Eosinophilic granuloma is a focal form of histiocytosis from Langerhans cells, which is manifested by tumor–like foci in the bones. The main cause of the disease is called genetic mutations that trigger abnormal cell proliferation. The manifestations of pathology depend on the localization of the tumor: bone pain, pathological fractures, tooth loss, exophthalmos and visual disturbances. For the diagnosis of granuloma, bone radiography, blood tests, histological analysis of bone foci are prescribed. Treatment is carried out surgically (curettage, resection), supplemented by pharmacotherapy and radiation therapy according to indications.
96.6 Unique histiocytosis from Langerhans cells
Eosinophilic granuloma occurs with a frequency of 3-5 cases per 1 million population, mainly in adolescence and adolescence. Men get sick 2 times more often than women. Cases of the disease among middle-aged and elderly patients are extremely rare. This type of benign tumor accounts for less than 1% of all volumetric neoplasms of bone tissue and up to 80% of cases of histiocytosis. In the Russian literature, granuloma is sometimes called Taratynov’s disease after a Russian pathologist who first described atypical lesions in bone tissue.
Despite numerous scientific studies, it has not yet been possible to establish the etiological structure of eosinophilic granuloma and other variants of histiocytosis. Great importance is attached to genetic mutations. The most common congenital anomaly of the BRAF gene, which is responsible for the division and survival of different cell types. The second most common mutation is the MAP2K1 gene, which encodes proteins of the signaling pathway and is involved in the process of cell proliferation.
The formation of a focus of eosinophilic granuloma is associated with the proliferation of Langerhans cells, which are of bone marrow origin. They belong to the components of the immune system and participate in the first stage of protection: they perform an antigen-presenting function. With histiocytosis, cells begin active division in the bone tissue, where they form tumor foci. This is facilitated by increased expression of proliferation factors and apoptosis inhibitors.
Histiocytes and eosinophils of pathological origin, which make up the granuloma, are at different stages of differentiation. They proliferate moderately, are poorly susceptible to physiological apoptosis, which is why they persist in the focus for a long time. Such features combined with monoclonality of cells and excessive activation of T-suppressors allow us to consider focal histiocytosis as a neoplastic process
Small tumors, which are located in the bones of the skeleton of the body, are asymptomatic for a long time. Occasionally, patients complain of moderate pain in the bones, swelling over the lesion. Significant clinical manifestations are observed with an increase in tumor size and a decrease in bone strength. Pathological fractures are possible, which occur with minimal mechanical damage to the limb or are not associated with trauma at all.
For eosinophilic granuloma, damage to the bones of the upper and lower jaw is typical. With such localization of the focus, loosening and loss of teeth in young patients, pathological fractures of the jaw, difficulties in carrying out dental manipulations are possible. Occasionally, the disease proceeds according to the type of multisystem lesion, when other organs are involved in the process. Histiocytosis can affect the liver, spleen, hematopoietic system
The disease is characterized by polymorphic skin rashes. They are located on any part of the body, including on the scalp and in the genital area. First, there are red spots and peeling plaques, which gradually turn into protruding tumor-like formations. Nodes acquire a bluish-purple color, reach 3-4 cm in size. Ulcers that do not heal for a long time are formed on the mucous membranes of the oral cavity and genitals.
The localized form of histiocytosis is characterized by a favorable benign course. The main problem is considered to be a violation of the integrity of bone structures: pathological fractures that occur at a young age violate the normal anatomy and functional ability of the limb. To relieve chronic bone pain, patients can use nonsteroidal anti-inflammatory drugs, uncontrolled intake of which causes NSAID-gastropathy.
With the location of eosinophilic granuloma in the temporal bone, partial obstruction of the auditory canal is possible, which contributes to recurrent otitis externa. If the focus is located near the eye socket, exophthalmos and visual disturbances of varying severity develop. Damage to the vertebrae, especially in children, is fraught with impaired posture and persistent deformities of the vertebral column.
With clinical signs of eosinophilic granuloma, patients most often turn to a dermatologist or orthopedic traumatologist, after which they receive a referral for a consultation with an oncogematologist. At the first stage of diagnosis, an examination of the skin and visible mucous membranes is carried out, palpation of soreness zones, clarification of the conditions and prescription of symptoms. To confirm the diagnosis , the following research methods are prescribed:
- Bone radiography. X-ray examination determines single or multiple tumor-like formations, areas of destruction, which can be located in both tubular and flat bones. If eosinophilic granuloma is suspected, an X-ray of the jaws must be performed.
- Ultrasound of the abdominal organs. The study is prescribed if a multi-focal form of histiocytosis is suspected, which occurs with damage to internal organs. In this case, the diagnosis reveals volumetric neoplasms with heterogeneous echostructure in the liver, spleen, intra-abdominal lymph nodes.
- Histological analysis. Eosinophilic granuloma is characterized by infiltrates from large oval cells that have irregular nuclei and a large amount of cytoplasm. Immunohistochemistry confirms the presence of Langerhans cells, a large number of eosinophils, a limited number of lymphocytes and neutrophils.
- Blood test. Hypochromic anemia with anisocytosis and poikilocytosis is found in the peripheral blood of most patients. Neutrophilosis with a shift to the left, monocytosis, thrombocytopenia are less common. When performing a coagulogram, an increase in blood clotting ability is detected.
- Analysis for cancer markers. To exclude bone cancer, patients undergo a blood test for tartrate-resistant acid phosphatase. An increase in the level of this marker is a reliable sign of an increase in the activity of osteoclasts and the development of the proliferative process.
- Analysis of the BRAF gene. The molecular genetic method of research is carried out for the clarifying diagnosis of histiocytosis. The detection of a gene mutation in granuloma cells helps to confirm the diagnosis, the presence of the same anomaly in peripheral blood is required to establish the risk group of a patient with histiocytosis.
To make a diagnosis, it is necessary to differentiate the disease with other causes of the appearance of bulky bone neoplasms. During the examination, oncopathology is excluded:
- osteogenic cancer;
- myeloma disease.
With severe pain and swelling, differential diagnosis with osteomyelitis is performed. Skin manifestations require differentiation with Papillon-Lefebvre syndrome.
In case of solitary foci in bone tissue, the main method of therapy is curettage with subsequent restoration of bone integrity. Due to oncological alertness, a wide resection of eosinophilic granuloma is often performed, which ensures complete elimination of the neoplasm, but has an undesirable functional result. After such an operation, bone grafting will be required to replace the iatrogenic defect.
Pharmacotherapy and radiation are justified in case of multiple granuloma, involvement in the pathological process of the skin and internal organs. There are no generally accepted therapy protocols, so the program is selected individually, taking into account the characteristics of the disease in a particular patient. Drug therapy includes cytostatics, which are used to slow cell proliferation, and glucocorticoids, which stimulate repair after curettage.
Localization of granulomas in the bones of the limbs and skull opens up wide possibilities of radiation therapy. Irradiation is performed as an alternative to surgical intervention if the neoplasm is unavailable for curettage, or the patient has contraindications to surgical treatment. After radiotherapy, complete remission is observed in 85% of patients, and control over the solitary focus of the disease can be obtained in 95% of cases.
An important place in the therapeutic program is the treatment of skin foci of histiocytosis. The therapeutic program is selected only after histological examination of biopsies. Patients are shown systemic therapy, which includes alpha-interferon, methotrexate and lenalidomide. They have anti-inflammatory, anti-angiogenic and immunomodulatory properties.
Prognosis and prevention
Solitary eosinophilic granuloma is recognized as the most benign form of histiocytosis. A more favorable prognosis for patients with isolated local manifestations and the absence of systemic complications of the disease. The multi-focal variant of histiocytosis proceeds less favorably. The exact causes and mechanism of the disease are not yet clear, so there are no effective preventive measures.