Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma is a heterogeneous group of lymphoproliferative malignancies, typically affecting middle-aged to older adults, characterised by genetic aberrations leading to lymphocyte proliferation and lymphadenopathy, typically presenting as multiple, peripheral, non-tender lymph nodes.

Description

Non-Hodgkin lymphoma, comprising a spectrum of lymphoid malignancies accounting for approximately 90% of all lymphomas, is primarily distinguished from Hodgkin lymphoma by the absence of Reed-Sternberg cells. Varying from indolent to highly aggressive subtypes, NHL is more prevalent in adults and typically diagnosed due to lymphadenopathy or extranodal masses.

Pathogenesis

NHL arises from genetic mutations and chromosomal translocations leading to unchecked growth and survival of lymphocytes, either B cells (~85% of cases), T cells (~15% of cases), or NK cells. The type of lymphocyte involved and the specific genetic aberrations underpin the behaviour, treatment response, and prognosis of the disease.

Subtypes

Non-Hodgkin lymphoma encompasses a diverse set of subtypes, distinguished by cell size, cell growth pattern, and specific cell markers:

• Diffuse large B-cell lymphoma (DLBCL): (~30% of cases). This is the most common subtype, predominantly affecting older adults. It typically presents as rapidly enlarging lymphadenopathy and is classified as an aggressive lymphoma. DLBCL often exhibits a diffuse growth pattern and the B cells are usually large.
• Follicular lymphoma: (~20% of cases). An indolent lymphoma affecting adults and elderly individuals. It often presents with painless lymphadenopathy and has a tendency to transform into a more aggressive lymphoma, such as DLBCL. It typically exhibits a follicular (nodular) growth pattern and the B cells can vary in size.
• Mantle cell lymphoma: (~6% of cases). An aggressive lymphoma that often affects middle-aged and older men. It may present with lymphadenopathy and often involves the gastrointestinal tract. The lymphoma cells are usually small to medium in size and exhibit a diffuse or nodular growth pattern.
• Small lymphocytic lymphoma: (~6% of cases). An indolent lymphoma closely related to chronic lymphocytic leukemia (CLL), usually affecting older adults. It often involves the lymph nodes, spleen, and bone marrow. The lymphoma cells are typically small and exhibit a diffuse growth pattern.
• Burkitt lymphoma: (~1-2% of cases). A highly aggressive lymphoma that may affect children and adults. It is associated with Epstein-Barr virus and commonly involves the abdomen. The lymphoma cells are medium-sized and exhibit a diffuse, “starry sky” growth pattern due to the presence of numerous macrophages.
• Peripheral T-cell lymphoma: (~10% of T-cell NHLs). A diverse group of aggressive lymphomas that affect adults. It often presents with skin lesions and may involve the lymph nodes, spleen, and liver. The lymphoma cells can vary in size and exhibit a diffuse growth pattern.
• Anaplastic large cell lymphoma: (~2% of all NHLs). This lymphoma often affects children and young adults and is associated with a genetic aberration involving the ALK gene. It may present with skin lesions, lymphadenopathy, or systemic symptoms. The lymphoma cells are usually large and have a hallmark “hallmark” cell appearance.

Epidemiology, Risk Factors & Associations

• Age (incidence increases significantly with age)
• Male gender (slightly higher incidence with a male-to-female ratio of 1.2:1)
• Immune system dysfunction or immunosuppression (e.g., HIV/AIDS increases risk by ~60-200 times, post-transplantation)
• Autoimmune diseases (e.g., rheumatoid arthritis, Sjogren’s syndrome)
• Viral infections (e.g., Epstein-Barr virus, human T-lymphotropic virus type 1)
• Exposure to certain chemicals and pesticides (e.g., agricultural chemicals)

Clinical Features

• Lymphadenopathy (most common, present in ~80% of patients)
• B symptoms: Fever, night sweats, and weight loss (~30% of patients)
• Pruritus
• Fatigue
• Abdominal pain or swelling (related to hepato/splenomegaly)

Complications

• Risk of transformation to more aggressive lymphoma.
• Potential for metastatic disease, most commonly to the liver (~40% of disseminated disease), lungs (~30% of disseminated disease), and central nervous system (~5% of aggressive NHL).

Pathological Features

Histopathology

• Macroscopic: Enlarged, non-caseating lymph nodes.
• Microscopic: Heterogeneous patterns, generally lymphoid cells proliferating in a disorganised manner.

Serology

• Lactate dehydrogenase (LDH) often elevated in high-grade lymphomas (~60% of aggressive NHL).

Biochemistry

• Hypercalcaemia can occur in high-grade lymphomas (10-20% of cases).

Radiological Features

General Features

• NHL typically manifests as lymphadenopathy, can be unilateral or bilateral, focal or diffuse.

CT

• Non-contrast: Enlarged lymph nodes
• C+ Arterial: Enhancement may be homogeneous or heterogeneous depending on subtype and stage.

MRI

• T1: Lymph nodes usually isointense to muscle and hypointense to fat.
• T2: Lymph nodes typically hyperintense.

US

• B-mode: Enlarged lymph nodes with preserved fatty hilum
• Colour: Vascular flow usually increased in malignant lymph nodes.

NM

• PET FDG: Lymphomas are typically FDG avid, helpful in staging, response assessment, and surveillance post-treatment.

Grading and Staging

NHL staging is done with the Ann Arbor staging system, accounting for the number of nodal sites involved and the presence of B symptoms.

Diagnosis

Diagnosis is primarily established by lymph node biopsy and histological examination. Immunohistochemical staining and molecular genetic testing further characterise the lymphoma subtype.

Differential Diagnosis

• Hodgkin lymphoma: Characterised by the presence of Reed-Sternberg cells on histology, often presenting with painless lymphadenopathy, and characteristically has a contiguous spread. The age distribution has a bimodal pattern, affecting young adults (20s) and older individuals (>55 years).
• Reactive lymphadenopathy: It is the most common cause of lymphadenopathy and can mimic lymphoma on imaging studies. Often has a history of recent infection or inflammatory process, and lymph node biopsy reveals benign reactive hyperplasia.
• Metastatic cancer: Malignancies such as lung, breast, melanoma, and others can metastasise to lymph nodes, mimicking the appearance of lymphoma on imaging. Key differentiating features would be a known primary cancer and the presence of nodal architecture distortion on histology.
• Leukaemia: Some forms of leukaemia, particularly chronic lymphocytic leukaemia, can manifest with lymphadenopathy similar to lymphoma. Notably, leukaemia more prominently involves the bone marrow and peripheral blood.
• Benign lymphoproliferative disorders: These include Castleman disease and reactive follicular hyperplasia, among others. They typically present with lymphadenopathy but lack the characteristic histological findings of lymphoma.
• Infectious mononucleosis: This condition, typically caused by the Epstein-Barr virus, can cause extensive lymphadenopathy, fatigue, and pharyngitis. It is more common in young adults and teenagers. Serology and the self-limiting course can help differentiate it from lymphoma.
• Sarcoidosis: This systemic granulomatous disease can present with bilateral hilar lymphadenopathy, potentially mimicking lymphoma. Diagnosis is typically via biopsy demonstrating non-caseating granulomas, and patients often have other organ involvement such as lungs and skin.

Prognosis

Prognosis varies substantially with NHL subtype and stage. Five-year survival rates range from 60-85% for indolent lymphomas and 30-60% for aggressive lymphomas.

Management

Management typically entails chemotherapy, sometimes combined with immunotherapy or targeted therapy. Radiation therapy is employed in specific scenarios. Referral to a hematologist is vital for guiding management.