introduction
Hodgkin's lymphoma
- risk factors
- clinical features
non-Hodgkin's lymphoma

lymphoma

introduction

lymphomas are the 6th most common type of cancer excluding non-melanoma skin cancers with 1 in 39 people developing a NH lymphoma and 1 in 414 people developing Hodgkin's lymphoma by age 85yrs
incidence is rising in Australia (doubled in past 20 yrs)¹⁾
85% of malignant lymphomas are non-Hodgkins lymphomas (NHL)
median age at diagnosis is in 6th decade with exception of Burkitt lymphoma and lymphoblastic lymphoma which occur in younger patients

Hodgkin's lymphoma

accounts for 12% of cases of lymphoma
first identified by Thomas Hodgkin in the 1830's
defined by the presence of Reed-Sternberg cells (discovered in 1898 and 1902 by Reed and Sternberg)
it is thought to develop from an abnormal response to EBV / glandular fever / infectious mononucleosis infection in those who are susceptible
possibly POT1 mutation ²⁾
most patients are young adults (20-35yrs old) or in the 70's.
5 year survival with Rx:
- stage I/II 90%
- stage III 84%
- stage IV 65%
~50% contain EBV / glandular fever / infectious mononucleosis genome, esp. in:
- patients with mixed cellularity tumours
- young children
- elderly

risk factors

genetic:
- twin with HL ⇒ 99x risk³⁾
- parent or sibling with HL or any blood or lymphatic cancer ⇒ 7x risk
infectious mononucleosis infection ⇒ 3x risk
- EBV infection in people with homozygous CD70 protein gene defect ⁴⁾
immunosuppression:
- HIV/AIDS ⇒ 11x risk
- organ transplantation
autoimmune diseases such as:
- rheumatoid arthritis, systemic lupus erythematosus and sarcoidosis
patients with psoriasis have almost 2x risk ⁵⁾
childhood affluence (presumably via delay in acquiring EBV, or less childhood infections resulting in altered immunity)
PH Non-Hodgkin's lymphoma ⇒ 4-16x risk
some alcohol consumption appears to reduce risk as does being breastfed

clinical features

painless and slowly progressive, rubbery lymphadenopathy
- 80% are above the diaphragm, 60-80% involve neck, <20% axillary, <20% groin
- <10% have pain at nodal sites precipitated by drinking alcohol
- if massive mediastinal nodes, may develop superior vena cava syndrome
extranodal involvement
- splenomegaly
- hepatosplenomegaly
- 40% have B symptoms
  - T > 38°C, night sweats
  - weight loss >10% from baseline within 6 months
- fatigue/weakness
- 35% have intermittent fever
- some have classic Pel-Ebstein fever
  - high fever for 1-2 wks followed by an afebrile period of 1-2 wks
- pruritus or itching
- chest pain, cough &/or SOB
- paraneoplastic syndromes
- rarely:
  - bone/back pain
  - haemoptysis

non-Hodgkin's lymphoma

85% of NHLs are of B-cell origin
15% are derived from T/NK cells
the remainder arise from macrophages
5 year survival is just over 60%
classification
- before the discovery of B-cells and T-cells in the mid 1960s, Rappaport had developed a classification in 1956 which consisted of well-differentiated, poorly differentiated and histiocytic lymphomas
- The Lukes-Collins classification was published in 1975 and attempted to relate cell morphology to immunologic function
- The Working Formulation for classifying non-Hodgkin's lymphomas was published in 1982 and it quickly replaced the Rappaport and Lukes-Collins classification with the introduction of three prognostic groups: low, intermediate and high grade
- the Revised European-American Classification of Lymphoid Neoplasms (REAL classification) was introduced in 1994 taking into account immunologic, genetic and clinical characteristics of the disorders and not solely histopathologic characteristics of the tumor cells. This was then adopted by WHO.

risk factors

EBV / glandular fever / infectious mononucleosis + malaria ⇒ endemic Burkitt's lymphoma in children
EBV / glandular fever / infectious mononucleosis + immunosuppression
- ⇒ post-transplant lymphoma
  - 13% of heart, and 33% of heart/lung recipients have been reported to develop NHL
  - The latest meta-analysis showed an 8-fold increased risk of NHL in transplant recipients
- ⇒ HIV-related lymphoma
  - HIV is 80x risk with 3-5% developing NHL and HIV accounts for 6% of NHL cases in developed countries
  - EBV is present in 2/3rds of AIDS-related NHL
strong association between Helicobacter pylori and lymphomas of mucosa-associated lymphoid tissue (MALT) in the stomach
- 4% of NHL cases in developed countries are due to infection with H.pylori
Hepatitis C virus infection ⇒ 2-2.5x risk
Human T-Cell Lymphoma Virus 1 causes a small number of cases of NHL in developed countries
auto-immune conditions
- haemolytic anaemia, systemic lupus erythematosus and Sjogren syndrome
- coeliac disease is associated with an increased risk of T-cell lymphoma specifically
patients with psoriasis have 50% increased risk - may be due to the higher risk of cutaneous T-cell lymphoma, which is markedly more common in people with severe psoriasis ⁶⁾
genetic:
- FH NHL ⇒ 2x risk
- FH coeliac disease in a sibling ⇒ increased risk
- POT1 mutation
  - “predisposes to pan-lymphoid malignancy syndrome associated with melanoma, sarcoma, and myeloproliferative neoplasms associated with long telemore (TL) and ageing of lymphocytes, sustaining lymphocyte clonal evolution especially in B cells. UK Biobank participants with pathogenic POT1 variants had long TL and higher lymphoid malignancy rates (45% by the age of 80 years; hazard ratio, 8.28; 95% confidence interval, 5.29-13.0). Haploinsufficient mutations in POT1 lead to an autosomal dominant cancer-prone syndrome mediated by long TL.7,13-15 POT1 binds single-stranded telomeric DNA and is essential for telomere protection,16 but POT1 heterozygous loss of function is permissive of telomerase elongation in the absence of a detectable DNA damage response. The prevalence of POT1 mutations in cancer has been limited to single-disease studies, and mutations have been identified consistently in ∼0.5% to 1% of multiple cancers.”⁷⁾
carcinogens:
- A meta-analysis of case-control studies reported a 35% increase in risk for people with occupational exposure to pesticides, increasing to 65% for more than 10 years' exposure
- Occupational exposure to benzene has been linked to a 22% increase in NHL risk in a meta-analysis
obesity:
- a 40% increased risk of diffuse large B-cell NHL for people with a BMI of 30 or higher.

sub-types of NHL

B cell tumours
- Diffuse Large B Cell Lymphoma (DLBCL)
  - Mann-type DLBCL
    - accounts for 1/3rd of DLBCL
    - discovered in 2025⁸⁾, does not respond well to conventional therapies
    - has mannose on the key B-cell receptor
- Follicular Lymphoma
  - the most common sub-type of indolent NHL, comprising 20% to 30% of all NHL
  - typically affects middle-aged or older adult
  - a small percentage will transform into a more aggressive form of NHL, usually a DLBC
- Mantle Cell Lymphoma
  - see mantle cell lymphoma (MCL)
  - 2 types of MCL⁹⁾:
    - classical MCL
      - usually composed of IGHV-unmutated B cells and SOX11 expression and involves lymph nodes and extranodal sites
    - leukaemic non-nodal MCL
      - generally composed of IGHV-mutated genes without SOX11 expression and involves the bone marrow, peripheral blood, and spleen; leukemic non-nodal MCL also typically has an indolent presentation
  - majority of people with MCL have stage IV disease at diagnosis
  - usually affects those over aged 50yrs (men have 2-7x risk) and accounts for 5-10% of NHL cases
  - increased risk of MCL is associated with certain autoimmune disorders, FH of hematopoietic malignancy, and Borrelia burgdorferi infection (Lyme disease)
- Burkitt’s Lymphoma (BL)
- Chronic Lymphocytic Leukeamia (CLL)/Small Lymphocytic Lymphoma (SLL)
- Marginal Zone Lymphoma (MZL)
- Waldenstroms Macrogloulineamia (WM)
- B Cell Acute Leukaemia/Lymphoma (B-ALL)
T cell tumours
- Cutaneous T Cell Lymphoma (CTCL)
- Anaplastic Large T Cell Lymphoma
- Adult T Cell Lymphoma/Leukaemia
- Peripheral T Cell Lymphoma (PTCL)
- T Cell Acute Leukaemia/Lymphoma (T-ALL)

clinical features

painless and slowly progressive lymphadenopathy
cytopenias
with advanced stages of low grade tumours, or early stages of high grade tumours:
- extranodal involvement
  - esp. GI/GU tracts (including Waldeyer ring), skin, bone marrow, sinuses, thyroid, CNS
  - splenomegaly
  - hepatosplenomegaly
  - testicular mass
  - skin lesions (mycosis fungoides)
- B symptoms
  - T > 38°C, night sweats
  - weight loss >10% from baseline within 6 months
- fatigue/weakness

grading of NHL

low grade, slow growing or indolent
- often can be watched conservatively with “watchful waiting”
- premature Rx may cause unnecessary side effects, and worse, may make subsequent Rx more resistant and likely to fail
- many follicular type NHLs fall into this category
higher grade, faster growing
- usually need urgent Rx such as chemotherapy, steroids, monoclonal antibody targeted Rx, radiotherapy +/- stem cell transplant