Castleman’s disease (CD) is one of the reactive lymphadenopathies of unknown origin and is relatively rare in clinical practice.
I. Introduction
Castleman’s disease (CD) is one of the reactive lymphadenopathies of unknown origin and is a relatively rare clinical condition. The pathology is characterized by distinct lymphatic follicles, blood vessels and plasma cells in varying degrees of hyperplasia, and is characterized clinically by significant enlargement of deep or superficial lymph nodes.
CD was first described in the 1820s, and in 1954 Castleman et al. formally reported a tumor-like mass confined to the mediastinum, with histology showing marked hyperplasia of lymphatic follicles and capillaries called vascular follicular lymphnode hyperplasia. 1969 Flendring and Schillings proposed another morphologic subtype of CD, characterized by plasma cell hyperplasia, often with systemic symptoms. The disease is also known as giant lymphnode hyperplasia because the enlarged lymph nodes are often very pronounced, sometimes reaching more than 250 px in diameter.
Etiology
The etiology of CD is unknown. Some authors have suggested that abnormal immune regulation is the initiating factor of CD. 25% of central cases are clinically confirmed to be associated with HHV-8 infection, and it is also believed that at least some CD is at risk of B-cell malignant hyperplasia, and a few multicentric types can be transformed into malignant lymphoma. However, most of the cases followed did not turn into malignant tumors.
III. Pathology
Biopsy of enlarged lymph nodes shows the specific pathological changes of CD described above. The lesions mainly involve lymphatic tissues anywhere in the body and may occasionally affect extra-nodal tissues CD pathology is divided into the following two types.
Hyaline vascular type: 80% to 90% of the cases. The lymph nodes are 3-175 px in diameter, with the larger ones reaching 625 px and weighing up to 700 g. Microscopically, many enlarged lymphatic follicle-like structures are seen in the lymph nodes, which are scattered. There were several small vessels penetrating into the follicles, and the endothelium of the vessels was obviously swollen, with thickened walls and glass-like changes in the later stages. There was a variable amount of eosinophilic or hyaline material distributed around the vessels. The follicles were surrounded by multiple layers of lymphocytes arranged in a circular center, forming a special onion skin-like structure or a cap-like band with more capillaries with thickened walls and lymphocytes, plasma cells, and immunoblasts between the follicles, and the lymphatic sinuses disappeared or were fibrotic. In some cases, the hyperplastic lymphoid follicles consist mainly of small lymphocytes, with only a few follicles containing small germinal centers, called the lymphocytic type. This type is most easily confused with follicular lymphoma.
Plasmacytoid type: 10% to 20% of cases. Patients often have systemic symptoms, such as fever, malaise, weight loss, anemia, increased erythrocyte sedimentation rate, increased blood gammaglobulin and hypoalbuminemia. Symptoms may disappear after lymph node dissection. Microscopic examination also shows follicular hyperplasia in the lymph nodes, but the lymphocytic proliferation around the small vessels and follicles is much less pronounced than in the clear-vessel type, and there is usually no typical onion skin-like structure. The main feature of this type is the proliferation of interfollicular plasma cells at all levels in patches, and Russell’s vesicles can be seen, while a few lymphocytes and immunoblasts are still present. This type has been described as the active phase of the hyaline vascular type and may have TCRβ or IgH gene rearrangement. A few patients with plasma cell type have been reported to have Kaposi’s sarcoma, with AIDS with CD being the most common.
A small number of patients have multiple lymph node involvement and extra-nodal multi-organ invasion, and the pathology of both types is called mixed type. A few patients with a single lesion that has both of the above two types of pathology are considered to have a mixed type in another sense.
Pathogenesis
Because of the presence of more than one angiogenic center in the follicles of lymph nodes, some cases also have angiolipoma components, and the lesions can also occur in areas where lymphoid tissue is not normally present, it has been considered to be a kind of malformation tumor, and the angiographic images are similar to those of other vascular malformations. CD with predominantly plasma cell hyperplasia is thought to be associated with infection (mainly viral) and inflammation because of its inflammatory pathology, such as plasma cell immunoblast and capillary hyperplasia with preservation of residual lymph node structures; clinical signs of inflammatory lesions, such as increased sedimentation, hypoalbuminemia, and polyclonal immunoglobulin increase in chronic disease anemia. Some authors have suggested that abnormal immune regulation is the initiating factor of CD, such as AIDS, a typical immunodeficiency disorder, can occur simultaneously with CD and Kaposi’s sarcoma, and a few CDs can be transformed into Kaposi’s sarcoma; clinically some patients have autoimmune hematocrit, positive antinuclear antibody rheumatoid factor or positive anti-human globulin test. Some authors have suggested that CD is a preneoplastic lesion because of the monoclonal nature of immunohistochemical staining of plasma cells in CD lesions, the presence of a single immunoglobulin in the blood of individual patients, and the transformation of a few patients with a multicentric phenotype into malignant lymphoma.
The involvement of IL-6 in the pathogenesis of CD has been more frequently reported, e.g., IL-6 gene transfer into hematopoietic stem cells of mice can successfully obtain a pathological model similar to CD. It has also been shown that B lymphocytes in the lymph node germinal centers of CD can secrete and produce large amounts of IL-6. After lesion excision, the increased serum IL-6 level decreases as the clinical condition improves. In addition, the involvement of human herpesvirus 8 (HHV-8), known as Kaposi’s sarcoma herpesvirus (KSHV), in the pathogenesis of CD has been confirmed in animal studies.
V. Symptoms
CD is clinically divided into focal type and multicentric type.
1. focal type It is more common in young people, with a median age of 20 years. 90% of the pathologies are hyaline vascular type. Patients present with painless enlargement of a single lymph node, which grows slowly to form a huge mass with a diameter from a few centimeters to about 500 px. It can occur in any part of the lymphatic tissue, but mediastinal lymph nodes are the most common, followed by cervical, axillary and abdominal lymph nodes. Most of them have no systemic symptoms and can survive for a long time after resection, i.e., benign course. 10% have plasma cell type pathology and abdominal lymph node involvement is common, often accompanied by systemic symptoms such as prolonged hypothermia or hyperthermia, lethargy and anemia, etc. The symptoms can all subside after surgical resection and do not recur.
2.Multicentric type is less common than focal type, with a later age of onset and a median age of 57 years. Patients have multi-located lymph node enlargement easily involving superficial lymph nodes. It is associated with systemic symptoms (e.g. fever) and hepatosplenomegaly, often with manifestations of multisystem involvement such as nephrotic syndrome, amyloidosis, myasthenia gravis, peripheral neuropathy, temporal arteritis, Schegren’s syndrome (dry syndrome), thrombotic thrombocytopenic purpura and inflammatory reactions of the oral cavity and cornea in 20% to 30% of patients. In a small number of patients, the presence of polyneuropathy, organ enlargement (liver, spleen), endocrinopathy, serum monoclonal immunoglobulin and skin lesions constitute clinical signs of POEMS syndrome. In addition, the multicentric form often has an aggressive clinical course and is prone to infections.
Complications.
1.About 1/3 of patients may have Kaposi’s sarcoma or B-cell lymphoma.
2. Combination of neurological, endocrine and renal lesions, as well as Schelgren’s syndrome (dry syndrome) and thrombotic thrombocytopenic purpura.
VI. Examination
Laboratory tests
1. Peripheral blood Mild to moderate orthocytic orthochromic anemia, some cases with leukocytosis and/or thrombocytopenia may also be manifested as chronic disease anemia of typical firepot network.
2.Bone marrow picture Some patients have elevated plasma cells ranging from 2% to 20%, with basically normal morphology.
3, blood biochemical and immunological examination liver function can be abnormal, manifested as serum aminotransferase and bilirubin levels rise in a few patients with renal involvement serum creatinine levels rise in serum immunoglobulin is polyclonal elevation, more common, a few serum appear M protein, blood sedimentation also increased accordingly. Some patients have positive anti-nuclear antibody rheumatoid factor and anti-human globulin test.
4, urinary routine urine protein is mildly elevated, if accompanied by nephrotic syndrome, there is a large amount of protein.
Other tests.
Pathological examination, X-ray, CT, ultrasound and ECG are selected according to clinical manifestations, symptoms and signs.
Related tests: Coombs test, monoclonal gammaglobulin, antinuclear antibody, plasma cells, rheumatoid factor, creatinine anhydride, protein quantification (urine), platelets, blood sedimentation.
Ancillary tests
1. Histopathology Biopsy of enlarged lymph nodes shows specific pathological changes of CD as described above. The lesions mainly involve lymphatic tissues anywhere in the body, and may occasionally spread to extra-nodal tissues CD pathology is divided into the following two types.
(1) hyaline vascular type: 80% to 90% of lymph nodes show many enlarged lymphoid follicle-like structures in a scattered distribution. There were several small vessels penetrating into the follicles, with marked swelling of the endothelium, thickening of the walls, and glass-like changes at a later stage. There was a variable amount of eosinophilic or hyaline material distributed around the vessels. The follicles were surrounded by multiple layers of lymphocytes arranged in a circular center, forming a special onion skin-like structure or a cap-like band with more thickened capillaries and lymphocytes, plasma cells, and immunoblasts between the follicles, and the lymphatic sinuses disappeared or were fibrotic. The lymph nodes were 3-175px in diameter, with the larger ones reaching 625px and weighing up to 700g.
(2) Plasma cell type: 10%-20%. The lymph nodes also show follicular hyperplasia, but the lymphocytic hyperplasia around the small vessels and follicles is much less obvious than that of the clear vascular type, and there is generally no typical onion skin-like structure. The main feature of this type is the proliferation of interfollicular plasma cells at all levels in patches, and Russell’s vesicles can be seen, while a few lymphocytes and immunoblasts are still present. This type has been described as the active phase of the hyaline vascular type and may have TCRβ or IgH gene rearrangement. In a small number of patients, the lesion involves multiple lymph nodes with extra-nodal multi-organ invasion, and the pathology is characterized by both of these types. A small number of patients with a single lesion that has both of these pathological features are also known as mixed type in another sense. It has been reported that a few patients with plasma cell type can have Kaposi’s sarcoma, and it is more common to have AIDS with CD.
2. X-ray, CT, ultrasound and electrocardiogram are selected according to clinical manifestations, symptoms and signs.
VII. Diagnosis
The clinical manifestations of CD are not specific. Any person with obvious enlargement of lymph nodes with or without systemic symptoms should think of the possibility of CD, and a lymph node biopsy should be performed to obtain the above-mentioned typical pathological changes of CD in order to make a diagnosis, i.e. the diagnosis of CD must be confirmed with pathological arguments, and then a typological diagnosis should be made according to clinical manifestations and pathology. Various possible related diseases should also be excluded before the diagnosis is confirmed.
Differential diagnosis.
CD should be differentiated from malignant lymphoma, various lymph node reactive hyperplasia (mostly due to viral infection), plasmacytoma, AIDS and rheumatic diseases. They have certain similar clinical manifestations and/or pathological changes, and careful pathological examination, including immunohistochemical examination, and the detection of certain primary diseases are the main points of differentiation. The enlarged lymph nodes of this disease must be distinguished from the following diseases.
Lymphoma may have persistent or periodic fever, generalized itching, splenomegaly, and wasting. In contrast, the clinical symptoms of this disease are mild, with only malaise or symptoms arising from organ compression.
2. Vascular immunoblast lymphadenopathy is an abnormal non-tumorigenic immunoproliferative disease. Clinically, it is mostly seen in women with fever, generalized lymph node enlargement may have rash and pruritus of the skin adjuvant examination leukocytosis, increased blood sedimentation, ineffective antibiotic treatment, hormone can improve the symptoms. Lymph node pathology shows destruction of lymph nodes and capillary wall hyperplasia as immunoblasts. Intervascular endothelial cells are PAS positive with amorphous material deposition and intercellular deposits of eosinophilic structureless material. Biopsy can be distinguished.
3, primary macroglobulinemia The disease is mainly a proliferation of lymph-like plasma cells secreting large amounts of monoclonal macroglobulin, and extensive infiltration of bone marrow and extramedullary organs. A large number of monoclonal IgM in the serum, no bone destruction without renal damage, clinical hepatic and splenic lymph node enlargement, about half with hyperviscosity.
Multiple myeloma is a common type of plasma cell disease in which proliferating plasma cells (or myeloma cells) infiltrate bones and soft tissues causing a series of organ dysfunctions, with clinical manifestations of bone pain, anemia, renal impairment and abnormal immune function, and hypercalcemia. Myeloma cells mostly infiltrate the liver, spleen, lymph nodes and kidney. CD lymph node enlargement is obvious and can be identified by lymph node biopsy.
VIII. Treatment
All focal CDs should be surgically removed, and the majority of patients can survive for a long time with few recurrences. Focal CD of plasma cell type, if accompanied by systemic symptoms, can disappear rapidly after removal of the diseased lymph nodes.
For multicentric CD, if the lesion only affects a few sites, it can be removed surgically, and chemotherapy or radiotherapy can be added after surgery. Chemotherapy is usually chosen as a combination chemotherapy regimen for malignant lymphoma. Autologous hematopoietic stem cell transplantation is also a treatment option.
IX. Prognosis
The prognosis is good in focal lesions, but poor in multicentric with monoclonal hypogammaglobulinemia and prone to malignant transformation or lymphoma.