Non-Hodgkin Lymphoma: Classification, Diagnosis, Staging, and Treatment

Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) is a malignant neoplasm that originates in the lymphatic system. Although it most commonly arises in the lymph nodes, NHL can also involve extranodal organs, including the spleen, bone marrow, liver, gastrointestinal tract, skin, and central nervous system.

Approximately 85% of NHL cases arise from B lymphocytes, while the remaining 15% originate from T lymphocytes or natural killer (NK) cells. NHL is the most common hematologic malignancy, accounting for approximately 4–5% of all cancers. Overall, it occurs more frequently in men than in women, although the incidence varies according to the lymphoma subtype. For example, diffuse large B-cell lymphoma (DLBCL) is slightly more common in women. NHL can occur at any age, but the median age at diagnosis is around 50 years. Aggressive (high-grade) lymphomas tend to affect younger individuals, whereas indolent (low-grade) lymphomas are more frequently diagnosed in older adults.

Etiology and Risk Factors

The exact cause of non-Hodgkin lymphoma remains unknown, but several genetic, infectious, environmental, and immunological factors have been associated with an increased risk of developing the disease (Table 1).

Chromosomal abnormalities play a key role in the pathogenesis of many lymphoma subtypes. For example, the t(14;18)(q32;q21) translocation is present in approximately 85% of patients with follicular lymphoma, leading to overexpression of the BCL2 gene and prolonged cell survival. Burkitt lymphoma is characterized by translocations involving chromosome 8q24, resulting in dysregulation of the MYC oncogene and uncontrolled cellular proliferation.

Environmental exposures may also contribute to lymphoma development. Studies have linked prolonged exposure to pesticides, herbicides, industrial solvents, and other organic chemicals with an increased risk of NHL. Exposure to ionizing radiation has likewise been associated with a higher incidence of lymphoma.

Several infectious agents have been implicated in lymphomagenesis through chronic antigen stimulation, immune dysregulation, and promotion of abnormal lymphocyte proliferation. Epstein–Barr virus (EBV) is strongly associated with Burkitt lymphoma and several other lymphoma subtypes. Approximately 5% of individuals infected with human T-cell lymphotropic virus type 1 (HTLV-1) eventually develop adult T-cell leukemia/lymphoma. Chronic hepatitis C virus (HCV) infection has been linked to lymphoplasmacytic lymphoma and Waldenström macroglobulinemia. Infection with Helicobacter pylori is also a well-established risk factor for gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

Both congenital and acquired immunodeficiency states substantially increase the risk of developing aggressive extranodal lymphomas. Patients with HIV infection, organ transplant recipients receiving long-term immunosuppressive therapy, and individuals with inherited immunodeficiency syndromes are at particularly high risk.

Table 1. Risk Factors

Risk Factor	Description
Immunodeficiency	Congenital: Wiskott–Aldrich syndrome, X-linked agammaglobulinemia
	Acquired: HIV infection, organ transplantation, immunosuppressive therapy, previous chemotherapy
Infections	Epstein–Barr virus (EBV), Human Immunodeficiency Virus (HIV), Helicobacter pylori, Hepatitis C virus (HCV), Human herpesvirus 8 (HHV-8)
Age	Older age (>50 years)
Sex	Male sex
Environmental factors	Herbicides, pesticides, radiation

Classification

Several classification systems are used for non-Hodgkin lymphoma (NHL). The current World Health Organization (WHO) classification categorizes NHL into two major groups based on the cell of origin: B-cell lymphomas and T-cell/NK-cell lymphomas. This classification incorporates morphological, immunophenotypic, genetic, and molecular characteristics to accurately define individual lymphoma subtypes (Table 2).

Table 2. World Health Organization (WHO) Classification of Non-Hodgkin Lymphomas

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Table 3. International Working Formulation (IWF) Classification of Non-Hodgkin Lymphomas

In clinical practice, lymphomas are also commonly classified according to their biological behavior. The National Cancer Institute's Working Formulation (IWF), which has been widely used internationally, including in Lithuania, groups lymphomas into three broad categories: indolent (low-grade), aggressive (intermediate-grade), and highly aggressive (high-grade) lymphomas (Table 3). Although modern WHO classification has largely replaced the Working Formulation, these clinical categories remain useful because they reflect differences in disease progression, treatment strategies, and prognosis.

Clinical Presentation and Diagnosis

The most common presenting feature of NHL is lymphadenopathy. Enlarged lymph nodes are typically painless, firm, and asymmetrical, involving either a single lymph node region or multiple groups simultaneously. The cervical, axillary, mediastinal, inguinal, abdominal, and pelvic lymph nodes are most frequently affected.

As lymph nodes enlarge, they may compress adjacent structures and cause symptoms related to the involved organs. For example, enlarged abdominal lymph nodes may result in intestinal obstruction, jaundice, or urinary tract obstruction, while enlarged mediastinal lymph nodes can compress the superior vena cava, causing dyspnea and superior vena cava syndrome.

Aggressive lymphomas usually present with rapidly enlarging lymph nodes and a rapidly growing tumor burden accompanied by constitutional, or "B," symptoms, including unexplained fever, drenching night sweats, and unintentional weight loss. The presence of B symptoms generally indicates more advanced disease and is associated with a less favorable prognosis.

By contrast, indolent lymphomas usually progress slowly and may present with gradually enlarging lymph nodes, hepatomegaly, splenomegaly, or cytopenias resulting from bone marrow involvement.

Approximately 10–35% of newly diagnosed NHL cases originate in extranodal sites rather than lymph nodes. The clinical manifestations depend on the organ involved. Primary gastrointestinal lymphoma may cause abdominal pain, nausea, vomiting, early satiety, or weight loss. Primary central nervous system lymphoma commonly presents with headaches, cognitive impairment, focal neurological deficits, seizures, or paralysis.

The diagnostic evaluation begins with a detailed medical history, including the duration of symptoms and the presence of constitutional (B) symptoms, followed by a thorough physical examination. Clinicians assess all accessible peripheral lymph nodes, palpate the liver and spleen, and carefully examine the skin for suspicious lesions or rashes that may indicate cutaneous lymphoma.

Excisional biopsy of an enlarged lymph node or another suspected involved organ remains the gold standard for diagnosing NHL. Histopathological examination, supported by immunohistochemistry, flow cytometry, cytogenetic analysis, and molecular testing when appropriate, establishes the lymphoma subtype. Accurate pathological diagnosis is essential for selecting the most appropriate treatment and estimating prognosis.

Bone marrow biopsy is frequently included in the staging work-up, particularly in patients with indolent lymphomas, where bone marrow involvement is detected in approximately 30–50% of cases. In some patients, bone marrow examination may provide the only tissue confirming the diagnosis.

Routine laboratory tests may initially be normal, particularly during early-stage disease. However, bone marrow infiltration may lead to anemia, thrombocytopenia, or leukopenia. Rapid tumor cell turnover is often associated with elevated serum lactate dehydrogenase (LDH) and uric acid concentrations. Liver involvement may cause elevated liver enzyme levels, while urinary tract obstruction secondary to enlarged abdominal lymph nodes can impair renal function.

Screening for viral infections—including HIV, Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B virus (HBV), and hepatitis C virus (HCV)—is recommended because these infections may contribute to lymphoma development or influence treatment decisions.

Imaging studies are essential for determining disease extent. Initial evaluation typically includes chest radiography, abdominal ultrasonography, and contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis. Magnetic resonance imaging (MRI) is particularly useful when central nervous system or spinal involvement is suspected.

Positron emission tomography combined with computed tomography (PET/CT) has become an important tool for both initial staging and treatment response assessment in FDG-avid lymphomas. During PET/CT, patients receive an intravenous injection of fluorine-18 fluorodeoxyglucose (^18F-FDG), a radiolabeled glucose analogue. Because malignant lymphoma cells exhibit increased glucose metabolism, areas of high FDG uptake indicate metabolically active disease. PET/CT can also assist in selecting the most appropriate biopsy site when diagnosis remains uncertain.

Following comprehensive clinical, pathological, laboratory, and imaging evaluation, clinicians determine the lymphoma subtype, disease stage, expected clinical behavior, and prognosis.

Staging and Prognosis

The Ann Arbor staging system remains the standard method for staging NHL in clinical practice (Table 4). Disease stage is determined according to the number and location of involved lymph node regions, whether disease is confined to one or both sides of the diaphragm, and the presence or absence of extranodal organ involvement.

Patient prognosis depends on multiple clinical and biological factors, including lymphoma histology, disease stage, age, performance status, tumor burden, serum LDH concentration, beta-2 microglobulin level, and the extent of extranodal disease.

The International Prognostic Index (IPI) is widely used to estimate the prognosis of patients with aggressive NHL and predict overall survival (Table 5). The index incorporates five adverse prognostic factors: Ann Arbor stage III or IV disease, elevated serum LDH, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, age over 60 years, and involvement of more than one extranodal site. Patients are stratified into different risk groups according to the number of adverse factors present, allowing clinicians to estimate long-term survival and guide treatment decisions.

Table 4. Ann Arbor Staging Classification

Stage modifiers:

• B – presence of B symptoms (fever, night sweats, unexplained weight loss).
• A – absence of B symptoms.
• E – localized extranodal involvement.

Table 5. International Prognostic Index (IPI) and 5-Year Overall Survival

Treatment

Non-Hodgkin lymphoma (NHL) can be treated using several different approaches. Treatment depends on the lymphoma subtype, disease stage, extent of spread, patient age, overall performance status, comorbidities, and prognostic risk factors. Patients with early-stage, indolent NHL who have no clinical symptoms may be managed with active surveillance ("watch and wait") without immediate treatment. Therapy is initiated once lymphadenopathy progresses or B symptoms develop. Treatment options include radiotherapy, combination immunochemotherapy, or monotherapy with agents such as chlorambucil, cyclophosphamide, or fludarabine. Combination chemotherapy with a monoclonal antibody is one of the most commonly used treatment strategies. For follicular lymphoma, the R-CVP regimen (rituximab, cyclophosphamide, vincristine, and prednisolone) may be prescribed. In patients with poor performance status who cannot tolerate immunotherapy, monotherapy is recommended. In the presence of unfavorable prognostic factors and a high risk of relapse, high-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) or allogeneic stem cell transplantation (allo-SCT) should be considered. Aggressive (intermediate-grade) NHL is more common, with diffuse large B-cell lymphoma being the most frequent subtype, followed by mantle cell lymphoma. As with indolent lymphomas, treatment depends on disease stage and the patient's overall condition.

The most commonly used treatment is immunochemotherapy with the R-CHOP regimen, consisting of rituximab (an anti-CD20 monoclonal antibody), cyclophosphamide, doxorubicin, vincristine, and prednisolone. Depending on the disease stage, patients usually receive 4 to 8 cycles of chemotherapy. After four treatment cycles, response is reassessed using imaging studies, including abdominal ultrasound, chest X-ray, computed tomography (CT), or positron emission tomography/computed tomography (PET/CT). In elderly patients or those with reduced functional status, chemotherapy doses may be adjusted to improve tolerability. If the lymphoma proves refractory to treatment or relapses early, alternative chemotherapy regimens such as R-ICE or R-DHAP may be used, and eligibility for high-dose chemotherapy followed by autologous stem cell transplantation should be evaluated.

In highly aggressive NHL, because of the increased risk of rapid dissemination to the central nervous system (CNS) and bone marrow, high-dose methotrexate is administered together with combination chemotherapy. Methotrexate may also be given intrathecally for CNS prophylaxis. Although chemotherapy is highly effective in treating NHL, it is associated with both short-term and long-term adverse effects. During active treatment, severe neutropenia (absolute neutrophil count <0.5 × 10⁹/L) substantially increases the risk of infections. Patients may also experience nausea, vomiting, diarrhea, and mucositis. Long-term complications include cardiotoxicity, infertility, and an increased risk of secondary malignancies.

Monitoring

After treatment, patients are followed up every 3 months during the first year, every 6 months during years 2–4, and annually thereafter. Follow-up includes a comprehensive clinical examination, complete blood count (CBC), electrocardiogram (ECG), lactate dehydrogenase (LDH) measurement, chest X-ray, abdominal ultrasound, and, when clinically indicated, computed tomography (CT).

Source: Lietuvos gydytojo žurnalas, No. 2, 2016.