Castleman disease is a lymphoproliferative disease that affects one or more groups of lymph nodes. Pathology has an unclear etiology, among the risk factors are HIV infection, autoimmune processes, infection with herpesviruses. The disease is manifested by an increase in one or more lymph nodes, intoxication syndrome, dyspeptic and dysuric phenomena. Instrumental imaging (ultrasound, CT, MRI), lymph node biopsy is performed to diagnose Castleman disease. Treatment includes surgical removal of hyperplasia foci, polychemotherapy and immunotherapy.
General information
Unusual clinical manifestations were first described by the American pathologist V. Castleman in 1954. 2 years later, based on the data obtained, a nosological unit was isolated, which was called Castleman disease (CD), or angiofollicular lymphoid hyperplasia. In 1972, the morphological features of the disease were established and its division into histological types was made. The estimated frequency of occurrence is 1 case per 100 thousand population, in total about 400 patients are described in the literature. In 70% of patients, symptoms develop before the age of 35.
Causes
In modern oncohematology there is no single concept on the etiological structure of the disease. Previously, theories of a dystopian thymus gland, a tumor of vascular origin, and an atypical variant of non-Hodgkin’s lymphoma were expressed. Such hypotheses have not received convincing evidence. The development of Castleman disease in immunocompromised patients is associated with herpes virus type 8 (HHV-8).
When studying the medical histories of patients with CD, a number of associated pathologies have been identified that increase the likelihood of lymphoproliferative syndrome. Castleman disease is combined with autoimmune processes, multiple myeloma, POEMS syndrome (11-24% of cases) and skin diseases (13%). An independent risk factor is called HIV infection, especially its terminal stage with a decrease in the level of CD4 lymphocytes less than 200 cells / ml.
Pathogenesis
Hyperproduction of interleukin-6 (IL-6) is called a key link in the formation of Castleman disease. The substance participates in the immune response, the processes of hematopoiesis and the development of an acute phase inflammatory reaction. Interleukin is produced by different types of cells in hyperplastic lymph nodes. Its effects on lymphocytes and blood vessels are associated with common symptoms of intoxication that occur in the multicentric form of CD.
The same mechanisms explain the viral etiology of the disease. HHV-8 secretes viral interleukin-6, which can directly bind to cellular receptors and cause a number of neoplastic changes. The virus stimulates the production of vascular endothelial growth factor, which is responsible for increasing capillary permeability and increased neoangiogenesis.
Classification
According to the location of foci of lymphatic hyperplasia, localized and multicentric forms are divided. Depending on the morphology, two variants of Castleman disease were previously distinguished: hyaline-vascular and plasmocellular. After clarifying the causal factors of the disease, a new histopathogenetic classification was adopted, according to which the existence of 4 variants of CD was recognized:
- Hyaline-vascular local. It is characterized by a lesion of one lymph node, an increase in the number of lymphoid follicles and increased blood circulation of the interfollicular zones. Histological examination determines hyalizinized germ centers and the absence of mitoses.
- Plasmocellular local. It differs from the previous version in the histological structure of the lymph nodes. Expanded germ centers with a narrow mantle zone, hyperplasized interfollicular regions are determined.
- Multicentric. This type of Castleman disease is characterized by multiple lesions of the lymph nodes, mixed cell or plasma cell morphology. It is accompanied by pronounced local and general clinical signs.
- HHV-8-associated plasmoblastic. A special variant of the multicentric form that occurs in people living with HIV. In 84%, it is combined with POEMS syndrome.
Symptoms
Most often, the disease affects the lymph nodes of the mediastinum. Typical localizations of hyperplasia also include cervical, axillary and retroperitoneal lymph nodes. The lymph node has a diameter of 1-25 cm, tumors of 6-7 cm are most often diagnosed. The skin above it is not changed, there are no subjective unpleasant sensations, so patients rarely consult a doctor at an early stage.
Multicentric and plasmocellular variants of pathology often cause systemic health disorders. Patients have subfebrile fever, excessive sweating, muscle weakness. Appetite decreases, so patients gradually lose weight. Hepatomegaly occurs in 63% of people with Castleman disease, in 33-79% of cases it is combined with an enlarged spleen.
In the later stages of the disease, clinical manifestations depend on the localization of hyperplastic lymphatic tissue. The defeat of the mediastinal nodes is accompanied by hoarseness of voice, difficulty breathing and swallowing, chest pain. The proliferation of intra-abdominal lymph nodes causes abdominal pain, dyspeptic disorders, urination disorders.
Complications
The multicentric form is recognized as the most dangerous, which is often accompanied by multiple organ failure – the main cause of death of patients with Castleman syndrome. The situation worsens when the disease is combined with Kaposi’s sarcoma and HIV infection, against which opportunistic infections join. The overall 5-year survival rate is at 55%.
With local forms, the main problem remains the violation of the function of neighboring organs. The defeat of intra-abdominal nodes is fraught with the development of mechanical intestinal obstruction, violation of the flow of bile into the duodenum. If the mediastinum is affected, respiratory failure is possible. At the same time, survival rates are much better: 94.5% of patients live longer than 5 years after diagnosis.
Diagnostics
In case of Castleman disease, a consultation of an oncogematologist is required. First, complaints and anamnesis are collected, then a physical examination is performed, lymphadenopathy is visually and palpationally determined, and nodes can be of different densities – from soft to stony hard. The program of advanced laboratory and instrumental diagnostics includes the following methods:
- Ultrasound of the lymph nodes. Ultrasound diagnostics is prescribed at the first stage of examination in order to differentiate inflammatory and tumor processes. With the help of sonography, it is possible to study the size, contours and internal structure of the lymph node.
- CT and MRI. Instrumental visualization is used to detect lymphoid hyperplasia, determine the size and localization of affected lymph nodes. In the images, the tumor mass looks like a homogeneous neoplasm with clear contours and an intense accumulation of contrast agent.
- Lymph node biopsy. To study the histological structure of the tumor and verify the diagnosis, an excision biopsy is prescribed, since a fine needle puncture biopsy is not informative enough. Immunohistochemical examination of a tissue sample allows to clarify the diagnosis.
- Blood test. In the hemogram, leukocytosis, thrombocytosis, anemia and increased ESR are detected. An increase in the level of C-reactive protein and other acute-phase indicators is characteristic. In the immunogram, an increase in interleukin-6 is detected, with a multicentric variant, a high level of immunoglobulin A, M G is determined.
Differential diagnosis
To diagnose Castleman disease, a complex differential diagnosis is performed between different lymphoproliferative pathologies. It is necessary to exclude:
- Hodgkin’s and non-Hodgkin’s lymphomas;
- sarcoidosis;
- Wegener’s granulomatosis;
- histiocytosis X.
With severe intoxication syndrome, reactive immunolymphoproliferative processes in viral, bacterial and parasitic invasions are excluded.
Treatment
Conservative therapy
Drug treatment is the method of choice for multicentric forms of pathology, the situation is complicated by the lack of uniform clinical recommendations, therefore, therapy methods are selected by oncogematologists individually, taking into account the clinical characteristics of each case. At the present stage of the development of medicine, such groups of drugs are prescribed:
- Cytostatics. To stop cell proliferation, alkylating drugs, anthracycline-type antitumor antibiotics, and semi-synthetic derivatives of podophyllotoxin are used.
- Monoclonal antibodies. The most studied activity of anti-CD20 antibodies (ritusuximab), which provide stable remission in 71% of patients with severe forms of Castleman syndrome. The new directions of therapy include the reception of anti-IL-6 antibodies.
- Proteosome inhibitors. Medications reduce the level of interleukin 6 in blood plasma, thereby reducing the severity of clinical symptoms and enhancing the response to combination therapy.
- Antiviral medications. With a proven correlation of Castleman disease with infection with herpesviruses, etiotropic drugs are prescribed. HIV-positive patients are required to undergo antiretroviral therapy according to one of the standard schemes.
Surgical treatment
In localized forms of the disease, radical surgical intervention is recommended – removal of the affected lymph node with subsequent histomorphological diagnosis. The best results are achieved with a hyaline-vascular type of tumor that does not relapse. In a multicentric process, surgical treatment is prescribed to remove particularly large foci that cause compression of neighboring organs.
Prognosis and prevention
In most patients with localized forms of Castleman disease, it is possible to achieve a complete cure. With multicentric variants, the prognosis is less favorable, especially in the group of patients with reduced immune status. After treatment, patients are under the medical supervision of a doctor for 3 years. Since the etiological factors of the disease are not precisely established, specific preventive measures have not been developed.