Incidental Finding of Hepatic Inflammatory Pseudotumor Immunoglobulin G4-Related Disease With Underlying Chronic Hepatitis C

Immunoglobulin G4-related disease (IgG4-RD) is a unique immunological disease that can impact multiple organs including a formation of a hepatic inflammatory pseudotumor (IPT). We present a case of a 67-year-old male with a history of chronic viral hepatitis C infection who had an accidental finding on magnetic resonance imaging (MRI) of a liver arterially enhancing lesion. With an extensive work-up, immunohistochemical stains for immunoglobulin G of the liver lesion was performed and showed markedly increased IgG4-positive plasma cells (> 50/HPF), which was consistent with hepatic inflammatory pseudotumor related to IgG4-RD. The patient was treated with prednisone with a complete resolution of the hepatic lesion. The diagnosis of hepatic IPT and IgG4-RD requires a high degree of clinical suspicion and coordination with a multi-disciplinary team, including pathologists. Early tissue acquisition and staining for IgG4 was essential for the early diagnosis and treatment in this case. We also provide a comprehensive summary of published reports of IgG4-RD presenting with IPT.


Introduction
Immunoglobulin G4-related disease (IgG4-RD) is an immune mediated condition that can affect multiple organs and lead to organ failure [1].The presentation of IgG4-RD can vary from asymptomatic to subacute multi organ failure; on occasion patients can present with mass-like lesions, which can be concerning for malignancy [1].IgG4 related inflammatory pseudotumor (IPT) presenting in the liver is a rare manifestation of IgG4-RD with few cases described [2].Hepatic IPTs make up roughly 8% of lesions associated with IgG4-RD [3].We present a patient with history of laparoscopic cholecystectomy complicated by common hepatic artery transection and damage to the confluence of right anterior and left hepatic ducts and chronic hepatitis C with incidental finding of hepatic IPT confirmed on liver biopsy.

Case Presentation
A 67-year-old male with a history of chronic viral hepatitis C (with a sustained virologic response following treatment with velpatasvir-sofobuvir and ribavirin seven years prior) without advanced hepatic fibrosis presented with a bile duct injury following laparoscopic cholecystectomy for symptomatic acute cholecystitis.His post operative course was complicated by multiple instances in which percutaneous drains placed at the time of surgery were dislodged and during one drain replacement, the tube was passed through the hepatic venous system and pleural space with subsequent bilo-thorax development.Magnetic resonance imaging (MRI) for drain assessment found an enlarging arterially enhancing lesion involving hepatic segment 3, measuring 2 cm, with associated washout and pseudo capsule, concerning for hepatocellular carcinoma (HCC) (Figure 1).His laboratory values at that time were alkaline phosphatase 263 U/L (40-129 U/L), aspartate aminotransferase (AST) 78 U/L (10-50), alanine aminotransferase (ALT) 102 U/L (10-50), total bilirubin 0.7 mg/dL (<1.2 mg/dL), direct bilirubin 0.29 mg/dL (0-0.30mg/dL), international normalized ratio (INR) 1.28 (0.85-1.15), and serum creatinine 1.39 mg/dL (0.67-1.17 mg/dL).

FIGURE 1: MRI image
Magnetic resonance imaging (MRI) revealed an arterially enhancing lesion arising exophytically in segment III of the liver with associated washout and pseudocapsule (red arrow).
A core needle biopsy of the liver lesion was performed and showed an inflammatory process composed of abundant lymphoplasmacytic inflammation with focal storiform-type fibrosis.Immunohistochemical stains for Immunoglobulin G (IgG) performed showed markedly increased IgG4 positive plasma cells (> 50/HPF), which was consistent with IgG4-RD.Alpha-fetoprotein collected two months prior was 4 ng/mL (<8.3 ng/mL).Immunological staining of the patient's gallbladder from his prior cholecystectomy did not demonstrate an elevated IgG4 to IgG plasma cell ratio suggesting IgG4-RD in the gallbladder.

FIGURE 2: Follow-up MRCP imaging
Magnetic resonance cholangiopancreatography (MRCP) image demonstrating lack of visualization of a previously noted lesion in segment III of the liver.

Discussion
Hepatic IPT is a rare benign tumor that can mimic liver cancer, such as HCC, on imaging.When evaluating hepatic lesions, cross-sectional imaging such as MRI and computerized tomography (CT) are often unable to differentiate concerns for malignancy from IgG4-RD.In the presenting case, there was a high suspicion of HCC because the lesion was exophytic, had enhancement on imaging, and the patient had a history of hepatitis C, although the patient had no evidence of advanced fibrosis.The diagnosis of IgG4-RD can be made clinically using the Japanese Comprehensive Clinical Diagnostic (CCD) criteria for IgG4-RD and histopathology [4].The Japanese CCD 2011 criteria for IgG4-RD are as follows: organ involvement, such as diffuse/localized swelling; elevated serum IgG4 concentrations > 135 mg/dl; and marked plasmacyte infiltration, defined as >10 IgG4+ cells per high-powered field (HPF) and a > 40% ratio of IgG4+/IgG + cells, accompanied by fibrosis on histopathological examination [4].The criteria for IgG4-RD was updated in 2020 by the original Japanese IgG4-RD team with the following change to clinical presentation: clinical and radiological features of one or more organs showing diffuse or localized swelling or a mass or nodule characteristic of IgG4-RD and in single organ involvement, lymph node swelling is omitted [4].Laboratory findings of IgG4 serum concentration greater than 140 mg/dL are seen in more than 70% of patients and elevation at least two times the upper limit of 140 mg/dL is 99% specific for IgG4-RD [5].
The patient did not obtain a serum IgG4 level until after steroid treatment and at that time, serum IgG4 levels were found to be within normal limits.A biopsy is essential to make the definitive diagnosis of IgG4-RD.The pathognomonic histology for IgG4-RD includes a dense lymphoplasmacytic infiltrate with a storiform pattern, evidence of obliterative phlebitis, and moderate eosinophilic infiltrate that is positive for IgG4 plasma cells; a diagnosis requires two out of three findings [1, 6,7].The patient's liver biopsy met these diagnostic criteria.There is a concern for seeding of the malignancy during a biopsy; seeding has been seen in 2.7% of cases following the biopsy of a malignant liver tumor [8].If the etiology of the mass is unclear following biopsy and there is a high suspicion of malignancy, surgical resection can be performed.Treatment for IgG4-RD relies on steroids or other immunosuppressants.The current recommendation for treatment includes four weeks of prednisone at a dose of 30-40 mg daily with a taper every two weeks of 5 mg or 0.6 mg/kg every 2-4 weeks over 3-6 months [1,9].Some cases have been shown to resolve spontaneously without steroid treatment at 1-year follow-up [3,10].
A literature search via PubMed using key terms -IgG4, -hepatic, and -pseudotumor found 38 case reports.After excluding cases without access to full text (n= 18) and patients of <18 years old (n= 1), 19 case reports remained (Table 1).The mean age of presentation was 60.7 years.The majority of Ig4-related liver diseases occurred in males (84%).A common factor amongst cases was that imaging findings were inconclusive in determining if the etiology was malignant or infectious.Ten of the 19 cases reviewed provided serum IgG4 levels, 70% (7/10) of the cases did not meet the serum IgG4 levels proposed by Nambiar and Oliver [5], which were proposed to be 99% specific for the diagnosis of IgG4-RD.Of all the papers found, there were no other case reports involving a patient with hepatic pseudotumor from IgG4-RD and a history of hepatitis C. The association between hepatitis C and IgG4-RD is currently unknown.One potential mechanism for the relationship is that immunoglobulins, such as IgG4, play a role in the disease course of both conditions.One study proposed that in hepatitis C infections, the presence of IgG4 antibodies was correlated with lower levels of viremia [11].However, further study is needed to determine the link between IgG4 levels, IgG4-RD and hepatitis C.

Conclusions
We incidentally discovered a patient with IgG4-RD with the presentation of hepatic IPT.The diagnosis of hepatic IPT and IgG4-RD requires a high degree of clinical suspicion and coordination with a multidisciplinary team, including pathologists.The Japanese CCD criteria can be used to determine the probability of the diagnosis.In cases such as this one, serum IgG4 levels may not be drawn prior to treatment.However, it is reassuring to see normal serum IgG4 levels following steroid treatment.Early tissue acquisition and staining for IgG4 was essential for the early diagnosis and treatment in this case.
Comparing this patient's case with previously published case reports of hepatic IPT, the patient's chronic