IgG4-related sclerosing thyroiditis (Riedel-Struma): a review of clinicopathological features and management

We present a thorough review of the literature on Riedel thyroiditis (RT) with emphasis on aetiology, diagnosis and management, using the PubMed, Sinomed, and China National Knowledge Infrastructure databases. Although the exact aetiology of RT remains obscure, the histopathological features are consistent with a localized form of IgG4-related systemic disease (IgG4-RSD). Nevertheless, IgG4-RSD as a systemic fibroinflammatory disorder per se rarely affects the thyroid in the context of multiorgan manifestations. The initial diagnosis of RT is based on clinical history and imaging, but confirmation by histopathological examination is mandatory. In contrast to the historical surgical approach, glucocorticosteroid therapy is currently considered first line therapy, in line with the RT currently being viewed as a manifestation of, or analogous to, IgG4-RSD. For disease relapse, immunomodulatory agents (azathioprine, methotrexate, rituximab) can be used.


Introduction
Riedel thyroiditis (RT) (Morbus Riedel, Riedel Struma, Riedel goitre) was first described in 1886 by the German surgeon Bernhard Riedel, who reported on three patients treated by thyroidectomy at the International Congress of Surgery in 1894 and 1896 [1][2][3]; Riedel used the descriptive term 'Eisenharte Struma' ('iron-hard goitre') for the condition [1]. Iron-hard thyroiditis and struma lignose have then been used interchangeably. However, similar observations had been made by Semple already in 1864 and later by Bolby in 1888, who also used similar terminology (thyroid as hard as iron). Moreover, clinicians also appreciated the rare occurrence of a hard thyroid described as a 'wooden' or 'stone' goitre [1][2][3].
The aetiology of RT has been a topic of controversy, with genetic factors [50], viruses (e.g. Epstein-Barr) [51], and smoking [7] being raised and discussed as potential aetiological factors, but all lacking convincing evidence. More plausible is the notion that, RT likely represents an autoimmune process and a form of primary fibrogenic disease [4]. Similarities to Hashimoto's thyroiditis and associations with other autoimmune diseases including Addison's disease, type 1 diabetes mellitus, and pernicious anaemia have also been explored [52][53][54][55]. Currently, RT is regarded as a form of IgG 4 -related disease (IgG 4 -RSD) [56] and, in this context, may be referred to as IgG 4 -related sclerosing thyroiditis. Recently, Dahlgren et al. [57] attempted to advance the notion of a relationship between RT and IgG 4 -RSD; they examined tissues from three patients immunohistochemically and reported IgG4:IgG ratios ranging from 44-56% in two cases but only 0-20% in the remainder.
In RT, fibroblasts or fibroblast-like cells proliferate via the action of cytokines released from B-and/or T-lymphocytes [5]. Eosinophils may also have a role; degranulation of these cells has been described in RT [58], leading to 'progressive fibrosis' [7]. Eosinophil infiltration and extracellular MBP (major basic protein) deposition were observed by Heufelder et al. [58] in 15 of 16 patients with histologically proven Riedel's invasive fibrous thyroiditis. Overall, the process has also been referred to as lymphoplasmacytosis with eosinophilia [59].
The present article reviews the current knowledge about RT with emphasis on clinical presentation, diagnostics, and management.
Occurrence of hypothyroidism varies. Percentages of about 30% have been reported [74], but the study conducted by the Mayo Clinic reported hypothyroidism in 14 (78%) of 19 patients. The remaining patients were euthyroid, but with elevated autoantibodies [antithyroglobulin (Tg-Abs) and antithyroid peroxidase (TPO-Abs) autoantibodies] [7]. Correlations between hypothyroidism and extent of fibrosis replacing the thyroid parenchyma are desirable.
Malignancy may co-exist with RT [40], including papillary thyroid carcinoma, anaplastic thyroid carcinoma [80], thyroid sarcoma [32], and lymphoma [79]. Hence, care should be taken not to overlook these diseases, as their clinical and gross the presentation may significantly overlap with that of RT.
The relationship between RT and IgG 4 -RSD has been addressed above. IgG 4 -RSD can involve multiple organs, though rarely the thyroid gland [84]. It is characterized by a dense lymphoplasmacytic infiltrate (with increased IgG4( +) subpopulations), obliterative phlebitis and diffuse storiform fibrosis [85]. For the first time in 2001, Hamano et al. [73] observed that sclerosing pancreatitis was associated with high serum IgG 4 levels and response to glucocorticoid therapy. Dahlgren et al. [57] suggested that IgG 4 -RSD, in addition to RT, is also associated with other diseases such as retroperitoneal fibrosis (pancreatitis) and Küttner tumour (also see summary below). Serum IgG 4 concentrations are usually elevated to more than 135 mg/ dL in IgG 4 -RSD, but this elevation is neither necessary (found in 75% or less of affected patients) nor sufficient for diagnosis of IgG 4 -RSD [57,84].
Significant stiffness of the thyroid can be seen during ultrasound elastography [83].

Tc thyroid scintigraphy
Isotope tests, such as thyroid scintigraphy using 99m Tc, show no tracer uptake within the affected tissue.

Computed tomography and magnetic resonance imaging
Computed tomography (CT) shows hypodense areas within the thyroid gland, which remain unaltered after administration of a contrast agent (iodine dye) [48]. Additional imaging of the chest or abdomen may show involvement beyond the thyroid gland, indicative of a systemic process [48,86].
Carotid artery encasement is characteristic and assists in differentiating from other thyroidopathies [7,83].

Positron emission tomography (PET)
Positron emission tomography (PET) using [ 18 1 Coronal T1-weighted MRI without (a) and after paramagnetic contrast application (b). Normal thyroid with homogenous slightly hyperintense signal compared to strap muscle was visible before contrast injection and homogenous increase of the signal after injection of the contrast was noted

Fine needle aspiration (FNA), core and open biopsies
Thyroid FNA is often inconclusive and less helpful in RT compared to other thyroid diseases. The examination may show inflamed fibrous tissue, with a keloid-like appearance, but diagnostic features such as destruction of thyroid parenchyma, storiform fibrosis, and extrathyroidal extension are only seen on core needle or open biopsy samples and in FNA specimens. An elevated number of IgG 4 ( +) plasma cells can be observed, but overall, the features are difficult to differentiate from other disorders with similar presentation like subacute thyroiditis, the fibrous subtype of Hashimoto thyroiditis or the paucicellular subtype of anaplastic thyroid carcinoma. An open biopsy is therefore often required and can be considered optimal.

Histopathology
Currently, histological examination remains the mainstay of the diagnosis and the decision to perform a biopsy is useful for the diagnosis of RT.
Resection specimens show replacement of most of or the whole thyroid by whitish poorly marginated hard fibrous tissue with variable elastic consistency and peripheral entrapment of brownish original thyroid tissue remnants and or adjacent periglandular soft tissue (Fig. 2). Microscopic examination shows thyroid tissue with architectural distortion due to the presence of extensive fibrosis, with severe atrophy of the follicles, dense inflammatory infiltrate, and abundant plasma cells (Figs. 3a, b,  c, d). Overall, RT shows the key features of IgG4-RSD including tumefactive lymphoplasmacytic inflammation, prominent storiform fibrosis and frequent obliterative angiitis (mostly phlebitis).

3
The coexistence of elevated serum IgG4 concentrations and their presence in the histopathological examination is necessary for the diagnosis of IgG4-RD. These features are included in the revised comprehensive diagnostic (RCD) criteria for IgG4-RD. The manifestation of Riedel's disease often meets all the IgG4-RD criteria, which may indicate the co-occurrence of these diseases [91]. Immunohistochemical evaluation for IgG and IgG 4 assists in reaching a diagnosis of RT, with more than 80 IgG 4 ( +) plasma cells/mm 2 and an IgG 4 /IgG ratio greater than 40% [92]. However, similar to the basic features of IgG4-RSD in other organs, these histopathological features may vary greatly based on the age of the process, from a more fibrous, paucicellular fibroinflammatory reaction to the reverse. Accordingly, in advanced stages, the predominant histopathological findings are marked tissue storiform fibrosis, absence of thyroid follicles and poor, lymphocyte-predominant cellularity. The processes characteristically extend into the perithyroidal adipose tissue, vessels (even with associated thrombosis), nerves, and even the trachea and muscles.

Management
Standards of care are not yet established for RT, but surgery and pharmacological treatments are considered.

Surgery
Several authors accept that surgical treatment is not indicated, at least initially [6,7,34]. However, particularly historically, total thyroidectomy has been attempted  to relieve compression symptoms [5,34,71]. Nonetheless, in the presence of significant extrathyroidal extension, surgery can be challenging and if the great vessels of the neck are encased (see above) may not be possible. After total thyroidectomy Levothyroxine is used as standard [22-25, 31, 33, 34]. If total thyroidectomy is not technically feasible, a decompressing isthmectomy maybe considered.
As the tissues in RT are very fibrous, surgical complications often occur (e.g., hypoparathyroidism or recurrence of compression symptoms) [13]. Calcium, along with calcitriol, can be usually included to counteract potential hypoparathyroidism [93].

Pharmacological treatment
The standard approach to suppress RT is the administration of both glucocorticoids [49,52,77,[94][95][96] and tamoxifen [97]. Fig. 3 a The thyroid gland parenchyma has been completely overtaken by asymmetrically distributed, variably concentrated, inflammatory cell infiltrates along with fibrosis (original magnification × 20). b A higher power shows bundled collagen interlacing at different angles (storiform fibrosis) and predominantly lymphoplasmacytic inflammatory infiltrates. An involved small nerve is discernible in the upper right quadrant (original magnification × 40). c There is marked (keloid-like) fibrosis in this area of the gland where no residual thyroid parenchyma is noted. There is a lymphoplasmacytic inflammatory aggregate in the lower left corner (high power) (original magnification × 40).
Side effects include an increase in triglyceride concentration, which may slightly increase the risk of pulmonary embolism, deep vein thrombosis, or stroke [68]. Cases of hepatotoxicity have been observed with a long-term use [106]. Tamoxifen may also cause non-alcoholic fatty liver disease in overweight and obese females [69].

Mycophenolate mofetil
Mycophenolate mofetil (MM) is the 2-morpholinoethyl ester of mycophenolic acid (MPA), which suppresses the immune system by cytostatically affecting T-and B-lymphocytes. MPA selectively and reversibly inhibits inosine monophosphate dehydrogenase, which is involved in the synthesis of the guanosine nucleosides necessary for the assembly of DNA. It does not, however, affect cytokine synthesis and does not reduce the activity of neutrophils [113]. MM is used to prevent acute rejection of organ transplants (heart, liver, kidney) in combination with cyclosporine and corticosteroids in allogeneic transplant recipients [114,115]. MM is also used in RT in combination with rituximab, as MPA alone is too weak [13].

Other methods of treatment
Management of RT relapses after glucocorticosteroid therapy has been addressed above.
There is little information on how vitamin D levels affect RT. However, because hypoparathyroidism is a side effect of RT, vitamin D is frequently mentioned in relation to the treatment. The adverse consequences of parathyroid hormone insufficiency are eliminated by using vitamin D and calcium [4,77,[116][117][118].

Conclusion
RT is a rare disease affecting the thyroid gland and adjacent tissues, clinically frequently mimicking locally advanced (cT4) malignancy. The disease leads to gradual progressive fibrosis with compression symptoms, pain, and hypothyroidism. Extrathyroidal extension in the central neck can also lead to hypoparathyroidism and vocal cord palsy. Rarely, RT may be limited to the thyroid gland. Imaging with the use of ultrasonography [48,74,76,81,82], CT [7,48,86], and MRI [48] or PET [79,81,83] assists in assessing the extent of lesions in the thyroid and the presence of additional manifestations in other organs. Diagnosis may be difficult without biopsy and histopathological difficulties in differentiating RT from anaplastic carcinoma [80] or thyroid sarcomas are experienced [32].
Upon diagnosis of RT, it is important to search for other systemic fibrosing manifestations in IgG4-RSD target organs (parathyroid glands, salivary glands, lacrimal glands, trachea, nervous system, cardiovascular system, retroperitoneum, mediastinum, lungs, etc.). Immunohistochemistry is recommended to assess the extent of IgG4 ( +) plasma cell population. Clinical trials have shown that in nearly 95% of RT cases, there are increased serum concentrations of IgG 4 antibodies [85]. Although serum IgG 4 levels may have a valuable role in diagnosis and post-treatment monitoring, currently, serum IgG4 level is not regarded as a specific marker in diagnosis and management of RT. Further research is desirable to verify the sensitivity and specificity of this finding [93].
It should be emphasized that RT cannot be completely cured. Glucocorticoids (prednisone, prednisolone) continue to be the initial treatment of choice. This has an anti-inflammatory effect and reduces the size of the gland, allowing the relief of compressive symptoms. Glucocorticosteroid therapy is effective but may be followed by relapses requiring the use of immunomodulatory agents, such as azathioprine, methotrexate, and recently rituximab [11,13,113]. In patients with symptomatic fibro-inflammatory disease in a hypothyroid phase, levothyroxine therapy should be started, and in special cases, anti-inflammatory drugs and vitamin D should be administered [4,77,93,[116][117][118]. Data Availability Data sharing not applicable.

Author's contribution
Declarations No tissue samples were analyzed for this study which is merely based on published literature.
Ethical approval Ethical clearance is not applicable.

Conflicts of interest
The authors have no financial or non-financial conflicts of interest to disclose.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.