IgG4-positive Hashimoto thyroiditis and its association with IgG4-related sclerosing disease

Abstract

A woman in her 50s was referred with suspected thyroid malignancy and underwent total thyroidectomy. Immunohistochemical analysis revealed IgG4-positive Hashimoto’s thyroiditis. IgG4-related thyroid disease is poorly understood, and thought to encompass various entities including IgG4-positive Hashimoto’s thyroiditis, Fibrosing Variant of Hashimoto’s thyroiditis, Reidel’s thyroiditis and Graves’ disease with elevated IgG4 levels. Furthermore, it may be associated with a systemic fibrosing condition called ‘IgG4-related sclerosing disease’. The clinical significance of IgG4-positive thyroid disease, however, remains unclear.

Background

Hashimoto’s thyroiditis (HT) is the most common cause of hypothyroidism in the UK. It has a reported incidence of between 0.1% and 2% and is 10 times more common in women than men.¹ It is an autoimmune condition diagnosed biochemically by the presence of raised thyroid-stimulating hormone (TSH) levels and the presence of antithyroid peroxidase (anti-TPO) or anti-thyroglobulin (anti-TG) antibodies. It can also be diagnosed on the basis of ultrasonographic findings of diffuse hypoechogenecity or the presence of hypoechoic nodules in the context of hypothyroidism. HT is treated medically with thyroid hormone replacement. Surgery is only indicated in cases of thyroid goitre causing compressive symptoms or suspicion of malignancy. There is a rare association of thyroid lymphoma in patients with HT, with a reported incidence of 0.6%.²

The diagnosis of HT can be confirmed by histological findings of lymphoplasmacytic infiltration, follicular hyperplasia and lymphoid follicles, presence of Hurthle cells and fibrosis.³ Routine immunohistochemical analysis by IgG4 staining is not carried out in patients with HT who undergo thyroidectomy in the UK. However, there have been numerous case reports describing a variant of HT mediated by IgG4-positive plasma cells.

IgG4-related sclerosing disease (IgG4-RSD) is a new disease entity, characterised by IgG4-mediated autoimmune fibrosis affecting various organs. Recently, IgG4-related thyroid disease (IgG4-RTD) has also been described, encompassing a spectrum of thyroid conditions including IgG4-related HT, fibrosing variant of HT (FVHT), Reidel’s thyroiditis and Graves’ disease with elevated IgG4 levels.⁴ However, the clinical significance of these IgG4-mediated diseases and their association with IgG4-RSD remains unclear.

We report the first case of IgG4-positive HT in the UK and discuss the value of immunostaining for this disease entity. We also discuss implications around diagnosing IgG4-positive HT and the management of this condition.

Case presentation

A woman in her 50s was referred by her general practitioner to the ear, nose and throat department via the suspected cancer referral pathway. She presented with a 2-week history of a painless lump in her anterior neck. She denied any heat or cold intolerance, palpitations or tremors. She also denied any aerodigestive symptoms including dysphagia, dysphonia or dyspnoea.

She had a previous medical history of hypothyroidism, for which she was on levothyroxine. Her recent TSH was normal at 1.54 mIU/L. She also had a past surgical history of a thyroglossal cyst, which had been excised 30 years ago. She smoked five cigarettes a day and her alcohol intake was 14 units per week. There was a positive family history of hypothyroidism.

Investigations

The patient initially had an urgent ultrasound scan of the neck, which showed a grossly abnormal appearing thyroid gland (figure 1). The thyroid gland was enlarged, hypoechoic and nodular, more so on the right side than the left. There was no associated lymphadenopathy. These features were reported to be suspicious for malignancy and the patient, therefore, underwent fine-needle aspiration (FNA) for cytology from the right thyroid lobe. This revealed thyroid follicular cells, lymphocytes with thin colloid and prominent Hurthle cells in a microfollicular architecture. The cytology was suggestive of lymphocytic thyroiditis. This was classified as ‘Thy3f’ (British Thyroid Association (BTA) guidelines for the management of thyroid cancer, 2014).⁵ However, a distinction between benign and malignant follicular neoplasm cannot be made on FNA cytology alone, necessitating a diagnostic hemithyroidectomy, as per the BTA guidelines.

Figure 1.

Ultrasound scan showing a grossly enlarged, hypoechoic and nodular thyroid gland, with changes more marked on the right than the left.

Differential diagnosis

The main differential diagnoses at this stage included thyroiditis and thyroid malignancy.

The most prevalent underlying cause of thyroiditis is Hashimoto’s disease, also known as chronic lymphocytic thyroiditis. It is an autoimmune inflammation of the thyroid, first described by Hashimoto in 1912, characterised by hypothyroidism, presence of anti-TPO or anti-TG antibodies in the serum, with or without a goitre. Histologically, HT demonstrates lymphoplasmacytic infiltration, follicular hyperplasia, parenchymal atrophy and the presence of Hurthle cells.⁶

Hurthle cells are thyroid epithelial cells with an eosinophilic, granular cytoplasm packed with mitochondria. Hurthle cells are not specific to any thyroid pathology and are found in both benign and malignant conditions of the thyroid.⁶ The presence of Hurthle cells in our patient’s cytology raised the possibility of Hurthle cell neoplasm.

Thyroid cancers are rare, accounting for less than 1% of all malignancies in the UK.⁵ Follicular cancer represents 10%–15% of all thyroid cancers.⁷ Follicular neoplasm includes follicular adenoma and follicular carcinoma, characterised by epithelial cells organised in a microfollicular architecture, with little to no colloid.⁸

Primary thyroid lymphoma is a much rarer thyroid malignancy, accounting for between 0.5% and 5% of thyroid cancers and with an incidence of two persons per million per year. Thyroid lymphoma is characterised by lymphoid infiltration of the gland.⁹ While the incidence of thyroid lymphoma in Hashimoto’s disease is low at around 0.6%, the relative risk of thyroid lymphoma is increased 67-times in patients with HT.

Treatment

The multidisciplinary team recommendation for ‘Thy3f’ was at least a diagnostic hemithyroidectomy. However, given the abnormal appearance of the whole of the thyroid gland, following a discussion with the patient, we agreed to undertake total thyroidectomy. Intraoperatively, the whole thyroid gland appeared abnormal, hard and nodular.

Outcome and follow-up

Following total thyroidectomy, the thyroid specimen was sent for histological evaluation. It weighed 30.8 g and its dimensions were 85×60×25 mm. The largest nodule in the right lobe measured 25×20×18 mm, in the context of multiple nodules throughout the thyroid.

The histological appearance was of HT, including lymphoid follicles, plasma cell infiltrates and sclerosing fibrosis (figures 2 and 3). Atrophic thyroid follicles and Hurthle cells were also seen. No histological changes suggestive of neoplasm were identified.

Figure 2.

Low power magnification image of thyroid histology with H&E staining. Thyroid histology showing replacement of normal follicular structure with diffuse lymphoplasmacytic infiltration arranged into nodules (purple, solid arrow) and interspersed fibrosis (pink, blank arrow).

Figure 3.

High power magnification image of thyroid histology with H&E staining. Areas of diffuse reactive lymphoid follicles and plasma cells (purple, solid arrow). Interspersed with areas of fibrosis (pink, blank arrow).

Thyroid samples are not routinely sent for immunostaining with IgG4. In this instance, owing to the degree of fibrosis seen on histology and the pathologist’s view that IgG4-related sclerosis can mimic features of malignancy, the thyroid sample was sent for IgG4 immunostaining. This proved positive, raising the possibility of IgG4-related sclerosing disease (figure 4). We report the first case of IgG4-positive HT in the UK.

Figure 4.

Intermediate magnification image of thyroid histology with IgG4 immunohistochemical staining. Light blue staining (blank arrow) represents IgG4-negative infiltrates (lymphoid and plasma cells). Dark blue/black staining (solid arrow) represents IgG4-positive plasma cells. Brownish areas likely to represent colour artefact.

The patient was discharged on the day following her operation without any complications. She remains on levothyroxine and has made a good postoperative recovery. A referral has been made to rheumatology for investigation into extra-thyroidal manifestation of IgG4-related sclerosing disease.

Discussion

The histological findings in the present case were in keeping with the diagnosis of HT. However, due to the extensive nature of the fibrosis seen and the clinical suspicion of malignancy, the sample was sent off for further immunostaining with IgG4. IgG4 immunostaining was positive, raising the possibility of an underlying IgG4-related sclerosing disease of the thyroid gland.

IgG4-related sclerosing disease was first described as an account of auto-immune pancreatitis.^{10 11} Since then, IgG4-related disease of various organs has been described, including gall bladder, salivary glands, kidney, retroperitoneum and prostate, characterised by a localised swelling of the involved gland, histological findings of predominantly IgG4-mediated lymphoplasmacytic infiltration and sclerosis and raised serum IgG4 levels. A sizeable proportion of patients with auto-immune pancreatitis was found to have hypothyroidism, prompting investigations into IgG4-related disease of the thyroid. A disease entity called ‘IgG4-RTD’ has emerged, encompassing a range of separate diseases with overlapping features.⁴ These include IgG4-positive HT, FVHT, Reidel’s thyroiditis and Graves’ disease with elevated IgG4 levels.

Li et al first reported a subclassification of HT based on the immunohistochemical finding of IgG4-positive plasma cells.^{12 13} In a case series of 70 patients, 27% of the patients had IgG4-positive HT (IgG4-positive plasma cells greater than 20/high power field and greater than 30% IgG4/IgG ratio). They found that IgG4-positive HT had distinct clinical, sonographic, biochemical and histological features, including raised serum IgG4 levels, and greater degree of lymphoplasmacytic proliferation and stromal fibrosis compared with non-IgG4 HT. Patients with IgG4-positive HT had faster disease progression and were more likely to present with compressive symptoms, requiring thyroidectomy.

Other studies, however, have not found any clinical differences between IgG4-positive and IgG4-negative HT. Zhang et al reported on 53 patients with HT, of which 23% were IgG4 positive. They did not find any significant differences in sex distribution, disease duration or serum IgG4 levels between IgG4-positive and negative HT patients.¹⁴ Similarly, Kojima et al, reporting on 33 patients, also did not find any significant clinical or histological differences between IgG4-positive and IgG4-negative HT.¹⁵ Of their 33 patients, 42% were IgG4 positive. Interestingly, other studies have shown that HT with elevated IgG4 levels may be separated from IgG4-positive HT and found it more likely to be associated with hypothyroidism,¹⁶ and for patients to require higher levels of thyroxine replacement.¹⁷

All of the above studies reported cases representative of a general population of HT requiring thyroidectomy. Zhang et al included patients who had HT with concurrent malignancy, whereas the other studies excluded patients with thyroid cancer. Jokisch et al reported on a case series of 216 patients, of which 13% had IgG4-positive HT.¹⁸ These patients were found to have a significantly greater degree of fibrosis compared with IgG4-negative HT. The authors, therefore, established a correlation between IgG4-positive Hashimoto’s disease and FVHT. FVHT is a subclassification of HT, first described in 1974 by Katz and Vickery.¹⁹ It is characterised by significant fibrous replacement of the thyroid parenchyma with changes related to HT in the remainder of the thyroid, without any extension of disease beyond the thyroid capsule. While it may present with a very firm, quickly progressive goitre, the clinical significance of diagnosing FVHT is not well described in the literature.

Deshpande et al have also reported on a correlation between histological features of IgG4-RSD and FVHT, including a similarity of the morphology of fibrosis seen in both.²⁰ They reported both higher levels of IgG4-positive plasma cells and higher IgG4 to IgG ratio in FVHT. Zhang et al had also previously reported a greater degree of fibrosis seen in IgG4-positive HT compared with IgG4-negative HT, without commenting on any correlation between IgG4-positive HT and FVHT.¹⁴ Raess et al, on the other hand, did not find any correlation between the degree of IgG4-positive plasma cell infiltration and fibrosis of the thyroid gland, in a case series of 38 patients.²¹

Another fibrotic process of the thyroid is Reidel’s thyroiditis, characterised by an inflammatory process extending to surrounding structures. Histologically, it is defined by the presence of a lymphoplasmacytic and eosinophilic infiltrate, often involving the venous structures causing a thrombophlebitis. Evidence on the link between Reidel’s thyroiditis and IgG4-related thyroid disease is sparse, being based on small case series, and does not demonstrate a clear link between the two.^{22 23}

Some recent studies have also elucidated a subset of patients with Graves’ disease and Graves’ ophthalmopathy with possible underlying IgG4-related disease.²⁴ Several studies have shown a subset of Graves’ disease and Graves’ ophthalmopathy patients to have elevated serum IgG4 levels and IgG4/IgG ratio. However, there is no clear evidence around the histopathological correlation or the clinical implications of Graves’ disease with elevated IgG4 levels. One study, evaluating 185 patients with Graves’ ophthalmopathy, found that 34.6% of these patients had IgG4-positive disease based on histology. IgG4-positive patients had higher serum IgG4 levels, IgG4/IgG ratio and higher degree of lymphocytic infiltration on histology, but did not have higher degree of fibrosis.²⁵

Various thyroid disease entities, including HT, FVHT, Reidel’s thyroiditis and Graves’ disease, seem to have a subset of patients with elevated IgG4 levels (serum IgG4, histologically IgG4 +cells or both). However, the clinical significance of this remains unclear based on the available evidence thus far. Further continuing research into the histological features of IgG4-mediated thyroid disease, its clinical correlations and its implications for treatment of these conditions is required.

Learning points.

• Hashimoto’s thyroiditis may be categorised based on IgG4-immunostaining, into IgG4-positive and IgG4-negative Hashimoto’s disease although the clinical significance of this categorisation is unclear.

• IgG4-positive Hashimoto’s thyroiditis, Fibrosing Variant of Hashimoto’s thyroiditis, Reidel’s thyroiditis and Graves’ disease with elevated IgG4 levels, collectively termed IgG4-related thyroid disease (IgG4-RTD), have all been associated with a multisystemic fibrotic condition called IgG4-related sclerosing disease (IgG4-RSD).

• Further research is required to clarify the links between IgG4-RSD and IgG4-RTD, and its implications on the diagnosis and management of these conditions

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