosurg. 2003;38(4):206-211.
4. Parihar A, Newaskar V. Management of polyostotic eosinophilic granuloma. Dent Res J (Isfahan). 2012;9(6):821-825.
5. Harris GJ, Woo KI. Eosinophilic granuloma of the orbit: a paradox of aggressive destruction responsive to minimal intervention. Trans Am Ophthalmol Soc. 2003;101:93-105.
6. Bertram C, Madert J, Eggers C. Eosinophilic granuloma of the cervical spine. Spine (Phila Pa 1976). 2002;27(13):1408-1413.
7. Yanagawa T, Watanabe H, Shinozaki T, et al. The natural history of disappearing bone tumours and tumour-like conditions. Clin Radiol. 2001;56(11):877-886.
8. Chu T, Jaffe R. The normal Langerhans cell and the LCH cell. Br J Cancer Suppl. 1994;23:S4-10.
9. Lilleyman J, Hann I, Blanchette V (eds) Pediatric hematology, 2nd edn. Churchill Livingstone, London; 1999.
10. Morimoto T, Matsumura T, Kitaichi M. Rapid remission of pulmonary eosinophilic granuloma in a young male patient after cessation of smoking [Article in Japanese]. Nihon Kokyuki Gakkai Zasshi. 1999;37(2):140-145.
11. Kishi K, Homma S, Kurosaki A, Kawabata M, Tsuboi E, Narui K, et al. Clinical course of pulmonary eosinophilic granuloma--CT evidence of lesion evolution [Article in Japanese]. Nihon Kokyuki Gakkai Zasshi. 2002;40(11):856-862.
12. Sudou A, Hashimoto T, Nakamura H, Hatao E, Ito M, Tsuchida F, et al. Improvement of extrapulmonary lesions of eosinophilic granuloma after cessation of smoking [Article in Japanese]. Nihon Kokyuki Gakkai Zasshi. 2002;40(4):326-330.
13. Nicholson HS, Egeler RM, Nesbit ME. The epidemiology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1998;12:379-384.
14. Stεlemark H, Laurencikas E, Karis J, et al. Incidence of Langerhans cell histiocytosis in children: A population based study. Pediatr Blood Cancer. 2008;51:76-81.
15. Jaffe ES, Harris NL, Stein H, Vardiman JW. Pathology and genetics of tumors of haematopietic and lymphoid tissues. Lyon: IARC Press; 2001.
16. Azouz EM, Saigal G, Rodriguez MM, Podda A. Langerhans' cell histiocytosis: pathology, imaging and treatment of skeletal involvement. Pediatr Radiol. 2005;35(2):103-115.
17. Jain A, Alam K, Maheshwari V, et al. Solitary eosinophilic granuloma of the ulna: Diagnosis on fine needle aspiration cytology. J Cytol 2008;25:153-156.
18. Kamimura M, Kinoshita T, Itoh H, et al. Eosinophilic granuloma of the spine: early spontaneous disappearance of tumor detected on magnetic resonance imaging. Case report. J Neurosurg. 2000;93(2):312-316.
19. DiCaprio MR, Roberts TT. Diagnosis and Management of Langerhans Cell Histiocytosis. J Am Acad Orthop Surg. 2014;22(10):643-652
20. Yang JT, Chang CN, Lui TN, Ho YS. Eosinophilic granuloma of the skull-report of four cases. Zhonghua Yi Xue Za Zhi. 1993;16:257–62.
21. Bulstrode C, Buckwalter J, Carr A, et al. Oxford textbook of orthopedics and trauma. 1st ed. Oxford University Press; 2003.
22. Woo KI, Harris GJ. Eosinophilic granuloma of the orbit: understanding the paradox of aggressive destruction responsive to minimal intervention. Ophthal Plast Reconstr Surg. 2003;19(6):429-439.
23. Jiang X, Tang X, Wang D, Chen X, Liu L. Diagnosis and treatment of eosinophilic granuloma of long bones in children. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2011;25(6):653-655.
24. Nauert C, Zornoza J, Ayala A, Harle TS. Eosinophilic granuloma of bone: diagnosis and management. Skeletal Radiol. 1983;10(4):227-235.
25. Han I, Suh ES, Lee S-H, et al. Management of Eosinophilic Granuloma Occurring in the Appendicular Skeleton in Children. Clin Orthop Surg. 2009;1(2):63-67.