ImmunologyTier 1Medical Sciences concept

Autoimmune disease-associated malignancy risk (Hashimoto's-thyroid lymphoma, Sjogren's-MALT lymphoma, coeliac-EATL)

Core concept

Three separable mechanisms - the exam wants you to say which is operating
- Chronic antigen-driven lymphoproliferation -> lymphoma at the site of inflammation (Sjogren's parotid, Hashimoto's thyroid, coeliac gut, RA joints)
- Paraneoplastic autoimmunity - the cancer causes the autoimmune disease (dermatomyositis)
- Immunosuppressive therapy - azathioprine, cyclophosphamide, calcineurin inhibitors, anti-TNF
Chronic tissue damage adds a fourth route: fibrosis -> lung cancer in scleroderma, oesophageal adenocarcinoma in scleroderma reflux

Key detail

Disease	Malignancy	Magnitude / detail
Dermatomyositis	Any solid organ - ovary, lung, pancreas, stomach, colorectal, nasopharyngeal (Asian)	The strongest association: SIR ~3-6x, concentrated in the first 1-3 years, highest with anti-TIF1-gamma and anti-NXP2 antibodies. Polymyositis risk is much lower
Sjogren's syndrome	MALT lymphoma (parotid) and other NHL	~15-20x - the largest relative risk of any autoimmune disease for a single cancer. Predictors: persistent parotid swelling, purpura, low C4, cryoglobulins, monoclonal band, lymphopenia, high focus score
Hashimoto's thyroiditis	Primary thyroid lymphoma	Rare absolutely, but Hashimoto's precedes almost every case; rapidly enlarging goitre
Coeliac disease	EATL (enteropathy-associated T-cell lymphoma), small bowel adenocarcinoma	Risk concentrated in refractory coeliac disease type II; a gluten-free diet reduces it
Rheumatoid arthritis	Lymphoma ~2x, lung cancer	Tracks cumulative disease activity, not therapy; Felty's syndrome -> large granular lymphocytic leukaemia
SLE	Non-Hodgkin lymphoma ~4x; cervical (HPV), vulvar, lung, thyroid	Breast, endometrial and ovarian risk is REDUCED
Systemic sclerosis	Lung (fibrosis), oesophageal adenocarcinoma, breast, haematological, bladder, tongue	Anti-RNA polymerase III -> cancer within ~2-3 years of scleroderma onset
IBD	Colorectal cancer, cholangiocarcinoma with PSC, small bowel in Crohn's	Risk with extent and duration of colitis -> surveillance colonoscopy
Polyarteritis nodosa, IgG4-RD	Solid tumours; lymphoma	Paraneoplastic and association

Therapy-attributable risk

Azathioprine/thiopurines - non-melanoma skin cancer (SCC), post-transplant lymphoproliferative disease (EBV-driven), hepatosplenic T-cell lymphoma (young men, thiopurine + anti-TNF)
Cyclophosphamide - bladder cancer (acrolein), therapy-related MDS/AML - cumulative dose dependent; mesna and hydration
Calcineurin inhibitors - skin cancer, PTLD
Anti-TNF - the lymphoma signal is now largely attributed to disease activity and prior thiopurine rather than the drug itself
Hydroxychloroquine and methotrexate carry little or no added risk (MTX-associated EBV+ lymphoproliferation regresses on withdrawal)

Clinical relevance

New dermatomyositis in an adult = a malignancy work-up: CT chest/abdomen/pelvis, mammography, CA-125 and pelvic imaging or transvaginal ultrasound, colonoscopy, nasopharyngoscopy in at-risk ethnicity; repeat annually for 3 years, and test myositis-specific antibodies to stratify
Sjogren's with a persistently enlarged parotid, new purpura, falling C4 or a paraprotein -> biopsy for lymphoma
Keep age-appropriate cancer screening up to date in every immunosuppressed patient, plus annual skin checks and rigorous sun protection, HPV vaccination and cervical screening in SLE
A rapid change in an autoimmune disease that had been stable is a reason to look for cancer, not simply to escalate immunosuppression

Correlations

Autoimmune disease pathogenesis and molecular mimicry
Alkylating agent toxicity; secondary malignancy after chemotherapy
Sjogren's syndrome; dermatomyositis; systemic sclerosis
Secondary immunodeficiency; post-transplant lymphoproliferative disease
Herpesvirus latency (EBV) and lymphoproliferation

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