Aetiology of lymphoma

Question 1

Overview

Answer 1

• Intro
• BG info
• Clinical features and lab results of HL
• Clinical features and lab results of NHL
• Pathophysiology of HL
• Pathophysiology of NHL
• Viruses and lymphoma
• Epstein Barr Virus
• HIV
• Other Viruses
• Bacterial infections
• Familial factors
• immune suppression
• Autoimmune diseases
• Conclusion

Question 2

-Intro to lymphomas

Answer 2

• Lymphoma: a semi-solid tumour of lymphoid lineage usually found in lymph nodes
  
  • Two main subtypes: HL and NHL
  • Objective: outline the aetiology of lymphoma
• Focus/exclusion: with a focus on infectious causes. Other malignancies will not be discussed. This report isn’t comprehensive.

Question 3

-BG info of lymphomas

Answer 3

• The main difference between HL and NHL is Reed-sternberg cells on lymph node histology
  
  • Presentation: asymetrical, painless lymphadenopathy, usually in neck
  • Splenomegaly, mediastinal involvement.
  • In advanced disease, systemic symptoms: fever, weight loss, bone marrow failure.

Question 4

-Clinical features and lab results of HL

Answer 4

• Normochromic, normocytic anaemia.
  
  • 1/3 of cases there is neutrophilia
  • Advanced disease: loss of cell-mediated immunity and pancytopenia due to BM
  • Diagnosis: Reed-Sternberg cells and CD30 and CD15 on flow cytometry.
  • Scanning methods: X-rays and CTs can gauge progression

Question 5

-Clinical features and lab results of NHL

Answer 5

• Similar
  
  • Lymphoma cells on blood film
  • BM aspirate, nodules of lymphoid tissue
  • Immunophenotyping and lack of RS cells confirm this diagnosis

Question 6

-Pathophysiology of HL

Answer 6

• Summarised as the acquired mutations of b cells causing a defect in the synthesis of full length Ig.
• HLA class I is usually absent and mutations of the Beta2-microglobulin gene occurs quite often

Question 7

-Pathophysiology of NHL

Answer 7

• Pathophysiology is very broad
  
  • Unregulated clonal proliferation of lymphoid cells forming a tumour
  • 85% B cell, 15% T cell
  • Cytogenetic abnormalities that affect Ig genes are frequent.
• Next generation sequencing has demonstrated many mutations to be associated with NH lymphoma; Namely those affecting the NFkappaB pathway of B-cell activation

Question 8

-Viruses and lymphoma

Answer 8

• Many viruses can contribute
  
  • The most significant examples outlined here: EBV, HIV-1, HTLV1, HHV8 and Hep C.
  • Mechanisms are numerous:
  • Viruses can express their own oncogenic proteins
  • Transactivating oncogenic proteins of the host genome
  • Induce antigenic chronic B-cell stimulation
  • Suppress T-cell function
  • Insertional mutagenesis: virus adds base pairs to exons of genes

Question 9

-Epstein Barr Virus in lymphoma

Answer 9

• Most prominent in lymphoma pathophysiology
  
  • Greatest range of causation
  • EBV has a strong association with Burkitts lymphoma (and Hodgkin lymphoma)
• Can interact with HIV, HHV8 and other bacterial/parasitic infections to form a lymphoma.
• In Burkitt’s, EBV encodes proteins that are oncogenic:
• Latent membrane protein 1: activates NFKB, favouring proliferation and cell survival
• LMP2: inhibits genes of B-cell maturation and stimulates genes that promote cell survival
• This process interacts with Malaria
• Malaria causes a state of chronic B-cell stimulation and suppression of T-cell activity.
• This interaction and its many factors cause mutations of the b-cell that cause Burkitt’s
• These mutations cause dysregulation of proto-oncogene c-myc and TS gene p53

Question 10

-HIV in lymphoma

Answer 10

• Also a significant virus in lymphoma pathogenesis
  
  • It’s able to interact with EBV similarly to Malaria
  • Causes T-cell suppression and leads to HIV-assocaited Burktitt’s
  • Also, HIV causes a systemic immunosuppressed state
• HIV allows opportunistic infections to exert their oncogenic effect

Question 11

-Other Viruses in lymphoma

Answer 11

• Other important viruses include human T-lymphotrophic virus (HTLV-1)
  
  • Associated with adult t-cell leukaemia/lymphoma (ATLL)
  • HTLV-1 predominantly infects CD4+ T-cells and activates host genes
  • Host genes such as ‘HBZ’ and ‘tax’ upregulate oncogenic pathways
  • Human Herpes Virus (HHV8) leads to primary effusion lymphoma
  • Hepatitis C causes Marginal zone lymphoma and low-grade B-cell NHL

Question 12

-Bacterial infections in lymphoma

Answer 12

• Also play a role in lymphoma pathogenesis
  
  • Helicobacter Pylori can cause an infection, usually in the stomach’s MALT
  • This infection causes Chronic antigenic stimulation of B-cells in its area
  • This leads to MALT lymphoma
  • This incidence of which is increased 6-fold by H. Pylori infection
  • Other species include: Campylobacter Jejuni and mycobacterium tuberculosis

Question 13

-Familial factors of lymphoma

Answer 13

• Familial factors also contribute
  
  • 2-3 fold increased risk if an immediate family member is effected
• Certain HLA groups that run within families can predispose to HL, which is characterised by a loss of HLA class I expression on tumour cells.

Question 14

-immune suppression in lymphoma

Answer 14

• Immune suppression is also important in the aetiology of lymphoma
  
  • Example: Already described with HIV and Burkitt’s
• Chemotherapy agents: methotrexate, immunosuppression in organ or stem cell transplants or inherited causes of immune deficiency can contribute to lymphoma
  
  • Opportunistic infections like the onse outline are enabled by these events.

Question 15

-Autoimmune diseases in lymphoma

Answer 15

• Autoimmune diseases, such as Coeliacs contribute

- Self antigens lead to chronic B-cell stimulation

Question 16

-Conclusion

Answer 16

• Lymphomas comprise a broad range of disease subtypes that can arise through a wide range of mechanisms
• Lymphoid lineage cells develop into semi-solid tumours after undergoing mutation, mainly by excess B-cell stimulation and proto-oncogene dysregulation.
• The main factor is viral infections that either produce their own oncofgenic proteins or upregulate oncogenic proteins of the host genome.