Disease related to immunoglobulin G4: Imaging findings

.www.analesderadiologiamexico.com
1665-2118/© 2019 Sociedad Mexicana de Radiologia e Imagen, AC. Published by Permanyer. This is an open access article under the CC CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Anales de Radiología México. 2019;18:36-45
ABSTRACT
hallazgos imagenológicos Mario I. Cárdenas Vargas1* and Mario I. Ortiz2
1Hospital General de Pachuca; 2School of Medicine, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo. Hidalgo, Mexico
REVIEW ARTICLE
Received in original form: 26-02-2019 Accepted in final form: 02-04-2019
This article must be quotes as: Cardenas-Vargas MI, Ortiz MI. Enfermedad relacionada con Inmunoglobulina G4: Hallazgos imagenológicos. Anales de radiología México. 2019;18(1):36-45
OBJECTIVE
The objective is to understand the basic con- cepts of the disease, learn about the most important sites for the disease, identify the key images that will help radiologists to sus- pect the disease, and determine the impor- tance of working closely with the physicians in the management of these patients.
INTRODUCTION
Clinical features and etiology
The key to suspect this disease is the tumor-like appearance in one or more organs that make us think of cancer. The organ growth may be easily found on physical examination (lacrimal or salivary glands, enlarged lymph nodes, or enlarged thyroid gland); likewise, it can also be incidentally found on imaging studies (pan- creas, liver, spleen, or kidneys) Multiple organ lesions may occur synchronically or meta chronically in one patient1-4.
In general terms, the immunoglobulin associated disease (immunoglobulin G4-related disease [IgG4-RD]) has a broad age range. Numerous cases of patients of different ages have been de- scribed, ranging between the second and ninth decade of life5. Males are more often affected and with greater intensity than women6,7. They all share the same histopathology findings. The disease tends to have a good response to ste- roids. So far there are no valid international diagnostic criteria. The pathophysiology hypoth- esis and the treatment approaches are still debated5,8,9. The key point in this disease is IgG4 infiltration into plasma cells. At present, the ex- act mechanism as to how this gamma globulin
triggers the mechanism that leads to systemic inflammation is unknown. It is thought that the IgG4 deposits of immune complexes in different membranes, such as endothelium of vessels, bil- iary ducts, gland ducts, skin layers, or the base- ment membrane of the kidney, are the cause of histologic damage10,11. There are other diseases such as asthma, atopic dermatitis, some parasitic diseases (helminthiasis), pemphigus vulgaris, and pemphigus foliaceus where the exogenous antigens are responsible for the high serum IgG4 concentration and the formation of immune complexes. However, in IgG4-RD, no exogenous or endogenous antigens have been found that give rise to this immune response10,12-15.
MATERIALS AND METHODS
The database of all patients over 18 years of age from the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán with the histopathology diagnosis of IgG4-RD up to December 2017 who had an active digital radiology file was reviewed. Fifteen patients met these criteria. Of these patients, the most representative images were selected, which represented the different levels of organ dis- turbance. A literature review was conducted in PubMed using different headings of med- ical subjects and Medical Subject Headings (MeSH), to have reference support for the cur- rent review paper.
RESULTS
Main imaging findings
IgG4-RD has a wide range of imaging findings. Most are also present in other
38
Anales de Radiología México. 2019;18
conditions that are considered different clinical diseases; therefore, the imaging crite- ria are not diagnostic per se but are rather very useful to help establish this diagnosis16.
Pancreas
Due to the high incidence of autoimmune pancreatitis (AP) in the patients in whom EgG4-RD is suspected, we must intentionally look for pancreatic disturbances. AP is a type of pancreatitis that is characterized by hyper- gammaglobulinemia and histologically by
lymphoplasmacytic inflammation of the pan- creas. In the microscopic examination, sever- al grades of fibrosis may be found, intense lymphocytic infiltration, neutrophils, and scattered plasma cells. Similarly, obliterating vasculitis may be found. Immunohistochem- istry is positive for IgG4 plasma cells6,17,18.
On imaging, the pancreas is visualized as a “sausage-shaped pancreas” (Fig. 1). This is the typical appearance of this disease, that is, the pancreas shows generalized enlargement. In some patients, the pancreatic growth is not
Figure 1. Imaging findings in the pancreas. A: axial computed tomography (CT) scan in venous phase. B: positron emission tomography with multislice CT, typical appearance of pancreatitis caused by immunoglobulin G4 with generalized hypermetabolism in the pancreatic parenchyma. C: pancreatic phase that shows enlarged tail of the pancreas, with peripheral low density (arrow). D: typical shape in “sausage pancreas.”
BA
M.I. Cárdenas Vargas, M.I. Ortiz: Disease related to immunoglobulin
diffuse but rather localized. This focal growth may occlude the biliary duct in its pancreatic portion. When this occlusion takes place, the imaging finding may be easily confused with a pancreatic mass. It is for this reason that a clinical examination and serology must be performed to rule out malignancies in these patients before establishing the IgG4-RD diag- nosis. It has also been found that the increased focal size may occur in the body or the tail of the pancreas, and this focalized enlargement may be the only morphologic anomaly in pa- tients with IgG4-RD. In some patients with an established diagnosis of IG4-RD, the pancreas may have a completely normal appearance. Some of these patients may have an irregular dilatation of the main pancreatic duct (beaded appearance). All of these imaging features may be properly visualized with computed tomography (CT) or magnetic resonance (MRI). The use of intravenous contrast, either with iodine for CT or gadolinium for MRI, is used to visualize areas of hypoperfusion. In spite of the use of contrast agents, it is not possible to differentiate these lesions from a
pancreatic tumor. This is the importance of the clinical context of patients18-24. Positron emission tomography with multislice CT (CT) is a diagnostic imaging technique by means of which usually a radiolabeled drug, F-fluo- rodeoxyglucose, is delivered to the patient, helping to obtain metabolic information that is not possible to identify with other imaging techniques. It is a tool that allows us to eval- uate the inflammatory processes that occur in the different organs in IgG4-RD and is also useful to evaluate the treatment response25.
Liver and biliary tract
The classic liver lesion in IgG4-RD is the in- flammatory pseudotumor (Fig. 2). This lesion was already known before being associated to IgG4-ER disease. It was once considered to be a very uncommon liver lesion of unknown etiology. Years back, patients were subjected to surgery as the primary treatment. Nowa- days, these lesions should be followed be- cause there is no potential risk for malignan- cy; histologically, they only show fibrosis in different grades. These lesions may appear as round and hypodense on CT with poor or no enhancement with contrast26.
It has been shown that some patients with autoimmune hepatitis (AIH) share clinical and pathological features with AP, such as high serum IgG levels and lymphoplasma- cytic infiltration, suggesting the presence of immune disturbances. Chung et al. proposed that the AIH with IgG4 in the liver biopsy may be part of the IgG4-RD spectrum; how- ever, the patients selected in the study showed IgG4 elevation in the liver biopsy, but with normal amounts in blood and showed no
Figure 2. Inflammatory pseudotumor. A: axial computed tomography with intravenous contrast in venous phase. A round, low-density image with poor enhancement in venous phase can be seen in the liver of a patient with immunoglobulin G4- (IgG4) related disease (IgG4-RD), suggesting a pseudoinflammatory tumor. B: magnetic resonance showing irregular left intrahepatic biliary dilatation.
A B
Anales de Radiología México. 2019;18
systemic disturbances. Therefore, it is still not clear if AIH may be considered within the spectrum of diseases that are present in IgG4-RD or if it is a completely different disease26-28.
Sclerosing cholangitis is another clinical feature of IgG4-RD. Unilateral or bilateral involvement of the biliary tree, and intra or extrahepatic lesions can be seen. On imaging studies, ste- notic areas of different lengths can be seen and dilation of the biliary ducts, thickening of the biliary duct wall can also be found. These mor- phologic changes are found in patients with primary sclerosing cholangitis, so this must be kept in mind when a differential diagnosis is
considered. Sclerosing cholangitis is suspected when the patient has jaundice and symptoms of hyperbilirubinemia29,30.
The morphology of the biliary ducts may be properly examined with ultrasound, where the biliary ducts will be dilated. With Dop- pler, these structures have no flow or spec- trum. The shape of the biliary tract can be accurately evaluated with CT and MRI, and confirms a stenotic appearance with areas of dilatation typical in these patients. Stenosis in the biliary tract can be seen in most of the patients with AP, due to the mass effect from the extrinsic compression of the head of the pancreas and the fibrosis of the biliary tract
Figure 3. Lung window computed tomography (CT). Inspiration (A) and expiration (B). Bilateral apical nodules can be seen and thickening of the bronchovascular markings and interlobular septa. These findings belong to type 1 and 4 of pulmonary disease in immunoglobulin G4-related disease. C and D: view of the main bronchi showing the diffuse bilateral thickening of bronchovascular markings and interlobular septa, multiple nodular images with left predominance.
A B
C D
M.I. Cárdenas Vargas, M.I. Ortiz: Disease related to immunoglobulin
Figure 4. A: salivary and lacrimal glands. B: diffuse bilateral symmetrical enlargement of the parotids and submandibular glands with uniform enhancement after intravenous contrast. C: symmetrical and bilateral thickening of the lacrimal glands in a patient with hyperimmunoglobulin G4 syndrome without gland dysfunction. In this patient, Sjögren’s syndrome was initially suspected.
A B C
due to the chronic inflammatory process. Af- ter treatment with steroids, there is clinical and radiological improvement of the biliary ducts unlike patients with primary sclerosing cholangitis that shows no improvement with this treatment30,31.
Lung
The disease can also involve the lungs (Fig. 3). In a recent study Inoue et al.32, the basic pat- terns of lung involvement in these patients were analyzed. Lung diseases can be classi- fied into four large patterns: (1) solid nodular (including masses), (2) round radio-opaque ground glass appearance, (3) interstitial alve- olar (visualized as a honeycomb, diffuse bronchiectasis), and (4) bronchovascular (thickening of bronchovascular bundles and interlobular septa). Therefore, we should al- ways look for these anomalies in suspicious patients or with IgG4-RD diagnosis, and try to classify them into one of these patterns. Histologically, the solitary nodular lesions have a diffuse lymphocytic infiltrate with
fibrosis. The difference in the location of fi- brosis and the lymphocytic infiltrate is exact- ly as shown in the imaging studies, for exam- ple, in type 2 lesions, this infiltrate is found in the alveolar interstitium, in type  4, in peribronchiolar or interlobular intersti- tium32,33.
Salivary and lacrimal glands
The damage in the salivary glands in this syndrome is found as sclerosing sialoadenitis. Clinically, patients have bilateral thickening and painless inflammation of the salivary glands (Fig.  4). Histologically, the sclerosing sialoadenitis shows remarkable diffuse infil- tration of lymphocytes and plasma cells and periductal fibrosis. Variable atrophy and de- struction of acini replaced by fibrotic tissue can be noted. The ductal architecture may be interrupted in some cases34.
When a patient suspected to have scleros- ing sialoadenitis is found, it is important to keep in mind the likelihood that the patient
42
Anales de Radiología México. 2019;18
can potentially be diagnosed with IgG4-RD, so we must look for other organ involvement. There are some diseases that must be includ- ed in the differential diagnosis; however, it is often difficult to make a distinction among them because of overlapping features. At present, investigators are trying to find out if all these diseases belong to the same group with a common etiology and different clinical presentation7,35. Mikulicz disease is a benign tumor where patients have pain and chronic inflammation of the lacrimal and salivary glands. Kuttner’s tumor is also a chronic
inflammatory disease of the salivary glands that often only involves a submandibular gland5,36-38.
On CT or MRI, the parotids, salivary, and submandibular glands may show a diffuse enlargement. Contrast images, in general, show uniform enhancement, indicating a be- nign feature. Nuclear medicine (Gallium 67) may be used when malignancy is suspected, in IgG4-RD lesions, there is no abnormal up- take, revealing a benign enlargement of these glands37,39,40.
The lacrimal glands may also be involved, so generally, they have a diffuse enlargement. With intravenous contrast, in general, uni- form enhancement can be seen. The enlarge- ment of these glands does not correlate with the grade of xerophthalmia. This is one of the important clinical features of patients with IgG4-RD. The diffuse bilateral enlargement of the lacrimal glands and normal function must point to the diagnosis of IgG4-RD7. In patients with clinically obvious lacrimal dysfunction and the same imaging findings (diffuse en- largement), Sjögren syndrome must be con- sidered first, before IgG4-RD34,36,37,40.
Retroperitoneal fibrosis
Patients with IgG4-RD may present with retroperitoneal fibrosis (Fig. 5). This condition may clinically show general malaise, abdom- inal pain, fatigue, fever, and weight loss. In 10-20% of cases, the patients have positive an- tinuclear antibodies, suggesting the autoim- mune nature of the disease. There is a good response to glucocorticoid treatment, but de- pending on the grade of fibrosis. Once that it
Figure 6. Renal lesion in immunoglobulin related disease. Axial view (A) and coronal view (B) in a computed tomography scan with intravenous contrast in arterial phase. Round-shaped low-density images can be seen involving the renal cortex.
A B
Figure 5. Retroperitoneal fibrosis in a patient with immunoglobulin related disease. Axial (A) and coronal (B) views. A mass surrounding the aorta, iliac arteries, and ureters can be seen. Note the aneurysmal dilatation and the calcium plaques on the wall of the aorta. The patient had an acute renal failure from the compression of both ureters.
A B
M.I. Cárdenas Vargas, M.I. Ortiz: Disease related to immunoglobulin
has been histologically established that fibro- sis predominates in the tissue, surgery is the treatment of choice to alleviate the symp- toms37-39. On CT without contrast, the density is similar to that of muscles, so it is described as a soft tissue mass. CT is adequate to eval- uate treatment response; however, fibrosis cannot be distinguished from active disease. On MRI, lesions have low signal intensity on TI and high signal intensity on T2; it is still the imaging modality of choice in patients with renal failure or those who have allergic reactions to the contrast agent with iodine41-43.
Kidney
There are also renal disturbances in IgG4-RD. In general, the kidney lesions associated to IgG4 are found on CT as small cortical hy- podense round or wedge-shaped lesions in contrast phase (Fig. 6). On MRI with gadolin- ium, renal lesions may seem iso/hypodense on potentiated T1 and T2 images, due to the dense cellular infiltration and fibrosis. The renal lesions may be reversible, depending on the extent of fibrosis at the time of diagnosis44.
DISCUSSION
IgG4-RD is a relatively new disease that at this time has raised interest due to its broad spectrum of signs and clinical symptoms that depend on the affected organs. It can easily be confused with other diseases; however, it must be suspected when patients do not completely fit into the well-established features of the dif- ferent diseases that are included in the differ- ential diagnosis. It must be kept in mind that one of the main differences is that IgG4-RD
has a good response to steroid treatment when treated on time, unlike the other diseases, of which we are trying to differentiate. The di- agnosis may be confirmed by histology and blood work, which is relatively simple. If the diagnosis is delayed and remains unsuspect- ed, the fibrosis will progress, leading to high morbidity and mortality in patients.
CONCLUSION
At present, radiology plays a very important role in the diagnosis of this disease. If we are familiar with the morphological changes found on CT as well as MRI, physicians will be able to accurately establish the diagnosis in these patients, and even keep this disease in mind when all other possibilities have been ruled out. The regression of radiologic findings sug- gests that the treatment has been adequate and that good long term outcomes can be expected and some patients may be definitively cured.
ACKNOWLEDGMENTS
– Jorge Vázquez Lamadrid, M.D. Head of the Radiology and Imaging Department at the Instituto Nacional de Ciencias Médi- cas y Nutrición Salvador Zubirán
– Ai-Lan Hitandhui Barrientos Priego. Staff doctor from the Radiology Department at the Instituto Nacional de Ciencias Médi- cas y Nutrición Salvador Zubirán.
CONFLICTS OF INTEREST
The authors declare that there is no financial or personal association with other persons or
44
Anales de Radiología México. 2019;18
organizations that might lead to conflicts of interest regarding this paper submitted for publication.
FUNDING
The authors declare that no financial support was received for this paper.
ETHICAL DISCLOSURES
Protection of persons and animals. The authors declare that no experiments in hu- man beings or animals have been conducted for this research.
Confidentiality of data. The authors declare that protocols in their worksite have been fol- lowed for the publication of the patients’ data.
Right to privacy and informed consent. The authors have obtained informed consent from the patients and/or subjects referred in this paper. The corresponding author holds the document.
REFERENCES
1. Brito-Zerón P, Bosch X, Ramos-Casals M, Stone JH. IgG4-related disease: advances in the diagnosis and treatment. Best Pract Res Clin Rheumatol. 2016;30:261-78.
2. Charrow A, Imadojemu S, Stephen S, Ogunleye T, Takeshita J, Lipoff JB. Cutaneous manifestations of IgG4-related disease (RD): a systematic review. J Am Acad Dermatol. 2016;75:197-202.
3. Kawasaki M, Tsujino M, Sato F, Sakurada M, Nishida K, Kise T, et al. IgG4-related Hypophysitis with subtle hypopituitarism in an elderly dia- betic patient: is treatment or observation preferable? Intern Med. 2017;56:2733-8.
4. Legatowicz-Koprowska M. IgG4-related disease: why is it so important? Cent Eur J Immunol. 2018;43:204-8.
5. Masaki Y, Dong L, Kurose N, Kitagawa K, Morikawa Y, Yamamoto M, et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoprolif- erative syndrome: analysis of 64  cases of IgG4-related disorders. Ann Rheum Dis. 2009;68:1310-5.
6. Neild GH, Rodriguez-Justo M, Wall C, Connolly JO. Hyper-IgG4 disease: report and characterisation of a new disease. BMC Med. 2006;4:23.
7. Kamisawa T, Takuma K, Egawa N. IgG4-related sclerosing disease. WSEAS Trans Biol Biomed. 2010;7:93-102.
8. Chiba T. Are immunoglobulin G4-positive multiorgan lymphoproliferative syndrome and autoimmune pancreatitis different manifestations of a com- mon clinicopathologic entity? Gastroenterology. 2010;138:781-4.
9. Maehara T, Moriyama M, Nakamura S. Pathogenesis of IgG4-related dis- ease: a critical review. Odontology. 2019;107:127-32.
10. Bateman AC, Deheragoda MG. IgG4-related systemic sclerosing dis- ease-an emerging and under-diagnosed condition. Histopathology. 2009;55:373-83.
11. Smit W, Barnes E. The emerging mysteries of IgG4-related disease. Clin Med (Lond). 2014;14 Suppl 6:s56-60.
12. Sato Y, Notohara K, Kojima M, Takata K, Masaki Y, Yoshino T. IgG4-related disease: historical overview and pathology of hematological disorders. Pathol Int. 2010;60:247-58.
13. Matsumoto Y, Kasashima S, Kawashima A, Sasaki H, Endo M, Kawaka- mi K, et al. A case of multiple immunoglobulin G4-related periarteritis: a tumorous lesion of the coronary artery and abdominal aortic aneurysm. Hum Pathol. 2008;39:975-80.
14. Nakamura M, Iwamoto O, Chino T, Todoroki K, Kusukawa J. Diagnos- tic dilemma of IgG4-related primary localized cervical lymphadenop- athy associated with aberrant IL-6 expression level. Diagn Pathol. 2016;11:43.
15. Akiyama M, Suzuki K, Yasuoka H, Kaneko Y, Yamaoka K, Takeuchi T. Follicular helper T cells in the pathogenesis of IgG4-related disease. Rheu- matology (Oxford). 2018;57:236-45.
16. Martínez-de-Alegría A, Baleato-González S, García-Figueiras R, Bermú- dez-Naveira A, Abdulkader-Nallib I, Díaz-Peromingo JA, et al. IgG4-relat- ed disease from head to toe. Radiographics. 2015;35:2007-25.
17. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T,…