Records of 122 patients over a follow-up period of 73±48 (12 to 260) months were reviewed. Three patients were diagnosed with cancer 85±27 (60 to 123) months before the diagnosis of IgG4-ROD: one with breast cancer, one with prostate adenocarcinoma, and one with diffuse large B cell lymphoma (DLBCL) of the ipsilateral cervical lymph node. The patient with breast cancer was subsequently diagnosed with endometrial adenocarcinoma at the time of IgG4-ROD diagnosis. Malignancies in 16 (13%) patients, including 12 males, were diagnosed at the time of or after the diagnosis of IgG4-ROD over 38±25 (7 to 84) months. Ocular adnexal lymphoma (OAL) was found in 9 patients (Table 1) and extra-orbital systemic malignancies (Table 2) in 7. Comparing these 16 patients diagnosed with malignancies at the time of or after the diagnosis of IgG4-ROD with the rest of the cohort without any history of cancer (104 patients), the age at IgG4-ROD diagnosis was significantly higher (66.3±7.9 years versus 55.2±15.0 years, p<0.05), while the male to female ratio was higher but not reaching statistical significance (12:4 versus 53:51 p=0.13). Nine (56%) of the 16 cancer patients had extra-orbital involvement of IgG4-RD, as compared to 53% in the rest of the cohort (p= 0.80). Also, 13 of the 15 tested (87%) among the 16 patients developed malignancies had elevated pre-treatment serum IgG4 compared to 90 of the 100 tested (90%) patients from the rest of the cohort (p=0.74), mean level was 2.5±1.7(1.3-5.7) times compared to 11±2.7 (1.1-22.8) times of normal in the rest of the cohort (p>0.05). Smoking status was similar (25% versus 24%, p=0.47). Totally 98 (74%) patients of the whole cohort were presented first with periocular symptoms, 14 (11%) patients with salivary gland and 6 (5%) patients with neck swelling (cervical lymphadenopathy). Type 1 autoimmune pancreatitis (AIP) were diagnosed in 4 (3%) patients with before presenting to us.
IgG4-related ocular adnexal lymphoma (OAL)
Nine (7.4%) patients, including 6 males, among all the 122 IgG4-ROD patients developed OAL at the time of or after the diagnosis of IgG4-ROD (Table 1). Seven were diagnosed concomitantly and 2 were diagnosed 24 and 48 months following the diagnosis of IgG4-ROD. One patient was a chronic smoker. Six patients had extranodal marginal zone B Cell lymphoma of MALT type (EMZL), affecting the lacrimal glands (n=3), the eyelids (n=2) and the orbital soft tissue (n=1). Two patients had follicular lymphoma affecting the lacrimal glands and 1 patient had orbital DLBCL. Comparing these 9 OAL patients with the rest of the cohort that had no history of cancer (104 patients), the male to female ratio was higher (6:3 versus 56:50, p>0.5), and the mean age of IgG4-ROD diagnosis older (64.9+/-7.1 vs 55.2+/-15.0, p<0.05). The commonest presentation was upper lid swelling (62% versus 71%, p=0.78), followed by proptosis (25% versus 20%, p=0.15) and palpable mass (22% versus 20%, p=0.37). Seven of the 8 tested (88%) among the 9 patients with OAL had elevated pre-treatment serum IgG4 compared to 90 of the 100 tested (90%) patients from the rest of the cohort (p>0.05). Radiologically, 7 patients had asymmetric enlargement of the lacrimal gland (78% versus 13%, p<0.05) (Figure1), and 5 patients showed retrobulbar extension. There was no frontal or infraorbital nerve enlargement, as defined by the nerve diameter equal to or larger than that of the ipsilateral optic nerve on coronal imaging, in all 9 OAL patients (0% versus 12%, 0% versus 36%, p<0.05). Four patients had extra-orbital involvement of the parotid glands (n=4), kidneys (n=4), lungs (n=2), liver (n=1), aorta (n=1) and mediastinal lymph node (n=1) (44% versus 65%, p>0.05) by IgG4-RD. Six patients had paranasal sinus involvement (75% versus 65%, p=0.20).
Extra-orbital systemic malignancies
Six of these 7 patients were diagnosed with extra-orbital systemic malignancies in 38±25 (range: 7-84) months after the IgG4-ROD, while 1 patient with history of breast cancer was found to have endometrial adenocarcinoma at the time of IgG4-ROD diagnosis (Table 2). One patient was diagnosed radiologically with primary lung cancer with metastasis as evident by a grossly elevated serum carcinoembryonic antigen (CEA) level of 2753ug/L (normal range <=5) and PET scan showing multiple hypermetabolic lesions in both lungs, liver and extensive lytic osseous lesions over different long bones. The average latency from IgG4-ROD diagnosis to the diagnosis of extra-orbital malignancies was 34±30 (0-84) months. Five of these 6 malignant lesions underwent additional IgG4 immunostaining. There were increased IgG4+ plasma cell infiltration (IgG4/IgG ratio= 49-62%) of the nearby cervix but not the endometrial adenocarcinoma. The other malignant lesions did not show any IgG4+ plasma cell infiltration. Comparing the 7 patients with extra-orbital malignancies to those without any history of cancer (104 patients), the male to female ratio was higher (6:1 versus 28:25, p=0.11), and the average age of diagnosis of IgG4-ROD was 13 years older (68.3±8.5 versus 55.2±15.0, p<0.05). Otherwise the initial clinical presentation, the mean level of and the percentage of patients with raised pre-treatment serum IgG4, radiological changes and pattern of extraorbital IgG4RD involvement were not statistically different between the 2 groups. Before the development of extra-orbital malignancies, 4 patients (57% versus 70%, p>0.05) received oral steroids (3 prednisolone and 1 dexamethasone) and one (14% versus 29%, p>0.05) patient received both steroid and steroid-sparing immunosuppressant (azathioprine). The percentage of patients receiving immunosuppressive therapy was similar between the 2 groups, 5 out of 7 (71%) vs 87 out of 106 (82%) in those without malignancies, p>0.05. The mean cumulative dosage of oral prednisolone (n=3) was 5745±3145 mg compared to 6006±4942 mg in patients who did not develop any malignancy (n=71) (p>0.05). Two (29% versus 19%, p>0.05) of these 7 patients opted not to receive any treatment in view of their stable IgG4-ROD.
Incidence of malignancies in the study cohort of IgG4-ROD (Table 3)
The overall incidence of OAL was higher (SIRs=10.0, 95%CI=4.5-17.6), especially within the first year of IgG4-ROD diagnosis (SIRs=46.7, 95%CI=18.5-87.6). The overall, age- and gender-adjusted incidence rates and SIRs of OAL were increased. On the contrary, the overall incidence of extra-orbital malignancies was comparable (SIRs=0.54, 95% CI=0.2-1.0) to the general population. The incidence was similar within the first 2 years of IgG4-ROD diagnosis (SIRs=1.2, 95% CI=0.4-2.5). The overall, age- and gender-adjusted incidence rate and SIRs of systemic malignancies were similar.
The overall incidence of malignancies (all types) diagnosed concomitantly with or subsequently after IgG4-ROD was comparable to the general population (SIR=1.03, 95% CI=0.6-1.6). The incidence of malignancies (all types) was higher within the first 2 years of IgG4-ROD diagnosis (first year: SIRs=3.5, 95% CI=1.6-6.1, first 2 years: SIRs=2.6, 95% CI=1.4-4.1) and similar to the level of the general population by the end of the third year (SIR=1.7, 95% CI=0.9-2.7).