Riedel’s Fibrosing Thyroiditis Associated with Elevated Serum IgG4 Levels

The diagnosis of IgG4-related disease of the thyroid was then suspected.

Discussion

RT is very rare. At Mayo Clinic, 21 cases have been identified between 1976 and 2008 (Fatourechi, 2011; Hennessey, 2011). Histologically, RT is characterized by lymphoplasmacytic infiltrations associated with local and systemic fibrosis (Papi, 2004). It can be suspected in patients with a rapidly progressive, indurated goiter. The evolution of the disease can be marked by the onset of symptoms of tracheal compression with stridor, dysphonia due to laryngeal nerve damage, or superior vena cava syndrome. In time, retroperitoneal and/or mediastinal fibrosis, orbital pseudotumors, sclerosing cholangitis, and polyserositis can also develop in patients with RT (Perimenis, 2008; Fatourechi, 2011; Hennessey, 2011; Papi, 2004; Erdogan, 2009; Yasmeen, 2002).

The IgG4-related syndrome was first described in Japan, in the form of the so-called autoimmune pancreatitis (AIP), the main histological and serum marker of which is IgG4. IgG4 is the smallest of the four subclasses of IgGs (IgG1, IgG2, IgG3, and IgG4). The IgG1 subclass constitutes nearly 70% of all IgGs, while the IgG4 subclass constitutes less than 5% of the total pool of IgGs. All subclasses play a major role in defense against infection, by taking part in the process of opsonization and activation of the complement. However, IgG4s do not have any activity on the complement and play a limited role in autoimmunity, or their role has not yet been identified (Kakudo, 2012).

The link between IgG4-related disease and RT has already been proposed in 2010 by Dahlgren et al., who reported three cases of RT and noted common features between this disease and IgG4-SD (Dahlgren, 2010). More recently, in 2012, Pusztaszeri et al. reported a case of IgG4-SD of the thyroid, identified at first as RT (Pusztaszeri,2012). However, no case of IgG4-SD of the thyroid associated with high serum IgG4 levels has ever been described. Recently, some authors also suggested a connection between IgG4-SD and Hashimoto’s thyroiditis, which is characterized by a lymphoplasmacytic infiltration, fibrosis, and an increase in the number of IgG4+ plasma cells in the thyroid (John, 2012).

Histologically, IgG4-SD is also characterized by the presence of dense, lymphoplasmacytic infiltrates (mostly T cells), vessel occlusions by microthrombi, moderate infiltrations of eosinophils, and the formation of a dense, fibrous mass dissecting the organ. In terms of immunity, it seems that the disease is mainly mediated by Th2 lymphocytes, which are the predominant elements in the affected sites. An increase in the levels of interleukins 4, 5, 10, and 13 can also be noted in affected tissues. These cytokines induce hypereosinophilia and an increase in IgE levels in approximately 40% of patients. They also induce a proliferation of B cells, which mature into IgG4-secreting plasma cells. In addition, an activation of Treg cells can be observed, which induces the hypersecretion of TGF-β at the origin of the phenomenon of fibrosis observed in this syndrome. However, the mechanism responsible for the specific overexpression of IgG4s has not yet been elucidated (Kakudo, 2012).

The main problem is the lack of validated criteria for the diagnosis of the disease. Most criteria proposed in the literature concern AIP. Here, we used the following criteria: (i) diffuse hypertrophy of an organ; (ii) serum IgG4 levels higher than 135 mg/dL; and (iii) histopathological findings including a lymphoplasmacytic infiltration and fibrosis rich in IgG4+ plasma cells, with a plasma IgG4s/IgGs ratio greater than 40%—50%, or an infiltration of IgG4+ plasma cells >10 by large field. The diagnosis of IgG4-related disease is established in patients with two criteria or the sole presence of the third criterion. Moreover, other conditions, such as neoplasia, lymphoma, and diseases related to IgG4-SD (Sjögren’s syndrome, sclerosing cholangitis, etc.), should be excluded (Kakudo, 2012; Ebbo, 2012).

IgG4 levels can also be normal (30% of AIP) and the tissue density in IgG4+ plasma cells can be low, if prednisone is administrated before the analyses are performed. IgG4-SD is known to be sensitive to cortisone, as perfectly shown in the present case. Thus, the patient had IgG4 levels of 333 mg/dL at the time of the recurrence, but three weeks after the start of corticosteroid therapy and after the biopsy of the jugular mass, the levels of IgG4s in serum dropped to 86 mg/dL. The histology revealed mostly dense, fibrous, and pauci-inflammatory tissue, and it was impossible to quantify the number of IgG4+ plasma cells. To confirm the hypothesis of IgG4-SD in this patient, additional histological analyses were performed on the biopsies of the thyroid, prior to treatment with corticosteroids in 2007.

Specific immunostainings revealed an increase in IgG+ plasma cells, especially IgG4+ plasma cells, with >10 IgG4+ plasma cells by large field of 0.6 mm in diameter (Illustration 1).

Illustration 1: Cytology and IgG- and IgG4-specific immunostainings of thyroid biopsies from 2007 (photographs 1 and 2) and of the left paravertebral mass from 2012 (photograph 3).

Photograph 1: Immunoperoxidase Staining of IgGs Resulting in a Brown Staining of Numerous Plasma Cells.

Photograph 2: Immunoperoxidase Staining of IgG4s: 12-14 IgG4+ Plasma Cells per Large Field of 0.6 mm of Diameter.

Photograph 3: Staining with Hematoxylin Erythrosin Saffron (HES) Showing a Very Weak Inflammation of the Fibrous Tissue.