Histiocytosis X is a systemic disease characterized by the formation of specific cellular granulomas in various organs and tissues. The most typical clinical manifestations include skin rashes, cough, unilateral exophthalmos. There is also tooth loss, an increase in peripheral lymph nodes, signs of diabetes insipidus (polyuria, polydipsia). The diagnosis is verified by histological examination of the skin, lungs or lymph nodes. Anti-inflammatory drugs (glucocorticosteroids), chemotherapeutic agents are used as treatment. In case of severe lung damage, organ transplantation is performed.
C96.0 C96.5 C96.6
Histiocytosis X (histiocytosis from Langerhans cells, pulmonary eosinophilic granuloma) is a systemic pathology in which active proliferation of Langerhans cells occurs in the tissues of the lungs, bones, central nervous system, reticuloendothelial system (in the liver, spleen, lymph nodes). The course of the disease varies depending on the form and can be benign with spontaneous remission or rapidly progressive with a high probability of death. The prevalence of histiocytosis is 5 per 1,000,000 people. Children, adolescents, and adults aged 20-30 suffer mainly. Histiocytosis X occurs only in representatives of the white race, more often in men (the ratio with women is 2:1).
To date, the exact cause of histiocytosis X is unknown. The role of immune autoaggression caused by infection with herpes virus type 6 is assumed. There is still a scientific debate about the hereditary nature of the disease. Somatic mutation of the V600E gene encoding intracellular signaling protein BRAF was detected in 50% of patients in pathological Langerhans cells. Smoking is considered as one of the main risk factors (more than 90% of patients are smokers). This is confirmed by the fact that the symptoms decrease after smoking cessation, even without the use of any treatment.
The mechanism of development of histiocytosis has not been sufficiently studied. The main link in pathogenesis is the accumulation of dendritic cells (Langerhans cells, or histiocytes) in tissues. Dendritic cells are synthesized in the bone marrow and migrate to the dermis, lung parenchyma, reticuloendothelial system, etc. Their main function is to absorb antigens coming from the environment and present T and B lymphocytes for the formation of an immune response. After contact with histiocytes, lymphocytes begin to secrete pro-inflammatory cytokines and mediators that increase the activity of histiocytes and give them high mobility.
With histiocytosis, for unknown reasons, the process of apoptosis (programmed cell death) is disrupted in dendritic cells. In combination with the growth factors secreted by lymphocytes, this leads to their intensive proliferation, followed by fusion with eosinophils. As a result, giant cell granulomas are formed, which gradually begin to replace the normally functioning tissue of an organ. The presence of a large number of T-lymphocytes in granulomas suggests the presence of a specific antigen.
According to the localization of foci, a monosystemic form with a single or multiple lesion of one anatomical area and a multisystemic form with or without signs of organ dysfunction are distinguished. Traditionally , the following clinical forms are distinguished:
- Disseminated (primary acute, Abta—Letterer—Sive disease). The course resembles a severe systemic infection. It is characterized by rapid generalization of the process, progression of pulmonary insufficiency and high mortality rate. It occurs more often in children from 6 months to 2 years.
- Primary-chronic (Hand—Schuller—Christian disease). The course is also systemic, but more favorable, various organs are involved gradually. The typical triad of Kryschen is diabetes insipidus, unilateral exophthalmos and destruction of the flat bones of the skull. It occurs in children and adolescents.
- Eosinophilic granuloma (Taratynov’s disease). The most benign kind. The predominant localization of granulomas is bones and lungs. In most cases, it develops in adults.
The clinical picture is extremely diverse. The disease begins with the appearance of general weakness, an increase in body temperature, which is mostly subfebrile, but can reach 40 ° C. Dyspeptic disorders are possible – nausea, vomiting, diarrhea. The skin is covered with itchy foci of hyperemia with scales or crusts. Sometimes there are hemorrhagic elements, long-term non-healing ulcers. Rashes are present on the scalp, the external auditory canal, in the area of natural folds (inguinal, axillary). Lymph nodes are enlarged throughout the body.
There is shortness of breath, persistent dry cough and chest pain. Difficulty breathing can only bother during physical activity or be present even at rest. Dull pains or heaviness in the right hypochondrium are added due to an enlarged liver (hepatomegaly). With severe liver damage, the skin becomes jaundiced. Enlargement of the spleen is accompanied by pain in the left hypochondrium. Some patients experience bone pain. Destruction of the bones of the eye socket leads to the formation of exophthalmos, more often one-sided. Ear pain is mistakenly diagnosed as bacterial or fungal otitis media and unsuccessfully treated with antibacterial and antifungal drugs. Osteolysis of the lower jaw leads to periodontitis and tooth loss.
With a prolonged course of histiocytosis, the patient begins to lose weight. In severe cases, there are signs of bone marrow insufficiency – anemic syndrome (pallor of the skin, dizziness, rapid heartbeat), a tendency to bleeding, reduced resistance to infections. The formation of histiocytic granulomas in the posterior lobe of the pituitary gland causes inhibition of the production of antidiuretic hormone. As a result, symptoms of diabetes insipidus develop – dry mouth, constant thirst (polydipsia) and increased urination (polyuria).
The wide variability of the clinical picture in histiocytosis causes a variety of complications. Pathological bone fractures, especially compression fracture of the spine, are considered the most characteristic. Typical complications from the lungs are pulmonary arterial hypertension due to diffuse fibrosis of the lung tissue, spontaneous pneumothorax due to rupture of thin–walled bullae. Massive infiltration of the liver causes cirrhosis with hepatic cell insufficiency. Rare complications include the adverse effects of antidiuretic hormone deficiency (diabetes insipidus) in the form of hyperosmolar hypohydration, manifested by motor anxiety, muscle cramps, impaired consciousness, up to a deep coma.
Patients with histiocytosis are treated by various doctors – hematologists, pulmonologists, pediatricians. The profile of the specialty depends on the age of the patient and mainly the affected organ. During a general examination, cyanosis (cyanosis) of the lips, participation in breathing of auxiliary muscles (with respiratory insufficiency) are noted. During auscultation of the lungs, hard breathing, dry wheezing is heard throughout the pulmonary fields. Additional examination includes:
- Laboratory tests. In the blood test, an acceleration of the erythrocyte sedimentation rate is detected, sometimes eosinophilia and pancytopenia (a decrease in erythrocytes, platelets and leukocytes). In the biochemistry of blood, an increase in liver enzymes (ALT, AST) and an increase in plasma osmolarity can be traced. In hepatic insufficiency, coagulogram parameters change (prolongation of prothrombin time, hypofibrinogenemia). In the analysis of urine, there is a low relative density (hypostenuria).
- Instrumental research. During radiography of the skeleton, foci of destruction and osteolysis are found, especially pronounced in the flat bones of the skull and long tubular bones. On the chest X-ray, bilateral small focal darkening (nodules, bullae), strengthening of the pulmonary pattern are visible. For more accurate visualization of lung tissue, a high-resolution computed tomography of the lungs is prescribed, which allows to determine their cellular deformation. The results of measuring the function of external respiration (spirography) show a deterioration in the diffusion capacity of the lungs.
- Verification tests. They allow to reliably establish the diagnosis of histiocytosis. Histological examination of a biopsy (more often skin, lymph nodes or lungs) reveals an excessive number of giant Langerhans cells with eosinophilic cytoplasm, bean-shaped nucleus, absence of nucleoli. Immunohistochemical analysis is performed to identify surface specific markers of histiocytosis (CD 1a and langerin).
The differential series includes a large number of nosologies and depends on the clinical symptoms of histiocytosis. Skin rashes need to be differentiated with eczema, psoriasis, atopic dermatitis. Lung damage should be distinguished from tuberculosis, sarcoidosis, lymphogranulomatosis. Generalized histiocytosis is differentiated with hematological diseases (hemophagocytic syndrome, acute leukemia). Foci of bone destruction require the exclusion of hyperparathyroidism, multiple myeloma, osteomyelitis.
Patients must be hospitalized in a hospital. In case of severe respiratory insufficiency, oxygen inhalation or transfer to artificial ventilation of the lungs are indicated. In the presence of signs of bone marrow insufficiency, blood components are transfused and granulocyte colony stimulating factor is used.
Etiotropic therapy of histiocytosis X does not exist. The most important stage in treatment is quitting smoking. Smoking cessation causes an improvement in the clinical, laboratory, and X-ray picture. Glucocorticosteroids (prednisolone, methylprednisolone), chemotherapeutic agents (vinblastine, mercaptopurine, etoposide) are used as pathogenetic therapy.
For the treatment of diabetes insipidus, hormone replacement therapy with vasopressin analogues (desmopressin) is prescribed in the form of an intranasal spray or in tablet form. With small osteolytic foci, curettage is performed, with pronounced infiltration of bones – resection or remote gamma therapy. With a massive destructive process in the lung tissue, lung transplantation is performed.
Prognosis and prevention
The course and prognosis of histiocytosis X is determined by the form of the disease. The primary acute form is characterized by a rapidly progressive course with an unfavorable prognosis. Death occurs in 70-80% of cases from pulmonary heart failure. The primary chronic form and eosinophilic granuloma have a more benign course. The risk of mortality is 15% and 1.5%, respectively. Sometimes there is a spontaneous recovery. Since the cause of histiocytosis is unknown, effective prevention methods have not been developed. Smoking cessation can reduce the risk of occurrence and relapse.
- Vade A. Congenital histiocytosis X / A. Vade, A. Hayani, K.L. Pierce // Pediatr. Radiol. — 1992. — Vol. 23. — P. 181-185.link
- Wee S.H. Generalized eruptive histiocytoma: a pediatric case / S.H. Wee, H.S. Kim, S.N. Chang et al. // Pediatr. Dermatol. — 2000. — Vol. 17. — P. 453-455. link
- Flores-Stadler E.M. Indeterminate-cell histiocytosis: immunophenotypic and cytogenetic findings in an infant / E.M. Flores-Stadler, F. Gonzalez-Crussi, M. Greene et al. // Med. Pediatr. Oncol. — 1999. — Vol. 32. — P. 250-254.
- Manente L. Indeterminate cell histiocytosis: a rare histiocytic disorder / L. Manente, C. Cotelessa, I. Schmitt et al. // Am. J. Dermatopathol. — 1997. — Vol. 19. — P. 276-283. link
- Ugurlu B.S. Necrobiotic xanthogranuloma: long-term outcome of ocular and systemic involvement / B.S. Ugurlu, G.B. Bartley, L.E. Gibson // Am. J. Ophthalmol. — 2000. — Vol. 129. — P. 651-657.