Thyroid 

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2022, Case 12, and is IgG4-related thyroiditis. The information provided in this case was accurate and correct at the time of publication in 2022. Any changes in terminology since the time of publication may not be reflected in this case.  

Microscopically, there is extensive fibrosis, marked lymphoplasmacytic inflammation, and lobules of atrophic thyroid follicles with focal oncocytic metaplasia. The fibrosis is keloid-like, with irregular broad bands coursing through residual thyroid parenchyma. Cytologic atypia, including nuclear features of papillary thyroid carcinoma, are absent. These morphologic features in addition to the increased number of IgG4-positive plasma cells by immunohistochemistry, elevated ratio of IgG4 to IgG-secreting plasma cells, and clinical evidence of elevated serum IgG4 support the diagnosis of IgG4-related thyroiditis.  

IgG4-related thyroiditis is a recently recognized subtype of thyroiditis. It is an evolving classification that is believed to encompass a spectrum of diseases varying from early IgG4-related Hashimoto thyroiditis (HT) pattern to late fibrosing HT or Riedel thyroiditis patterns. IgG4-related HT usually affects a younger age group compared to classic HT, with a lower female: male ratio. The disease has a more rapid course, and patients often present with a large goiter, subclinical hypothyroidism, diffuse low echogenicity on ultrasound, and very high titers of antithyroid peroxidase (TPO) antibodies. Fine-needle aspiration is often low yield because of marked fibrosis.  

Macroscopically, in IgG4-related HT, the thyroid is markedly enlarged without a dominant mass, and the cut surface is tan-yellow and firm, with a nonadherent and easily separated capsule. Histologically, thick collagen bands often with dense storiform-type fibrosis separate lobules of atrophic thyroid follicles. Other changes seen in the classic type of HT, including follicular atrophy, oncocytic metaplasia, and marked lymphoplasmacytic infiltration, are present. Squamous metaplasia may also be seen. Unlike IgG4-related disease in other organs, obliterative phlebitis or intense eosinophilia are not common features. Diagnostic criteria for IgG4-related disease and an IgG4 cut-off value in the thyroid have not yet been established, but increased numbers of IgG4-positive plasma cells by immunohistochemistry and an IgG4:IgG-secreting plasma cell ratio of more than 40% have been suggested by some experts as features of the IgG4-related HT, although lower ratios have also been proposed.  

Riedel thyroiditis (RT) is also part of the IgG4-related disease spectrum and is associated with systemic fibrosclerosing diseases such as retroperitoneal fibrosis and sclerosing mediastinitis. It mainly occurs in women aged 30 to 60 years. Patients present with painless goiter, which progresses to produce symptoms of pressure and compression of surrounding structures. Histologically, there is dense, sclerotic, keloid-like fibrous tissue extending to the adjacent extrathyroidal soft tissue and parathyroid glands and a marked inflammatory infiltrate. Distinction between the IgG4-related HT and RT can be difficult. RT shows more prominent obliteration of follicles, and unlike HT, the fibrosis extends to adjacent structures, such as skeletal muscle and adipose tissue. In addition, the presence of oncocytic cells suggests HT, but these cells are typically absent in RT. Also, Riedel patients do not have high serum antibody titers.  

About 10% of HT cases fall into the category of the fibrous (sometimes called sclerosing) variant, which was first described in 1974 and is characterized by fibrous replacement of more than one-third of the thyroid parenchyma but with preservation of lobulated architecture and changes typical of HT in the remaining tissue. As compared to the classic HT, the fibrous variant is more common in men than in women, and unlike IgG4-related HT, it mostly occurs in older patients. There is some controversy over whether some of these cases are part of the spectrum of IgG4-related disease. Immunostaining for IgG and IgG4 and correlation with clinicopathologic and laboratory findings may allow for determining whether any given case might be classified as IgG4-related thyroiditis.  

Primary thyroid classic Hodgkin lymphoma, nodular sclerosis subtype is rare and has a female predominance. Patients often present with a rapidly enlarging, firm thyroid mass causing compression or infiltration of the surrounding neck organs. A subset of patients have a prior history of HT. Imaging studies reveal a diffusely enlarged thyroid, mimicking thyroiditis. Histologically, there is prominent fibrosis admixed with cellular areas that contain a mixed population of lymphocytes, histiocytes, plasma cells, eosinophils, and large atypical mononuclear and multinucleated cells, consistent with Reed–Sternberg (RS) cells and variants. By immunohistochemistry, the RS cells are CD30-positive, confirming the diagnosis of classic Hodgkin lymphoma.

Graves disease is an autoimmune process characterized by hyperthyroidism due to circulating autoantibodies against the TSH receptor. Grossly, the gland is diffusely enlarged with a beefy-red cut surface. Histologically, the follicles are hyperplastic with papillary infoldings and scant colloid. These features may not be seen in medically treated patients. There is also a variable patchy lymphoid infiltrate in the stroma. However, unlike IgG4-related thyroiditis, there is minimal fibrosis. A small subset of patients with Graves disease are found to have elevated serum IgG4 levels and elevated ratios of IgG4:IgG; but the histologic changes in this subset are not fully defined.

Papillary thyroid carcinoma (PTC), diffuse sclerosing subtype mostly occurs in younger patients, accounting for approximately 10% of PTC  seen in children exposed to the radioactive iodine following the Chernobyl accident. It is often associated with lymphocytic or autoimmune thyroiditis, and antimitochondrial and antithyroid antibodies may be present. Radiologically, a “snowstorm appearance” is common due to excessive calcifications within the tumor. The thyroid undergoes rapid and diffuse enlargement of one or both lobes, showing prominent stromal fibrosis, dense lymphoplasmacytic infiltrates, numerous psammoma bodies, and squamous metaplasia. The neoplastic cells, which are not a feature of IgG4-related HT, are arranged in solid, papillary, or follicular patterns and have characteristic papillary carcinoma cytomorphologic features, including enlarged cells with irregular contours and nuclear clearing, membrane irregularity, grooves, and pseudoinclusions. This variant is more aggressive than classical PTC and is commonly associated with local recurrence and lymph node and distant metastasis, mainly to lungs. RET gene rearrangements are seen in 30% of cases.  

1. Which of the following is true regarding IgG4-related Hashimoto thyroiditis?  
    
   1. Fibrosis often extends beyond the thyroid capsule and into the surrounding structures.
   2. Foci of oncocytic metaplasia are commonly found.
   3. Obliterative phlebitis is commonly observed.  
   4. Patients present with a slow-growing mass in one lobe.
   5. Thyroid follicles show papillary infoldings with frequent nuclear pseudoinclusions.
2. Which of the following is correct regarding papillary thyroid carcinoma, diffuse sclerosing subtype?
    
   1. Indolent behavior
   2. Lack of psammoma bodies  
   3. Mostly in older patients  
   4. Prominent lymphoplasmacytic infiltrate
   5. Rare lymph node metastasis  
3. Which of the following is a feature of IgG4-related Hashimoto thyroiditis?
    
   1. Beefy-red cut surface on gross examination
   2. Cellular fine needle aspirate
   3. Circulating antibody against TSH receptor
   4. Enlarged thyroid gland
   5. Large atypical mononuclear and multinucleated CD30 positive cells 

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1. Foci of oncocytic metaplasia are commonly found. (b)
2. Prominent lymphoplasmacytic infiltrate (d)
3. Enlarged thyroid gland  (d)