Hemophagocytic lymphohistiocytosis and associations with malignancies

In immune homeostasis, natural killer cells and cytotoxic T cells are responsible for clearance of virus-infected and tumor transformed cells, but also for turning off the immune response. Patients with familial hemophagocytic lymphohistiocytosis (HLH) have impaired cytotoxic function due to genetic aberrations in genes in the perforindependent cytotoxic pathway. This results in an inability to turn off the immune response and, typically, a fatal hyperinflammation, often with onset already during the first months of life. The only curative treatment is hematopoietic stem cell transplantation. Patients with hypomorphic, ‘milder’, mutations in HLH-causing genes often have later onset of disease. Notably, an increased risk of hematological malignancies has been reported in these patients. The hyperinflammation of HLH can also occur in individuals without known Mendelian genetic predisposition. In these cases, often occurring later in life, it is termed ‘secondary HLH’ and it is most often triggered by an infection or a malignancy. In paper I we established the incidence of malignancies in relatives to patients with familial HLH by combining two incidence studies of familial HLH in Sweden with the Swedish multigeneration register and the Swedish national cancer register. We report an almost three-fold increased incidence rate of all cancers in mothers of patients with HLH compared to matched controls (4.4 vs 1.6, p=0.0014). In paper II we investigated individuals diagnosed with lymphoma in a defined population in northern Sweden. We found a higher prevalence of the most common HLH-causing aberration in Sweden, an inversion of UNC13D, in patients with lymphoma (3.1% vs 1%, p=0.002). In paper III, we investigated the incidence of secondary HLH in patients with malignancies. All patients with an ICD-10 diagnosis of HLH and cancer between 1997 and 2018 were identified from the Swedish inpatient register and the Swedish cancer register. During the 22 years studied, the incidence increased 10-fold, and at least 0.6% of all patients with hematological malignancies were affected. The last seven years the incidence corresponded to 0.45 per 100 000 individuals annually in Sweden. Importantly, the shortterm survival in malignancy-associated HLH was improved. By reporting a higher risk of malignant disease in relatives of patients with familial HLH as well as a higher frequency of the HLH-causing UNC13D inversion in patients with lymphoma, the studies included in this thesis further support the notion that malignant disease and HLH are tightly linked together. A striking increase in incidence of malignancy-associated HLH is reported over the 22 years studied. This and the improved short-term survival is likely a result of increased awareness of HLH, high-lighting the value of increasing awareness even further