IgG4‐related retroperitoneal fibrosis: A case report of a challenging disease

Abstract

Immunoglobulin G4 (IgG4)‐related disease (IgG4‐RD) is a multi‐organ immune‐mediated fibroinflammatory disorder that may imitate malignancy, infectious or any other inflammatory disorder. IgG4‐related retroperitoneal fibrosis (IgG4‐RPF) is a rare form of IgG4‐RD, diagnosis of which is often relied on radiological technology. Herein, we describe a case of 60 year old male, presenting with low back pain and weight loss for a period of 2 months and 15 days. Imaging studies showed a retroperitoneal tumorous mass along with bilateral hydroureteronephrosis, which was later confirmed to be IgG4‐related retroperitoneal fibrosis on the basis of extensive histopathological analysis. Immunosuppressive therapy resulted in a decrease in fibrosis and restoration of renal function.

INTRODUCTION

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic immunological disease characterized by tumor like fibroinflammatory lesions that affect any organ of the body. The disorder can be recognized by exclusive histological findings such as lymphoplasmacytic infiltration, storiform fibrosis, obliterative phlebitis, and an abundance of plasmablasts or plasma cells expressing IgG4 in affected tissues.^1–4 IgG4-RD, which was previously thought to be unrelated, unites a number of well-known conditions, including Mikulicz's disease, Riedel's thyroiditis, Morbus Ormond, Kuttner's tumor, multifocal fibrosclerosis, and other entities.⁵ As a consequence of vast range of clinical and radiological symptoms, diagnosis is frequently cumbersome and takes time. The diagnosis thus depends on extensive histopathological investigation. The epidemiology of the disease is unclear; however, it often affects predominantly male individuals starting in their middle years.⁶ According to a 2011 Japanese study, the prevalence of IgG4-RD ranged from 0.28 to 1.08/100,000 people, with a median age of 58 years.⁴

Numerous investigations have been carried out and several hypotheses implied to clarify the immunopathological mechanism of IgG4-RD since the inception of the condition. In a healthy individual, the concentration of IgG4 is the lowest among all the IgG molecules present. Despite what the name suggests, IgG4 itself is considered nonpathogenic and noninflammatory.^7,8

The exact immune mechanism of the disease is still under investigation; however, immune cells such as CD4⁺ cytotoxic T-lymphocytes (CD4⁺ CTL), T follicular helper (TFH) cells, and B cells play a significant role in the pathophysiology of IgG4-RD.⁹ Autoantigens like annexin A11 and galactin-3 have been linked to the condition.¹⁰ In IgG4-RD, plasmablasts or activated B cells specific for annexin A11 or galactin-3 are oligoclonally restricted, causing the CD4⁺ CTL to clonally expand in affected tissues.⁹ CD4⁺ CTLs are a specific group of cytolytic cells, found in IgG4-RD, chronic infection and other malignant conditions, responsible for secreting perforin and granzymes A and B responsible for cell lysis as well as profibrotic cytokines including interleukin (IL)-1β, transforming growth factor β1 (TGF-β1), and interferon γ (IFN-γ).^9,11 An increase in cytokines such as interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-10 (IL-10), and interleukin-13 (IL-13) in IgG4-RD indicates the abundance of T helper cell type-2 (TH2) and TFH in the peripheral blood. The proliferation of regulatory T cells (Treg) in peripheral blood as well as affected tissues is another hallmark of IgG4-RD as the function of Treg is commonly impaired in classic autoimmune diseases. Both Treg and TH2 produce TGF-β, which promotes fibrosis.^8,9,12

IgG4-RD can be presented with various clinical manifestations that include lacrimal and parotid gland swelling, lymphadenopathy, low back pain, jaundice, nausea and vomiting, respiratory symptoms, and others.¹³ The myriad syndromes obscure a clear clinical picture of the disease which often leads to missed and delayed diagnoses. At present, a definite diagnosis can be reached with extensive histopathological analysis, radiological imaging supported by immunological tests as well as academic knowledge on the disease, so as to suspect the circumstantial evidences associated with IgG4-RD.

Here, we describe a particular case of IgG4-RD, which to our best of knowledge is one of the earliest diagnosed case of this disease from Bangladesh.

CASE REPORT

A 60-year-old, nondiabetic, hypertensive, male presented with a history of low back pain for two and half months in July, 2020. He then developed abdominal pain associated with anorexia and nausea and lost around 6 kg weight in two and half months. Prior to this episode, he did not have a history or symptoms of abdominal disturbance. His vital signs were normal. Blood analysis yielded hemoglobin 11.30 g/dL, increased erythrocyte sedimentation rate (72 mm at first hour), total white cell count 10.5 × 10⁹/L and platelets 390 × 10⁹/L. Elevated serum creatinine (1.8 mg /dL) and urinary albumin (++) were reported. Abdominal ultrasound displayed bilateral hydroureteronephrosis along with thickening of the retroperitoneal tissue encroaching the aorta and inferior vena cava. Within a span of few days, serum creatinine level increased to 4.38 mg/dL. Further evaluation with computed tomography (CT) scan revealed a well-defined homogeneous soft tissue mass (14.83 cm × 7.25 cm) in the retroperitoneum encasing the abdominal aorta, inferior mesenteric artery, inferior vena cava and ureters extending from the infra-renal part up to the proximal common iliac artery on right side and up to the bifurcation of common iliac artery on the left side (Figure 1).

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The initial clinical and radiological findings were highly suggestive of malignancy. However, serum concentration of cancer biomarkers such as prostate specific antigen (PSA), carcinoembryonic antigen (CEA), alpha fetoprotein and CA 19–9 were within normal ranges. The Bence–Jones protein test was conducted to rule out multiple myeloma, and was found to be negative. Given that the patient presented with an acute retroperitoneal mass together with raising serum creatinine and progressively decreasing urine volume, the decision was made to perform bilateral double J ureteric stent placement. Following stenting, core biopsy was done; histology and immunocyto-histochemistry analysis of sections of para-aortic mass revealed the tumor cells to be desmin and CD 246 Alk protein negative. Initially, based on this finding, the condition was diagnosed as inflammatory pseudotumor. Further histopathological assessment of the para-aortic mass demonstrated fibroadipose tissue with dense hyalinization and collagenous deposition along with dense inflammatory infiltrate comprising of histiocytes, lymphocytes, and plasma cells. Immunohistochemistry staining displayed significant IgG4 expression seen in plasma cells (approximately 20/high power field in the most active area). The measurement of serum IgG4 was significantly raised to >3.5 g/L (reference range: 0.03–2.01 g/L). Based on these immunological and histological findings the patient was finally diagnosed as a case of IgG4 related retroperitoneal fibrosis (IgG4-RPF). He was treated with oral glucocorticoids in tapering dose as well as immunosuppressive drug, methotrexate. Oral prednisolone was prescribed in tapering dose as follows: 50 mg for 10 days, 40 mg for 10 days, 30 mg for 10 days, 20 mg for 1 month, 15 mg for 1 month, 10 mg for 3 months and lastly 5 mg for 6 months. His clinical conditions improved and a serial repeat CT scan at 4, 10, 18 and 36 months later showed that the size of the retroperitoneal mass has reduced, measuring about 2.89 × 1.79 × 11.03 cm after 10 months and further reduced in size after 36 months showing that the mass receded from ureters completely (Figure 2). The mass was also reduced in all antero-posterior, transverse and cranio-caudal dimensions. Routine investigations such as complete blood count, serum creatinine and C-reactive protein were repeated every month and were found to be within normal range. Considering the patient's condition to be improved significantly, the ureteric stent was removed after a period of 20 months.

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DISCUSSION

IgG4-RD is an uncommon systemic disease usually affecting middle-aged men and can involve various organs of the body. The concept of IgG4-RPF is relatively new for which there is no conclusive report regarding morbidity or mortality. The percentage of patients with IgG4-related RPF in IgG4-RD was estimated to be around 10% based on 13 review articles, covering 1103 IgG4-RD patients, of which 109 patients (9.9%) had the condition.¹⁸ According to studies, the proportion of injured retroperitoneal tissues to IgG4-RD ranges from 3% to 19%.^18,24

In order to reach an accurate diagnosis of IgG4-RPF, it is vital to differentiate the condition from non- IgG4-RPF (mostly idiopathic) and exclude malignancy. Abdominal CT and magnetic resonance imaging (MRI) are the most frequently utilized diagnostic radiological technologies. On imaging, the retroperitoneal mass may have a distinct or hazy border, and one or both sides may also demonstrate hydronephrosis.¹⁸ In our reported case, imaging tests revealed a retroperitoneal tumorous mass encasing the abdominal aorta, inferior mesenteric artery, inferior vena cava along with bilateral hydronephrosis. Similar findings were reported by Gormley et al. and Razok et al. in patients with IgG4-RPF.^14,15 However, imaging techniques cannot distinguish IgG4-RPF from non-IgG4-RPF. Histopathological examination being the key diagnostic test can exclude benign and malignant lesions and can particularly perceive the presence of inflammatory infiltrates in IgG4-RPF. Typical histopathological features of the disease are: presence of lymphocyte and plasmacyte infiltrations along with fibrosis; multicenter lymphoid follicles and an abundance of IgG4 positive plasma cells with more than 10 IgG4⁺ cells/HPF.¹³ The immunohistochemical analysis of our patient, done in India, exhibited plasma cells expressing IgG4 about 20/HPF, confirming the diagnosis. Unfortunately, the IgG4 immunohistochemical stain is not commonly performed in the histopathological laboratories in Bangladesh owing to the rarity of the condition. Our case raises the possibility whether IgG4 immunohistochemical staining should be performed in all cases of retroperitoneal mass in the presence of potential clinical features, in order to avoid a diagnostic dilemma. The serum IgG4 level is also a supportive diagnostic test, as more than 2.8 g/L IgG4 in serum is considered highly specific for IgG4 related diseases.²⁵ The serum IgG4 level of our reported patient was >3.5 g/L, which is analogous with that of other reported cases of IgG4-RPF, as shown in Table 1. The serum IgG4 level can also be used as a prognostic marker, as the concentration gradually decreases with immunotherapy. This is another drawback in developing countries like Bangladesh, as the test is not cost-effective for patients due to rarity of the condition. Furthermore, usually middle-age to elderly male patients present with IgG4-RPF while non-IgG4-related RPF are usually found in relatively young female patients.²⁶

TABLE 1 Summary of clinical features, investigations and management of reported cases of IgG4-RPF.

Sl.	Age and gender	Presenting complaints	Investigation findings	Treatment	Outcome	Reference
1	73 y/o M	Pain in left flank radiating to the groin; dark urine	Serum IgG4–3.26 g/L; Histopathology- increased plasma cells and storiform fibrosis; CT- soft tissue changes around the abdominal aorta and common iliac arteries causing left ureteral obstruction and moderate hydronephrosis of the left kidney	Oral steroid therapy and mycophenolate mofetil	Asymptomatic in 15 months follow-up.	14
2	40 y/o M	Flank pain and weight loss	Serum IgG4–2.04 g/L; Histopathology- increased plasma cells in perivascular arrangement with obliterative endophlebitis; CT-retroperitoneal soft tissue mass with vascular encasement of the abdominal aorta and inferior vena cava	Oral prednisolone	Asymptomatic in 6 months follow-up	15
3	61 y/o M	Generalized weakness, anorexia, and abdominal pain	Histopathology- plasma cells scattered throughout with variable cellularity with 20 positive staining cells per high-power field; CT- lobular soft tissue surrounding the aorta and the iliac arteries with mild medial deviation of the ureters	Oral prednisolone and rituximab	Asymptomatic in 2 months follow-up	16
4	51 y/o F	Orthopnea, chest discomfort, and facial and leg edema	Serum IgG4–0.93 g/L; histopathology-lymphoplasmacytic infiltration with more than 10 IgG4-positive plasma cells per high-power field in the peritubular interstitial area; MRI- soft tissue lesion with low signal intensity on T1 weighted image and relatively homogeneous enhancement on contrast-enhanced image, in the paraspinal and presacral area	Oral prednisolone	Asymptomatic in 4 months follow-up	17
5	55 y/o F	Pain in the left flank that irradiated to the lumbar region	Histopathology-nodular retroperitoneal fibrosis associated with IgG4, with Ki67-positive in germinal centers (5%) and IgG4-positive (40 plasma cells in 3 fields); CT-cystic tumor in the retroperitoneal region which compressed the ureter	Surgical intervention with oral steroids	Not mentioned	18
6	69 y/o M	Left lower abdominal pain	Serum IgG4–9 g/L- Histopathology- infiltration of lymphocytoplasma cells, fibrosis and fibrin accumulation; CT-left hydronephrosis and a periaortic mass	Oral prednisolone	Asymptomatic in 6 months follow-up	19
7	79 y/o M	Right lower extremity oedema	Serum IgG4–22 g/L; Histopathology- fibrous connective tissue with IgG4-positive plasma cells infiltration; CT- right hydronephrosis and ureteral dilatation	Oral prednisolone and methotrexate	3 weeks after treatment, his symptoms and chest CT image had improved	20
8	46 y/0 M	Low back pain, Low grade fever, bilateral flank pain and bilateral leg swelling	Histopathology- lymphoplasmacytic chronic inflammation with increased IgG4 positive plasma cells; CT- soft tissue mass encasing the infrarenal abdominal aorta up to bifurcation of iliac vessels.	Oral prednisolone	Asymptomatic in 3 months follow-up	21
9	57 y/o F	General weakness, moderate back pain, decreased appetite, and weight loss.	Histopathology-diffuse moderate expression of IgG4 (up to 15–20 IgG4 positive plasma cells per field); CT- bilateral ureterohydronephrosis, right kidney enlargement and retroperitoneal mass with bilateral ureteral compression	Oral prednisolone	Asymptomatic in 2 months follow-up	22
10	71 y/o M	Left flank pain and gross hematuria	Serum IgG4-8.46 g/L; CT-Left hydronephrosis and a thick retroperitoneal soft tissue mass around ureteropelvic junction	Oral prednisolone	Asymptomatic in 2 months follow-up	23

For all patients with active IgG4-RD, glucocorticoids are typically recognized as the first-line treatment for remission induction.²⁷ After treatment, the blood IgG4 concentration will decrease and the mass will be reduced or even eliminated in about half of the patients.²⁸ The reported patient was immediately treated with oral prednisolone in tapering dose and the prognosis was assessed with imaging technique. Patients may require urgent surgical intervention because uncontrolled disease involving certain organs may cause irreversible damage. In our case, immediate double J stenting was performed as there was progressive hydronephrosis along with acute kidney injury. Low-dose glucocorticoids may be used as maintenance therapy. The ideal time frame for maintenance therapy has not yet been investigated.²⁹ Immunosuppressive medications such azathioprine, methotrexate, rituximab, and cyclophosphamide are used as second-line treatments for cases that are resistant or refractory.³⁰ However, there is little evidence to suggest that they are efficacious in IgG4-RD, and their efficacies have not been examined in prospective trials.²⁹ Although there is no clear agreement on the follow-up approach, these individuals should be monitored for imaging and renal function.

CONCLUSION

It is uncommon for IgG4 illness to manifest as a retroperitoneal tumor, and it can be challenging to make the diagnosis. The condition is not well-known or established in Bangladesh, which has likely contributed to missed diagnoses. Early diagnosis of the IgG4-RPF based on histopathological analysis and radiological study aids in complete recovery of the patient with immunosuppressive medications instead of surgical resection of the fibrous mass.

AUTHOR CONTRIBUTIONS

Saika Farook: Conceptualization; data curation; formal analysis; methodology; project administration; resources; software; supervision; writing – original draft; writing – review and editing. Shariful Alam Jilani: Conceptualization; data curation; formal analysis; project administration; supervision; writing – review and editing. Kamrul Islam: Formal analysis; investigation; methodology; project administration; resources; validation; writing – review and editing. Shamima Rahman: Formal analysis; investigation; methodology; supervision. Rumana Ashraf: Data curation; formal analysis; investigation; methodology; supervision. Naval Mendiratta: Formal analysis; investigation; methodology; validation. Sudhir Kumar Rawal: Formal analysis; investigation; methodology; supervision.

FUNDING INFORMATION

No fund was available for this study.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study. However, all investigations reports are available and upon demand may be shared as pdf file to ensure authenticity of the data mentioned in the article.

CONSENT

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his clinical information to be reported in the journal. The patient understand that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

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