Riedel thyroiditis, or Riedel's thyroiditis (RT), is a rare, chronic inflammatory disease of the thyroid gland characterized by a dense fibrosis that replaces normal thyroid parenchyma. The fibrotic process invades adjacent structures of the neck and extends beyond the thyroid capsule. This feature differentiates RT from other inflammatory or fibrotic disorders of the thyroid. Extension beyond the thyroid also differentiates this from the fibosing variant of Hashimoto thyroiditis. Gross pathology is shown in the image below. (See Etiology and Workup.)
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Gross pathology of Riedel thyroiditis. The cut edge is avascular, with a characteristic white color. Image courtesy of SL Lee.
Involvement in RT may be unilateral or bilobar. Thyroid function depends on the extent to which the normal thyroid gland has been replaced by fibrotic tissue. Most patients are euthyroid, but hypothyroidism is noted in approximately 30% of cases. Rarely, hyperthyroidism can occur, but this is probably secondary to a coexisting condition. (See Prognosis, Presentation, and Workup.)
Some experts have traditionally believed that RT is not primarily a thyroid disease but rather that it is a manifestation of the systemic disorder multifocal fibrosclerosis. Approximately one third of RT cases are associated with clinical findings of multifocal fibrosclerosis at the time of diagnosis. (See Etiology.)
In 1883, Professor Bernhard Riedel first recognized the disease. He published a description of 2 cases in 1896 and of a third case in 1897.[1] Riedel used the term eisenharte struma to describe the stone-hard consistency of the thyroid gland and its fixation to adjacent structures. He noted the presence of chronic inflammation with fibrosis and the absence of malignancy on microscopic examination. Simple wedge resection of the thyroid isthmus was used to alleviate tracheal obstruction and is still the preferred surgical therapy for RT.
Complications
Because of the encroachment beyond the thyroid capsule, nonthyroid problems can be associated with RT. Complications of Riedel thyroiditis can include the following:
Airway obstruction
Dysphonia
Hoarseness - Due to recurrent laryngeal involvement
The etiology of Riedel thyroiditis (RT) is unknown, but it may be related to a relatively new group of rare disorders, IgG4-related systemic disease (IgG4-RSD).[2] One theory of pathogenesis postulates that RT results from an autoimmune process. A second theory holds RT to be a primary fibrotic disorder. However, IgG4-RSD may unify these 2 seemingly disparate etiologies.
Autoimmune theory
The following evidence supports an autoimmune pathogenesis for RT:
The presence of antithyroid antibodies in a significant percentage of patients with RT (67% of 178 cases reviewed in one study)[3]
The pathologic features of cellular infiltration, including lymphocytes, plasma cells, and histiocytes
The frequent presence of focal vasculitis on pathologic examination
The favorable response of a subset of patients with RT to treatment with systemic corticosteroids
However, the presence of normal lymphocyte subpopulations and normal serum complement levels weighs against an autoimmune mechanism. Elevated levels of antithyroid antibodies may merely reflect the immune system's exposure to sequestered antigens released by the destruction of thyroid parenchyma from a primary fibrotic disorder.
Primary fibrotic disorder theory
The theory that RT is a primary fibrotic disorder is supported by its association with multifocal fibrosclerosis. This uncommon idiopathic syndrome is characterized by fibrosis involving multiple organ systems. The extracervical manifestations of multifocal fibrosclerosis can include retroperitoneal fibrosis, mediastinal fibrosis, orbital pseudotumor, pulmonary fibrosis, sclerosing cholangitis, lacrimal gland fibrosis, and fibrous parotitis. RT may be but 1 manifestation of this multifocal disease.
The histopathologic changes of RT closely resemble those observed in multifocal fibrosclerosis. Additionally, one third of published RT cases have demonstrated at least 1 manifestation of extracervical fibrosclerosis. The ability of systemic corticosteroids and tamoxifen to inhibit fibrogenesis accounts for the favorable effect of such treatment in both conditions.[4]
IgG4-RSD disorder
IgG4-RSD is a relatively new group of disorders that share similar presentations. These disorders have in common a preponderance of excess IgG4. The disorders are characterized by lymphoplasmacytic infiltrates containing IgG4-positive plasma cells.[5] These infiltrates ultimately lead to fibrosis and elevated serum levels of IgG4.[6, 7]
Riedel thyroiditis (RT) is a very rare condition. At the Mayo Clinic, 37 cases of RT were diagnosed in a series of 57,000 thyroidectomies performed between 1920 and 1984, for an incidence of 0.06%. The overall incidence among outpatients was 1.6 cases per 100,000 population. Based on large databases in referral centers, it appears that over the previous decades, the incidence of RT has been decreasing.
Race-, sex-, and age-related demographics
Although predominantly reported in whites, RT has been described in all races. RT is most often seen in women; in a review of 178 patients with RT, 83% were female. In the same study, the mean age at diagnosis of RT was 47.8 years (range, 23-77 y).[3]
Riedel thyroiditis (RT) is generally a self-limited disease with a favorable prognosis. Death due to airway compromise is very rare in treated patients. Occasionally, spontaneous remission has been reported. Patients can also relapse.
In RT, morbidity is most frequently related to local compressive symptoms, such as dysphagia, dyspnea, hoarseness, and cough. Hypothyroidism is present in 30% of cases. Fibrotic invasion of adjacent anatomic structures may infrequently result in symptoms related to recurrent laryngeal nerve paralysis or hypoparathyroidism.
One third of patients with RT ultimately develop at least 1 extracervical manifestation of multifocal fibrosclerosis (such as retroperitoneal fibrosis, mediastinal fibrosis, or sclerosing cholangitis).[8] In such patients, the prognosis essentially becomes that of extracervical fibrosclerosis. Therefore, when RT is diagnosed, it is essential to perform abdominal and chest imaging studies to exclude concomitant, extracervical entities from multifocal fibrosclerosis. Fibrosclerosis of the surrounding tissue by RT can lead to serious morbidity and death.
A retrospective institutional review of a rare form of invasive thyroiditis from the Mayo Clinic discussed the common presenting symptoms and extrathyroidal involvement of the systemic fibrosclerosis. Treatments used in the 21 reported patients included partial thyroidectomy, tamoxifen, and corticosteroid therapy. Other, less well validated studies include mycophenolate mofetil[9] and rituximab.[10] Of note, no cause-specific mortality was noted, and the fibrotic process stabilized or partially resolved in all patients.[4]
Riedel thyroiditis (RT) is characterized by the replacement of normal thyroid parenchyma with dense fibrotic tissue and by the extension of this fibrosis to adjacent structures of the neck. Most patients are euthyroid, but hypothyroidism is noted in approximately 30% of cases. Rarely, hyperthyroidism can occur, but this is probably secondary to a coexisting condition.
Clinical features of RT closely resemble those of anaplastic carcinoma of the thyroid. Patients note a nonpainful, rapidly growing thyroid mass.
Patients typically present with a hard, fixed, painless goiter. The character of the thyroid gland is often described as stony or woody. The onset of the goiter may be sudden, but it is usually gradual.
Local compressive symptoms are frequent and can include the following:
Neck tightness or pressure
Dyspnea
Dysphagia
Hoarseness
Choking
Cough
Such symptoms are the result of the increasing thyroid mass or are due to the extension of the fibrotic process to adjacent neck structures (eg, strap muscles, trachea, esophagus, recurrent laryngeal nerve).
Hypoparathyroidism is rare and presumably reflects fibrotic involvement of the parathyroid glands. Recurrent laryngeal nerve paralysis is also uncommon, but it can be observed in extensive disease.[11]
Approximately one third of patients with RT have an associated extracervical manifestation of multifocal fibrosclerosis. These manifestations can include the following[8] :
One distinguishing feature of Riedel thyroiditis (RT) is the absence of associated cervical adenopathy. However, accurate diagnosis of RT requires open biopsy.[12]
Imaging studies may suggest a diagnosis of RT, but findings can be nonspecific. The laboratory findings in RT are also nonspecific. The erythrocyte sedimentation rate (ESR) is generally elevated. Most patients remain euthyroid, but approximately 30% of patients become hypothyroid. Rarely, patients are hyperthyroid.[3]
Although clinical features of RT closely resemble those of anaplastic carcinoma of the thyroid, RT and anaplastic carcinoma can be distinguished from each other by immunohistochemistry.
In one review, antithyroid antibody levels (TG-Ab and TPO-Ab) were found to be elevated in 67% of 178 cases of Riedel thyroiditis.[3] However, it is not certain whether such autoantibodies are pathogenic or whether their presence merely reflects exposure of the immune system to sequestered antigens released by the fibrotic destruction of normal thyroid parenchyma.[13]
IgG4 levels can be measured in the serum and are elevated in over 95% of cases. The levels can be as high as 25 times the upper limit of normal.[14, 15] However, levels can occasionally be normal, and evaluating IgG4/IgG ratios or immunohistochemical examinations can be helpful. As noted previously, the disorder is characterized by lymphoplasmacytic infiltrates containing IgG4-positive plasma cells.
Enlargement of the affected thyroid gland and compression or invasion of adjacent structures, such as the strap muscles, trachea, esophagus, or carotids, may be observed on computed tomography (CT) or magnetic resonance imaging (MRI) scans. However, these studies cannot reliably distinguish between Riedel thyroiditis (RT) and invasive thyroid malignancy.
CT scanning shows affected areas of the thyroid to be hypodense. The area is usually isodense with the neck muscles. The use of iodinated contrast has occasionally been reported as causing increased enhancement, but usually it is decreased, especially if extensive fibrosis is present.
On MRI scans, the affected thyroid gland is typically hypointense on T1- and T2-weighted images. Decreased enhancement has usually been reported with gadolinium contrast use, but occasionally, increased enhancement has been reported.
Nuclear scanning
Nuclear thyroid scans generally demonstrate a cold area of uptake at the site of the affected thyroid gland.
Ultrasonography
Thyroid ultrasonography has been reported to be homogeneously hypoechoic, with loss of clear demarcation of the gland when fibrotic invasion of adjacent anatomic structures exists.
PET scanning
The role of positron emission tomography (PET) scanning in the diagnosis of RT, although promising, has not yet been established. Fluorodeoxyglucose (FDG) labeled with the radioactive tracer isotope fluorine-18 (18 F) is concentrated in areas of increased glucose metabolism. In RT, such increased glucose metabolism results from stimulated inflammatory cells.
Drieskens and colleagues,[16] as well as Kotilainen and coauthors,[17] showed in a patient with RT an increased uptake of FDG in the involved thyroid and a decrease in activity in response to successful corticosteroid therapy.
Additionally, whole-body FDG-PET can be used to identify other sites involved by multifocal sclerosis, such as retroperitoneal fibrosis. However, increased uptake of FDG on PET is not specific to RT.
Fine-needle biopsy in patients with Riedel thyroiditis (RT) demonstrates fibrotic changes in the thyroid gland; however, these cannot be reliably distinguished from the fibrotic changes that are often associated with anaplastic thyroid carcinoma. The fibrotic changes and the paucity of thyroid follicular cells usually result in an inadequate fine-needle aspiration biopsy.
For this reason, histologic confirmation via an open surgical biopsy is essential for establishing the correct diagnosis. The biopsy is most often performed in the course of a wedge resection of the thyroid isthmus designed to simultaneously alleviate compressive symptoms.
The involved portion of the thyroid gland in patients with Riedel thyroiditis (RT) is typically described as stony or woody. Involvement is most often unilateral but may also be bilateral. The thyroid mass is generally well circumscribed but not encapsulated.
Extension of the fibrotic process to adjacent structures of the neck results in fixation of the thyroid mass and loss of tissue planes. Fibrosis may invade the strap muscles, trachea, esophagus, carotids, parathyroid glands, and laryngeal nerves. When incised, the involved tissue is relatively avascular, "cuts like cartilage," and is often white or pale gray. RT cannot be distinguished from anaplastic carcinoma based on gross pathologic findings.
In 1957, Beahrs and colleagues established the microscopic criteria for the diagnosis of RT. These criteria, since modified, include the following[18] :
A fibroinflammatory process that involves all or a portion of the thyroid gland
The presence of gross or microscopic extension of the fibrosis beyond the thyroid capsule into adjacent anatomic structures
Infiltrates of inflammatory cells without giant cells, lymphoid follicles, oncocytes, or granulomas
Evidence of occlusive vasculitis
Absence of neoplasm
Collagen-laden fibrous bands infiltrate the involved portion of the thyroid gland. Ultimately, the thyroid acini are reduced or obliterated. A cellular infiltrate of lymphocytes, plasma cells, and eosinophils accompanies the fibrosis. Inflammatory cells within the walls of small arteries and veins may produce a local vasculitis. Invasion of the fibroinflammatory process beyond the thyroid capsule erases normal anatomic planes. (See the images below.)
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Riedel thyroiditis. The atrophic thyroid follicles are surrounded by a dense, inflammatory infiltrate composed of lymphocytes, plasma cells, and eosin....
View Image
Riedel thyroiditis. This vein shows infiltration of its wall by a heavy, inflammatory infiltrate.
View Image
Riedel thyroiditis. The inflammatory infiltrate and dense, pink bands of fibrosis can obliterate thyroid follicles. Image courtesy of SL Lee.
The rarity of Riedel thyroiditis (RT) makes controlled studies of RT therapy impractical. Recommendations for medical treatment have been largely based on empirical experience. Pharmacologic therapy includes the use of corticosteroids and tamoxifen. For patients resistant to these therapies, there are less well validated studies, which have included mycophenolate mofetil[9] and rituximab.[10] Levothyroxine can be used to treat the approximately 30% of patients who develop hypothyroidism. Calcitriol can be used for the rare complication of Hypoparathyroidism.
Surgery for patients with RT serves the dual purpose of establishing the diagnosis and relieving tracheal compression. A wedge resection of the thyroid isthmus remains the preferred method for accomplishing these ends. Surgery is indicated when tissue is needed for diagnosis, medical treatment shows no benefit, or compressive symptoms are very severe.[19]
The patient with RT should be followed for progression of the disease and for the development of multifocal fibrosclerosis. Repeat imaging of the neck by CT scanning or MRI should be performed at intervals defined by the rate of progression.
The patient's thyroid-stimulating hormone (TSH) level should be routinely checked and maintained in the reference range, with levothyroxine administered as necessary.[20]
Currently, corticosteroid therapy is the medical treatment of choice for patients with Riedel thyroiditis (RT).[21] Corticosteroids are believed to act by reducing inflammation and by inhibiting the actions of fibrinogenic cytokines. Most studies note a reduction in goiter size and the relief of local compressive symptoms, although some patients show no benefit.
Some investigators believe that a favorable response is more likely early in the course of the disease. Improvement is less likely to occur in patients with advanced RT when the affected portions of the thyroid gland have been completely replaced by fibrotic tissue.
No consensus has been reached on the corticosteroid dosing regimen. However, all studies advocate an initially high dose to alleviate compressive symptoms, followed by gradual tapering over months to a lower, maintenance dose.
The effectiveness of therapy can be judged by symptomatic improvement and by following the reduction of the ESR and the thyroid autoantibody levels. Many patients can be weaned from therapy, but others require more prolonged treatment.
Tamoxifen has been used in patients with Riedel thyroiditis (RT) as a first-line therapy, but it has also been employed after the failure of corticosteroid treatment. The usual dose that has been found to be effective is 20mg taken orally twice daily.[12] Patients who respond can be tapered to 20mg once each day or to 10mg twice daily. Because of the relatively infrequent occurrence of RT, comparison studies with tamoxifen and steroid therapy have not been undertaken.
Few and colleagues advocated tamoxifen use in a study of 4 patients with progressive RT who were not responsive to corticosteroids or surgical decompression.[22] Each patient had a decrease of 50% or more in the size of the thyroid mass, with 1 patient having total resolution. Since then, additional reports have described successful treatment of RT with tamoxifen.[23, 24, 25]
An oral dose of 20mg twice daily provided each patient with symptomatic improvement, as well as a reduction in the size of the involved tissue as measured on CT scan.
Estrogen receptors have not been demonstrated in RT tissue. Therefore, the mechanism of action was not proposed to be tamoxifen's antiestrogen activity but rather its induction of transforming growth factor beta, a potent inhibitor of fibroblast proliferation.[22]
Mycophenolate (Cell-Cept) is an immunosuppressive therapy often used to prevent rejection after transplantation and/or in graft versus host disease. It has been used in disorders characterized by systemic fibrosis. In one study, significant improvement was noted after 90 days when used in combination with prednisone.[26]
Rituximab has been used to facilitate B-cell destruction, and has been used as part of therapy for other patients with IgG4-RSD. In one study, the patient recieved IV rituximab 1000 mg (375 mg/m2) monthly for 3 months while on tamoxifen therapy.[10]
Use levothyroxine therapy to correct hypothyroidism associated with Riedel thyroiditis (RT).[20] Many authorities advocate not only thyroid replacement but also suppression of TSH in all patients with RT, regardless of thyroid function. However, the degree to which TSH stimulates the fibroinflammatory processes of RT, if at all, is unknown. Consequently, recommendations for TSH suppression must be regarded as empirical.
Open surgical biopsy is essential for definitively establishing a diagnosis of Riedel thyroiditis (RT) and for excluding carcinoma.
A wedge resection of the isthmus relieves tracheal compression. Grossly, the affected tissue is stony and hard and is white or pale gray. It has a similar feel to cartilage when incised.
More extensive thyroid surgery is generally discouraged because extrathyroid fibrosclerosis alters the anatomy and obliterates surgical planes. The trachea, esophagus, carotids, recurrent laryngeal nerves, or parathyroid glands may be encased by fibrotic tissue and are at increased risk for iatrogenic surgical damage.[4]
As previously stated, corticosteroid therapy is the medical treatment of choice for patients with Riedel thyroiditis (RT).[21] These drugs have been found in most studies to reduce goiter size and relieve local compressive symptoms, although apparently not all patients benefit from treatment.
Tamoxifen can be used as a first-line therapy in patients with RT, or it can be employed as an alternative treatment if corticosteroid treatment fails. Levothyroxine is used to correct RT-associated hypothyroidism.[20]
Clinical Context:
Prednisone is an immunosuppressant for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. The drug stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
Clinical Context:
Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is a commonly used oral agent.
Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.
Clinical Context:
The proposed mechanism of action for tamoxifen is not antiestrogen activity but rather the induction of transforming growth factor beta (a potent inhibitor of fibroblast proliferation).
Clinical Context:
The proposed mechanism of action is inhibition of both T- and B- cell lymphoctye proliferation. It may also directly inhibit fibrosis, at least in animal models.[25]
Tamoxifen is used to treat progressive Riedel thyroiditis (RT) that is not responsive to corticosteroids or surgical decompression, or is administered to patients with contraindications to corticosteroid therapy. It provides symptomatic improvement, as well as size reduction of the involved tissue as measured on CT scans.
Mycophenolate is an immunosuppressive therapy often used to prevent rejection after transplantation and/or in graft versus host disease. It has been used in disorders characterized by systemic fibrosis. In one study, significant improvement was noted after 90 days when used in combination with prednisone.[26]
Clinical Context:
Levothyroxine rapidly inhibits the release of thyroid hormones via a direct effect on the thyroid gland; it also inhibits the synthesis of thyroid hormones. Iodide also appears to attenuate cyclic adenosine monophosphate (cAMP) ̶ mediated effects of TSH. In active form, levothyroxine influences the growth and maturation of tissues. It is involved in normal growth, metabolism, and development.
Chris K Guerin, MD, FACE, Director, Diabetes Education Services, Chief, Division of Endocrinology, Tri-City Medical Center; Assistant Clinical Professor of Medicine, University of California, San Diego, School of Medicine
Disclosure: Nothing to disclose.
Chief Editor
George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
John Boone, MD, Consulting Staff, Department of Otolaryngology, Naval Hospital Oak Harbor
Disclosure: Nothing to disclose.
Acknowledgements
Stephanie L Lee, MD, PhD Associate Professor, Department of Medicine, Boston University School of Medicine; Director of Thyroid Health Center, Associate Chief, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center; Fellow, Association of Clinical Endocrinology
Stephanie L Lee, MD, PhD is a member of the following medical societies: American College of Endocrinology, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Kent Wehmeier, MD Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Kent Wehmeier, MD is a member of the following medical societies: American Society of Hypertension, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.
References
Riedel BM. Die chronische, zur Bildung eisenharter Tumoren fuhrende Entzundung der Schilddruse. Verh Dtsch Ges Chir. 1896. 25:101-5.
Kotilainen P, Airas L, Kojo T, et al. Positron emission tomography as an aid in the diagnosis and follow-up of Riedel's thyroiditis. Eur J Intern Med. 2004. 15:186-9.
Jung YJ, Schaub CR, Rhoades R, et al. A case of Riedel's thyroiditis treated with tamoxifen: another successful outcome. Endocr Pract. 2004. 10(6):483-6.
Gross pathology of Riedel thyroiditis. The cut edge is avascular, with a characteristic white color. Image courtesy of SL Lee.
Riedel thyroiditis. The atrophic thyroid follicles are surrounded by a dense, inflammatory infiltrate composed of lymphocytes, plasma cells, and eosinophils and accompanied by dense fibrosis. The wide bands of keloid-type collagen located between the individual follicles and surrounding clusters are a common feature of this condition.
Riedel thyroiditis. This vein shows infiltration of its wall by a heavy, inflammatory infiltrate.
Riedel thyroiditis. The inflammatory infiltrate and dense, pink bands of fibrosis can obliterate thyroid follicles. Image courtesy of SL Lee.
Gross pathology of Riedel thyroiditis. The cut edge is avascular, with a characteristic white color. Image courtesy of SL Lee.
Riedel thyroiditis. The atrophic thyroid follicles are surrounded by a dense, inflammatory infiltrate composed of lymphocytes, plasma cells, and eosinophils and accompanied by dense fibrosis. The wide bands of keloid-type collagen located between the individual follicles and surrounding clusters are a common feature of this condition.
Riedel thyroiditis. This vein shows infiltration of its wall by a heavy, inflammatory infiltrate.
Riedel thyroiditis. The inflammatory infiltrate and dense, pink bands of fibrosis can obliterate thyroid follicles. Image courtesy of SL Lee.
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