Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

Abstract

Background: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in CTLA4 can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown. Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled. Results: Among the 184 CTLA4 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected CTLA4 mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated. Conclusion: Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected CTLA4 mutation carriers.

Keywords: CMV; CTLA4; EBV; cancer predisposition; combined immunodeficiency; malignancy; primary immunodeficiency.

Figure 1

Hyperinflammation, exemplified in a CTLA-4-insufficient-patient. Panel (A) shows a liver biopsy taken from patient H.II.1 at the age of 17 years with a cholestatic giant cell hepatitis (bile marked by arrowhead, exemplary). Panels (B,C) show bone marrow trephine biopsies with nodular lymphocytic aggregates (of T-cell origin, by IHC). In (B), subtotal replacement of hematopoiesis by fibrosis and stromal edema can be seen.

Figure 2

Lymphomas in CTLA-4-insufficient-patients (A–D) showing classical Hodgkin lymphomas (mixed cellularity subtype), exemplary Reed-Sternberg cells are highlighted by arrowhead. All cases were EBV-associated.

Figure 3

Gastric cancer and precursor lesions in CTLA-4-insufficient-patients. (A) Poorly differentiated EBV associated adenocarcinoma at the age of 41 years (inlet displays chromogen in situ hybridization of EBV coded mRNA/EBER ISH). (B) Same patient at the age of 44 years with a well-differentiated EBV associated adenocarcinoma (inlet with EBER ISH). (C) Infiltration of the lamina propria through discohesive carcinoma cells in a 25-years-old patient. (D-F) 34-years-old patient with small poorly differentiated adenocarcinoma (D,e for macroscopy; E for histology) and larger well-differentiated adenocarcinoma (D,f for macroscopy; F for histology). (G,H) Pyloric biopsies taken at the age of 43 years showing high grade dysplasia (G) and viral inclusions (H, highlighted by arrowhead).

Figure 4

Other malignancies in CTLA-4-insufficient-patients. (A) Superficial spreading melanoma of the ear (at the age 24 years) and metastasis (B; at the age of 25 years) infiltrating striated muscle fibers. (C) Amyloid deposits (highlighted by arrowhead) were immunohistochemically positive for amyloid p in this 75-years-old patient with multiple myeloma.

Figure 5

Incidences of selected malignancies in the averaged German and US population (reference cohort, general population, 2009–2014) and incidences in affected CTLA4 mutation carriers (2009–2017).

Figure 6

Survival rate per entity of malignancies in CTLA4 mutation carriers (n = 17), time range from day of diagnosis to last follow-up (days).