Abstract
Background/Aim: IgG4-related disease (IgG4RD) is a rare autoimmune proinflammatory condition that mimics other cancers and has unique pathological findings. The effects of radiotherapy in patients with IgG4RD remain unknown. Case Report: A male patient in his seventies who received radiotherapy (68 Gy/39 fr) for bladder cancer 5 months prior, presented to our hospital with fatigue and swelling in both legs. The patient had a history of IgG4-related sclerosing cholangitis, a subtype of IgG4RD. Leg edema gradually worsened despite treatment with a diuretic agent. Computed tomography showed hyperdense soft-tissue lesions in the irradiated area. The serum level of IgG4 increased to 1,380 mg/dl. One month after administration of a corticosteroid (10 mg per day) as an ex juvantibus treatment for IgG4RD, leg edema disappeared. Soft-tissue lesions in the irradiated area decreased in size. The adverse event was ultimately diagnosed as the recurrence of IgG4RD in the irradiated area. To the best of our knowledge, this is the first case report of an adverse event of radiotherapy for a patient with IgG4RD. Conclusion: We experienced a unique adverse event of radiotherapy in a patient with IgG4RD. Caution is advised on radiotherapy administration in patients with IgG4RD.
IgG4-related disease (IgG4RD) is a rare autoimmune proinflammatory condition that mimics other cancers and has unique pathological findings (1). An elevated serum IgG4 level is often observed. This condition and elevated serum IgG4 generally respond rapidly to corticosteroids. More than one million cancer patients receive radiotherapy each year worldwide (2). Although radiotherapy for patients with some autoimmune diseases results in severe toxicities, the effects of radiotherapy in patients with IgG4RD remain unknown.
Case Report
A male patient in his seventies who received radiotherapy for bladder cancer 5 months prior presented to our hospital with fatigue and swelling in both legs. The patient had a history of IgG4-related sclerosing cholangitis (IgG4SC), a subtype of IgG4-related disease (IgG4RD). IgG4SC presented with jaundice (serum bilirubin, 3.0 mg/dl) and swelling of the bilateral submandibular glands 11 months before radiotherapy. The serum level of IgG4 at that time was 1,620 mg/dl (normal range: 11-121 mg/dl). Abdominal computed tomography (CT) showed enlarged intrahepatic bile ducts. Localized stenosis of the lower bile duct was noted on magnetic resonance (MR) images and by endoscopic retrograde cholangiopancreatography (Figure 1), while lesions were not detected in the pancreas or bile duct on CT or MR images. A pathological examination of the bile duct revealed diffuse lymphoplasmacytic infiltration and mild fibrosis extending from the bile duct mucosa to the serous membrane with poor IgG and IgG4 staining. On the other hand, the pathology of the liver showed lymphocyte and plasma cell infiltration and mainly IgG4 positivity in immunohistochemical staining (Figure 2). Neither storiform fibrosis nor obliterative phlebitis was detected. Based on clinical, pathological, and serological findings, IgG4SC was confirmed, and prednisolone was orally administered at 40 mg per day. Five months after the initiation of corticosteroid treatment, jaundice improved and the serum level of IgG4 decreased to 260 mg/dl. The disease was considered to be in remission 6 months after the first diagnosis. The corticosteroid treatment was gradually tapered to 1 mg per day.
(A, B) Endoscopic retrograde cholangiopancreatography showed that the upper part of the common bile duct was dilated, and the lower part was stenosed (red arrows). (B) Lesions suggesting biliary calculus or tumors were not observed on MR images (T2-weighted images) or contrast-enhanced CT.
Pathological images of a liver specimen. (A) Hematoxylin-eosin staining (magnification ×40), (B) CD138 immunostaining, (C) IgG immunostaining, (D) IgG-4 immunostaining. Many plasma cells (CD138-positive) and lymphocytes were observed in the Glisson’s capsule. Many fibroblasts were noted, and fibrosis occurred in the interlobular ducts. The ratio of IgG4-positive plasma cells/IgG-positive cells was >40% and there were 30-40 IgG4-positive plasma cells in the high-powered field.
At the same time, the patient underwent urinary diversion with an ileal conduit as a treatment for bladder cancer (cT3N0M0, stage III in the American Joint Committee on Cancer staging). Cystectomy was initially attempted but was not successful because complete resection was not considered feasible due to tumor invasion to the left internal iliac vein and pubic bone. Definitive radiotherapy was initiated as alternative radical therapy. The prophylactic area was irradiated with 50 Gy/25 fr (Figure 3B) and the visible bladder tumor with 18 Gy/9 fr. The treatment period was 62 days. After the completion of radiotherapy, prednisolone was discontinued to control body weight.
(A) Non-contrast-enhanced CT before radiotherapy. (B) Dose distribution (100% dose is 50 Gy) of radiotherapy for the prophylactic area, (C) contrast-enhanced CT, 6 months after radiotherapy started. Hyperdense soft-tissue lesions, as shown by red arrows in C, appeared in an area that received 45 Gy or more, as indicated by the orange area on the dose distribution image (B). (D) Contrast-enhanced CT 4 months after administration of the corticosteroid showed decreases in the sizes of these lesions (arrowheads). CT: Computed tomography.
Four months after initiation of radiotherapy, the patient developed leg edema, which gradually worsened, and visited our Hospital. Despite treatment with a diuretic agent, leg edema continued to deteriorate. Two months after the development of this symptom, follow-up CT showed hyperdense soft-tissue lesions in the irradiated area (Figure 3C). The serum level of IgG4 was elevated at 1,380 mg/dl, while the serum level of bilirubin and other liver laboratory tests were within normal limits. Bile duct stenosis and hepatobiliary-pancreatic opacity were not detected as the recurrence of IgG4SC on CT or MR images. Furthermore, findings suggestive of deep venous thrombosis were not observed on lower limb venous ultrasound images. Differential diagnoses included radiation-induced fibrosis and the recurrence of IgG4RD. A corticosteroid was orally administered (10 mg a day) as an ex juvantibus treatment for IgG4RD. One month after initiation of the corticosteroid treatment, leg edema disappeared. Hyperdense soft-tissue lesions in the irradiated area decreased in size (Figure 3D). Other hematological malignancies were not observed in the 3-year follow-up. Therefore, adverse events were ultimately diagnosed as the recurrence of IgG4RD in the irradiated area.
Patient consent for publication. Consent was directly obtained from the deceased patient’s relative.
Discussion
More than one million cancer patients receive radiotherapy each year worldwide. Ionizing radiation induces damage not only to tumor cells, but also normal tissue in the radiation field (3). The response of normal tissue to irradiation is mainly influenced by the radiosensitivity of individual patients. Although radiotherapy for patients with some autoimmune diseases is known to result in severe toxicities, the effects of radiotherapy in a patient with IgG4RD remain unknown (4).
IgG4RD is a rare autoimmune proinflammatory condition that mimics other cancers (1). It characteristically involves various organs, such as the pancreas, salivary glands, and bile duct. The commonly shared features of this disease include tumor-like swelling of the involved organs, a lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells, and a variable degree of fibrosis that has a characteristic “storiform” pattern in pathological findings. In addition, the serum level of IgG4 is elevated in 60 to 70% of patients with IgG4RD. Treatment with corticosteroids is effective in 90% of cases. Although the exact pathogenesis is unknown, it is considered to be an autoimmune proinflammatory condition mediated by fibroblasts (5).
The diagnosis of IgG4RD is based on a combination of histopathological, serological, and radiological findings. The Revised Japanese Comprehensive Clinical Diagnostic criteria for IgG4RD include the following: (a) one or more organs show diffuse or localized swelling or a mass or nodule characteristic of IgG4RD; (b) an elevated serum level of IgG4 (>135 mg/dl); and (c) histopathological findings of IgG4RD [definite: (a)+(b)+(c); probable: (a)+(c); possible: (a)+(b)] (1). Pathological findings need to be positive for two of the following criteria: a) dense lymphocyte and plasma cell infiltration with fibrosis, b) a ratio of IgG4-positive plasma cells/IgG-positive cells >40% and >10 IgG4-positive plasma cells per high-powered field, c) typical tissue fibrosis, particularly storiform fibrosis, or obliterative phlebitis. IgG4SC is a distinct type of IgG4RD with cholangitis (6). Its diagnosis requires characteristic biliary imaging findings in addition to the coexistence of IgG4RD. A differential diagnosis from primary and secondary sclerosing cholangitis, cholangiocarcinoma, and pancreatic cancer is necessary because these conditions show similar cholangiograms to IgG4SC.
In this patient, the Clinical Diagnostic criteria for IgG4RD, (a)+(b)+(c) were satisfied. The bile duct stenosis was observed, while other malignancy possibility was clinically eliminated as diagnosis. Thus, IgG4SC was finally diagnosed. Hyperdense soft-tissue lesions appeared in the pelvic-irradiated area without recurrence in the liver or bile duct. Lesions responded to corticosteroids as IgG4RD. Radiation-induced fibrosis is an adverse event in the irradiated area. It generally occurs 4-12 months after treatment, does not respond well to corticosteroids, and progresses over several years. In this patient, fibrosis was observed 6 months after irradiation and rapidly improved after the administration of a corticosteroid. This course is consistent with the recurrence of IgG4RD rather than typical radiation-induced fibrosis.
Regarding the pathogenesis that caused this adverse event, radiation injury triggers inflammation and ultimately stimulates the transdifferentiation of fibroblasts into myofibroblasts, which produce excess collagen and other extracellular matrix components (7). The transition of fibroblasts into myofibroblasts is a common feature of fibrosis-related diseases and the underlying mechanism is regarded as one of the pathogenetic features of IgG4RD (5). Therefore, irradiation may have induced the recurrence of IgG4RD in the treated area. The discontinuation of the corticosteroid after radiotherapy may have partially contributed to the adverse event in this patient. To the best of our knowledge, this is the first case report of an adverse event of radiotherapy for a patient with IgG4RD. Attention should be paid to the systematic condition in radiotherapy for patients with a history of IgG4RD.
Conclusion
We experienced a unique adverse event of radiotherapy in a patient with IgG4RD. Caution is advised regarding radiotherapy for patients with IgG4RD.
Footnotes
Authors’ Contributions
MO experienced the patient and conceived the idea of the study. HA, KT and TM drafted the original manuscript. WN and IM contributed to the interpretation of the surgical and pathological results. MH and TI supervised the conduct of this study. All authors reviewed the manuscript draft and revised it critically on intellectual content. All authors approved the final version of the manuscript to be published.
Funding
This work was supported by the JSPS KAKENHI Grant Number 23K07197.
Conflicts of Interest
The Authors do not have any conflicts of interest.
- Received June 8, 2023.
- Revision received July 19, 2023.
- Accepted July 26, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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