Immunoglobulin G4-related disease mimicking an appendiceal neoplasm: a case report

Abstract

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by chronic activation of the immune system and a tendency to form tumorous lesions. IgG4-RD is frequently characterized by the presence of tumor-like masses affecting multiple organs and is easily mistaken for a malignant neoplasm. However, IgG4-RD affecting the appendix is extremely rare, with only seven cases reported previously. We report the case of a woman in her early 60s who presented with insidious abdominal pain and radiological findings mimicking appendiceal neoplasms. After diagnosing appendiceal neoplasms, surgery was performed. The patient had a serum IgG4 concentration of <1.35 g/L, which did not satisfy one of the three revised comprehensive diagnostic criteria for IgG4-RD. A pathological examination was conducted, and the patient was diagnosed with appendiceal IgG4-RD. To the best of our knowledge, there have been no previously reported cases of IgG4-RD affecting the appendix in patients with low serum IgG4 concentrations. This report may prove beneficial for the future understanding of IgG4-RD and for the revision of diagnostic and treatment strategies.

Introduction

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by chronic activation of the immune system and a tendency to form tumorous lesions.^1,2 In IgG4-RD, elevated serum IgG4 concentrations are found, along with distinct clinicopathological features. ³ Many previous studies have shown that the sensitivity and specificity of IgG4 serum concentrations for diagnosing IgG4-RD are limited, causing a challenge in distinguishing it from primary sclerosing cholangitis or cholangiocarcinoma.^4,5 Histopathological characteristics of patients with IgG4-RD show remarkable similarities across various disease locations. ⁶ Although the organ most commonly affected by IgG4-RD is the pancreas, any organ system can be involved.^7,8 Some cases involving the retroperitoneum or mesentery have been reported.^9–22 However, IgG4-RD affecting the vermiform appendix is extremely rare, with only seven cases reported previously.^23–29 We report the case of a woman in her early 60s who presented with clinical symptoms and radiological findings mimicking appendiceal neoplasms.

Case report

A woman in her early 60s was referred to our hospital with mild anemia and right lower quadrant (RLQ) abdominal pain for 1 year. The pain was insidious at onset and progressed slowly. She had associated anorexia and a 7-kg weight loss over 4 months. She did not have any remarkable medical or family history. A physical examination showed diffuse abdominal tenderness with peritoneal signs. Laboratory investigations showed a hematocrit of 34.5%, hemoglobin concentration of 110.00 g/L, and white blood cell count of 4.08 × 10⁹/L (normal: 4.5–11.0 × 10⁹/L). The blood urea nitrogen concentration was 8.18 mmol/L (normal: 2.14–7.14 mmol/L) and the creatinine concentration was 191.83 µmol/L (normal: 44.20–79.56 µmol/L). Gastroduodenoscopy and colonoscopy showed no mass or lesions. Abdominopelvic computed tomography showed an approximately 3.2-cm lobulated enhancing mass in the RLQ, with adjacent omental fat infiltration. The vermiform appendix was obliterated (Figure 1(a), (b)).

Figure 1.

(a, b) Abdominopelvic computed tomography image shows an approximately 3.2-cm lobulated enhancing mass (arrows) in the right lower quadrant of the abdomen, with adjacent omental fat infiltration. (c) Positron emission tomography with 2-deoxy-2-(fluorine-18])fluoro-D-glucose shows hot uptake (arrow) at the corresponding site of the right lower quadrant and (d) right hemicolectomy specimen shows an ill-defined yellow nodule (arrows) in the mesenteric fat tissue, which causes bowel loop adhesion.

Positron emission tomography with 2-deoxy-2-(fluorine-18) fluoro-D-glucose demonstrated hot uptake at the corresponding site of the RLQ (Figure 1(c)). The radiological differential diagnoses for a lobulated mass lesion in the peri-appendiceal mesentery include appendiceal tumors, such as adenocarcinoma and neuroendocrine tumor, and peri-appendiceal tumors, such as extragastrointestinal stromal tumor and inflammatory myofibroblastic tumor (IMT). The possibility of these malignant neoplasms cannot be ruled out. Therefore, we recommended a right hemicolectomy and the patient consented to the procedure. Subsequently, the patient underwent right hemicolectomy. A histopathological examination of the right hemicolectomy specimen showed an ill-defined yellow nodule infiltrating the mesenteric fat tissue, which caused bowel loop adhesion (Figure 1(d)). The mucosa of the proximal vermiform appendix was intact 5(Figure 2(a)). However, the distal vermiform appendix was obliterated. The lesion showed extensive storiform fibrosis (Figure 2(b)) and dense infiltration of lymphoplasmacytic cells (Figure 2(b), (c)). Obliterative phlebitis was frequently detected (Figure 2(d)), and foci of arteritis were occasionally noted (Figure 2(d)). Acid-fast staining of the surgical tissue sample was negative, and real-time polymerase chain reaction for Mycobacterium tuberculosis complex and nontuberculous mycobacteria was also negative. Extensive immunohistochemistry analysis was conducted and showed that the cells were negative for CD34, CD117, and DOG-1, ruling out the above-mentioned initial differential diagnosis of an extragastrointestinal stromal tumor. Further immunohistochemical analysis showed the presence of immunoglobulin G (IgG)-positive plasma cells (Figure 2(e)) and IgG4-positive plasma cells (Figure 2(f)). The ratio of IgG4-positive plasma cells to IgG-positive plasma cells was >40%. The patient’s serum IgG4 concentration was 0.25 g/L (normal, 0.04–0.86 g/L). On the basis of the pathological findings, she was diagnosed with probable IgG4-RD, meeting the criteria specified in Items 1) and 3) of the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. ³⁰ After a surgical procedure, the patient recovered well and was discharged from the Emergency Department. At a 3-year follow-up, she had no recurrence of symptoms, and her imaging findings remained unremarkable.

Figure 2.

Images from a histopathological examination. (a) A lower power of magnification shows an ill-defined fibrotic solid nodule (*) infiltrating mesenteric fat tissues (hematoxylin and eosin, ×100). The mucosa of the proximal vermiform appendix is relatively unremarkable (inset: hematoxylin and eosin, ×20). There are extensive storiform fibrosis (b) (hematoxylin and eosin, ×200) and dense lymphoplasmacytic infiltration (c) (hematoxylin and eosin, ×400). (d) In the lesion, multifocal obliterative phlebitis and arteritis (arrows) can be seen (hematoxylin and eosin, ×200). Immunohistochemical staining for immunoglobulin G (e) and immunoglobulin G4 (f) shows immunoglobulin G-positive plasma cells and immunoglobulin G4-positive plasma cells. The ratio of immunoglobulin G4-positive plasma cells to immunoglobulin G-positive plasma cells was >40% (e, f) (×400).

We followed the CARE guidelines to report this case study. ³¹ All of the patient’s details were deidentified for this case report. Therefore, informed consent was not considered necessary for publication. This study was approved by the institutional review board of Uijeongbu St. Mary’s Hospital (UC23ZISI0). The patient provided written informed consent for treatment before the study.

Discussion

This patient visited our hospital’s Emergency Department with insidious pain in the RLQ. The pain was associated with clinical symptoms and radiological findings mimicking appendiceal neoplasms. After the clinical diagnosis of an appendiceal neoplasm, surgery was performed because obstructive symptoms were occurring. The patient recovered well.

The present patient had a serum IgG4 concentration of <1.35 g/L, which did not satisfy one of the three revised comprehensive diagnostic criteria for IgG4-RD. A pathological examination also showed an ill-defined yellow nodule. Immunohistochemistry showed that the ratio of IgG4-positive plasma cells to IgG-positive plasma cells was >40%. The clinical features of this patient, such as diffuse abdominal tenderness with peritoneal signs and radiological findings of a mass formation in the RLQ with adjacent omental fat infiltration, met items 1 and 3 of the 2020 RCD criteria for IgG4-RD, but did not meet item 2 of the serological diagnosis. Therefore, the patient was diagnosed with probable IgG4-RD. ³⁰

The 2020 RCD criteria for IgG4-RD were suggested by the Japan IgG4-RD Working Group and consist of the following three items: 1) one or more organs showing diffuse/localized swelling or a mass or nodule characteristic of IgG4-RD; 2) serum IgG4 concentrations >1.35 g/L; and 3) positivity for two of the following three pathological criteria: dense lymphocyte and plasma cell infiltration with fibrosis, IgG4-positive cells/IgG-positive cells >40% and IgG4-positive cells/high-power field >10, and typical tissue fibrosis, particularly storiform fibrosis or obliterative phlebitis. ³⁰ Patients who fulfill all three criteria are diagnosed with definite IgG4-RD. Patients who fulfill items 1) and 3), but do not have increased serum IgG4 concentrations, are diagnosed with probable IgG4-RD. Patients who fulfill items 1) and 2), with negative results on histopathology or without a histopathological examination, are diagnosed with possible IgG4-RD.

We conducted a literature search of PubMed, Scopus, and Web of Science and found 22 cases of IgG4-RD involving the retroperitoneum, mesentery, and vermiform appendix (Table 1).^{9–12,14–18,20–29} According to the 2020 RCD criteria for IgG4-RD, 12 patients were diagnosed as “probable” and 10 patients were diagnosed as “definite.” Among these 22 cases, 7 cases occurred in the vermiform appendix. In these patients with appendiceal IgG4-RD, only two had a serum IgG4 concentration >1.35 g/L. However, most of the seven reported cases fulfilled the criteria of a ratio of IgG4-positive plasma cells to IgG-positive cells >40% and a number of IgG4-positive plasma cells >10/high-power field. Except for a case of appendiceal IgG4-RD reported by Kim et al., ²⁷ the other six cases had fibrosis, which was mostly storiform. Three of the seven patients had obliterative phlebitis.

Table 1.

Comparison of previously reported clinicopathological characteristics of patients with IgG4-related disease involving the retroperitoneum, mesentery, and vermiform appendix.

Case	Ref. no.	First author	Year	Age range (years)	Sex	Serum IgG4 concentrations (g/L)	IHC IgG4-positive plasma cells/HPF	IHC IgG4-positive plasma cells/IgG-positive cells (%)	Fibrosis	Obliterative phlebitis	Lesion site	Diagnosis
1	22	Yamamoto	2009	30–35	M	NA	32	50.8	NA	+	Retroperitoneum	Probable
2	22	Yamamoto	2009	65–70	F	NA	72	47.3	NA	+	Retroperitoneum	Probable
3	10	Chetty	2011	55–60	F	NA	67	72	+	–	Cecum	Probable
4	19	Nomura	2011	80–85	F	1.71	130	75.9	+	+	Mesentery	Definite
5	18	Minato	2012	50–55	M	1.27	74.8	64	+	+	Mesentery	Probable
6	15	Ko	2013	40–45	M	NA	>50	NA	+	+	Distal ileum	Probable
7	14	Hiyoshi	2014	70–75	F	1.02	150	50	+	+	Mesentery	Probable
8	11	Das	2014	50–55	M	1.89	<45	50	+*	+	Mesentery	Definite
9	13	Gundara	2015	70–75	F	NA	NA	NA	+	NA	Mesentery	Probable
10	17	Liu	2020	65–70	M	1.45	>50	>40	+	−	Mesentery	Definite
11	12	Fukuda	2020	70–75	M	0.508	81	80.4	+	+	Mesentery	Probable
12	16	Kozono	2021	60–65	M	6.65	>100	55.4	+	−	Mesentery	Definite
13	21	Syu	2021	40–45	M	1.69	>50	NA	NA	NA	IC valve	Definite
14	9	Bertoni	2022	70–73	F	1.45	20	50	+	−	Mesentery	Definite
15	20	Pehlivan	2022	35–40	M	4.57	70	64	+	−	Mesentery	Definite
16	24	Comtesse	2014	20–25	F	NA	NA	>40	NA	+	Appendix	Probable
17	27	Kim	2016	50–55	M	NA	NA	>50	−	−	Appendix	Probable
18	29	Veerankutty	2018	55–60	M	NA	NA	41.66	+*	NA	Appendix	Probable
19	28	Kwon	2019	45–50	F	NA	>100	>50	+*	NA	Appendix	Probable
20	26	Hojo	2020	40–45	F	NA	112	78.3	+	–	Appendix	Probable
21	25	Dias	2020	40–45	F	1.80	21	>40	+*	+	Appendix	Definite
22	23	Cabrales	2021	15–20	M	5.24	>50	NA	+*	+	Appendix	Definite
Present case		Kim	2024	60–65	F	0.247	> 50	>40	+*	+	Appendix	Probable

IgG4, immunoglobulin G4; IHC, immunohistochemistry; HPF, high-power field; IgG, immunoglobulin G; F, female; M, male; NA, not available

*

Storiform fibrosis.

IgG4-RD is a fibroinflammatory condition characterized by chronic activation of the immune system and a tendency to form tumorous lesions. However, IgG4-RD can affect a wide range of organs, including the pancreas, bile ducts, major salivary glands, lacrimal glands, periorbital tissues, kidneys, lungs, and retroperitoneum. ³² In addition, IgG4-RD has been diagnosed as a distinct systemic disease entity that includes Mikulicz disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, Küttner tumor, interstitial pneumonitis, interstitial nephritis, retroperitoneal fibrosis, inflammatory aortic aneurysm, and aortitis. ³⁰ Mesenteric IgG4-RD is rarer than IgG4-RD at other sites and has been previously diagnosed as sclerosing mesenteritis. This condition shows pathological findings of chronic inflammation and thickening of the mesentery with marked lymphoplasmacytic infiltration.^10,13,18 A few studies have attempted to differentiate IgG4-RD from IMTs, although both diseases share a morphological appearance with prominent fibroblastic/myofibroblastic proliferation and lymphoplasmacytic infiltration.^10,13,18 Most reported patients with IMT differ from those with IgG4-RD regarding low levels of IgG4-positive cell infiltration and a lack of obliterative phlebitis. In addition, patients with IMT (mean age, 21.4 years) are younger than those with IgG4-RD (mean age, 59.1 years). ²² The present case was consistent with IgG4-RD rather than IMT. ³⁰

Most patients with IgG4-RD typically respond well to steroid treatment, rendering surgical intervention unnecessary. However, in patients in whom appendiceal neoplastic disease is suspected on the basis of preoperative imaging and there is no leukocytosis indicating appendicitis in laboratory tests, surgical treatment may become unavoidable. In fact, among the seven reported cases of IgG4-RD involving the appendix (Table 1), distinguishing neoplastic lesions as a potential diagnosis preoperatively proved challenging. As a result, five of these seven patients underwent right hemicolectomy (a wide resection), while the remaining two opted for limited surgical interventions; one had an appendectomy and the other underwent cecectomy. Interestingly, in our patient, the vermiform appendix was obliterated, and this was likely due to inflammation-induced destruction. Retrospectively, if the possibility of a malignant tumor could have been ruled out through an emergency biopsy during surgery of our patient, the extent of surgical intervention could have been minimized. Therefore, surgeons need to have a comprehensive understanding of this disease, which can manifest in the retroperitoneal, mesenteric, or appendiceal regions.

Conclusion

IgG4-RD is a recently identified disease entity that can affect multiple organs. Diagnosing IgG4-RD is challenging, especially in differentiating it from tumors, and IgG4-RD can often be misdiagnosed in the clinical setting. Recently, the 2020 RCD criteria for IgG4-RD have been used for diagnosing IgG4-RD. Our case highlights the tumor-mimicking features of appendiceal IgG4-RD. Awareness of IgG4-RD and its characteristics is important to avoid diagnostic pitfalls and reach the correct diagnosis.