Introduction to Lymphoma
Lymphomas are a complex group of tumors of the hematopoietic system. Pathologically, they can be divided into two categories: Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). Lymphoma ranks 8th among the most common types of tumors in China, with an incidence rate of about 6.68/100,000, and the incidence rate is increasing year by year. Different pathological subtypes of lymphoma differ greatly in pathogenesis, clinical manifestations, treatment modalities and prognosis.
Pathological classification]
The current pathological classification of lymphoma is the WHO classification of lymphoma established in 2008, which follows the principle of MICM, i.e. morphology, immunohistochemistry, FISH (cytogenetic) and gene rearrangement detection (molecular) to form Comprehensive diagnosis. It should be noted that the primary site of the lesion and the clinical manifestations are crucial to the pathological typing of lymphoma (e.g., primary cutaneous interstitial large cell lymphoma, diffuse large B-cell lymphoma (leg type)), so clinicians should provide as much detailed medical history as possible when sending specimens for examination. In addition, the pathological diagnosis of lymphoma requires adequate pathological specimens, so specimens should be retained for excision or excisional biopsy as much as possible, and fine needle aspiration biopsy should be avoided as much as possible.
For HL, the 2008 WHO classification divides it into nodular lymphocyte-dominant HL and classic HL, which is further divided into nodular sclerosis, mixed cell type, lymphocyte attenuated type and lymphocyte-rich type.
In contrast, the classification of NHL is more complex, and there is still some disagreement about certain subtypes. According to the cell source, there are two major categories of B-cell NHL and T/NK-cell NHL.
Clinical manifestations
1. Lymph node enlargement. Lymph node enlargement of unknown cause is the most common and typical clinical manifestation of lymphoma, and HL mostly invades superficial lymph nodes, and the involvement is mostly continuous. In contrast, the lymph nodes involved in NHL are mostly jumpy.
The proportion of extra-nodal invasion in NHL is 20-50%, and the common sites of extra-nodal invasion include gastrointestinal tract, nasal cavity and skin. When extra-junctional organ invasion may have gastrointestinal bleeding, perforation, nasal congestion, epistaxis, rash and other manifestations.
3. Systemic symptoms. Patients with lymphoma may show systemic symptoms such as unexplained fever, wasting, night sweats (collectively called group B symptoms), as well as anemia and cachexia caused by tumor.
[Pre-treatment examination and staging
The main staging examinations for lymphoma include: (1) routine blood, biochemical and coagulation tests; (2) whole-body CT or MR imaging to clarify the extent of lesions; in recent years, PET-CT has played an increasingly important role in guiding the treatment and prognosis of lymphoma, so patients who have the conditions should try to have PET-CT examination; (3) bone marrow aspiration and biopsy to clarify whether there is bone marrow invasion; (4) (4) Endoscopy is required for lymphoma in certain specific primary sites (e.g. nasopharynx, gastrointestinal tract); (4) Hepatitis screening: patients with lymphoma have a high rate of hepatitis B infection and are at risk of viral activation during treatment, so screening should be improved and appropriate preventive measures should be taken; (5) Special pathogenic screening: the development of certain lymphomas is closely related to pathogenic infections, such as MALT lymphoma (Helicobacter pylori), NK/T cell lymphoma (EBV), etc.
The Ann Arbor staging system is currently the common staging system for HL and NHL, as shown in Table 2. It should be noted that this staging system does not apply to certain specific types of lymphoma, including chronic lymphocytic leukemia, primary cutaneous T-cell lymphoma, primary gastric lymphoma, and central nervous system lymphoma. Each of these subtypes has its own independent staging system.
【Treatment
1.Chemotherapy
For most lymphomas, chemotherapy is still the main treatment. The chemotherapy regimen and number of cycles vary depending on the type of pathology, stage and number of risk factors. For HL, ABVD is still the first-line chemotherapy regimen of choice. For advanced patients with high IPS scores, an increased-dose BEACOPP regimen may also be preferred, and salvage regimens such as DHAP, ESHAP, GVD, and ICE may be chosen for relapsed/refractory patients. The preferred chemotherapy regimen for diffuse large B-cell lymphoma remains CHOP, and the addition of a CD20 monoclonal antibody (melphalan) may further improve overall survival. The R-ACVBP regimen is also available for younger patients, and the R-miniCHOP regimen is available for older patients. For relapsed/refractory diffuse large B, salvage chemotherapy regimens available include GDP, Gemox, DHAP, ICE, etc. For follicular lymphoma that has achieved remission after chemotherapy, melova maintenance therapy can further improve progression-free survival. For small lymphocytic lymphoma/chronic lymphocytic leukemia, first-line chemotherapy can be chosen from the R-FC regimen, with Meroval alone or in combination with nitrogen mustard phenylbutyrate or bendamustine in the elderly and frail. For highly aggressive B-NHL such as Burkitt’s lymphoma, “double whammy” lymphoma, gray zone lymphoma, primary mediastinal large B-cell lymphoma, and condyloma, more intense combination chemotherapy regimens should be chosen for primary treatment, including R-EPOCH, R-CODOX-M/IVAC, R- HyperCVAD, etc., along with lumbar puncture sheath injection or high-dose MTX to prevent central invasion.
For most T-cell lymphomas (e.g. peripheral T-cell lymphoma non-specific, mesenchymal large cell lymphoma, etc.), CHOP is still mostly preferred as the first-line chemotherapy regimen due to the small number of cases and the lack of high-quality randomized controlled studies. However, the efficacy is worse than that of B-NHL, and further exploration of more appropriate chemotherapy regimens and new drugs is needed. Extranodal NK/T-cell lymphoma is not sensitive to conventional regimens such as CHOP, and regimens combined with menadionease, such as SMILE, AspaMetDex, and P-Gemox, should be preferred.
For lymphoma with primary CNS or testis, the chemotherapy regimen should be based on high-dose methotrexate combined with high-dose cytarabine or temozolomide because conventional chemotherapeutic agents have difficulty crossing the blood-brain or blood-testis barrier.
In recent years, targeted therapy for lymphoma has gained tremendous progress, and various new drugs have emerged, such as BTK inhibitor Ibrutinib and PI3K inhibitor Idelalisib. These drugs have further improved the prognosis of lymphoma patients, but it will take time before they are available in China.
2.Radiotherapy
Radiation therapy has an important place in the comprehensive treatment of lymphoma. Although most lymphomas are systemic tumors, the control of local lesions by radiotherapy can still improve the prognosis. In some early stage lymphomas, radiotherapy is the main treatment, including: early stage 1-2 follicular lymphoma, small lymphocytic lymphoma, mucosa-associated tissue lymphoma, nodular lymphocyte-dominant HL, and extra-nodal NK/T-cell lymphoma, etc. These early stage lymphomas can achieve good long-term survival with radiotherapy alone. In certain lymphomas that have achieved remission after initial chemotherapy, radiotherapy can further consolidate the efficacy, such as primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma and grade 3 follicular lymphoma, Hodgkin’s lymphoma, and primary testicular lymphoma.
In terms of irradiation fields, with the continuous improvement of chemotherapy efficacy, there is a tendency to gradually reduce the irradiation fields of lymphoma. For example, Hodgkin’s lymphoma used to be irradiated in a wide range of cloak field or inverted Y field, which had high therapeutic toxicity and long-term side effects. In recent years, the irradiation field of HL has been gradually reduced to irradiation of the involved field or even the involved lymph nodes. For other NHLs such as diffuse large B-cell lymphoma, irradiation of the involved field is now mostly used. For tumors such as extranodal NK/T-cell lymphoma, where chemotherapy is relatively ineffective and radiotherapy is highly sensitive, expanded field irradiation is still recommended to ensure efficacy.
The dose of irradiation varies by lymphoma subtype. The current NCCN guidelines recommend 24-30 Gy for small lymphocytic lymphoma, follicular lymphoma, and extranodal marginal zone lymphoma, and 30-36 Gy for primary cutaneous mesenchymal large-cell lymphoma and early-stage set of cell lymphoma. For NK/T-cell lymphoma, a dose of 50 Gy or more is recommended.
3. Hematopoietic stem cell transplantation
Hematopoietic stem cell transplantation is also an important treatment for lymphoma. For certain relapsed/refractory lymphomas, autologous/allogeneic hematopoietic stem cell transplantation can further improve the prognosis after remission with second-line chemotherapy, including diffuse large B-cell lymphoma and peripheral T-cell lymphoma. For some patients with primary high-risk lymphoma, transplantation can also be chosen for consolidation after remission with first-line therapy, such as diffuse large B-cell lymphoma, set of cell lymphoma, Hodgkin’s lymphoma, etc.
4.Surgical treatment
For lymphoma, surgery is not only an important means of obtaining tissue specimens, but also a treatment for certain specific lymphomas. For example: limited cutaneous lymphoma, early primary gastrointestinal lymphoma, primary splenic lymphoma, primary testicular lymphoma, etc.
[Prognosis].
The prognosis of lymphoma is related to the patient’s age, general condition, pathological type, stage, and treatment. For non-Hodgkin’s lymphoma, patients can be prognostically stratified using the International Prognostic Index (IPI), which consists of five factors, each accumulating one point: age > 60 years, ECOG physical score 2-4, stage III-IV, extra-nodal lesion > 1, and elevated LDH. 0-1 is classified as low risk, 2-3 as intermediate risk, and 4-5 as high risk. With the gradual refinement of lymphoma staging, independent prognostic scoring systems have been proposed for each pathological subtype, such as the IPS score for advanced HL, the FLIPI score for follicular lymphoma, and the MIPI score for set cell lymphoma. We will not repeat them here.