Non-Hodgkin Lymphoma: B Symptoms, Differential Diagnosis, and Comprehensive Evaluation

Non-Hodgkin lymphoma (NHL) represents a diverse group of cancers originating in the lymphatic system, primarily affecting the lymph nodes. These malignancies can stem from chromosomal abnormalities, exposure to toxins, infections, and chronic inflammatory conditions. This article provides an in-depth review of the evaluation and management of non-Hodgkin lymphoma, emphasizing the crucial role of an interprofessional healthcare team in patient care. A key aspect discussed is the “B symptoms” presentation of NHL and its differential diagnosis, vital for accurate and timely clinical decisions.

Introduction

Non-Hodgkin lymphoma (NHL) is characterized by neoplasms of lymphoid tissues, encompassing B cell precursors, mature B cells, T cell precursors, and mature T cells. This category includes a wide array of subtypes, each distinguished by unique epidemiological profiles, underlying causes, immunophenotypic and genetic characteristics, clinical manifestations, and therapeutic responses. NHL is broadly classified into ‘indolent’ and ‘aggressive’ forms, reflecting the variable prognosis associated with different subtypes. Among mature B cell neoplasms, follicular lymphoma, Burkitt lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, marginal zone lymphoma, and primary CNS lymphoma are most prevalent (refer to Image. Mantle Cell Lymphoma). Adult T cell lymphoma and mycosis fungoides are the most frequently observed mature T cell lymphomas.[1] Treatment strategies for NHL are highly individualized, guided by factors such as tumor stage, grade, lymphoma subtype, and patient-specific considerations including symptoms, age, and overall performance status.

The clinical course of NHL varies considerably. Indolent lymphomas are typically characterized by a fluctuating pattern of lymph node enlargement over extended periods. In contrast, aggressive lymphomas often manifest with systemic “B symptoms”—unexplained weight loss, night sweats, and fever—and can be rapidly fatal if left untreated. Lymphoma subtypes typically associated with indolent presentations include follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and splenic marginal zone lymphoma. Aggressive lymphomas encompass diffuse large B cell lymphoma, Burkitt lymphoma, precursor B and T cell lymphoblastic leukemia/lymphoma, adult T cell leukemia/lymphoma, and various peripheral T cell lymphomas.

Peripheral lymphadenopathy is the presenting sign in up to two-thirds of NHL patients. Less frequent initial symptoms include skin rashes, heightened reactions to insect bites, persistent fatigue, itching (pruritus), general malaise, fever of unknown origin, fluid accumulation in the abdomen (ascites), and pleural or pericardial effusions. Secondary extranodal disease develops in approximately half of all patients during the course of their illness, while primary extranodal lymphoma is diagnosed in 10% to 35% of patients at initial presentation. Primary gastrointestinal tract lymphoma may present with symptoms such as nausea, vomiting, food aversion, unintentional weight loss, abdominal fullness, early satiety, and symptoms related to visceral obstruction. In some cases, patients might exhibit signs of acute gastrointestinal perforation and bleeding, or features of malabsorption syndrome. Primary central nervous system (CNS) lymphoma can manifest with headaches, symptoms of spinal cord compression, lethargy, specific neurological deficits, seizures, and paralysis (refer to Image. Central Nervous System Lymphoma, MRI).

Etiology

The development of NHL is multifactorial, with associations identified across infections, environmental exposures, states of immunodeficiency, and chronic inflammation. Specific infectious agents have been linked to the pathogenesis of different NHL subtypes.

• Epstein-Barr virus (EBV): This DNA virus is implicated in the etiology of certain NHL types, notably the endemic variant of Burkitt lymphoma.
• Human T-cell leukemia virus type 1 (HTLV-1): HTLV-1 is the causative agent of adult T-cell lymphoma. It triggers chronic antigenic stimulation and dysregulation of cytokines, leading to uncontrolled proliferation of B or T cells.
• Hepatitis C virus (HCV): HCV infection can result in clonal B-cell expansions. Splenic marginal zone lymphoma and diffuse large B-cell lymphoma are among the NHL subtypes associated with HCV.
• Human herpesvirus 8 (HHV-8): HHV-8 is linked to primary effusion lymphoma (PEL), a rare, high-grade B-cell NHL that is also associated with Kaposi sarcoma.
• Helicobacter pylori: Infection with Helicobacter pylori is associated with an elevated risk of gastric mucosa-associated lymphoid tissue (MALT) lymphomas, a form of primary gastrointestinal lymphoma.

Certain medications, such as phenytoin, digoxin, and TNF antagonists, have also been implicated in NHL development. Furthermore, exposure to organic chemicals, pesticides, phenoxy-herbicides, wood preservatives, dust, hair dyes, solvents, chemotherapy agents, and radiation are considered environmental risk factors for NHL.[2][3]

Congenital immunodeficiency syndromes that increase NHL risk include Wiskott-Aldrich syndrome and severe combined immunodeficiency disease. Acquired immunodeficiency states, such as immunosuppression following organ transplantation or AIDS (Acquired immunodeficiency syndrome), also elevate risk. Primary CNS lymphoma is notably more common in patients with AIDS.

Autoimmune disorders such as Sjögren syndrome, rheumatoid arthritis, and Hashimoto thyroiditis are associated with an increased incidence of NHL. Hashimoto’s thyroiditis, in particular, is linked to primary thyroid lymphomas.[4] Celiac disease is also recognized as a condition that increases the risk of developing NHL.

Epidemiology

The incidence of NHL subtypes exhibits geographical variation; follicular lymphoma is more prevalent in Western countries, while T cell lymphomas are more common in Asia. Overall, NHL incidence peaks in individuals aged 65 to 74, with a median age at diagnosis of 67 years. Epstein-Barr virus-related (endemic) Burkitt lymphoma is particularly common in Africa. This endemic variant is concentrated in equatorial Africa and New Guinea, with an incidence rate approximately 50 times higher than in the United States.[5] In children, peak incidence is between 4 and 7 years of age, with a male-to-female ratio of approximately 2:1. The sporadic variant of Burkitt lymphoma is more frequently observed in the United States and Western Europe, accounting for about 30% of pediatric lymphomas.

Mantle cell lymphoma constitutes approximately 7% of adult NHL cases in the United States and Europe, with an annual incidence of 4 to 8 cases per million people. Incidence increases with age and appears to be rising in the United States. Approximately 75% of patients are male, and individuals of White race are affected nearly twice as often as African Americans. The median age at diagnosis for mantle cell lymphoma is 68 years.[6][7]

NHL ranks as the fifth most common pediatric cancer diagnosis in children under 15 years old, representing about 7% of childhood cancers in developed nations. In the United States, approximately 800 new pediatric NHL cases are diagnosed annually, with an incidence of 10 to 20 cases per million children per year. High-grade lymphomas, such as lymphoblastic and small noncleaved lymphomas, are the most frequently observed NHL types in children and young adults. Lymphomas are rare in infants (≤1%), accounting for approximately 4%, 14%, 22%, and 25% of neoplasms in children aged 1–4, 5–9, 10–14, and 15–19 years, respectively. A male predominance is noted, and White children are more commonly affected than African American children.

Pathophysiology

NHL development originates from B, T, or natural killer cells due to chromosomal translocations, mutations, or deletions. Chromosomal translocations can activate proto-oncogenes, while chromosomal deletions or mutations can inactivate tumor suppressor genes. The t(14;18) translocation is the most common chromosomal abnormality in NHL, most frequently observed in follicular lymphoma. The t(11;14) translocation is characteristically associated with mantle cell lymphoma, leading to overexpression of cyclin D1, a key cell cycle regulator. The t(8;14) translocation involving c-myc (8) and the heavy chain Ig (14) is linked to Burkitt lymphoma. Alterations in BCL-2 and BCL-6 are commonly found in diffuse large B-cell lymphoma. Primary CNS lymphoma is strongly associated with HIV/AIDS.[8]

Histopathology

Histologically, NHL commonly presents in follicular and diffuse patterns. Follicular lymphoma is characterized by a follicular pattern with uniform nodularity throughout the lymph node, showing minimal variation in follicle size and shape. The diffuse pattern involves effacement of the normal lymph node architecture by infiltration of small lymphocytes. In Burkitt lymphoma, the lymph node is completely effaced by a monomorphic infiltrate of lymphocytes, interspersed with clear spaces containing reactive histiocytes with phagocytic debris. Mantle cell lymphoma can exhibit diffuse, nodular, mantle zone, or mixed histologic patterns. Most cases are composed of small to medium-sized lymphoid cells with slightly irregular or “notched” nuclei. Tumor cells are typically monomorphous small to medium-sized B lymphocytes with irregular nuclei, although the degree of irregularity is generally less pronounced than that of centrocytes in germinal centers and follicular lymphoma.[9]

History and Physical

Patients with NHL often present with constitutional symptoms, commonly referred to as “B symptoms,” which include fever, unintentional weight loss, and night sweats. These systemic B symptoms are more frequently observed in patients with high-grade NHL variants. Painless peripheral lymphadenopathy is the presenting symptom in over two-thirds of patients. Waxing and waning lymphadenopathy, accompanied by other systemic symptoms, can be indicative of low-grade lymphoma. Clinical presentations vary significantly depending on the specific site of lymphoma involvement and the subtype. Key clinical features associated with specific subtypes include:

Burkitt Lymphoma: Characterized by rapidly growing tumor masses, Burkitt lymphoma frequently presents with tumor lysis syndrome.

Endemic (African) Burkitt Lymphoma: Jaw or facial bone tumors are common in 50% to 60% of cases. Abdominal involvement is less frequent. The primary tumor can spread to extranodal sites such as the mesentery, ovaries, testes, kidneys, breasts, and meninges.

Non-endemic (Sporadic) Burkitt Lymphoma: Typically involves the abdomen, often presenting with massive ascites and affecting the distal ileum, stomach, cecum, mesentery, and bone marrow. Symptoms related to bowel obstruction or gastrointestinal bleeding are common, sometimes mimicking acute appendicitis or intussusception. Approximately 25% of cases involve the jaw or facial bones. Lymphadenopathy, if present, is usually localized. Bone marrow and CNS involvement are observed in 30% and 15% of cases, respectively, at initial presentation, but are more frequent in recurrent or treatment-resistant disease.[10] Kidney, testis, ovary, and breast involvement can also occur.

Immunodeficiency-related Burkitt Lymphoma: Patients present with symptoms related to their underlying immunodeficiency (e.g., AIDS, congenital immunodeficiency, acquired immunodeficiency due to transplantation). Lymph nodes, bone marrow, and the CNS are the most commonly involved sites.

Mantle Cell Lymphoma: Most patients (70%) have advanced-stage disease at diagnosis. Lymphadenopathy is the initial presentation in approximately 75% of patients, while extranodal disease is primary in the remaining 25%.[11] Common sites of involvement include lymph nodes, spleen (45% to 60%), Waldeyer’s ring, bone marrow (>60%), blood (13% to 77%), and extranodal sites like the gastrointestinal tract, breast, pleura, and orbit. Systemic B symptoms are present in up to one-third of patients at diagnosis.

Gastrointestinal Lymphoma: Typically presents with nonspecific symptoms such as epigastric pain or discomfort, anorexia, weight loss, nausea or vomiting, occult gastrointestinal bleeding, or early satiety.

Primary Central Nervous System (CNS) Lymphoma: Patients may present with headache, lethargy, focal neurologic deficits, seizures, paralysis, spinal cord compression, or lymphomatous meningitis.

A comprehensive physical examination should include palpation of lymphoid sites such as Waldeyer’s ring (tonsils, base of tongue, nasopharynx), and cervical, supraclavicular, axillary, inguinal, femoral, mesenteric, and retroperitoneal nodal regions. The liver and spleen should be palpated for enlargement. Head and neck examination should assess for preauricular node enlargement and tonsillar asymmetry, suggesting head and neck involvement, including Waldeyer’s ring. Orbital structures (eyelids, extraocular muscles, lacrimal apparatus, conjunctivae) can be involved, particularly in marginal zone lymphoma, mantle cell lymphoma, and primary CNS lymphoma, necessitating careful examination.

Mediastinal involvement can occur in primary mediastinal large B cell lymphoma or secondary spread. Patients with mediastinal lymphoma may present with persistent cough, chest discomfort, or be asymptomatic, often with abnormal chest X-rays. Superior vena cava syndrome can be a presenting feature. Retroperitoneal, mesenteric, and pelvic node involvement is common across NHL subtypes. Ascites may result from lymphatic obstruction, often chylous in nature. Approximately 50% of patients develop secondary extranodal disease, while 10% to 35% have primary extranodal lymphoma at diagnosis.[12] The gastrointestinal tract is the most frequent site of primary extranodal disease, followed by the skin. Aggressive NHL subtypes can also involve the testis, bone, and kidney. Less common sites include the ovary, bladder, heart, adrenal glands, salivary glands, prostate, and thyroid. Extralymphatic symptoms are more typical of aggressive NHL and less common in indolent lymphomas.

Testicular NHL is the most common malignancy affecting the testis in men over 60. It typically presents as a testicular mass and accounts for 1% of all NHL and 2% of extranodal lymphomas.[13] Epidural spinal cord compression (ESCC) can cause irreversible neurological deficits. NHL typically involves paraspinal soft tissues initially, then invades the spinal cord via the vertebral foramen without causing bony destruction.[14]

Evaluation

The diagnostic workup for NHL includes:

• Complete blood count (CBC): May reveal anemia, thrombocytopenia, leukopenia, pancytopenia, lymphocytosis, or thrombocytosis. These hematologic abnormalities can result from bone marrow infiltration, hypersplenism, or gastrointestinal blood loss.
• Serum chemistry tests: Help assess for tumor lysis syndrome, particularly relevant in rapidly proliferative NHLs like Burkitt or lymphoblastic lymphoma (see Image. Burkitt Lymphoma, Lymphoblasts). Elevated lactate dehydrogenase (LDH) levels can indicate high tumor burden or liver infiltration.
• Imaging: Typically involves CT scans of the neck, chest, abdomen, and pelvis, or PET scans. Targeted imaging, such as brain and spinal cord MRI or testicular ultrasound, may be necessary.
• Lymph node or tissue biopsy: Biopsy is indicated for lymph nodes exhibiting significant enlargement, persistence for over 4 to 6 weeks, or progressive size increase. Lymph nodes larger than 2.25 cm (e.g., 1.5 x 1.5 cm biperpendicular diameters) or 2 cm in single diameter are preferred for biopsy due to higher diagnostic yield. Excisional lymph node biopsy is the gold standard for diagnosis, providing sufficient tissue for histologic, immunologic, and molecular analyses by hematopathologists.[15][16] Fine needle aspiration is generally avoided. Diagnostic yields from peripheral lymph nodes vary: supraclavicular nodes (75% to 90%), cervical and axillary nodes (60% to 70%), and inguinal nodes (30% to 40%).
• Lumbar puncture: Reserved for patients at high risk of CNS involvement, including those with highly aggressive NHL (Burkitt lymphoma, diffuse large B cell lymphoma, peripheral T cell lymphoma, grade 3b FL, mantle cell lymphoma, precursor T or B lymphoblastic leukemia/lymphoma, HIV-positive NHL), epidural, bone marrow, testicular, or paranasal sinus involvement, or multiple extranodal sites. Cerebrospinal fluid (CSF) is analyzed by cytology and flow cytometry.
• Immunophenotypic analysis: Performed on lymph node, peripheral blood, and bone marrow samples. In Burkitt lymphoma, tumor cells express surface immunoglobulin (Ig) of the IgM type and immunoglobulin light chains (kappa more common than lambda), B cell-associated antigens (CD19, CD20, CD22, CD79a), germinal center markers (CD10 and BCL6), and HLA-DR and CD43. CD21 expression, the EBV/C3d receptor, depends on tumor EBV status. Endemic Burkitt lymphoma is EBV-positive and CD21+, while non-endemic Burkitt lymphoma in immunocompetent patients is usually EBV-negative and CD21-. Mantle cell lymphoma cells express high levels of surface membrane IgM and IgD (sIgM±IgD), often lambda light chain type, pan-B cell antigens (CD19, CD20), CD5, and FMC7. Nuclear cyclin D1 (BCL1) staining is present in >90% of cases, including CD5-negative cases.
• Bone marrow aspiration and biopsy: May be needed for NHL staging, although their utility is decreasing with PET scan use.

Treatment / Management

NHL treatment is tailored to the lymphoma type, stage, histopathological features, and patient symptoms. Common treatment modalities include chemotherapy, radiotherapy, immunotherapy, stem cell transplantation, and, rarely, surgery. Chemoimmunotherapy, particularly rituximab combined with chemotherapy, is frequently used. Radiation therapy is a primary treatment for early-stage (I, II) NHL. Stage II with bulky disease, stage III, and IV are typically treated with chemotherapy combined with immunotherapy, targeted therapy, and sometimes radiation. Treatments based on lymphoma subtype are outlined below:

B Cell Lymphoma

Diffuse Large B cell lymphoma (DLBCL): For Stage I or II, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is often given for 3 to 6 cycles, with or without radiation to the affected lymph node region. Stage III or IV DLBCL is typically treated with 6 cycles of R-CHOP. PET/CT scans evaluate treatment response after 2-4 cycles. Intrathecal chemotherapy or high-dose intravenous methotrexate is administered to patients with or at high risk of CNS involvement. For “Double-hit” lymphomas (MYC and BCL2 or BCL6 translocations), DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) is preferred. Relapsed or refractory DLBCL can be treated with salvage chemotherapy followed by bone marrow transplantation in eligible patients, or CAR-T cell therapy.[17] CAR-T therapy, an immunotherapy, genetically modifies a patient’s T lymphocytes to express a chimeric antigen receptor (CAR) targeting cancer cells. It has shown efficacy against refractory CD19-expressing B lymphoid malignancies.[18]

Follicular lymphoma: Indolent in nature, follicular lymphoma responds well to treatment but is often not curable, with relapses common. Asymptomatic patients with low-burden disease may be observed without immediate treatment. Radiotherapy is preferred for early stage I and II disease. Chemoimmunotherapy is another option. Stage III, IV, and bulky stage II lymphoma treatment includes a monoclonal antibody (rituximab or obinutuzumab) plus chemotherapy. Chemotherapy options include bendamustine or combination regimens like CHOP or CVP (cyclophosphamide, vincristine, prednisone). Maintenance therapy after initial treatment response is debated.

Mantle cell lymphoma: Multisite mantle cell lymphoma is often treated with aggressive chemotherapy plus rituximab in eligible patients. Intense chemotherapy regimens include R-Hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate and cytarabine), alternating R-CHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone/rituximab, dexamethasone, cytarabine, cisplatin), NORDIC regimen (dose-intensified induction immunochemotherapy with rituximab + maxi-CHOP alternating with rituximab + high-dose cytarabine), or RDHAP. High-dose therapy followed by autologous stem cell transplantation is considered for eligible patients post-chemotherapy response, typically followed by rituximab maintenance for 3 years.

Burkitt lymphoma: A very rapidly growing lymphoma, Burkitt lymphoma treatment regimens include Hyper-CVAD alternating with high-dose methotrexate and cytarabine + rituximab, CODOX-M alternating with IVAC + rituximab, or dose-adjusted EPOCH + rituximab.[19] Intrathecal methotrexate is given for CNS involvement. Tumor lysis syndrome is common, requiring prophylaxis and monitoring.

Primary CNS lymphoma: High-dose methotrexate-based chemotherapy is the most effective initial treatment. High-dose therapy followed by autologous stem cell transplantation may be considered for eligible patients who achieve complete response to initial chemotherapy.

T Cell Lymphoma

Anaplastic large cell lymphoma (ALCL): This aggressive lymphoma primarily affects lymph nodes. Brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, prednisone) is preferred. Other regimens include CHOP or CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone).

Adult T cell leukemia/lymphoma (ATLL): Linked to HTLV-1 infection, ATLL has four subtypes with varying treatments. Smoldering and chronic subtypes are slow-growing and may not require immediate treatment. If treatment is needed, options include interferon and the antiviral drug zidovudine for HTLV-1 infection, or skin-directed therapy for cutaneous involvement. Acute and lymphoma subtypes are treated with chemotherapy (typically CHOP regimen). Allogeneic stem cell transplant may be considered if response to chemotherapy is achieved in the acute subtype. Antiviral therapy is less effective for the lymphoma subtype, which may involve the brain and spinal cord, requiring intrathecal chemotherapy.

Enteropathy-associated T cell lymphoma (EATL): Strongly associated with celiac disease. Combination chemotherapy is preferred. Surgical evaluation is needed at diagnosis due to high risk of perforation or intestinal obstruction. Stem cell transplant may be considered if lymphoma responds to chemotherapy.

Other

HIV-associated lymphoma: Patients with HIV often develop aggressive lymphomas like DLBCL, primary CNS lymphoma, or Burkitt lymphoma. Highly active antiretroviral therapy (HAART) to treat HIV is used in combination with chemotherapy ± immunotherapy.

Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach: If Helicobacter pylori infection is present and lymphoma is localized to the stomach and perigastric nodes, antibiotics and H2 blockers can eliminate the antigenic stimulus, potentially causing lymphoma regression.

Mycosis fungoides: A cutaneous T-cell lymphoma with an indolent course, best treated with skin-directed therapies: topical steroids, topical retinoids, skin irradiation, psoralen-associated ultraviolet exposure, topical chemotherapy. Systemic biologic therapies are used if skin-directed therapies fail.

Differential Diagnosis

Several medical conditions can mimic NHL symptoms, making differential diagnosis crucial. These conditions include:

• Hodgkin lymphoma
• Epstein-Barr virus infection (infectious mononucleosis)
• Systemic lupus erythematosus (SLE)
• Intussusception
• Appendicitis
• Toxoplasmosis
• Metastasis from primary tumors (e.g., nasopharyngeal carcinoma, soft tissue sarcoma)
• Malignancies or lymphoproliferative disorders such as granulocytic sarcoma and multicentric Castleman disease
• Mycobacterial and other bacterial infections causing benign lymph node infiltration and reactive follicular hyperplasia

These conditions can present with localized or generalized lymphadenopathy and must be differentiated from NHL. When diagnostic uncertainty exists, a second opinion from expert hematopathologists should be sought before initiating treatment. Flow cytometry and cytogenetics are valuable tools in distinguishing between these conditions. Specifically concerning B Symptoms Differential Diagnosis, it’s important to note that fever, night sweats, and weight loss are not specific to lymphoma. Infections (like EBV, tuberculosis, and bacterial infections), autoimmune diseases (like SLE and rheumatoid arthritis), and other malignancies must be considered in the differential. A thorough history, physical exam focusing on lymphadenopathy characteristics, and appropriate investigations are essential to differentiate NHL from these mimicking conditions.

Radiation Oncology

Radiation therapy plays a significant role in NHL management in specific scenarios:

• Early-stage (stage I or II) NHL: Radiation therapy can be used as a single modality or in combination with chemotherapy.
• Advanced and aggressive lymphomas: Chemotherapy is typically the primary treatment. However, radiation therapy can be used for palliative purposes, such as pain relief or managing lymphadenopathy causing obstruction of the urinary or gastrointestinal tract.

Radiation therapy regimens typically involve daily treatments over several weeks, usually 5 days per week for curative intent. Palliative radiation courses are generally shorter.

Toxicity and Adverse Effect Management

Treatment-related complications in NHL vary depending on the chemotherapy regimen, radiation therapy, and surgical interventions. Common chemotherapy adverse effects include myelosuppression, neutropenic fever, and immunosuppression. Myelosuppression is managed with blood product transfusions (red cells and platelets) or colony-stimulating factors (e.g., granulocyte colony-stimulating factor). Neutropenia increases infection risk from bacteria, viruses, and fungi. Management depends on neutropenia severity and presence of fever. Patients are also susceptible to varicella-zoster virus infections, requiring post-exposure prophylaxis.

Chemotherapeutic agents commonly induce nausea and vomiting, managed with antiemetic serotonin receptor antagonists or benzodiazepines. Anthracyclines, particularly doxorubicin, can cause cardiotoxicity. Dexrazoxane has shown benefit in mitigating anthracycline-induced cardiotoxicity. Radiation therapy can also cause heart failure via different mechanisms, including myocardial fibrosis and pericardial fibrosis, often with preserved left ventricular ejection fraction. Vincristine can cause neurotoxicity.

Long-term fatigue is a common symptom in NHL survivors, often improving within a year post-treatment but persisting for months or years in many patients. The risk of second malignancies is increased in long-term NHL survivors, varying by NHL subtype and treatment received. Myelodysplastic syndrome and acute myeloid leukemia risk is elevated. Follicular lymphoma survivors have increased risk of lung cancer and cutaneous melanoma. Radiation therapy can increase the risk of squamous cell carcinoma of the head and neck and breast cancer, depending on the radiation field.

Radiation to the neck and mediastinum can lead to hypothyroidism. Hematopoietic cell transplantation with total body irradiation conditioning has been linked to growth hormone deficiency, hypogonadism, insulin resistance, and dyslipidemia. NHL survivors are at risk of endocrine abnormalities like gonadal dysfunction and hypothyroidism. Cytotoxic agents and radiation therapy can cause gonadal dysfunction in both sexes. Fertility preservation options, including cryopreservation of embryos, oocytes, and spermatozoa, should be offered.

Cranial irradiation, intrathecal chemotherapy history, older age at treatment, and hematopoietic cell transplantation can lead to neurologic and psychiatric complications, including post-traumatic stress disorder. Patients treated with anti-CD20 monoclonal antibodies (rituximab) are at risk of progressive multifocal leukoencephalopathy (PML). Neurocognitive impairment screening is recommended for at-risk patients to facilitate appropriate occupational therapy and social services referrals.

Staging

The Lugano classification, based on the Ann Arbor staging system, is used for NHL staging. It considers the number of tumor sites (nodal and extranodal) and their location.

• Stage I: NHL involving a single lymph node region (stage I) or a single extralymphatic organ or site (stage IE) without nodal involvement. A single lymph node region can include one node or adjacent nodes.
• Stage II: Two or more involved lymph node regions on the same side of the diaphragm (stage II) or localized involvement of an extralymphatic organ or site (stage IIE).
• Stage III: Lymph node involvement on both sides of the diaphragm (stage III).
• Stage IV: Widespread involvement of one or more extralymphatic organs (e.g., liver, bone marrow, lung) with or without associated lymph node involvement.

The subscript “E” indicates limited extranodal extension; extensive extranodal disease is Stage IV. Spleen involvement is considered nodal.

Prognosis

NHL prognosis is primarily determined by histopathology, disease extent, and patient factors. The International Prognostic Index (IPI) and its variants are key prognostic tools for NHL, predicting overall survival after standard treatment. IPI factors include age >60 years, elevated serum LDH, ECOG performance status ≥2, clinical stage III or IV, and >1 extranodal site. One point is assigned for each factor, with total scores (0-5) determining risk: low risk (0-1 factor), intermediate risk (2 factors), and poor risk (≥3 factors). Congenital or acquired immunodeficiency is associated with poorer prognosis and treatment response.[20] Modified IPIs exist for specific NHL subtypes, such as FLIPI for follicular lymphoma and MIPI for mantle cell lymphoma. Aggressive T- or NK-cell lymphomas generally have a worse prognosis. Low-grade lymphomas have longer survival, typically 6 to 10 years, but can transform into high-grade lymphomas.

Complications

Life-threatening emergent complications of NHL require prompt recognition and management during initial evaluation and workup. These can include:

• Febrile neutropenia
• Hyperuricemia and tumor lysis syndrome: Presenting with fatigue, nausea, vomiting, decreased urination, numbness, tingling, and joint pain. Laboratory findings include increased uric acid, potassium, creatinine, phosphate, and decreased calcium. Prevention involves vigorous hydration and allopurinol.
• Spinal cord or brain compression
• Focal compression: Depending on location and NHL type, may cause airway obstruction (mediastinal lymphoma), intestinal obstruction/intussusception, ureteral obstruction.
• Superior or inferior vena cava obstruction
• Hyperleukocytosis
• Adult T-cell leukemia-lymphoma: Can cause hypercalcemia.
• Pericardial tamponade
• Lymphoplasmacytic lymphoma with Waldenstrom macroglobulinemia: Can cause hyperviscosity syndrome.
• Hepatic dysfunction[21]
• Venous thromboembolic disease[22]
• Autoimmune hemolytic anemia and thrombocytopenia: Can occur with small lymphocytic lymphoma.

Deterrence and Patient Education

Patients should receive comprehensive information about treatment options, chemotherapy adverse effects, prognosis, and potential oncologic emergencies requiring emergency department visits. Psychosocial counseling referrals are appropriate for patients experiencing anxiety and depression. Lifestyle modifications, including smoking cessation, healthy diet, exercise, and moderate alcohol consumption, are important for cancer survivors.[23][24] These improve quality of life, reduce recurrence risk, and potentially improve mortality. Long-term survivors should be educated about secondary malignancies and cardiovascular complications.

Enhancing Healthcare Team Outcomes

NHL patient care requires a multidisciplinary team, including medical oncologists, radiation oncologists, mid-level practitioners, nurses, and others. Effective communication is essential. The patient’s primary care physician (PCP) remains involved throughout treatment and follow-up. Survivorship care planning should be collaborative between PCPs, oncologists, and specialists. Survivorship care plans guide the transition from oncology to primary care, addressing emotional, social, legal, and financial needs, and include specialist referrals and healthy lifestyle recommendations.[25] Survivorship clinics and well-defined roles facilitate coordinated care. Psychological effects of cancer, financial implications, and symptom management need to be addressed.

Review Questions

Burkitt Lymphoma Morphology

Microscopic view of Burkitt Lymphoma lymphoblasts using Wright stain, demonstrating high proliferation and apoptosis, creating a “starry sky” appearance in tissue sections.

Histopathology of Mantle Cell Lymphoma

High-power hematoxylin and eosin (H&E) stained image of mantle cell lymphoma showing uniform mature lymphocytes with slightly irregular nuclei, and a pink histiocyte marked with a black arrow.

MRI of Central Nervous System Lymphoma

Gadolinium-enhanced MRI of the brain, the primary diagnostic imaging modality for suspected primary central nervous lymphoma, showing lesion characteristics and location.

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