Non-Hodgkin Lymphoma (NHL)

How to investigate, diagnose and treat Non-Hodgkin Lymphoma (NHL) – for doctors’ exams, medical student finals, OSCEs, PACES and CPD

• Non-Hodgkin lymphoma (NHL) is an umbrella term for many cancers deriving from lymphocytes, which predominantly are found in lymphoid tissue (lymph nodes, spleen and mucosa-associated lymphoid tissue a.k.a. MALT)
• ‘Lymphoproliferative disease’ is often used interchangeably
  • However, while NHL makes up the majority of lymphoproliferative diseases, this term includes others such as Hodgkin disease, and acute lymphoblastic leukaemia
• Lymphadenopathy is the most common clinical syndrome seen in NHL, but sometimes lymph nodes are unaffected, and the disease is only found in bone marrow or in extranodal sites
• Leukaemia means the presence of circulating cancerous white blood cells, and implies bone marrow involvement. In some types of NHL, leukaemia is common (e.g. chronic lymphocytic leukaemia), and in many others it is a rarely encountered manifestation

Types (classification) of Non-Hodgkin Lymphoma

• NHL can be classified according to:
  • Pathological grade (high grade or low grade)
  • Cell of origin (B cell or T cell)
  • Histological features:

Classification of Non-Hodgkin Lymphoma (NHL)

Diagnosis	Grade	Proportion of NHL cases	B or T cell
Chronic lymphocytic leukaemia	Low	26%	B cell
Follicular lymphoma	Low	12%	B cell
Marginal zone lymphoma	Low	13%	B cell
Lymphoplasmacytic lymphoma, a.k.a. Waldenström’s macroglobulinaemia	Low	1%	B cell
Mantle cell lymphoma	Variable	3%	B cell
Diffuse Large B cell lymphoma	High	31%	B cell
Burkitt’s lymphoma	High	1%	B cell
T cell lymphoma (various)	Variable	4%	T cell

Epidemiology of non-Hodgkin lymphoma (NHL)

• Accounts for 5% of all cancers (UK-based data)
• Incidence of high grade NHL: 18 per 100,000 per year
  • It is rising for reasons that are not well understood
• 10 year prevalence of low grade NHL: 106 per 100,000
• Median age at diagnosis 70 years

Video on the pathophysiology and types of non-Hodgkin lymphoma

Risk factors for non-Hodgkin lymphoma (NHL)

• In most cases of NHL no particular risk factors can be identified. However, some risk factors include:
• Infection
  • Untreated HIV infection is associated with high grade NHL
  • H. pylori can cause marginal zone lymphoma, especially affecting gastric MALT
  • Epstein-Barr virus is associated with various types of NHL, especially post-transplant lymphoproliferative disease (PTLD) seen in recipients of solid organ transplants
  • Human T cell lymphotropic virus-1 (HTLV-1) is associated with T cell lymphoma
• Ionising radiation (most commonly due to previous cancer treatment)
• Immunosuppressant medication (e.g. ciclosporin)
• Autoimmune disease (e.g. Sjögren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus)
• Coeliac disease is associated with enteropathy-associated T cell lymphoma (EATL)

Pathogenesis of non-Hodgkin lymphoma (NHL)

• Many subtypes of lymphoma have characteristic genetic changes, causing overexpression of particular genes which drive proliferation or promote survival. Many involve translocations with genes highly expressed in lymphocytes, such as immunoglobulin heavy chain.

Presentations of non-Hodgkin lymphoma (NHL)

Due to its anatomical and pathological variety, NHL has a myriad of presentations:

• Symptoms due to local mass effect
  • Enlarged lymph nodes noted by patient, their family or a healthcare professional
  • Extrinsic compression of structures by lymphadenopathy e.g. biliary obstruction causing jaundice or cholangitis, ureteric obstruction causing hydronephrosis and renal failure, collapse of a lung lobe due to bronchial obstruction
  • Symptomatic splenomegaly (LUQ pain, early satiety, abdominal swelling)
  • Extralymphatic mass effect (e.g. spinal cord compression due to lymphoma in vertebrae or the spinal canal)
  • Rarely, T cell lymphomas affecting the skin present as raised red or purple plaques.
• Symptoms due to local inflammation
  • Malignant pleural effusion
  • Ascites
  • Malignant meningitis which may cause hydrocephalus
• Systemic symptoms (‘B symptoms’)
  • Night sweats (drenching)
  • Fever
  • Unintentional weight loss
• Symptoms due to bone marrow infiltration
  • Anaemia causing shortness of breath or fatigue.
  • Thrombocytopenia causing petechiae, bleeding or bruising.
  • Neutropenia causing recurrent infection
• Incidental findings
  • Lymphadenopathy or soft tissue deposits identified on scans
  • Raised lymphocyte count
  • Abnormal lymphocytes on blood film
  • Incidental paraprotein on serum electrophoresis
• Symptoms due to immune system dysfunction
  • Hypogammaglobulinaemia causing recurrent infection
  • High levels of IgM paraprotein causing hyperviscosity
  • Autoimmune haemolytic anaemia or immune thrombocytopenia purpura (ITP)
  • Paraneoplastic neuropathy
  • Amyloidosis
• Metabolic disturbance
  • Hypercalcaemia (lethargy, dehydration, renal failure)
  • Tumour lysis syndrome (renal failure due to products of high cell turnover, seen in high grade lymphoma)

Differential diagnosis of non-Hodgkin lymphoma (NHL)

Classification of diagnosis	Diagnosis
Other malignancy	Lymphatic metastasis from solid organ malignancy
Non-malignant	Reactive lymphadenopathy, to a lesion (infectious, traumatic or malignant) in the tissues drained by the affected lymph node
Non-malignant	Associated with connective tissue disease
Non-malignant	Viral infection (particularly acute Epstein-Barr virus infection, and HIV)
Non-malignant	Granulomatous disease (Tuberculosis, sarcoidosis)
Non-malignant	Toxoplasmosis, Cat-scratch disease
Non-malignant	Castleman's disease

Staging of non-Hodgkin lymphoma (NHL)

This is based on the Ann Arbor staging system, which was originally developed for Hodgkin disease:

• Stage I involves only one lymph node area
• II involves 2 or more on one side of the diaphragm
• III involves 2 or more on both sides of the diaphragm
• IV involves any extra-lymphatic tissue (including bone marrow)
• The presence of ‘B symptoms’ is denoted by adding B as a suffix

65% of NHL is stage III or IV at presentation

Patient-focused and slightly dated video on overview of NHL

Initial management of non-Hodgkin lymphoma (NHL)

• Urgent treatment is rarely needed. In cases where the disease is very rapidly progressing, or compressing a vital structure (e.g. spinal cord), a course of glucocorticoids (e.g. prednisolone PO 1mg/kg once daily for 7 days) will temporarily shrink the disease
• However this causes necrosis which severely impairs histology findings, so if possible a biopsy should be taken prior to starting steroids

Investigation to confirm the diagnosis:

• Core biopsy or excision biopsy of an affected lymph node or other organ
  • Note a fine needle aspirate (FNA) will not give enough histological detail to make a diagnosis of lymphoma. It is only an appropriate first line investigation to rule out metastatic carcinoma/adenocarcinoma, where there is a clinical suspicion
  • If there is no readily accessible disease sites a bone marrow biopsy may yield a diagnosis but is often inconclusive
  • The only type of NHL which does not usually require a biopsy is chronic lymphocytic leukaemia, which has a characteristic immunophenotype and can usually be diagnosed on immunophenotyping of peripheral blood

• Blood tests to check for:
  • Underlying causes (HIV serology)
  • Complications (FBC, U&E, LFT, calcium and phosphate, LDH, immunoglobulins, serum electrophoresis)
  • Co-incident conditions which affect treatment (Hepatitis B and hepatitis C, Group and screen).
  • Uric acid if suspicion of tumour lysis syndrome
• Urine for Bence-Jones protein (free light chains)

• A staging CT scan (with iv contrast) of neck, chest, abdomen and pelvis
  • Comprehensive staging also requires a bone marrow biopsy, but this may be omitted if the stage is already known to be advanced (III or IV), and there is no suspicion of a co-incident different bone marrow pathology

Treatment of low grade NHL

• Treatment is not indicated if the disease is asymptomatic, so a watch-and-wait strategy may initially be adopted
• Early stage disease (stage I or II) may be treated with local radiotherapy only if local tissues are not very radio-sensitive
• Disseminated disease is treated with chemotherapy, often in combination with a monoclonal antibody e.g. R-CVP (rituximab, an anti-CD20 monoclonal antibody, combined with cyclophosphamide, vincristine and prednisolone, given as 6-8 cycles of 21 days each)
• Low-grade NHL is not generally considered curable. At relapse retreatment with further chemotherapy or radiotherapy can be undertaken, but response rates are lower
• Recently new kinase inhibitors (ibrutinib, which inhibits the Bruton’s tyrosine kinase, and idelalisib, which inhibits phosphoinositide 3-kinase) have been licensed for use in low grade NHL, which have higher response rates than previous treatments

Treatment of high grade NHL

• High grade NHL is potentially curable in patients fit enough to tolerate treatment
• For those with localised disease, a short course of chemotherapy may be combined with local radiotherapy
• Most patients have disseminated disease and require combination chemotherapy e.g. R-CHOP (As R-CVP but with the addition of doxorubicin, an anthracycline)
• Those with central nervous system involvement or breast involvement should also receive intrathecal treatment, such as intrathecal methotrexate or systemic high dose methotrexate
• If patients relapse, they can receive a course of salvage chemotherapy followed by high dose chemotherapy with autologous stem cell rescue (also known as an autograft)
• For those too frail or co-morbid for high dose therapy, lower intensity chemotherapy regimens may be used to slow progression

Complications of non-Hodgkin lymphoma

• Spinal cord compression / cauda equina syndrome
• For low-grade lymphoma: Transformation to high grade lymphoma (‘Richter’s Transformation’)
• Tumour lysis syndrome
• Hypercalcaemia
• Hypogammaglobulinaemia
• Hyperviscosity syndrome
• Paraneoplastic autoimmune conditions (autoimmune haemolytic anaemia, ITP, neuropathy)
• Neutropenic sepsis

Prognosis of non-Hodgkin lymphoma (NHL)

• With treatment, the 5 year survival of low-grade NHL is 83%, but these disorders continue to relapse and 10 year survival is approximately 50%
• Mantle cell lymphoma has the poorest prognosis, with 40% 5-year survival
• High grade lymphoma has a 2 year survival rate of 55%. Those who survive treatment and do not suffer early relapse are generally cured, and go on to have a normal life expectancy
• Within these numbers there is variation, and a number of prognostic scoring systems exist and are well validated. These are based on the international prognostic index (IPI), which uses the following to generate prognostic groups:
  • Age
  • Serum LDH
  • Performance status
  • Stage
  • Number of extranodal sites
• Scoring systems have been adapted for follicular lymphoma (FLIPI) and mantle cell (MIPI)

Related page: Questions about non-Hodgkin lymphoma and differential diagnosis of lymphoma

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