Megalymph node hyperplasia (Castleman’s isease, CD), also known as vascular follicular lymphoid hyperplasia, is a rare lymphoproliferative disorder. The disease was first reported by Castleman et al. in 1956 (1), and the two main clinical types are monocentric and multicentric. The monocentric type is mostly limited to a single lymph node, while the polycentric type typically presents with multiple enlarged lymph nodes throughout the body. Histology is divided into three main types: 1) hyaline vascular type 2) plasma cell type and 3) mixed type. Hyaline vascular CD accounts for approximately 90% of patients with monocentric CD (2). Whereas the majority of patients with multicentric CD are plasma cell type, the mixed type has both. The disease is mostly located in the thorax, especially in the mediastinal region, and is predominantly monocentric and rare in the multicentric form. The monocentric form can be cured by surgical excision, but the multicentric form is very difficult to treat and has a poor prognosis. Although the research has been progressing, there is still a lack of in-depth understanding of the pathogenesis, clinical features, treatment and prognosis of this disease, and the diagnosis and treatment are limited.
Pathogenesis.
The pathogenesis of CD is still unknown, and recent studies have mostly shown that the origin of the disease is due to an overproliferation of B lymphocytes and plasma cells in the lymph nodes caused by a defect in immune regulation (3). Similarly, there are immunological studies confirming that the pathogenesis of CD may be related to viral infections. Conversely, there are case reports suggesting that CD can occur without evidence of significant viral infection (4). A few cases have been reported to be associated with the development of Kaposi’s sarcoma (5). Recent studies have found that human herpesvirus 8
,HHV-8) sequence is present in multicenter CD, suggesting that HHV-8 may play a role in the pathogenesis of CD (6). It has also been found that CD may be associated with certain diseases such as HIV infection,, POEMS syndrome, amyloidosis, renal insufficiency, and lymphoma (7-10).
Morbidity.
Giant lymphatic graft hyperplasia is a rare benign lymph node hyperplastic disease, and no exact incidence has been reported so far. More than 500 cases have been reported internationally so far, and the maximum number of cases abroad is 85, reported by Sarrot-ReynauldF et al. in 1998 (11), and the maximum number of cases in China is 43, reported by Ye Bo and Sun Kling et al. in 2009 (12). The most common type reported so far is the monogenic CD described by Castleman et al. in 1956
(1), while multiple types are relatively uncommon. Interconversion of monocentric type with polycentric has not been reported so far.
Pathological typing.
CD pathology is divided into three main types: 1) hyaline vascular type 2) plasma cell type 3) mixed type. 90% of monocentric CD is hyaline vascular type
(2), most patients with multicentric CD are plasma cell type, and the mixed type has both. The pathology of the hyaline vascular type is characterized by follicular hyperplasia of the lesioned lymph nodes and interfollicular small vessel hyperplasia and hyaline changes, with some small lymphocytes arranged in a circular pattern around the germinal center (resembling an onion skin-like structure). The pathology of the plasma cell type is characterized by enlarged follicles with patches of plasma cells in the diseased lymph nodes, and the vascular hyperplasia is less than that of the hyaline vascular type. The pathological manifestations of the mixed type are marked thickening of the lymph node perithelium, increased number of lymphatic follicles, some active follicles, capillary penetration, and concentric arrangement of small lymphocytes in the follicular coat. Plasma cells, small lymphocytes and small blood vessel proliferation are evident between the follicles.
Clinical features.
CD can occur at any age and can even occur in infants and children, with adult onset being more common. The mean age of onset of CD is approximately 35 years in two large domestic studies (12,13). The monogenic form has no obvious clinical manifestations and may occasionally present with local symptoms due to compression of the surrounding airways by enlarged lymph nodes, whereas the polymorphic form may be associated with significant systemic symptoms.
The onset of CD is widespread, and can develop in any tissue with lymph nodes. The disease is mostly located in the thorax, especially in the mediastinal region. According to Gotway MB et al, the most frequent site of CD is the thoracic cavity, with monocentric CD accounting for 60% to 70%. A domestic study by Zhou Naikang et al. showed that the good sites of CD in the chest included the right upper mediastinum, right posterior mediastinum, left upper mediastinum, left hilar, right hilar, and right upper lobe of the lung (13). In contrast, Ye Bo and Sun Kling et al. showed that CD was more frequent in the chest in about 50% of cases, followed by the neck and abdomen, while other sites were not common (12).
The systemic and primary symptoms of CD are also related to its histologic classification. 97% of patients with hyaline vascular CD may have no obvious symptoms at presentation, but some may have symptoms of tracheobronchial or peripheral vascular compression due to enlarged lymph nodes, such as dyspnea, dry cough, chest pain, hemoptysis, and venous irritation. This type is mostly benign and has a self-limiting trend, with a five-year survival rate of nearly 100%, and symptoms can disappear after surgical excision of the lesion. Although plasma cell type is a rare type in CD classification, it progresses faster clinically (2). Although the lesions may be limited, they may be accompanied by systemic symptoms such as fever, night sweats, malaise, anemia, increased ESR, weight loss, polyclonal hypogammaglobulinemia, and plasmacytosis in the bone marrow (14), and there may be multi-organ lymph node invasion. Most of these systemic symptoms may disappear after surgical removal of the lesion.
Diagnosis.
Megalymph node hyperplasia is a complex clinical disease with histological features completely different from lymphoma, although its clinical presentation resembles lymphoma.CD usually presents as polyclonal lymph node hyperplasia and rarely as lymphoma-like monoclonal hyperplasia. CD has also been found to be associated with some acquired immunodeficiency diseases, HIV infection, Kaposi’s sarcoma, some tumors and hematologic diseases, and membranous glomerulonephritis.
Nowadays, there is still no significant progress in the preoperative diagnosis of CD, relying mostly on preoperative chest radiographs, CT and other imaging examinations and various laboratory tests. However, the preoperative diagnosis of CD is very difficult due to the possibility of CD in any tissue with the presence of lymph nodes (5). In terms of imaging, conventional imaging examinations are difficult to achieve a definitive diagnosis. It has been demonstrated that the reason why ultrasound, CT, MRI, FDG-PET, etc. have been used to diagnose CD but are difficult to confirm the diagnosis is that the imaging manifestations of CD are extremely similar to a variety of diseases that are difficult to distinguish, such as lymphoma, tuberculosis, nodular disease, retroperitoneal sarcoma, etc. (15). In terms of laboratory tests, although the multicentric type is often associated with hepatosplenomegaly, anemia, renal insufficiency, POEMS syndrome, and can be accompanied by Kaposi’s sarcoma and immunodeficiency syndrome, laboratory tests can reveal abnormalities in blood routine, liver function, ESR, and renal function, but no specific laboratory tests have been found for the diagnosis of CD.
Therefore, a correct diagnosis of CD requires a comprehensive analysis of clinical manifestations, histology, imaging and immunohistochemistry first (16), and relies on pathological findings to make the final diagnosis.
Treatment.
Existing treatments for CD include surgical resection, chemotherapy, and radiotherapy. There is no consensus on the exact treatment of CD. Surgical resection is so far considered to be the most appropriate treatment for monocentric CD. Hee Yeon Seo et al. applied CHOP chemotherapy regimen and Harada N et al. applied interleukin-6 receptor antagonist to treat inoperable CD with good results (4,17). The widespread use of thoracoscopy in the resection of some benign mediastinal lesions also suggests that thoracoscopic resection of hyperplastic lymph nodes can be an effective alternative to traditional open thoracotomy (18,19). In terms of surgical treatment, CD requires adequate preoperative preparation because of its rich blood supply, complex surrounding anatomy, and close proximity to blood vessels and nerves. Domestic studies have shown that CD surgery takes a long time and can involve a large amount of blood loss during surgery, so comprehensive preoperative imaging and adequate blood preparation are necessary for the surgical treatment of CD. In terms of chemoradiotherapy, there are many chemotherapy regimens reported in the literature, and there is no uniform chemotherapy regimen. Some chemotherapy regimens have achieved good results, such as the CHOP chemotherapy regimen applied by Hee Yeon Seo et al. Some scholars have also achieved good results in treating monocentric CD that cannot be surgically resected by radiotherapy.
The prognosis of CD can vary depending on the histological staging and clinical staging. Monocentric types tend to have a good prognosis, and monocentric and some multicentric types are less likely to recur after complete surgical resection, but recent literature has reported that multicentric CD has a poor prognosis and is prone to recurrence or development of non-Hodgkin’s lymphoma, Kaposarcoma, and Hodgkin’s disease leading to death (8,20).
Given the rarity of giant lymph node hyperplasia and the diversity of clinical presentations, it has not been studied prospectively in a very effective way so far. Therefore, there are still many unanswered questions. For example, the pathogenesis, the role of HHV-8 in the disease, the pathological relationship between CD and lymphoma and the choice of treatment for multicentric CD. However, by analyzing the existing literature, we found that there is a clear difference between monocentric and multicentric types. The monocentric type mostly has no obvious clinical symptoms and recovers well after surgical resection of the lesion with lower recurrence; the multicentric type mostly has systemic symptoms and recurrence is seen after surgical resection.