Immunoglobulin G4-related disease (IgG4-RD) is a chronic systemic inflammatory disease of uncertain etiology described in the early years of the 21st century in the Asian population. It is considered an immune-mediated fibroinflammatory condition that can affect multiple organs showing mass-like lesions, elevated serum IgG4 concentrations, and typical pathological findings such as lymphoplasmacytic infiltration with IgG4-positive plasma cells, various degrees of fibrosis and obliterative phlebitis (1). In the head and neck region, IgG4-RD can be observed as tumefactive enlargement as part of the systemic disease or in isolation, with the orbit and the salivary and lacrimal glands being the most frequently affected sites (2).
Salivary gland involvement, known as IgG4-related sialadenitis (IgG4-RS), is a rare condition that is currently considered part of the spectrum associated with IgG4-RD (3). IgG4-RS is found in 27% to 53% of IgG4-RD patients (4), mainly in the submandibular gland (5). Histologically, IgG4-RS is distinguished by an infiltration of IgG4-bearing plasma cells into salivary gland tissue. Clinically, it presents as a swollen, painless mass in either major or minor salivary gland, unilateral or bilateral, which poses a diagnostic challenge for the clinician and pathologist since, at times, can simulate a malignancy. Furthermore, not only is the diagnosis of IgG4-RS difficult to establish, which can lead to a misdiagnosis of malignancy, but there is also a range of malignancies associated with this condition. However, very few cases of IgG4-RS and salivary gland carcinoma have been reported. Isolated cases of marginal zone B-cell lymphoma and salivary duct carcinoma have been notified, as well as one case of adenoid cystic carcinoma arising in the context of this disease (6-8). Here, the authors report an unusual clinical case of a patient with unilaterally located IgG4-RS in the parotid gland who underwent a parotidectomy revealing a simultaneous adjacent ductal carcinoma.
We present the following case in accordance with the CARE reporting checklist (available at https://dx.doi.org/10.21037/gs-21-90).
A 42-year-old man presented with a painless, slow-growing swelling located in the right parotid gland with a 12-month evolution. Physical examination revealed a 4 cm mass in the preauricular area without skin infiltration or evidence of facial nerve dysfunction. On palpation, there was a firm, smooth-surfaced and poorly defined tumor. The patient did not present other associated symptoms and was otherwise healthy. MRI imaging showed an ill-delineated infiltration with predominantly involvement of parotid gland superficial lobe, hypointense on T1 (Figure 1). The contrast highlighted a homogeneous enhancement with some scattered dilated cystic areas and ductus that were better appreciated on T2 weighted images. Fine needle aspiration cytology (FNAC) and open biopsy were nonconclusive in determining the origin of the lesion, reporting that the mass contained a heterogeneous lymphoid population with minimal inflammatory changes. No histological evidence of malignancy was found.
With the presumed diagnosis of chronic parotitis, oral methylprednisolone was prescribed at 30 mg/day for three weeks along with conventional measures such as hydration and glandular massage. Due to poor response to medication, a total parotidectomy preserving the facial nerve was performed to remove the lesion and establish the diagnosis. The histological examination described a consistent morphologic appearance of diffuse IgG4-RS in combination with a poorly differentiated multifocal ductal carcinoma (pT2N0Mx, stage II) with perineural invasion and without vascular or lymphatic invasion (Figure 2). The immunohistochemical study identified abundant IgG4 plasma cells (more than 10 cells per high-power field with an IgG4/IgG ratio greater than 40%) and an obliterative phlebitis image due to lymphoplasmacytic infiltration of the venule walls. Subsequent serological examination, including IgG subtypes, was normal. There were no systemic manifestations on the whole-body 18F-FDG PET/CT. In accordance with the above, the diagnosis of IgG4-RS synchronous to infiltrating ductal carcinoma of the parotid gland was suggested. The postoperative course was uneventful except for a temporary facial paresis (grade III according to the House-Brackmann classification system) that resolved completely within 5 months. Adjuvant radiotherapy with a total dose of 67.5 Gy on the tumoral bed and 54 Gy on levels I-II-III of the neck in 5 weekly fractions for 6 consecutive weeks was recommended by the multidisciplinary head and neck tumour board of our institution. The patient showed good tolerance, without the need for interruption. At 24 months of follow-up, the patient was doing well with no recurrence or evidence of systemic involvement.
A timeline concisely showed the medical procedure of our unusual case (Table 1).
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Our patient reported the following about his experience: “Throughout the process of my clinical care, I was informed about the concerns, doubts and problems that raised the diagnosis and treatment of my disease. I was aware of the risks of the surgical procedure, especially of facial nerve damage. Although during the first postoperative months I was concerned about the difficulty in moving my facial muscles, over time I have recovered normal facial mobility. Currently I can do my usual activity without any problem. However, I perceive a slight hollow in the preauricular area, but I am happy with the result obtained.”
Few reports have described the association between IgG4-RS and synchronous development of malignancies appearing in a background of IgG4-RD. To the best of our knowledge, this report is the first documented case of IgG4-RS with unilateral involvement of the parotid gland that occurred simultaneously with an infiltrating ductal carcinoma of the adjacent tissue in the same gland.
IgG4-RS diagnosis is based on a set of clinical-radiological, serological, and histopathological criteria, none of which are pathognomonic (9,10). Diagnosis can sometimes be complex due to the number of overlapping and similar clinical conditions that can affect the parotid glands. In our clinical case, the clinical presentation as persistent glandular swelling, imaging tests and pathological findings were compatible but not conclusive with those of chronic parotitis described by other authors (5,11). FNAC was a limited tool to obtain a valid and conclusive sample to evaluate IgG4 positive plasma cells. Therefore, it is very important that the surgeon can obtain an adequate biopsy sample with enough tissue to carry out a correct pathological evaluation (12). However, the incisional biopsy performed was unable to initially diagnose the presence of an occult tumor foci that was hidden within IgG4-RS involvement. Percutaneous core needle biopsy under ultrasound guidance is an alternative tool to FNAC for the preoperative evaluation of patients with lesions of the salivary glands, but we ruled it out due to the risk of bleeding and possible damage to hypervascularized intraparotid vessels.
The diagnosis of IgG4-RS in our patient was established according to the Okazaki et al. (13) and Umehara et al. (14) criteria: (I) persistent inflammation (>3 months) of single or multiple major salivary glands; (II) histopathological and immunohistochemical examination showing a marked lymphocyte and plasmacyte infiltration of IgG4 plasma, cells ratio of IgG4/IgG cells >40% and >10 IgG4 plasma cells per high-power field; (III) obliterative phlebitis; and (IV) exclusion of other diseases that present with glandular swellings. The total serum IgG and IgG4 concentration was normal, which is consistent with up to 30–50% of IgG4-RD cases (15). These normal levels of IgG4 in peripheral blood can be explained by the fact that our patient had mainly an infiltration component located in a single gland without excessive active inflammation, and by the previous corticosteroids that had been administered (16).
Given the finding of an isolated parotid gland mass in the context of parotid IgG4-RS, the first mandatory key point is to exclude a primary salivary gland tumor and other neoplasms such as lymphoma or metastatic tumors (8). Next, the differential diagnoses closest to IgG4-RS include chronic sialadenitis and Sjogren’s syndrome (17). Chronic sialadenitis typically affects the submandibular gland and has no characteristic pattern with marked lymphocyte and plasmacyte infiltration of IgG4 plasma cells or obliterative phlebitis. Sjogren’s syndrome is associated with xerostomia, xerophthalmia and glandular destruction accompanied by an increase in related antinuclear antibodies (anti-SSA). Among other entities that could mimic an IgG4-RS are granulomatous disorders and storage diseases such as sarcoidosis or amyloidosis, Castleman’s disease, eosinophilic granulomatosis with polyangiitis, and Heerfordt syndrome (18).
The treatment indicated in symptomatic patients with IgG4-RD is corticosteroids with an initial prednisolone dose of 30 mg/d, tapered in 5-mg reductions every 2 weeks (1,10). However, this approach was not effective in our patient, probably due to 12-month delay in consultation, the relatively large mass with isolated involvement that was very difficult to reduce with medication, or the underlying synchronous ductal carcinoma. Although we performed a total parotidectomy to ensure the histological diagnosis and rule out other pathologies, IgG4-RS would not usually require such radical surgery, since in case of residual disease or recurrence it could be easily treated with corticosteroids (16). On the other hand, there is no general agreement on the best therapeutic approach for infiltrating ductal carcinoma, but a total parotidectomy is usually recommended, even in T1 tumors, because local recurrence regularly has a very poor prognosis (19). In cases of apparent involvement of the facial nerve and locoregional extension, a surgical resection with wide margins should be considered. Postoperative radiotherapy is recommended when extraparotid extension, positive surgical margins, neck lymph node metastasis, or perineural invasion is found (19). In our clinical case, the multidisciplinary head and neck tumour board proposed postoperative radiotherapy to the tumoral bed and elective radiotherapy to the neck since the histopathological diagnosis was made after parotidectomy (20).
A higher incidence of various neoplasms has been reported in association with IgG4-RD, including solid tumors located in the pancreas, gastrointestinal tract, lung and prostate, and also lymphomas (21,22). Recently, a prospective cohort study showed that IgG4-DR Chinese patients have a 2.78-fold increased risk of metachronous malignancy over a median 61.4-month follow-up, with the gastrointestinal tract being the most common site of malignancy (23). The etiopathogenesis of this event is unknown. Long-lasting chronic inflammation appears to play a fundamental role in cancer development through the carcinogenesis process associated with inflammation (23), although it has also been speculated that IgG4-RD could be considered a type of paraneoplastic syndrome (14). The risk of association between IgG4-RD and a synchronous tumor has not yet been elucidated, nor is its pathogenic relationship. Our case report stands out the difficulties involved in the clinical diagnosis of this rare condition insofar as it could only be established through a histopathological evaluation after performing a parotidectomy.
In conclusion, this rare case report adds to the growing literature describing salivary gland involvement in patients with IgG4-RD. Considering the low occurrence of IgG4-RS located in the parotid gland, the clinician must be aware of this condition to establish a correct differential diagnosis, ensure its proper management, and carry out long-term follow-up to eventually detect the involvement of additional sites and organs at one or more parts in the body. Furthermore, this report highlights the importance of considering the possibility of an underlying carcinoma in the presence of a single parotid gland mass in the context of IgG4-RS and the management problems that can arise when both conditions occur synchronously. Discarding local or distant synchronous or metachronous malignancies is especially relevant if, as in the case presented, the diagnostic difficulty increases because there was no clear response to prior steroids medication.
We express many thanks to the patient for generously authorizing us to share his rare case.
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://dx.doi.org/10.21037/gs-21-90
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/gs-21-90). Pedro Infante-Cossio serves as an unpaid editorial board member of Gland Surgery from Mar 2019 to Feb 2021. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this Case report and any accompanying images.
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- Khosroshahi A, Wallace ZS, Crowe JL, et al. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis Rheumatol 2015;67:1688-99. [Crossref] [PubMed]
- Ana-Magadia MG, Takahashi Y, Valencia MRP, et al. Immunoglobulin G4-related periorbital soft-tissue destruction. J Craniofac Surg 2019;30:e26-e28. [Crossref] [PubMed]
- Martínez-Valle F, Orozco-Gálvez O, Fernández-Codina A. Update in ethiopathogeny, diagnosis and treatment of the IgG4 related disease. Med Clin (Barc) 2018;151:18-25. [PubMed]
- Brito-Zerón P, Ramos-Casals M, Bosch X, et al. The clinical spectrum of IgG4-related disease. Autoimmun Rev 2014;13:1203-10. [Crossref] [PubMed]
- Thompson A, Whyte A. Imaging of IgG4-related disease of the head and neck. Clin Radiol 2018;73:106-20. [Crossref] [PubMed]
- Gill J, Angelo N, Yeong ML, et al. Salivary duct carcinoma arising in IgG4-related autoimmune disease of the parotid gland. Hum Pathol 2009;40:881-6. [Crossref] [PubMed]
- Shimo T, Yao M, Takebe Y, et al. A case of adenoid cystic carcinoma associated with IgG4-related disease. Int J Surg Case Rep 2015;10:12-6. [Crossref] [PubMed]
- Gurwale SG, Gore CR, Gulati I, et al. Immunoglobulin G4-related chronic sclerosing sialadenitis: An emerging entity. J Oral Maxillofac Pathol 2020;24:S135-S138. [Crossref] [PubMed]
- Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25:1181-92. [Crossref] [PubMed]
- Takano K, Yamamoto M, Takahashi H, et al. Recent advances in knowledge regarding the head and neck manifestations of IgG4-related disease. Auris Nasus Larynx 2017;44:7-17. [Crossref] [PubMed]
- De Cocker LJ, D'Arco F, De Beule T, et al. IgG4-related systemic disease affecting the parotid and submandibular glands: magnetic resonance imaging features of IgG4-related chronic sclerosing sialadenitis and concomitant lymphadenitis. Clin Imaging 2014;38:195-8. [Crossref] [PubMed]
- Cohen O, Azoulay O, Feldberg E, et al. Minor salivary IgG-4 related sialadenitis—clinical and diagnostic challenges. J Oral Maxillofac Surg Med Pathol 2017;29:478-81. [Crossref]
- Okazaki K, Uchida K, Koyabu M, et al. Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease. J Gastroenterol 2011;46:277-88. [Crossref] [PubMed]
- Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 2012;22:21-30. [Crossref] [PubMed]
- Carruthers MN, Khosroshahi A, Augustin T, et al. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann Rheum Dis 2015;74:14-8. [Crossref] [PubMed]
- Gutiérrez Santamaría J, Romagosa Pérez-Portabella C, Mogedas Vegara A, et al. Locally destructive mandibular pseudotumor as a manifestation of immunoglobulin G4-related disease. Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:e40-3. [Crossref] [PubMed]
- Hong X, Li W, Xie XY, et al. Differential diagnosis of IgG4-related sialadenitis, primary Sjögren syndrome, and chronic obstructive submandibular sialadenitis. Br J Oral Maxillofac Surg 2017;55:179-84. [Crossref] [PubMed]
- Puxeddu I, Capecchi R, Carta F, et al. Salivary gland pathology in IgG4-Related disease: A comprehensive review. J Immunol Res 2018;2018:6936727 [Crossref] [PubMed]
- Pons Y, Alves A, Clément P, et al. Salivary duct carcinoma of the parotid. Eur Ann Otorhinolaryngol Head Neck Dis 2011;128:194-6. [Crossref] [PubMed]
- D'heygere E, Meulemans J, Vander Poorten V. Salivary duct carcinoma. Curr Opin Otolaryngol Head Neck Surg 2018;26:142-51. [Crossref] [PubMed]
- Hirano K, Tada M, Sasahira N, et al. Incidence of malignancies in patients with IgG4-related disease. Intern Med 2014;53:171-6. [Crossref] [PubMed]
- Wallace ZS, Wallace CJ, Lu N, et al. Association of IgG4-related disease with history of malignancy. Arthritis Rheumatol 2016;68:2283-9. [Crossref] [PubMed]
- Tang H, Yang H, Zhang P, et al. Malignancy and IgG4-related disease: the incidence, related factors and prognosis from a prospective cohort study in China. Sci Rep 2020;10:4910. [Crossref] [PubMed]