Eosinophilic granuloma (EG) is the mildest variant of Langerhans cell histiocytosis. In 1940, Lichtenstein and Jaffe first introduced the term EG. Lichtenstein in 1953 included eosinophilic granuloma, Hand-Schuller-Christian disease, and Letterer-Siwe disease under the disorder histiocytosis X referring to the proliferation of histiocytes (Langerhans cells) due to an unknown etiology. They are now known as Langerhans cell histiocytosis (LCH). EG is a benign tumor-like disorder characterized by abnormal proliferation of antigen-presenting cells of dendritic origin known as Langerhans cells. These Langerhans cells originate from meloid dendritic cells rather than skin. EG is the most common form of Langerhans cell histiocytosis.
The disease mostly affects the axial skeleton, namely skull, jaw bone, spine, pelvis, ribs, and long bones. Lesions in the long bones are primarily located in the diaphysis. It frequently involves the soft tissues adjacent to the bone. The site of bone involvement is different in children and adults. In children most commonly involved bone is the skull (frontal bone), in contrast to adults, where the jaw is more frequently involved. The thoracic spine is most often involved in children as opposed to the cervical spine in adults. Other less commonly affected sites include the skin, pituitary gland, lung, brain, liver, spleen, and the gastrointestinal tract. EG accounts for less than 1% of all bone tumors. The presentation of EG is either solitary, which rarely requires treatment or multisystem, which requires aggressive therapy.
Langerhans Cell Histiocytosis Classification
There is an ongoing debate on whether eosinophilic granuloma (EG) is a reactive or neoplastic process. The abnormal proliferation of Langerhans cells characterizes EG. Langerhans cells are derived from a mononuclear cell and dendritic line precursors. They are generally found in the bone marrow with the ability to migrate into tissues and act as antigen-presenting cells to T lymphocytes. The proliferation of Langerhans cells may be induced by a viral infection (Epstein-Barr virus, Human Herpes virus-6), bacteria, and immune dysfunction leading to an increase in cytokines such as interleukin-1 and interleukin-10. EG of the lung has a strong association with cigarette smoking. Langerhans cell histiocytosis is now considered as an inflammatory myeloid neoplasm in the revised 2016 Histiocyte Society classification.
The accumulation of Langerhans cells in the lungs occurs in response to exposure to cigarette smoke. Supporting this hypothesis is the finding that the initial histologic and radiographic findings are peribronchial. Antigenic stimulation from one or more components of cigarette smoke is likely responsible for the disease.
Eosinophilic granuloma (EG) is a rare disorder with an incidence of 4 to 5 cases per million per year in children's less than 15 years, while the incidence is 1 to 2 cases per million per year in adults. The incidence is higher in the white population of northern European descent and Hispanics than in the black race. It affects children, adolescents, and young adults, with the most commonly affected age group being 5 to 10 years. The mean age group for the patients with single bone lesions is 5.5 years, and with multiple bone lesions are 4.5 years. Males are slightly more affected than females 1.2:1. There are few reported cases of EG in the same family members. The pattern of inheritance is not well recognized.
Eosinophilic granuloma in the lungs is a rare disorder, and true prevalence is not known. Less than 5% of patients who had lung biopsy for interstitial lung disease were diagnosed with EG of the lung. A Japanese study estimated the prevalence of lung EG at 0.27 males and 0.07 females per 100,000 population-based on hospital discharge diagnosis over a year.
The pathophysiology of eosinophilic granuloma (EG) is not clearly understood. Langerhans cells are differentiated cells of the dendritic cell system and are closely related to the monocyte-macrophage line. These antigen-presenting cells are normally found in the skin, reticuloendothelial system, heart, pleura, and lungs. They may be identified by immunohistochemical staining or by the presence of Birbeck granules via electron microscope. It is believed that it can be either due to a reactive or neoplastic process. There have been reports suggesting somatic mutations (gain of function mutation) in the BRAF V600E gene in 50% of cases. Also, MAP2K1 mutations are found in 21% of the cases. Langerhans cell histiocytosis had been associated with Ras-ERK pathway mutations.
Studies have since reported that 100% of the cases show ERK phosphorylation. The protein produced by the BRAF gene is a part of the signaling pathway known as the RAS/MAPK pathway that regulates proliferation, differentiation, migration, and apoptosis of the cells. This mutation leads to an overactive protein that constantly sends the signal to the nucleus for growth and proliferation, which subsequently leads to the formation of EG due to abnormal proliferation of the Langerhans cells. This can either involve the skeletal system or other organ systems. Depending on the maturation stage of the dendritic cell when the mutation occurs, it is the clinical presentation—the more mature the cell, the less systemic involvement. Langerhans cells infiltrating multiple organ systems are found to have the BRAF gene mutation, which has shown a good response to chemotherapy.
Histopathological examination is required for the diagnosis of Eosinophilic Granulomatosis (EG) to differentiate from other conditions like infections, malignancy, and benign tumors of the bone as their clinical presentation and laboratory findings are somewhat similar.
Eosinophilic granuloma (EG) is a multi-system disease with a diverse presentation. It can involve a single bone or multiple bones, and the clinical presentation varies with the involved bone and surrounding structures. Other than bones, less commonly involved organs include skin, pituitary gland, liver, spleen, and lungs. The clinical features, according to involved structures, are as follows:
The evaluation of eosinophilic granuloma (EG) is multicentric that includes laboratory tests, radiographic tests, and biopsy for histopathological findings to reach an accurate diagnosis.
The treatment can be divided into two groups:
The differential diagnosis for eosinophilic granuloma (EG) involving the spine includes
They have similar radiological findings; however, minimal laboratory findings and lack of constitutional symptoms favor EG. The biopsy of the lesion confirms the diagnosis.
For lesions involving the skull bone, the differential diagnosis includes
For lesions involving the long bones of the extremities, the differential diagnosis includes
In the case of pulmonary EG following differentials to be kept in mind
Biopsy and histopathological analysis, staining for CD1a, and electron microscopic finding help in differentiating EG with these conditions.
Patients with solitary bone lesions may regress spontaneously and have a good prognosis. High-risk patients like multisystem involvement, skeletally mature patients, more than one bone involvement, and skull-base bone involvement (sphenoid, ethmoid, orbital, and temporal bones) have a high risk for recurrence, complications, and subsequent worse prognosis. Operative treatment offers more prompt pain relief when compared to non-operative treatment. Over 10% of patients die of this disease, including a few cases with reactivations and long term morbidity.
The prognosis for pulmonary eosinophilic granuloma (EG) varies and is related to smoking cessation. Those who continue to smoke experience disease progression, but those who quit disease stabilizes or regresses. Extreme age, large cysts, and honeycombing radiological, multiorgan involvement, and prolonged corticosteroid therapy have a worse prognosis.
The complications associated with eosinophilic granuloma (EG) are as follows:
Patients with eosinophilic granuloma (EG) should get multiple consultations according to the involved organs and presenting complaints. These are:
Eosinophilic granuloma (EG) is the mild form of Langerhans cell histiocytosis, most commonly affecting the axial skeleton. It is more common in children and adolescents. The presenting complaints, laboratory findings, and radiographic features might be similar to some other conditions like infections, malignancy, and metastasis. Thus, histopathological features along with staining with CD1a, S-100 protein, and electron microscopic features are required to differentiate from other conditions mimicking EG.
EG can present as either single bone involvement, multiple bone involvement, or multiple system involvement. Thus, a multicentric approach is required while evaluating a suspected case of EG. Solitary lesions generally require no treatment and have a good prognosis. While the orthopedic surgeon is almost always involved in the care of patients with EG, it is essential to consult with an interprofessional team of specialists that include an ophthalmologist, pulmonologist, hematologist-oncologist, otolaryngologist, neurosurgeon, and neurologist. The nurses are also vital members of the interprofessional group as they will assist with the education of the patient and family. In the postoperative period for pain and wound infection, the pharmacist will ensure that the patient is on the right analgesics and appropriate antibiotics. The radiologist also plays a vital role in determining the cause. Without providing a proper history, the radiologist may not be sure what to look for or what additional radiologic exams may be needed.
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