Non-Hodgkin lymphoma in familial amyloid polyneuropathy patients in Sweden

To the editor:

Amyloidosis is characterized by deposition of fibrillar protein amyloids in a single organ or systematically in many organs.^1,2  At least 27 precursor proteins to amyloids are known.^1,2  Some forms of amyloidosis are associated with neoplasms, most notably immunoglobulin light-chain amyloidosis with multiple myeloma, monoclonal gammopathy of unknown significance, and, rarely, with non-Hodgkin lymphoma (NHL).^2,3  The most common and widespread hereditary amyloidosis, familial amyloid polyneuropathy (FAP), is caused by transthyretin mutations.⁴  It is endemic in northern Sweden, showing variable presentation even for the same mutations; the mean age of onset is 56 years and the range of survival time is 5 to 15 years.⁵  The ultimate treatment is liver transplantation. Because there are no data linking FAP to cancer, we carried out a follow-up study of Swedish FAP patients identified from the nationwide Hospital Discharge Register (1997-2010) and the Outpatients Register (2001-2010); the data sources and calculation of standardized incidence ratio (SIR) were described elsewhere;⁶  the reference cancer patients without FAP, diagnosed in the same period, were from the endemic northern provinces. The start of follow-up in 1997 was the first year when FAP could be identified from the records. Cancers were identified from the Swedish Cancer Registry (1997-2010).

The population included 224 men and 145 women with FAP in whom a total of 30 cancers were diagnosed (Table 1, data shown for cancers with at least 2 cases). Only NHL was significantly increased to an SIR of 5.02. The increase was significant both for diffuse large B-cell NHL and the “other” types, which were nonspecified forms of B-cell NHL (2 patients), NHL (2 patients), and T-cell NHL (1 patient). When stratified by gender, the SIR in women was 7.81 compared with 4.13 in men. All NHL cases were diagnosed in FAP patients older than 60 years at hospitalization. The first hospitalization for FAP was concurrent to or before the diagnosis of NHL in 6 patients; in 2 patients, NHL diagnosis appeared to be 3 to 4 years earlier, but because FAP is chronic disease, the disease was in progress probably years before. According to the Hospital Discharge Register, none of the 8 patients had undergone liver transplantation; none were first-degree relatives to each other. No cases of myeloma were recorded. The overall cancer risk was decreased to 0.68, which may be a result of underdiagnosis or underreporting of cancer in seriously ill patients with a progressive disease.

One can only speculate about the mechanisms. NHL is often related to immune suppression or excessive immune stimulation. It is possible that amyloid particles elicit an immune stimulation either directly or through inflammation in tissue deposits. Even though FAP is a rare disease, wild-type transthyretin is the amyloid precursor in senile amyloidosis, which at least in Sweden and Finland is the most common systemic amyloidosis, affecting up to 25% of individuals older than 70 or 85 years.^7,8  Thus, an urgent question is whether NHL would also associate with this common wild-type transthyretin-related senile amyloidosis.