A history of invasive malignancy appears to be associated with later development of immunoglobulin G4-related disease (IgG4-RD), according to Boston researchers reporting in Arthritis & Rheumatology.
They observed a prevalence of malignancy in IgG4-RD patients that was 2.5 times higher (95% CI 1-3.6) than expected from the Surveillance, Epidemiology, and End Results (SEER) database. In addition, compared with the rate for matched controls, a history of cancer was 3.5 times higher in IgG4-RD patients (OR 3.1, 95% CI 1.6-6.2).
"This finding may support and advance contemporary hypotheses about the relationships between malignancy and the subsequent development of immune-mediated conditions," wrote John H. Stone, MD, MPH, of Massachusetts General Hospital in Boston, and colleagues.
Occurring as mass lesions in the pancreas, orbits, retroperitoneum, lung, kidneys, lymph nodes, and other organs, IgG4-RD is often mistaken for malignancy, and patients may experience substantial iatrogenic morbidity before being correctly diagnosed, the authors noted in previous research.
In the new study, those with a history of invasive malignancy were identified in a cohort of 125 IgG4-RD patients treated in the hospital's rheumatology division and compared regarding their cancer history with two U.S. reference groups: the general population and controls. The mean age at IgG4-RD onset was 50.3+14.9 years, 61% of patients were male, 95 (76%) were non-Hispanic white, and 20 (16%) had been diagnosed with a range of 21 different malignancies before the IgG4-RD diagnosis.
Stone and associates calculated a standardized prevalence ratio (SPR) against estimates from SEER, and using up to five age- and gender-matched controls per case, determined the odds of malignancy among patients versus controls via conditional logistic regression.
The researchers said that based on U.S. population estimates, the expectation was that there would be 8.0 malignancies in the 125 IgG4-RD patients (adjusting for age group by decade), but in actuality there were 20 first-time malignancies (95% CI 11.2-28.8). The SPR of malignancy among IgG4-RD patients was 2.5 (95% CI 1.1-3.6). By gender, in male patients, 5.8 malignancies were expected versus the actual 15 that were observed, corresponding to an SPR of 2.6 (95% CI 1.9 to 3.3). Among females, 2.6 were expected and five were observed (SPR 1.9, 95% CI 1.1-2.7).
Prostate cancer was the most common malignancy in both controls and patients, but lymphoma accounted for 19% of the malignancies in the IgG4-RD cohort versus just 4% in the control cohort.
In an interview with MedPage Today, Stone noted that the study provides a new perspective on whether this systemic fibro-inflammatory condition is associated with cancer. He said that some clinicians have the perception – perhaps because IgG4-RD often presents with a mass lesion and is frequently associated with lymphadenopathy -- that the disease is a premalignant condition. "It is clear, however, that the great majority of IgG4-RD cases have no relationship to cancer," he said. "This study takes that point one step further and suggests that the converse relationship may be true in some cases -- that is, that a history of malignancy may actually be a risk factor for IgG4-RD in a minority of cases, rather than the other way around."
Interestingly, no cases of IgG4-RD diagnosed after malignancy occurred in the organ previously affected by cancer. Those with past malignancy developed IgG4-RD at a later age and had higher serum IgG4 concentrations compared with those with no malignancy.
Asked for his perspective, Petros Efthimiou, MD, of New York Methodist Hospital in Brooklyn, N.Y., told MedPage Today: "This single-center, retrospective study suggests that a subset of patients with invasive malignancy may develop IgG4-RD later in life, even years after the original cancer was thought to be in remission. Larger prospective studies will be needed to confirm that association."
The detection of masses on imaging often leads to resections in the urgency to treat potential malignancy, he added: "In the case of IgG4-RD, however, the histology comes back suggestive of IgG4-RD with storiform fibrosis and IgG4 staining plasmablasts, effectively ruling out malignancy. Unfortunately, the patient may sustain complications from the surgery. And to complicate things even more, there are several cases of actual cancer, not necessarily at the same location or chronically at the same time, being associated with IgG4-RD; some experts consider IgG4-RD a paraneoplastic phenomenon."
Among explanations for the association, the investigators pointed to possible shared risk factors for IgG4-RD and cancer, to cancer's triggering of autoantigen expression leading to IgG4-RD, and to an increased risk of IgG4-RD due to immune dysregulation caused by cancer treatment such as chemotherapy and radiation.
While the pathogenesis of IgG4-RD remains unclear, autoimmunity seems a plausible mediator, the authors noted. In addition, observed associations between allergic conditions and IgG4-RD suggest a shared pathogenesis, while environmental exposures to tobacco and occupational hazards may also contribute.
Further research is required to determine whether IgG4-RD patients with a history of malignancy have specific autoantibodies that might be pathogenic and distinguish them from patients without a similar history of malignancy, the team said.
"The next steps in a more definitive evaluation of this question would ideally involve careful data collection on larger numbers of patients, perhaps from multiple centers in the context of a prospective registry," Stone said.
Addressing their retrospective study's limitations, the researchers noted the ethnic preponderance of non-Hispanic whites, which limited generalizability, as well as the small sample size, which prevented the detection of differences in IgG4-RD organ involvement, ethnicity, and other factors between those with and without malignancy. In addition, some patients may have been misclassified with regard to previous cancer status. Incomplete records of risk factors such as smoking ruled out evaluating potential confounders of the cancer-IgG4-RD relationship.
The authors reported no study funding and no competing interests.
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