Epidemiology and risk factors
The incidence of lymphomas depends on the tumor type, age, and comorbid conditions. Hodgkin lymphoma (HL) is characterized by a bimodal distribution: the first peak in incidence is observed in young adults (20–30 years), and the second in older age. Non-Hodgkin lymphomas (NHL) demonstrate an exponential increase in the number of cases in individuals over 20 years of age.
Overall, lymphomas are slightly more common in men (with a ratio of up to 1.4:1) and Caucasians. Infectious and immune factors play a huge role in pathogenesis:
- Viruses: Epstein-Barr virus (EBV) is found in more than 90% of endemic Burkitt lymphoma cases and frequently in HL (mixed cellularity variant). T-lymphotropic virus (HTLV-1) causes adult T-cell leukemia/lymphoma, while human herpesvirus type 8 (HHV-8) is associated with primary effusion lymphoma in HIV-infected individuals.
- Bacteria: Helicobacter pylori is a key factor in the development of gastric MALT lymphoma.
- Immunosuppression: The risk of NHL increases sharply in HIV infection, following organ transplantation, and in patients with severe congenital immunodeficiencies. Autoimmune processes (Hashimoto thyroiditis, Sjögren syndrome) provoke local MALT lymphomas.
- Genetics: A positive family history increases the risk of hematopoietic tumors in general, without attachment to a specific type (relatives may have HL, NHL, or leukemias).
Hodgkin Lymphoma (HL)
A distinctive feature of HL is the presence of blastic multinucleated Reed-Sternberg cells (and their mononuclear variants, Hodgkin cells). Paradoxically, these tumor cells constitute an absolute minority within the tissue. The rest of the lymph node volume consists of a reactive background of non-tumor T-lymphocytes, eosinophils, fibroblasts, and plasmacytes.
Two main groups of HL are distinguished:
- Classical HL (95% of cases):
- Nodular sclerosis (75%): Nodules are separated by thick collagen bands. It often manifests as a large (bulky) conglomerate in the anterior mediastinum. This is the only variant without male predominance.
- Mixed cellularity (15–20%) and Lymphocyte depletion (<5%): Aggressive variants, more frequently diagnosed at advanced stages. Typical for HIV patients and residents of developing countries.
- Lymphocyte-rich (5%).
- Nodular lymphocyte-predominant HL (5% of cases): Characterized by an indolent (slow) course, excellent survival rates, and no association with EBV. Most commonly affects middle-aged men.
Non-Hodgkin Lymphomas (NHL)
The classification of NHL is constantly evolving (from the REAL classification of 1994 to the modern 2017 WHO classification). Today, tumors are categorized by hematopoietic lineages (lymphoid, myeloid, histiocytic/dendritic) taking into account genetics and immunophenotype.
Molecular profiling allows lymphomas to be divided into subtypes with different prognoses. For example, diffuse large B-cell lymphoma (DLBCL) is divided into germinal center B-cell-like and activated B-cell-like tumors. Specific forms are also distinguished: primary central nervous system DLBCL, pediatric follicular lymphoma, and gray zone lymphoma (combining features of DLBCL and classical HL).
Clinical Presentation and Staging
Most commonly, patients complain of painless lymph node enlargement (in 75% of cases, cervical). In 40% of patients, B-symptoms are observed: fever, drenching night sweats, and a loss of more than 10% of body weight over the past six months. Severe skin itching and pain in the nodes after alcohol consumption are less common.
A rigorous algorithm is used for diagnosis and staging:
- Biopsy: Surgical excisional biopsy (complete node removal) is mandatory. Core-needle biopsy is not suitable as it does not allow evaluation of the tissue architecture.
- Imaging: 18F-FDG PET/CT is the standard (covering the neck, chest, abdomen, and pelvis).
- Bone marrow evaluation: Due to the high accuracy of PET/CT, invasive bone marrow biopsy is no longer required unless the scan shows marrow involvement.
The historical Ann Arbor staging system with the Cotswolds modification of 2014 has been replaced by the Lugano classification, which conceptually divides the process into limited and advanced stages.
Briefly: answers to topical questions
What stage categories are distinguished in lymphoma staging according to the Lugano classification?
When staging lymphomas according to the Lugano classification, limited and advanced stages are distinguished.
- Limited stage (Limited Stage) includes stage I (involvement of a single lymph node region), stage IE (single extra-lymphatic lesion), stage II (involvement of two or more regions on the same side of the diaphragm), and stage IIE (contiguous extralymphatic extension).
- Advanced stage (Advanced Stage) includes stage III (involvement of lymph node regions on both sides of the diaphragm or lymph nodes above the diaphragm with splenic involvement) and stage IV (diffuse or disseminated involvement of an extralymphatic organ, non-contiguous extranodal involvement with stage II, or any extralymphatic organ involvement with stage III).
- Stage II bulky can be classified as either a limited or advanced stage depending on histology and the presence of unfavorable prognostic factors.
In which cases is an invasive bone marrow biopsy mandatory for a patient with confirmed lymphoma?
When staging Hodgkin lymphoma by CT, if 18F-FDG PET/CT is unavailable, iliac crest trephine biopsy is mandatory, preferably bilateral, and indicated for all stages. An exception is possible if the following conditions are simultaneously met:
- stages I–II A;
- lymph node involvement exclusively above the diaphragm;
- absence of risk factors;
- absence of cytokine release signs in blood tests;
- absence of cytopenia or thrombocytosis.
If FDG PET/CT is available and shows no signs of bone marrow involvement, bone marrow biopsy is not required.
What diagnostic imaging methods are used to assess the extent of lymphomas if 18F-FDG PET/CT is unavailable or uninformative?
When PET/CT is unavailable or for lymphomas with low radiotracer uptake, computed tomography is the primary method for assessing dissemination. In such cases, the Lugano CT-based criteria (Lugano CT based criteria) are used, and the standard protocol includes CT of the neck, chest, abdomen, and pelvis. Magnetic resonance imaging (MRI) is additionally used for staging. This method can detect multifocal bone marrow lesions even before the development of diffuse infiltration, and it is effective even with false-negative iliac crest biopsy results.
What radiological and CT features are characteristic of anterior mediastinal involvement in nodular sclerosis Hodgkin lymphoma?
Nodular sclerosis Hodgkin lymphoma is characterized by the presence of a massive (bulky) space-occupying lesion in the anterior mediastinum. On contrast-enhanced computed tomography, this mass is frequently accompanied by involvement of the internal mammary lymph node chain (internal mammary chain). Additionally, enlarged pretracheal and axillary lymph nodes may be detected. Anterior mediastinal involvement is found in almost all patients with this histological subtype of the disease.
Class and exam questions
What is the main histological difference in Hodgkin lymphoma?
The presence of giant Reed-Sternberg cells (and their mononuclear analogues). They are surrounded by a massive background of reactive, non-tumor cells (lymphocytes, eosinophils, fibroblasts).
What are B-symptoms in lymphoma?
This is the triad of symptoms: fever, drenching night sweats, and unexplained weight loss (more than 10% of baseline over the past 6 months).
Why can't you just perform a fine-needle aspiration of the node when lymphoma is suspected?
Puncture (or core-needle biopsy) yields too little material. For an accurate diagnosis, the pathologist needs to evaluate the architecture of the entire lymph node, which is why surgical excisional biopsy is preferred.
Is bone marrow trephine biopsy mandatory nowadays?
No. If the patient has undergone diagnostic 18F-FDG PET/CT and it shows no signs of bone marrow involvement, an invasive biopsy is no longer required due to the high sensitivity of the scan.
What else to study on this topic
- Pathogenesis of gastric MALT lymphoma in the context of Helicobacter pylori infection
- Clinical features and treatment of Burkitt lymphoma
- Lugano classification compared to the Ann Arbor system
- Grey zone lymphoma — diagnostic criteria
- Mechanisms of virus-associated oncogenesis in EBV infection
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