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CLINICAL CASE SEMINAR |
Division of Endocrinology and Metabolism, University of Illinois (T.Y., A.d.B.), Chicago, Illinois 60612; Section of Endocrinology, Advocate Christ Medical Center (S.G.P., A.d.B.), Oak Lawn, Illinois 60453; Departments of Clinical Pathology (W.A.R.) and Surgery (S.K., E.L.K.), University of Chicago, Pritzker School of Medicine, Chicago, Illinois 60637; and Little Company of Mary Affiliated Physicians (F.A.G.), Evergreen Park, Illinois 60805
Address all correspondence and requests for reprints to: Andree de Bustros, M.D., M.P.H., University of Illinois, Advocate Christ Medical Center, 4440 West 95th Street, Oak Lawn, Illinois 60453. E-mail: . andree.debustros{at}advocatehealth.com
Abstract
A 42-yr-old woman presented with hyperthyroidism and a large, firm, irregular goiter. Within a few weeks she became hypothyroid. Five months later she developed increasingly severe neck pain and compressive symptoms. The goiter had become rock hard. A fine needle aspiration biopsy showed features of chronic thyroiditis and fibrosis. She partially responded to a course of glucocorticoids. Tamoxifen was added, with marked improvement in goiter size and pain. Both medications were tapered off. Two months later the patient experienced paresthesias of the fingertips, perioral numbness, and a seizure. She was found to have spontaneous primary hypoparathyroidism. Three months later the patient became hoarse and experienced difficulty in breathing. She was found to have a massively enlarged thyroid with compression of the right internal jugular vein and encasement of the right carotid artery as well as tracheal narrowing. She also had right vocal cord paralysis due to recurrent laryngeal nerve involvement. Because of airway compromise, an emergency isthmusectomy was performed, and the patient was given a postoperative course of glucocorticoids with gradual improvement. Postoperative diagnosis was Riedel’s thyroiditis. Two months later she presented with near-syncope and was found to have bradycardia, hypotension, and right Horner’s syndrome, presumably due to compression of the right carotid sheath. She was given iv glucocorticoids and tamoxifen. Six months later and 18 months after her initial presentation, the patient is doing remarkably well. Her goiter has regressed by more than 50%, and she no longer has any pain or difficulty breathing. She remains a little hoarse and has persistent hypothyroidism and hypoparathyroidism. She is taking prednisone (5 mg, this is being tapered very slowly) and tamoxifen (20 mg) daily. This case illustrates the protean manifestations of Riedel’s thyroiditis, a rare but fascinating disease. The epidemiology of this disease, its pathophysiology and complications, and the roles of surgery and medical therapy are reviewed.
RIEDEL’S STRUMA, also known as invasive fibrous thyroiditis, is a rare disorder of unknown etiology in which fibrous tissue replaces the normal thyroid gland and extends into adjacent tissues. This disease was first recognized in 1896 by Bernhard Riedel, who described two patients with tracheal compromise secondary to a hard fibrotic thyroid gland (1). He used the term eisenharte strumititis to characterize the peculiar consistency of the gland as stony hard in nature and noted the presence of chronic inflammation on microscopic examination (1). In recent decades the incidence of Riedel’s thyroiditis (RT) appears to be decreasing (2), making the diagnosis and management of patients with this disease at times challenging. RT presents with an enlarging hard neck mass, often with pain and compressive symptoms, and has the potential of being mistaken for a malignancy. The etiology of RT is unclear, and there is still controversy as to whether it is a primary autoimmune process, a variant of Hashimoto’s thyroiditis, or a primary fibrotic disease. Here we describe a patient with biopsy-proven RT who over the course of 18 months developed sequential hyperthyroidism, spontaneous primary hypoparathyroidism, acute compressive neck symptoms requiring emergency isthmusectomy, vocal cord paralysis, and a near-syncopal episode with bradycardia and Horner’s syndrome due to compression of the right carotid sheath.
Case Report
A 42-yr-old woman presented with an enlarging thyroid and neck discomfort. She complained of fatigue and palpitations, but no weight loss. She was a heavy smoker, and her father had hypothyroidism. On physical examination she looked anxious. Blood pressure was normal, and heart rate was elevated. She had a diffusely enlarged, slightly irregular, and very firm thyroid gland with an estimated weight of 60 g. Thyroid function tests revealed suppressed TSH at 0.01 mIU/liter (normal, 0.4–5.0) and a free T4 of 16.22 pmol/liter (normal, 6.43–20.59) or 1.26 ng/dl (normal, 0.5–1.6). 131I uptake was 4.4% after 24 h. The patient was not taking thyroid hormone and had not been exposed to pharmacological amounts of iodine in the time preceding the thyroid uptake test. A technetium 99m scan revealed an enlarged gland with an inhomogeneous appearance. Ultrasound did not show any distinct nodules. Methimazole was begun for a presumptive diagnosis of hyperthyroidism due to toxic multinodular goiter. Two months later, TSH was 38.7 mIU/liter and methimazole was stopped. Thyroid peroxidase antibodies were positive at 4150 x 103 IU/liter (normal, <20 x 103). The patient was started on levothyroxine, and the dose was subsequently adjusted accordingly to keep TSH at a low normal level.
Five months later the patient was complaining of excruciating pain and compressive symptoms on the right side of her neck. On physical examination her thyroid appeared to be larger and firmer, with an estimated weight of 80 g. TSH was normal with levothyroxine treatment (0.125 mg). Ibuprofen was begun, and because of lack of effectiveness, prednisone was started at 40 mg daily with some relief of symptoms. Fine needle aspiration biopsy with a 23-gauge needle was suggestive of RT or the fibrous variant of Hashimoto’s thyroiditis (Fig. 1
). Tamoxifen (10 mg twice daily) was begun. As the patient improved, prednisone was tapered off over a few weeks, and tamoxifen, which had been increased to 20 mg twice daily, was discontinued because of hot flashes.
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Three months later the patient acutely developed pain in the right lobe of her thyroid associated with progressive difficulty in breathing. Computerized tomography of the neck revealed a massively enlarged thyroid extending superior to the floor of the mouth with encasement and narrowing of the right common artery, right internal carotid artery, and right internal jugular vein (Fig. 2). The trachea was also encased, with compression of the subglottic area to a diameter of 6 mm in transverse dimension. Due to acute airway compromise, emergency isthmusectomy was performed. The thyroid gland was woody hard and fibrotic, with no visible normal thyroid tissue. Encasement of the right internal jugular vein and right common carotid artery was noted. Pathology revealed chronic inflammation with extensive fibrosis consistent with RT (Fig. 3). Postoperatively, prednisone (50 mg daily) was started with resulting improvement in neck pain and relief of obstructive symptoms. Prednisone was tapered off gradually. The patient was maintained on levothyroxine, calcitriol, and calcium supplements. Serum TSH, calcium, and phosphorus remained normal on this therapy.
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There was a dramatic response in symptoms. As her Horner’s syndrome resolved and hoarseness improved, the patient was switched to 40 mg prednisone daily, and tamoxifen was restarted at 10 mg twice a day. The improvement was gradual and sustained over a period of 6 months. Presently the patient continues to do extremely well, with a marked reduction in thyroid size, no compressive symptoms whatsoever, and a residual mild hoarseness. She continues on levothyroxine, calcium, and calcitriol supplements. Prednisone has been tapered to 5 mg daily, and 10 mg tamoxifen twice daily is well tolerated.
Discussion
RT is an extremely rare chronic fibro-inflammatory lesion of the thyroid characterized by dense and invasive fibrosis involving the gland and its surrounding tissue (3). It is the least common form of thyroiditis. Based on Mayo Clinic experience between 1920 and 1984, the operative incidence of RT is estimated to be 0.06% (4). Only 37 cases were found upon review of histology of 57,000 thyroidectomies (4). The overall incidence in out-patients was 1.06/100,000 (4). Women are 4 times more likely to be affected than men, and it most commonly occurs between 30–50 yr of age (5).
Patients classically present with a stony hard, painless, indolent thyroid mass that tends to extend to the surrounding tissues, making clinical distinction from malignancy very difficult. Compressive symptoms are common, including dyspnea, stridor, a feeling of suffocation, dysphagia, and hoarseness. The differential diagnosis of RT includes carcinoma, lymphoma, and Hashimoto’s thyroiditis, but the extent of the fibrosis in these disorders is much less, and these entities usually do not extend beyond the thyroid.
RT has no characteristic biochemical findings. The majority of patients are euthyroid, whereas a minority are hypothyroid (2). This is probably due to the extent of the nonfunctioning fibrous infiltration of the gland at the time of diagnosis. In the Cleveland Clinic series, 64% of the patients were found to be euthyroid, 32% hypothyroid, and 4% hyperthyroid (2). Two other large series have revealed prevalence rates of hypothyroidism of 25% and 29%, respectively (5, 6). Typically, hyperthyroidism is associated with absent radioactive iodine uptake. Our patient had a unique presentation; she had a low, but not completely absent, uptake, suggesting the presence of functioning thyroid tissue, a finding more consistent with "Hashitoxicosis" than RT.
Sedimentation rate may be normal or elevated. As seen with our patient, antithyroid antibodies are present in 40–70% of patients (2, 7). The criteria used to make a diagnosis of RT, as reported by Woolner et al. (5) and further modified by Schwaegerle et al. (2), are 1) gross description of a visible fibro-inflammatory process involving all or a portion of the thyroid gland, 2) gross and/or histological evidence of extension into adjacent structures, 3) absence of granulomatous reaction, and 4) absence of neoplasm.
Fine needle aspiration biopsy is usually nondiagnostic in RT because most often only follicular cells are obtained and not the fibrous material characteristic of this type of thyroiditis. In our patient, however, fine needle aspiration was very suggestive of RT vs. the fibrotic variant of Hashimoto’s thyroiditis. In many patients, the diagnosis is established pathologically only by open biopsy or postoperatively. On pathological examination, the resected thyroid tissue is well circumscribed, but not encapsulated. The classic description is that of a stony hard gland, fixed to local structures. It may be unilateral or bilateral, but it is usually localized to only one portion of the thyroid, with sharp demarcation from the remaining functioning part of the gland (8). The fibro- inflammatory process characteristically extends through the capsule to extensively involve adjacent structures of the neck, including the carotid sheaths, trachea, strap muscles, and nerves (5).
On histological examination, early lesions show an intense infiltration of lymphocytes, plasma cells, neutrophils, and eosinophils (2). Subsequently, dense fibrous bands divide the thyroid into progressively smaller lobules. Eventually, dense hyalinized fibrous tissue with a few lymphocytes, plasma cells, and eosinophils replaces the thyroid parenchyma (5). The fibrosis extends beyond the thyroid into adipose tissue and muscle and may encase blood vessels as in our case. The tissue planes are obliterated, making surgical extirpation virtually impossible. There may be associated phlebitis with thrombosis (9). This occlusive phlebitis results from diffuse infiltration of the walls of small and medium-sized veins by lymphocytes and plasma cells. This phenomenon has been observed in other manifestations of multifocal fibrosis, but not in other forms of thyroiditis (10, 11, 12, 13, 14).
The imaging features of RT are nonspecific. On thyroid radionuclide imaging, a heterogeneous pattern of isotope uptake or very low uptake is usually seen, similar to other forms of thyroiditis. On sonography, RT is reported to be homogeneously hypoechoic due to fibrosis (15). The extent of fibrosis is best defined by computerized tomography, in which the thyroid appears hypodense to normal, and invasion of nearby tissues is seen, with slight enhancement after contrast medium (16). On magnetic resonance imaging, the thyroid is reported to be hypointense on both T1 and T2 weighted images (15, 17).
Although there has been considerable debate as to whether RT is a primary thyroiditis, a variant of Hashimoto’s thyroiditis, or even end-stage DeQuervain’s thyroiditis, current evidence suggests that RT might be a local manifestation of a systemic fibrosing disease (6, 8, 18, 19, 20). An autoimmune mechanism is suggested by 1) the presence of mononuclear cell infiltration and vasculitis within the fibrous tissue and the serum antithyroid antibodies present in so many patients (21); 2) occasional reports of the coexistence of RT with autoimmune disorders such as Addison’s disease, type 1 diabetes, pernicious anemia, Graves’ disease, and Hashimoto’s thyroiditis (22, 23, 24, 25); and 3) the favorable response to glucocorticoid therapy (26). However, the autoantibodies are thought to be reactive to antigens released from destroyed thyroid tissue (21). The association with other autoimmune diseases is rare and probably coincidental (21, 22, 23), and the response to glucocorticoid therapy may be due to decreased production of cytokines with strong fibrogenic properties (26). The absence of other autoantibodies and the presence of a normal serum complement level and a normal lymphocyte subpopulation are also inconsistent with an autoimmune mechanism (27).
It is now widely believed that RT is more likely to be an isolated or local manifestation of a systemic disease called idiopathic multifocal fibrosclerosis. This is a primary fibrotic disorder with fibroblast proliferation induced by cytokines produced by B or T lymphocytes (21). An association between RT and other fibrosing lesions, including mediastinal fibrosis, was first described by Barrett (28) in 1958. Since then, a large number of cases of RT in association with retroperitoneal fibrosis (13, 19, 29, 30, 31), mediastinal fibrosis (13, 32, 33, 34, 35), sclerosing cholangitis (11, 36), and pseudotumor of the orbit (37, 38) have all been reported, suggesting they may be variable manifestations of a systemic multifocal fibrosing disorder. It has also been reported that one third of patients with RT will develop other associated fibrosing disorders over 10 yr (4).
The clinical importance of RT lies in its ability to result in local obstructive phenomena, in its potential for being confused with carcinoma, especially lymphoma (39) and sarcoma, and in its variable association with fibrosing processes elsewhere in the body. The local complications of RT are protean and range from thyroid dysfunction, tracheal and esophageal compression with fibrous mediastinitis (35), bilateral fibrous parotitis (40), occlusive vasculitis (30, 41) causing an extensive sterile neck abscess (41), superior vena cava syndrome (42), cerebral venous sinus thrombosis (43), obstruction of a ventriculoperitoneal shunt (44), to pituitary failure (45). Spontaneous hypoparathyroidism secondary to RT appears to be rare. Only nine previous cases of primary hypoparathyroidism secondary to RT have been reported (6, 16, 46, 47, 48, 49, 50, 51, 52), and only two of these demonstrated parathyroid recovery (17, 48). Parathyroid autoantibodies were tested in some cases and were negative. Our patient had no clinical evidence of other autoimmune features, such as vitiligo, alopecia areata, or adrenal insufficiency, to suggest the hypoparathyroidism, adrenal insufficiency, mucocutaneous mycosis syndrome. Gradual fibrotic infiltration of the glands is believed to be the etiological mechanism, although histological examination of the affected parathyroid glands has not been documented. Vascular compromise and progressive ischemia may also contribute to parathyroid dysfunction. In our patient we believe that primary hypoparathyroidism may be permanent, because of the persistently low normal calcium and high normal phosphorus levels on an adequate regimen of calcitriol and calcium supplements.
Our patient also developed spontaneous recurrent laryngeal nerve injury unrelated to surgery and probably secondary to mass effect or fibrotic infiltration of the nerve (2, 4, 16, 53). After aggressive treatment with prednisone, a dramatic recovery of vocal cord function was described in two patients (4, 16) and correlated with a reduction in thyroid size. Our patient’s hoarseness has improved markedly on glucocorticoid treatment.
In addition, our patient developed acute vagal symptoms of bradycardia, near syncope, and right Horner’s syndrome believed to be secondary to RT. Horner’s syndrome has occasionally been related to benign thyroid pathology, for example, multinodular goiter (54). Reversibility after thyroidectomy has also been reported. However, to our knowledge this is the first case of Horner’s syndrome secondary to RT. We believe that Horner’s syndrome, which has now completely resolved in our patient, was the result of fibrotic infiltration of the cervical sympathetic trunk.
Untreated RT is usually slowly progressive, although it may stabilize or even regress spontaneously. Hypothyroidism should be treated with levothyroxine, although it rarely has an effect on goiter size or the progressive spread of fibrosclerosis. Thyroidectomy or neck dissection is not recommended, because the lack of resection planes and the risk of injury to adjacent structures make surgery quite hazardous (21). Recurrence after surgery has also been reported (21). Surgery is sometimes indicated for tracheal or esophageal compression and occasionally to exclude carcinoma. The operation should be limited to relief of obstruction, for example, by wedge excision of thyroid isthmus.
Due to the rarity of RT, there have been no extensive clinical trials of the efficacy of medical therapy. Nevertheless, small studies and case reports consistently show a good response to glucocorticoids (21, 48, 55, 56). These drugs are often used as first-line therapy because of the progressive perithyroidal infiltration and fibrosis with potentially life-threatening destruction of local structures. In some instances dramatic responses to glucocorticoids have been described as well as lasting benefit even after withdrawal (2, 27). In other instances relapses have occurred when these drugs were stopped (27, 56). Glucocorticoids are considered to be more effective when given early in the disease (56).
Tamoxifen, an antiestrogen drug with inhibitory properties for connective tissue proliferation, has been used successfully in the treatment of RT. In one series of four patients with RT who had progressive symptomatic disease despite glucocorticoid therapy and surgery, tamoxifen resulted in both subjective and objective improvements (3). Each of the four patients had a decrease in goiter size of 50% or more, and one had total resolution of the disease. Although not fully understood, tamoxifen’s effectiveness in treating disorders such as RT could have been related to the stimulation of TGFß production. TGFß is a known potent growth inhibitor of both immature fibroblasts and epithelial cells (57). Until more effective drugs are found, it may be the drug of choice for managing intractable RT. Side-effects of tamoxifen include hot flashes, menstrual irregularity, and increased risk of endometrial cancer in women. Men report decreased libido. Although our patient could not tolerate tamoxifen at the dose of 20 mg twice daily that was used in the study by Few et al. (3), she continues to do well on 10 mg twice daily.
This patient’s course of 18 months illustrates the wide array of manifestations of RT and reminds us that this disease presents a difficult diagnostic challenge, necessitating rapid interventions and a collaborative effort of both medical and surgical teams. Much remains to be learned about the pathophysiology and treatment of this rare but fascinating disorder.
Acknowledgments
Footnotes
Abbreviation: RT, Riedel’s thyroiditis.
Received February 7, 2002.
Accepted April 4, 2002.
References
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