1. Introduction to the disease
Hodgkin Lymphoma, once known as Hodgkin’s disease, Hodgkin’s disease, or Hodgkin’s lymphoma. It is a cancer that originates in lymphocytes. The name “Hodgkin’s” comes from Thomas Hodgkin who first described this unique malignant disease of the lymphatic system in 1832. It often begins in a group of lymph nodes and then spreads to other lymph nodes or extra-nodal organs and tissues. Its histopathology is characterized by the presence of malignant Reed-Sternberg (Rice-S) cells. Currently, the application of chemotherapy, radiotherapy and bone marrow transplantation in the treatment of Hodgkin’s lymphoma has made it a curable tumor. Ou Jinping, Department of Hematology, Peking University First Hospital
2.Disease classification and pathology
The pathology of Hodgkin’s lymphoma is characterized by (1) total or partial destruction of the normal lymphoid tissue structure of the lymph nodes at the lesion site. (2) Multiple non-neoplastic reactive cellular components are present, mostly lymphocytes, and plasma cells, eosinophils, neutrophils, histiocytes, fibroblasts and fibrous tissue are also seen. A variable number of typical RS cells and their variants are scattered in the background of multiple reactive cellular components. They are the true tumor cells of Hodgkin’s lymphoma. Positive expression of CD15 and CD30 antigens in RS cells of classic Hodgkin’s lymphoma is an important immunological marker for identifying RS cells. Recent tests have demonstrated that RS cells are derived from lymphocytes, mainly B-lymphocytes. Hodgkin’s lymphoma often begins in one or a group of lymph nodes and gradually spreads to adjacent lymph nodes and to distant sites; Hodgkin’s lymphoma that originates outside the lymph nodes is rare. The lymph nodes involved in Hodgkin’s lymphoma are enlarged, non-adherent and mobile in the early stages, and cannot be easily pushed if they invade adjacent tissues. The lymph nodes adhere to each other and form large nodular masses. The cut surface is white and fish-like and may have small yellow focal necrosis.
The latest WHO classification divides Hodgkin’s lymphoma into nodular lymphocyte-predominant (NLPHL) and classical Hodgkin’s lymphoma (HL). The nodular lymphocyte-predominant type has a nodular growth pattern with a background of mostly lymphocytes and epithelial-like histiocytes, typical RS cells are rare, and most are variant lymphocytes and histiocytes called L/H (lymphocytic/ histocytic) cells with pleomorphic nuclei with vacuoles, small nucleoli, subnuclear perinuclear, and resembling “L/H cells express positive B-cell associated antigens (CD19, CD20, CD22, CD79a) and positive epithelial cell membrane antigen (EMA) while CD15 and CD30 are negative. The clinical manifestations are mostly limited lesions in the neck, with good local therapeutic efficacy and good prognosis. The classic Hodgkin’s lymphoma is divided into four subtypes: nodular sclerosis, lymphocyte-rich classical HL, mixed cellularity HL and lymphocyte depletion HL. The lymphocyte-depletion type is the least common, and the lymphocyte-dominant type is more likely to convert to the other types. The histological subtypes are the main factors in determining the clinical presentation, prognosis and selection of treatment options.
3. Causes
The etiology of Hodgkin’s lymphoma is still unknown, but the etiology of EBV has received the most attention, as EBV genomic fragments can be detected in RS cells of about 50% of patients. Patients with immunodeficiency and autoimmune diseases are known to be at increased risk of developing Hodgkin’s lymphoma. The 99-fold increased risk of Hodgkin’s lymphoma in siblings of monozygous twins may be due to the same genetic susceptibility to the cause and/or the same immune abnormalities.
4. Clinical manifestations
Hodgkin’s lymphoma accounts for 0.1% to 0.2% of all tumors. The annual incidence rate is 1/100,000~4/100,000 population, which is less common in Asia. In 1989, the annual incidence rate of Hodgkin’s lymphoma was 1.1/100,000 population in Shanghai, China, and it accounts for 16.5%~22.5% of lymphoma (34.6%~51.6% in western countries). There are more males than females (1.3 to 1.4:1). The age of onset is bimodal in developed countries, with the first age peak at 15-35 years old and the second age peak after 55 years old. In China and Japan, there is no bimodal distribution of the age of onset, and the onset is mostly in the 40s.
Hodgkin’s lymphoma is one of the most common malignancies in young people. The lesions mainly occur in lymph nodes, with cervical and supraclavicular lymph nodes being the most common, followed by mediastinal, retroperitoneal, and para-aortic lymph nodes. The lesion starts from one or a group of lymph nodes and usually shows regular station-by-station dissemination from the primary focus to the adjacent lymph nodes along the lymphatic tract. In advanced stages, hematogenous dissemination may occur, invading blood vessels and involving the spleen, liver, bone marrow, and gastrointestinal tract.
The common clinical manifestations of Hodgkin’s lymphoma are as follows.
(1) Lymph node enlargement is the most common clinical manifestation of Hodgkin’s lymphoma. 90% of patients present with lymph node enlargement, about 70% show cervical lymph node enlargement, and 50% have mediastinal lymph node enlargement. Lymph node enlargement is often painless and progressive. The enlarged lymph nodes can compress the adjacent organs and tissues, resulting in functional disorders and corresponding clinical manifestations. For example, edema of one limb, thoracoabdominal fluid, oliguria, etc.
(2) Clinical manifestations of extra-lymph node organ involvement: Hodgkin’s lymphoma with primary extra-lymph node organs or tissues is rare (<10%), but primary extra-lymph node or advanced involvement of extra-lymph node organs can cause anatomical and functional disorders of the corresponding organs, resulting in a variety of clinical manifestations. The common sites are the small intestine, stomach and pharyngeal lymphatic rings. It may involve the nervous system and cause paraplegia, skeletal involvement and pathological fracture, and may invade the bone marrow, breast and thyroid gland.
(3) Systemic symptoms can appear in 55% of patients at the first consultation, and 20% to 30% of patients show fever, night sweats and emaciation. The fever may be low fever, and 1/6 of patients have periodic fever (Pel-Ebstein fever), characterized by a gradual increase in body temperature over several days, reaching 38~40℃, which lasts for several days and then gradually decreases, and after an interval of 10 days or more, the body temperature rises again, and the interval is gradually shortened. In addition, there may be pruritus, weakness, and painful lymph nodes after drinking alcohol.
(4) Clinical manifestations of different histological types: nodular lymphocyte-dominant type accounts for 4% to 5% of HL. The median age of onset is 35 years old, with a male predominance and a male to female ratio of 3:1. The lesions usually involve the peripheral lymph nodes and are mostly early limited lesions at the time of initial diagnosis, with about 80% being stage I and II. The natural course of the disease is slow and the prognosis is good. The complete remission rate of treatment can reach 90%, and the 10-year survival rate is about 90%. However, patients with advanced stages (stages III and IV) have a poor prognosis. Lymphocyte-rich classic Hodgkin’s lymphoma accounts for about 6% of cases, is older on average, and is more common in men. Clinical features are intermediate between nodular lymphocyte-dominant type and classic Hodgkin’s lymphoma, often presenting as early term focal lesions, rare giant lesions, mediastinal lesions and B symptoms, with a better prognosis but lower survival rate than NLPHL. The nodular sclerosing type of classic Hodgkin’s lymphoma is most common in developed countries, accounting for 60% to 80% of cases. It is most commonly seen in young adults and adolescents, and is slightly more common in women. It often presents with lymphadenopathy in the mediastinum and other parts of the septum. The prognosis is better. The mixed cell type accounts for 15% to 30% of cases in Europe and the United States. It can develop at different ages. Clinical manifestations of abdominal lymph nodes and splenic lesions are more common, and about half of the patients are already in advanced stages (stages III and IV) at the time of consultation, with a poorer prognosis. The lymphocytic decompensation type is rare, about 1%. It is most common in the elderly and in patients with human immunodeficiency virus (HIV) infection. It often involves the abdominal lymph nodes, spleen, liver and bone marrow, and is usually widely disseminated at the time of diagnosis and prone to hematogenous dissemination. It is often associated with systemic symptoms, rapid disease progression and poor prognosis.
Clinical staging: The extent of Hodgkin’s lymphoma is determined by the Ann Arbor staging system.
Stage I Lesions are limited to one lymph node area or a single extra-nodal organ (IE).
Stage II The lesion involves two or more lymph node areas ipsilateral to the diaphragm, or the lesion is limited to invade extra-lymph node organs and more than one lymph node area ipsilateral to the diaphragm (IIE).
Stage III Lymph node lesions are present both above and below the diaphragm. It may be associated with splenic involvement (IIIS), limited extra-nodal organ involvement (IIIE), or splenic and limited extra-nodal organ involvement (IIISE).
Stage IV Extensive disseminated invasion of one or more extra-nodal organs, with or without lymph node enlargement. Any involvement of the liver or bone marrow is considered stage IV.
Group A: No systemic symptoms
Group B: With systemic symptoms: including unexplained fever (>38℃, for three consecutive days) or night sweats or weight loss (more than 10% within 6 months)
5.Diagnosis and differential diagnosis
The diagnosis of Hodgkin’s lymphoma depends mainly on the pathological examination of the diseased tissues, so surgical biopsy of the diseased lymph nodes or coarse needle aspiration biopsy of the deep tissues is especially important. After pathological diagnosis, the scope of lesions should be determined according to systemic symptoms, physical examination, laboratory tests and imaging examinations, and clinical staging should be clarified. Accurate staging is an important basis for formulating the correct treatment plan.1) Laboratory tests
(1) Blood picture shows that anemia is mostly seen in patients with advanced stage, which is orthopigmented and orthocytic anemia. Hemolytic anemia is occasionally seen, and Coombs test is positive in 2% to 10% of patients. Neutrophilia may be seen in a few cases, combined with immune thrombocytopenic purpura. Pancytopenia is seen in progressive cases or in patients with lymphocytic decompensation. Peripheral blood lymphocytopenia (<1.0×109/L), increased sedimentation, and elevated serum lactate dehydrogenase can be used as indicators to monitor the disease. Biochemical examination can be seen as hypercalcemia and hyperglycemia.
(2) Immunological examination suggests the presence of cellular immune deficiency in this disease, showing delayed cutaneous immune response hypoplasia and reduced CD4+ cells.
2）Imaging
(1) X-ray plain film: asymmetric nodular shadow is usually seen in the anterior and superior mediastinum bilaterally.
(2) CT: It may show multiple soft tissue masses without necrosis, hemorrhage or cystic changes within them, which are enhanced on enhanced scan. Enlarged nodules may eventually lead to significant occupying effects.
(3) MR: It can show a homogeneous signal mass with low T1WI signal and high T2WI signal intensity due to edema and inflammation. low T2WI signal can help to exclude the possibility of recurrence after treatment.
(4) PET-CT: The combination of FDG distribution and CT can be used to effectively assess the extent of the patient’s lesions and the degree of recurrence. Testing after two courses of chemotherapy is an important basis for evaluating whether there are risk factors for treatment failure and whether such patients can benefit from intensive therapy.
(5) Bone radiographs and bone scans are examined when skeletal invasion is suspected.
(3) Differential diagnosis
The differential diagnosis of this disease often requires differentiation from lymphatic tuberculosis, viral infections such as infectious mononucleosis, nodular disease, and non-Hodgkin’s lymphoma. It should also be distinguished from metastatic cancer. Enlarged lymph nodes in the neck should be excluded from nasopharyngeal carcinoma and thyroid carcinoma, mediastinal masses should be excluded from lung cancer and thymoma, and enlarged lymph nodes in the axilla should be distinguished from breast cancer. The differentiation of the above diseases mainly relies on pathological histological examination. Clinicians should make a comprehensive diagnosis by integrating the clinical manifestations and pathological examination results, including the pathological type and clinical stage grouping of Hodgkin’s lymphoma.
6.Disease treatment
The treatment of Hodgkin’s lymphoma is a combination treatment plan with chemotherapy as the mainstay and radiotherapy as a supplement.
The application of modern chemotherapy and radiotherapy has made Hodgkin’s lymphoma a curable tumor, but the follow-up results of a large number of long-term surviving patients show that the 15-year mortality rate is 31% higher than that of the general population, and the second tumors account for 11% to 38% of the causes of death (solid tumors and acute non-lymphoblastic leukemia), 13% of acute myocardial infarction, and 1% to 6% of pulmonary fibrosis. Alkylating agents (nitrogen mustard, cyclophosphamide) and procarbazine in MOPP and COPP chemotherapy regimens can cause acute non-lymphocytic leukemia and infertility, and anthracyclines such as adriamycin in ABVD regimens can cause delayed cardiac damage such as heart failure. Bleomycin can produce pulmonary fibrosis. Radiotherapy can cause solid tumors (e.g., lung, breast, gastric, bone, and thyroid cancer), cardiac damage that increases the risk of acute myocardial infarction threefold (cape field irradiation), radiation pneumonia (cape field irradiation) and infertility (irradiation of ovaries and testes). Based on the new understanding of the distant complications of HL treatment, new treatment strategies to prevent and reduce severe distant complications and improve the quality of survival have been proposed. The current treatment of early-stage Hodgkin’s lymphoma is mainly based on the clinical stage of patients combined with prognostic factors to develop new treatment strategies. The main poor prognostic factors include: age >50 years, B symptoms (mainly referring to fever and wasting), mediastinal or splenic giant mass lesions (giant mass refers to a maximum mass diameter ≥10 cm, and mediastinal giant mass refers to a maximum mass diameter ≥1/3 of the internal diameter of the thoracic cavity at the level of 5-6 thoracic vertebrae on posterior anterior chest X-ray), lesions with involvement of ≥3 lymph node areas, rapid hematocrit (≥30 mm/h with B symptoms, ≥ Since the 1990s, analysis of the treatment data of millions of electron volt X-rays has resulted in 98% tumor control rate in the irradiated field, 32.4 Gy for subclinical foci, 36.9 Gy for <6 cm tumors, and 37.4 Gy for >6 cm tumors. new data suggest that the irradiation dose can be reduced appropriately. According to the different characteristics of radiotherapy and chemotherapy and the difference of long-term complications, the organic combination of strengths and weaknesses can be used to reduce the radiation dose and radiation field, while the number of chemotherapy cycles and the application of alkylating agents can be reduced appropriately. Appropriate application of anthracyclines and bleomycin can reduce the complications of cardiac damage and pulmonary toxicity. The use of ABVD chemotherapy regimen can avoid second tumors and sterility, thus reducing long-term complications and improving the quality of life while maintaining or improving the cure rate of early-stage (stage I and II) Hodgkin lymphoma. Because the treatment response rate, progression-free survival and toxicity tolerance of ABVD chemotherapy regimens are superior to those of conventional MOPP regimens or MOPP/ABVD alternate regimens, this regimen is now the first choice for Hodgkin’s lymphoma treatment.
Treatment of advanced (stage III and IV) Hodgkin’s lymphoma: Combination chemotherapy is the main treatment for advanced (stage III and IV) Hodgkin’s lymphoma. The commonly used combination chemotherapy regimen is the ABVD regimen, which has a treatment complete remission rate of 75% to 82%. A total of 6 to 8 cycles are usually required. The cure rate for stage III and IV patients is 50% to 70%. Macroscopic lesions or residual lesions should be treated with additional focal field radiotherapy.
1) There are three popular chemotherapy regimens.
(1) ABVD regimen: born in Italy in the 1970s, it is currently the preferred chemotherapy regimen. The four letters of the name come from the four drugs used in the therapy, Adriamycin, Bleomycin, Vincristine, and Dacarbazine.
(2) Stanford Ⅴ regimen: It was born in 1988. It is usually half the course of chemotherapy as ABVD, but with a higher dose of drugs. The 5-year survival rate is higher with the ABVD regimen than with this regimen. This regimen focuses on radiotherapy for masses larger than 5 cm in diameter and large spleens.
(3) BEACOPP regimen: Invented by the Hopkins Research Group in Germany, it is popular in Europe. This therapy is mainly for patients after stage II. The drugs used include: adriamycin, bleomycin, vincristine, procarbazine, etoposide, and prednisone. Studies have shown that the cure rate of this therapy for non-early stage patients is 10%-15% higher than that of ABVD for similar patients, but there is no statistical difference in overall survival and secondary progression-free survival.
(2) Principles of chemotherapy
(1) Stage IA-IIA non-megaloblastic patients are treated with ABVD regimen × 4 courses, and local radiotherapy (20~30Gy) in the involved field after remission. It can also be radiotherapy alone.
(2) Stage I A-II A giant mass type patients are treated with ABVD regimen × 4~6 courses and local radiotherapy after remission (36Gy for initial lesion >5cm in the involved field), radiotherapy should include mediastinum and bilateral supraclavicular region.
(3) Patients with stage I B-II B and stage III-IV and all stages of lymphocytic decompensation should be treated with ABVD protocol × 6~8 courses of local radiotherapy after remission (36Gy for initial lesions >5cm in the involved field and 36Gy for lesions in the splenic area).
(4) Patients with NLPHL stage IA-IIA can be irradiated with the involved field alone. Stage III-IV can be combined with chemotherapy alone, together with post-remission irradiation of the involved field. Chemotherapy is chosen to include an alkylating agent-based regimen, and melphalan can be added to the treatment to improve the efficacy.
(5) Salvage therapy: Refractory cases that cannot achieve complete remission with combination chemotherapy in primary treatment or relapsed cases after complete remission need to be given salvage therapy. Chemotherapy regimens such as ICE, DHAP, ESHAP, Mini-BEAM, MINE, etc. can be chosen. Chemotherapy combined with local radiotherapy is used for recurrence after radiotherapy alone. Short-term (within 12 months) relapse cases and refractory cases that cannot achieve complete remission with primary treatment combined with chemotherapy regimen should be treated with high-dose chemotherapy combined with autologous hematopoietic stem cell transplantation, in which cases that are still sensitive to chemotherapy have better efficacy with long-term survival rate of 30% to 50%. Allogeneic hematopoietic stem cell transplantation is an option for young patients in the progressive stage. The reduced pretreatment dose of transplantation reduces transplantation-related mortality and is a transplantation modality that is likely to be widely performed in the future.
(6) New drugs for the treatment of recurrent classic Hodgkin’s lymphoma: clinical trial results of the targeted drugs CD30 monoclonal antibody, SGN35 and Panobinostat, an inhibitor that acts on histone deacetyl kinase, show promising applications. Meroval, lenalidomide and autologous LMP2 protein-specific CTL for the treatment of recurrent EBV+ Hodgkin’s lymphoma have opened new paths for the control of this tumor.
7. Disease prognosis
(1) Poor prognostic factors for primary Hodgkin’s lymphoma.
(1) Macroscopic lesions: mediastinal mass (chest X-ray): maximum diameter of the mass/maximum intrathoracic diameter > 1/3; mass exceeding 35% of the intrathoracic diameter at T5-6; CT showing any mass > 10 cm in diameter
(2) ESR≥50mm/1h
(3) More than three sites
(4) B symptoms
(5) Extra-nodal lesions
(2) International prognostic factors for progressive lesions.
(1) Albumin <40g/L
(2) Hemoglobin <105g/L
(3) Male
(4) Age ≥45 years
(5) Stage IV lesions
(6) leukocytosis, ≥15×109/L
(7) Lymphocytopenia, <8% and/or 0.6×109/L
Each increase in one of the above factors decreased the 5-year progression-free survival rate by 7%. The overall survival rate decreased from 84% (0/7 prognostic factors) to 42% (5-7/7 prognostic factors).
8. Disease prevention
The main measures for prevention of malignant diseases of the hematological system, including malignant lymphoma, should pay attention to avoiding the factors that cause the development of the disease.
(1) Prevention of viral infections, such as EBV, adult T-lymphocytic leukemia virus, HIV, etc., prevention of colds in spring and autumn, strengthening their own protection and overcoming bad habits.
2) Remove environmental factors, such as avoiding exposure to various rays and some radioactive substances. Avoid contact with relevant toxic substances, such as benzene, vinyl chloride, rubber, arsenic, gasoline, organic solvent paint, etc.
3) Prevention and control of autoimmune deficiency diseases, such as immune deficiency status after various organ transplants, autoimmune deficiency diseases, after chemotherapy for various cancers, etc. Because graft-versus-host disease or immunosuppressants can activate the virus and promote its proliferative effect of inducing lymphoid tissue.
4) Long-term surviving patients should have regular annual chest and breast examinations for early detection of treatment-related complications and the possibility of second tumors.
5) Maintaining a healthy attitude of optimism and self-confidence and appropriate physical exercise will help the stability of the body’s immune function and clear the invasion of foreign factors in a timely manner.
(6) Early diagnosis and early comprehensive treatment should be achieved for those at risk or those with risk factors found. The treatment of the disease should be comprehensive, including nutritional supplementation, central venous cannulation and total parenteral nutrition if necessary, and supplementation of blood products as needed, in addition to treatment for the cause of the disease.
The success or failure of comorbidity control often has a significant impact on the prognosis of the disease, especially the control of opportunistic infections during the immunosuppression phase. Particular attention should be paid to tuberculosis, fungal infections, hepatitis and cytomegalovirus infections.