Infiltrative thyroid disease

INTRODUCTION — Infiltrative thyroid diseases are rare and may occur as an isolated abnormality or as a manifestation of generalized disease. The infiltration usually presents as progressive thyroid enlargement that is painless, firm, and bilateral, and it may be confused with autoimmune thyroiditis (Hashimoto's thyroiditis), nontoxic multinodular goiter, subacute thyroiditis, infectious thyroiditis, or occasionally thyroid cancer or lymphoma. The clinical course, pathologic findings, and management of the most common forms of infiltrative thyroid disease, excluding those of autoimmune, infectious, or malignant origin, are reviewed here. Most of these diseases involve other organs, but the focus here will be on the thyroid manifestations.

Hashimoto's thyroiditis, thyroiditis, thyroid nodules, and goiter are reviewed separately. (See "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)" and "Overview of thyroiditis" and "Diagnostic approach to and treatment of thyroid nodules" and "Clinical presentation and evaluation of goiter in adults".)

GENERAL APPROACH — Painless, progressive enlargement of the thyroid is the most common presentation of infiltrative thyroid disease. Changes in thyroid function tests are less commonly seen, although infiltration of the thyroid can be associated with hypothyroidism.

●We routinely measure thyroid function tests (thyroid-stimulating hormone [TSH] and free thyroxine [T4]) when thyroid enlargement or nodular thyroid disease is noted on physical examination. Many thyroid experts also check serum thyroid peroxidase (TPO) antibodies in patients with diffuse thyroid enlargement (regardless of the TSH level) to confirm the diagnosis of autoimmune thyroiditis. (See "Clinical presentation and evaluation of goiter in adults", section on 'Approach to evaluation'.)

●We perform thyroid ultrasonography to assess the morphology of the thyroid gland when infiltration is suspected. Fine-needle aspiration (FNA) of a suspicious nodule or expanding mass in the thyroid may be considered to further evaluate the variable pathology of this entity. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Fine-needle aspiration biopsy'.)

There are no clinical trials on the efficacy of therapy for infiltrative thyroid disease because of the rarity of this condition. When infiltrative thyroid disease occurs as a manifestation of generalized disease, the underlying disease should be treated. Patients with hypothyroidism require treatment with thyroid hormone replacement (T4 [levothyroxine]) (see "Treatment of primary hypothyroidism in adults"). Surgical intervention is often necessary when there are signs of obstruction from tracheal or esophageal compression.

Treatment of the individual forms of infiltrative thyroid disease is reviewed below. These are all rare diseases, and the order of the discussion below does not reflect prevalence.

AMYLOID GOITER — Amyloidosis is a diverse group of diseases characterized by extracellular tissue deposition of a fibrous insoluble protein generically termed amyloid. In the thyroid, amyloid is most often detected in the stroma in medullary thyroid cancers [1]. Rarely, it is diffusely deposited in the thyroid as a manifestation of primary or secondary systemic amyloidosis [2-5]. (See "Overview of amyloidosis", section on 'Types of amyloidosis'.)

Symptomatic amyloid goiter has been reported in 0.04 percent of patients with systemic primary amyloidosis [2]. In patients with amyloidosis secondary to familial Mediterranean fever (FMF), the prevalence of amyloid goiter is higher, ranging from 0.27 to 45 percent, depending on the method of detection (higher prevalence with ultrasound screening) [5-7]. It occurs more often in patients with end-stage chronic kidney disease treated with hemodialysis [5].

Clinical manifestations — Amyloid goiter is characterized by gradual, painless, diffuse, firm thyroid enlargement, occasionally sufficient to cause tracheal compression, sometimes with chronic hoarseness [3,8]. Most symptomatic patients present with a neck mass that is growing over weeks to months [9] and can be misdiagnosed as a thyroid malignancy [10]. Thyroid ultrasound findings are variable and may show goiter with a heterogeneous or hyperechoic echotexture, diffuse goiter with normal echotexture, or goiter with multiple nodules [5].

Subclinical amyloid infiltration of the thyroid is more common than symptomatic disease. Subclinical thyroid dysfunction is infrequent, with both hypothyroidism and hyperthyroidism described in the literature, especially in the case of extensive infiltration [11-13]. Occasionally, symptomatic amyloid goiter will precede other clinical evidence of systemic amyloidosis [14].

Diagnosis — The presence of amyloid as the cause of goiter should be suspected in patients in whom the diagnosis of amyloidosis has already been established or in those with otherwise unexplained nephrotic syndrome, renal or heart failure, and a chronic inflammatory disease that may be associated with secondary amyloidosis (eg, rheumatoid and other inflammatory types of arthritis, osteomyelitis, tuberculosis, Crohn disease), or a serum or urinary paraprotein. (See "Overview of amyloidosis", section on 'Diagnosis'.)

Fine-needle aspiration (FNA) biopsy with Congo red staining shows characteristic apple-green birefringence [3,15]. However, it may be difficult to obtain adequate specimens with FNA [8,16]. In addition, FNA cannot reliably distinguish between amyloid goiter and stromal amyloid deposition resulting from another cause of thyroid enlargement. Occasionally amyloid detected on FNA can be mistaken for colloid [15]. Thyroid neoplasms, primarily medullary cancer, are associated with the deposition of amyloid. Thus, either a core-needle biopsy or surgical specimen biopsy is usually necessary for definitive diagnosis.

Histopathology — Amyloid is deposited extracellularly between or replacing the thyroid follicles and around blood vessels as an amorphous eosinophilic fibrillar material (picture 1) [9].

Amyloid in cytology specimens may appear as either flocculent maternal or irregularly shaped fragments with scalloped and pointed edges and can be misinterpreted as colloid. The amorphous fragments stain eosinophilic to cyanophilic with Papanicolaou stain and deep blue with Diff-Quick cytology stain [17]. Congo red staining results in a unique green birefringence of the amyloid deposits when sections are viewed by polarized light microscopy (picture 2).

Other histologic findings include focal lymphocytic thyroiditis, foreign body giant cells, and, rarely, focal squamous metaplasia of the follicular epithelium. The thyroid follicular cells are often flattened and atrophic. Focal and diffuse fatty infiltration with hyalinized stroma has been reported in an amyloid goiter [18,19] (see 'Diffuse lipomatosis' below). Amyloid has also been reported in an adjacent parathyroid gland in a patient with normocalcemia [20].

Once amyloid has been detected in thyroid tissue, the type of fibril can be determined by immunochemical staining using specific antibodies to kappa and lambda light chain amyloid, amyloid A, and other forms of amyloid. Secondary amyloidosis can be confirmed by the presence of amyloid AA immunoreactivity. Electron microscopy will show nonbranching 9-nm amyloid fibrils. (See "Overview of amyloidosis", section on 'Diagnosis'.)

Treatment — The treatment of amyloidosis is directed both toward the affected organ and to the specific type of amyloidosis, although there are little data available regarding the effect of treatment of primary amyloidosis on amyloid goiter. One report described the treatment of primary amyloid with dexamethasone and a peripheral blood autologous stem cell transplant resulting in improvement of parameters such as kappa free light chains and renal function, as well as a decrease in the size of the goiter [2]. Hypothyroidism should be corrected, if present, and thyroidectomy may be indicated in patients with obstructive symptoms [3]. (See "Treatment of AA (secondary) amyloidosis" and "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

BLACK THYROID — Black thyroid is an incidental finding of diffuse black discoloration of the thyroid noted during gross specimen examination associated with prior minocycline therapy.

Clinical manifestations — Patients are typically asymptomatic with normal thyroid function. It is usually noted incidentally in the pathologic evaluation after thyroidectomy for other unrelated thyroid pathology. Minocycline and other tetracycline derivatives have been implicated as the causative agents, even after exposure as short as 12 days. It was first reported in 1976, with approximately 60 case reports published since that time [21-25].

Pathology — Gross examination shows a diffused black thyroid gland; in contrast, benign and malignant thyroid neoplasms are often hypopigmented [23]. Pigment accumulation occurs as black amorphous aggregates in the thyroid follicular cell and colloid (picture 3) [21,22,26]. Electron microscopy shows the subcellular localization in thyrocyte lysozymes (picture 3) [23,26]. Cytology after fine-needle aspiration (FNA) is usually negative for pigmentation [21]. Minocycline is a competitive inhibitor of thyroperoxidase, and the pigment deposition is apparently a result of the oxidation interaction between thyroid peroxidase and the drug.

Treatment — There is no specific treatment for black thyroid syndrome as there is no thyroid dysfunction or pathology associated with this condition.

CYSTINOSIS — Cystinosis (lysosomal disease) is an autosomal recessive disorder characterized by intracellular accumulation of cystine in the kidneys, thyroid, brain, and eyes in children. Cystine accumulation leads to a variety of abnormalities including visual impairment, hypothyroidism, and end-stage kidney disease. (See "Cystinosis".)

Clinical manifestations — Approximately 50 to 75 percent of patients with cystinosis have subclinical or overt hypothyroidism [27,28]. In one series, 10 of 18 (47.6 percent) of children had overt or subclinical hypothyroidism [28,29]. In an adult series, 31 of 36 patients who had received renal transplants for cystinosis were hypothyroid [27].

Pathology — The thyroid gland of a patient with cystinosis contains large amounts of cystine, including intracellular cystine crystals, which seem to result in destruction of thyroid follicular cells and fibrosis [29].

Treatment — Renal transplantation has allowed survival of children with cystinosis into the second decade. Although survival is increased, hypothyroidism continues to progress. Thus, all patients with cystinosis should be evaluated regularly for hypothyroidism and T4 (levothyroxine) therapy should be initiated in those with high serum TSH concentrations. Treatment with cysteamine may delay the need for T4 therapy [30]. (See "Cystinosis".)

DIFFUSE LIPOMATOSIS — Extensive infiltration of the thyroid by mature adipose cells (diffuse lipomatosis) can rarely result in diffuse goiter and may be part of the spectrum of amyloid goiter [18,19,31,32]. (See 'Amyloid goiter' above.)

Clinical manifestations — Patients may be asymptomatic with normal thyroid function, and fatty infiltration is noted incidentally on histology after thyroidectomy for amyloid goiter. Other patients may present with slowly progressive enlargement of the thyroid gland [19,31]. Ultrasonography shows a diffusely enlarged thyroid with heterogeneous echogenicity [18,31]. In one report, computed tomography (CT) scan showed a diffusely enlarged thyroid with a density slightly greater than fat (-40 Hounsfield units) [19].

Pathology — In case reports, cytology after fine-needle aspiration (FNA) showed droplets of fat within the sample [19]. On histology, extensive replacement of thyroid follicles by fatty infiltration has been noted [18]. In patients with coexistent amyloid goiter, small amounts of hyalinized stroma contain amyloid protein [33].

Treatment — There is no specific treatment for diffuse lipomatosis thyroid syndrome unless there are obstructive symptoms or thyroid dysfunction. Thyroid resection will relieve obstructive symptoms from the enlarged thyroid.

HEREDITARY HEMOCHROMATOSIS — Hereditary hemochromatosis and hemosiderosis due to iron overload from repeated red blood cell transfusions result in excessive iron accumulation in multiple tissues, including the pituitary and thyroid, causing parenchymal damage and fibrosis [34-37]. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

Clinical manifestations — Thyroid dysfunction occurs slowly as iron accumulates in the thyroid or the pituitary gland. Pituitary dysfunction (from iron deposition in the pituitary thyrotrophs) with resultant central hypothyroidism is more commonly observed than primary hypothyroidism from thyroid infiltration. Thyroid infiltration is not typically associated with thyroid enlargement [35,38]. In a study of 34 men and 15 women homozygous for the hemochromatosis gene, three men but none of the women had hypothyroidism and high serum antithyroid antibody concentrations; the risk of hypothyroidism in the men with hemochromatosis was 80 times that of men in the general population [34]. Tissue deposition of iron may be confirmed by the characteristic low-intensity signals on T1 and T2-weighted magnetic resonance imaging (MRI) images, similar to the background [37].

Pathology — Autopsy studies have demonstrated iron deposition in the thyroid of nearly all patients with hemochromatosis. Iron accumulation in the thyroid may damage the follicular epithelium, causing lymphocytic inflammation, fibrosis, and thyroid follicular cell destruction [34].

Treatment — Reducing iron overload, usually by serial phlebotomy in hereditary hemochromatosis or chelation in patients with a continued requirement for red cell transfusion, improves thyroid function [36,39], but T4 should be given to any patient who has hypothyroidism. (See "Management and prognosis of hereditary hemochromatosis".)

LANGERHANS CELL HISTIOCYTOSIS — Langerhans cell histiocytosis (LCH; histiocytosis X) is a rare, proliferative monoclonal histiocytic disease of unknown cause that can involve many or very few organ systems [40-42]. The biological behavior of LCH is highly variable, leading to a wide range of clinical presentations and a variable course, ranging from a single indolent lytic lesion in bone to a progressive leukemia-like disease. Mortality in adults is approximately 3 percent [43]. The histiocytes are similar in phenotype to dendritic Langerhans cells.

Intermediate forms of the disease are characterized by a chronic course of a multiorgan involvement, including skin lesions, lytic bone lesions, interstitial lung disease, arginine vasopressin deficiency (previously called central diabetes insipidus) due to hypothalamic involvement, as well as goiter [44]. Rarely, LCH can involve primarily the thyroid with fewer than 40 cases in the reported literature both in adults and children. Males account for 80 percent of thyroid Langerhans pediatric cases, while as adults, women are afflicted more commonly than men [43,45].

Clinical manifestations — Patients with LCH of the thyroid may present with a solitary nodule, a nodular goiter, diffuse goiter, or a lymphocytic thyroiditis. Most adults are euthyroid, but some young children with severe systemic disease have had hypothyroidism as well as goiter that preceded the involvement of other organs by several months. Thyroid involvement is generally confined within the gland, but extrathyroidal extension has rarely been described [46]. In patients with systemic disease, thyroid involvement is usually found incidentally at autopsy.

Pathology — On gross examination, thyroid LCH is frequently nodular. The tissue appears whitish, with areas of hemorrhage. Histologically, either diffuse or focal histiocytic involvement of the thyroid gland is characterized by infiltration with histiocytes (large cells with bean-shaped, lobulated, or folded nuclei), eosinophils, and lymphocytes. Destruction of thyroid follicles may be seen.

Thyroid LCH must be distinguished from poorly differentiated or undifferentiated cancer. The histiocytes stain with antibodies to S-100 protein, CD68, CD1a, lysozyme, and KP-1 [40,41] and contain Birbeck granules by electron microscopy.

Fine-needle aspiration (FNA) biopsies of the thyroid in these patients show infiltration with mononuclear cells (histiocytes) with only scant follicular cells [46,47].

Treatment — Therapy is determined by the extent and rate of progression of the disease. Occasionally, lesions spontaneously remit over time. Treatment options for patients with localized disease include observation, glucocorticoids, or local excision. A review of the literature suggests that disease limited to a single thyroid nodule does not recur after lobectomy [43].

Patients with goiter of sufficient size to cause obstructive symptoms and with disease limited to the thyroid are best treated surgically. In one study, four patients with only thyroid involvement underwent thyroidectomy and were alive with no evidence of systemic disease 3 to 19 years later; in contrast, three patients with thyroid and systemic disease died within one year after diagnosis [40].

Patients with thyroid and systemic disease may be treated with combination therapy including thyroid surgery, radiotherapy, and chemotherapy [48,49]. Chemotherapeutic agents that have been used for treatment include glucocorticoids, vinblastine, vincristine, etoposide, cyclophosphamide, cyclohexylchloroethylnitrosourea, methotrexate, doxorubicin, and 2-chlorodeoxyadenosine. Monoclonal anti-CD1, pentostatin (2-deoxycofomicin), and thalidomide are other treatments that have been suggested. Single-patient case reports have shown successful resolution of LCH goiter after treatment with vincristine and oral prednisone [50] and vinblastine with oral prednisolone [51].

There are no clinical trials comparing medical (glucocorticoids, chemotherapy) therapy with surgical therapy for this disorder because of its rarity. A review of cases involving primarily the thyroid reported that 40 percent of children and 79 percent of adults were treated by thyroidectomy, while 10 and 25 percent of children and adults, respectively, were treated with chemotherapy. In addition, 20 percent of children and 25 percent of adults received multiple forms of therapy. After treatment, over 80 percent of adults did not have thyroid recurrence and 5 percent had nonfatal recurrent disease [43].

RIEDEL'S THYROIDITIS — Riedel's thyroiditis (invasive fibrous thyroiditis) is a fibrotic process associated with a mononuclear cell inflammation that extends beyond the thyroid into the perithyroidal soft tissue. The perithyroidal fibrosis can involve the parathyroid glands (causing hypoparathyroidism), the recurrent laryngeal nerves (causing hoarseness), the trachea (causing compression), the mediastinum, and the anterior chest wall [52,53]. In contrast, other infiltrative and inflammatory conditions of the thyroid do not extend beyond the thyroid capsule.

Riedel's thyroiditis is extremely rare, with an outpatient incidence of 1 in 100,000 and prevalence of 0.05 percent or less of surgical thyroid diseases [54,55]. Women are four times more likely than men to be affected, and it most commonly occurs between the ages of 30 and 50 years [56,57]. In a meta-analysis involving 212 patients with Riedel's thyroiditis, 81 percent were women and the mean age was 47 years [55].

Etiology — The etiology of Riedel's thyroiditis is not known. Riedel's disease is often believed to be the local involvement of the thyroid in a systemic disease and may occur with other fibrosing conditions such as retroperitoneal fibrosis, fibrosing mediastinitis, sclerosing cholangitis, pancreatitis, lacrimal fibrosis, orbital pseudotumor fibrosis, and tumefactive fibroinflammatory lesions of the head and neck [54,58].

Riedel's thyroiditis may occur within the spectrum of immunoglobulin G4 (IgG4)-related systemic disease [59]. The hallmarks of IgG4-related systemic disease are lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and small lymphocytes accompanied by fibrosis, obliterative phlebitis, and elevated serum levels of IgG4. Excessive numbers of IgG4-positive plasma cells have been identified in thyroidectomy samples from three patients with Riedel's thyroiditis [60].

Clinical features

●History and physical examination – Patients often present with a slowly growing goiter; they may have anterior neck pressure and pain, dysphagia, hoarseness, dyspnea, or hypoparathyroidism if the process has extended beyond the thyroid [52,61-63]. Local obstructive pneumonia and superior vena cava syndrome have been reported as presenting symptoms [64]. Although only approximately one-third of patients may experience hypothyroidism, many patients with Riedel's thyroiditis experience generalized malaise and fatigue.

On physical examination, the size of the thyroid gland varies from small to large. Usually both lobes are enlarged, but the enlargement may be asymmetric and occasionally is limited to one lobe. The goiter is typically nontender, "stony" hard, and densely adherent to the adjacent soft tissue and muscles, including the sternocleidomastoid, sternohyoid, and sternothyroid muscles; as a result, the thyroid gland often moves poorly with swallowing. The fibrotic process may encase the esophagus and trachea, and adjacent lymph nodes may be enlarged, raising the suspicion of an invasive thyroid cancer.

The findings on physical examination alone are sufficient to establish the diagnosis in some patients. A careful search for other physical signs of systemic fibrosclerotic disease should then be performed.

●Thyroid function tests – Many patients with Riedel's thyroiditis have normal serum thyroid hormone and TSH concentrations at presentation. From 25 to 67 percent have subclinical or overt hypothyroidism due to nonfunctioning fibrous infiltration and thyroid parenchymal destruction or concurrent Hashimoto's thyroiditis [55-57,61,65]. Up to two-thirds of patients have elevated serum thyroid autoantibody concentrations, but the titer may be less than that seen in Hashimoto's thyroiditis [61,66]. As an example, in one analysis in which 92 patients were tested, 43 percent had positive thyroid peroxidase antibodies and 27 percent had positive antithyroglobulin autoantibodies [55]. (See "Laboratory assessment of thyroid function".)

●Other laboratory tests – Serum calcium and phosphorus should be measured to identify those with coexistent hypoparathyroidism [52,62]. The white blood cell count is usually normal. In one series, C-reactive protein and erythrocyte sedimentation rate were elevated in 72 and 97 percent, respectively, of patients tested [55].

●Imaging – Ultrasonography shows heterogeneous hypoechoic lesions that may infiltrate the perithyroid muscles, and color-flow Doppler shows absence of vascular flow in the Riedel's regions [67]. In two cases, ultrasound showed thyroid tissue circumferentially surrounding the carotid artery [68]. The extent of the fibrosis is best defined by CT or MRI, which shows focal homogenous hypointensity in T1 and T2 weighted images. These imaging modalities can show that the lesions may infiltrate the thyroid, peripheral organs, and the vasculature of the neck. In one large study, radiographic evidence of tracheal compression was seen in 75 percent of patients [55].

On fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scans, Riedel's thyroiditis is hypermetabolic [68-70]. The abnormal FDG metabolism may track with clinical activity of the disease.

●Cytology – Fine-needle aspiration (FNA) biopsy is often nondiagnostic due to insufficient thyroid epithelial cells but may reveal mononuclear cells and fibrous tissue [71]. The differential diagnosis based on FNA includes subacute thyroiditis, a fibrosing variant of Hashimoto's thyroiditis, radiation-induced thyroiditis, and malignancy, specifically a paucicellular variant of anaplastic cancer [72]. In many patients, the diagnosis can be established pathologically only by open biopsy.

●Pathology – Pathologic examination of resected thyroid tissue reveals hard, white, avascular tissue (picture 4). Histologic sections from lesions early in the disease will show intense infiltration of lymphocytes, plasma cells, neutrophils, and eosinophils. Later in the disease process, specimens will show infiltration of the thyroid with dense, hyalinized fibrous tissue that contains few lymphocytes, plasma cells, and eosinophils and almost no thyroid follicles (picture 5) [56]. The fibrosis often extends beyond the thyroid into adipose tissue, muscle, and nerves, and it may encase vessels, parathyroid glands, the trachea, and the esophagus [73]. The tissue planes are obliterated, making surgical extirpation virtually impossible. The pathology should confirm the absence of a granulomatous reaction and cancer [61].

There may be an associated phlebitis with thrombosis [55,74]. This occlusive phlebitis results from a diffuse infiltration of the walls of small and medium-sized veins by lymphocytes and plasma cells. Adenomas or cysts (degenerative or hemorrhagic) occur within the fibrous mass in approximately 25 percent of patients [56].

Thyroid fibrosis is also seen in Hashimoto's thyroiditis and an infiltrating variant form of papillary cancer, but the extent of the fibrosis in these disorders is much less and it does not extend beyond the thyroid as it does in Riedel's thyroiditis. The paucicellular variant of anaplastic thyroid cancer has been described that may mimic Riedel's thyroiditis because it is characterized by an infiltrative, hard, fibrotic thyroid mass that may extend into perithyroid tissue [75]; however, scattered within the fibrous tissue are spindle cells that obliterate large blood vessels and contain epithelial-cell markers detected by immunohistochemistry.

Association with chronic autoimmune thyroiditis (Hashimoto's thyroiditis) — Riedel's thyroiditis can occur in association with Hashimoto's thyroiditis [76] and, as noted above, many patients with Riedel's thyroiditis have elevated serum antithyroid antibody concentrations [55,61] and lymphocytic infiltration may be seen in thyroid FNA. The following findings help distinguish between the disorders, although their pathogenic importance is not known.

●Venulitis and fibrous tissue invasion into perithyroidal tissues are features of Riedel's thyroiditis that are not seen in the fibrous variant of Hashimoto's thyroiditis. Hürthle cells, while frequently seen in Hashimoto's thyroiditis, are absent from Riedel's thyroiditis.

●Immunotyping demonstrates a predominance of lambda light chain-containing lymphocytes in Riedel's thyroiditis and kappa light chain-containing lymphocytes in Hashimoto's thyroiditis [77].

●In addition to Hashimoto's thyroiditis, there are several reports of other autoimmune disorders, such as primary adrenal insufficiency, type 1 diabetes, pernicious anemia, and Graves' disease associated with Riedel's thyroiditis [78-80].

●Riedel's thyroiditis has rarely been reported in association with subacute thyroiditis [66,81,82]. These patients are typically female and do not have thyroid autoantibodies present.

Treatment — Untreated, Riedel's thyroiditis is usually slowly progressive and may stabilize or even regress spontaneously [54]. Mortality is typically attributed to recurrent pneumonia due to bronchial compression and dyspnea. Treatment is aimed at both hypothyroidism, if present, and the manifestations related to fibrosclerosis. Hypothyroidism should be treated with T4 (levothyroxine), but it rarely has any effect on the goiter or the progressive spread of fibrosclerosis. (See "Treatment of primary hypothyroidism in adults".)

There are no clinical trials on the efficacy of medical therapy for Riedel's thyroiditis because of the rarity of this condition. Nevertheless, empiric therapy may be indicated with the progressive perithyroidal infiltration, fibrosis, and potentially life-threatening destruction of local structures. In one series of 21 patients with Riedel's thyroiditis undergoing treatment utilizing various modalities, 17 patients followed for a mean period of 9.5 years showed improvement in the fibrotic process, and seven were felt to have stable disease [57]. In an analysis of 171 patients with Riedel’s thyroiditis followed for a median of 12 months, 90 percent showed improvement or resolution of symptoms, 3 percent showed minor improvement, and 7 percent showed no improvement, including two who died from progressive disease [55].

●Glucocorticoids – Treatment with glucocorticoids has reduced thyroid enlargement and induced softening of the neck mass in a few patients [62,78], especially when used early in the course of the disease. Treatment with glucocorticoids is typically long-term, as disease recurrence has been seen when doses of steroids are tapered. In the meta-analysis of 212 patients, 70 percent received glucocorticoids for an average duration of three months. A typical regimen involved prednisone 40 mg daily for three months [55].

●Tamoxifen – Tamoxifen has also been used successfully in some patients with Riedel's thyroiditis. As an example, in one series of four patients who had progressive symptomatic disease despite glucocorticoid therapy and surgery, tamoxifen resulted in both subjective and objective improvement in all, including at least a 50 percent reduction in the size of the goiter. However, in another series, three of six patients with Riedel's thyroiditis progressed while taking tamoxifen [57]. In the large meta-analysis including 212 cases, tamoxifen was given to 28 patients, using a median dose of 20 mg daily for an average duration of eight months (range 1 to 48 months) [55]. The mechanism of tamoxifen's effect is unknown, but may relate to the reduction of cytokine-mediated (namely, transforming growth factor [TGF]-beta) fibroblast proliferation [83].

●Rituximab and mycophenolate mofetil – Rituximab and mycophenolate mofetil have been used as therapy for disorders associated with systemic fibrosclerosis (IgG4-releated disease) (see "Treatment and prognosis of IgG4-related disease"). In one case report, a woman with Riedel's thyroiditis who did not have a response to treatment with tamoxifen and prednisone was subsequently treated with 1 g mycophenolate twice daily and 100 mg of prednisone daily [84]. She had subjective improvement of compressive symptoms and an objective decrease in thyroid mass. In another case report, a woman who had no improvement with glucocorticoids and eventual progression after two years of tamoxifen had symptomatic, biochemical, and radiological improvement after treatment with intravenous rituximab (375 mg/m² monthly for three months) [85,86]. The improvement has persisted for 14 months.

●Surgery – Surgery is frequently indicated to relieve tracheal or esophageal compression or to rule out malignancy. In one series, 18 of 21 patients required surgical excision of at least part of the thyroid for symptomatic relief, but complete resection was not possible in any [57]. In the meta-analysis of 212 cases, 37 patients required surgery, including tracheostomy in 20 patients, isthmectomy in 13, total thyroidectomy in 70, and hemithyroidectomy in 25 [55]. An additional 40 patients had an unspecified surgery. In general, surgery should be limited to relieving the obstruction, eg, by excising a wedge of thyroid isthmus to relieve tracheal compression. Extensive resection (ie, total thyroidectomy) is not indicated, because of the lack of resection planes and risk of injury to adjacent adhering structures, including the parathyroid glands and the recurrent laryngeal nerves.

●Radiation – Low-dose radiation therapy has been used in cases that are refractory to other treatments.

Retroperitoneal fibrosis causing ureteral obstruction has been treated with methylprednisolone pulse therapy in combination with azathioprine or penicillamine [87]. However, the effectiveness of this regimen has not been studied in patients with Riedel's thyroiditis.

SARCOIDOSIS — Sarcoidosis is a multisystem disorder of unknown etiology that often involves the lymph nodes, lungs, eyes, and skin. The disease can affect any organ system, including the thyroid gland. (See "Overview of extrapulmonary manifestations of sarcoidosis".)

Clinical manifestations — Sarcoidosis can cause diffuse goiter or rarely solitary or multiple thyroid nodules [88-91] that resemble a malignancy, especially when associated with cervical adenopathy [92].

Although most patients are euthyroid, both hypothyroidism and hyperthyroidism have been reported [93,94]. The rarity of thyroid dysfunction suggests chance association rather than a cause-and-effect relationship, but it is possible for thyroidal sarcoidosis to be sufficiently extensive to destroy the thyroid or cause thyroid inflammation leading to transient hyperthyroidism.

Most patients have other evidence of sarcoidosis, although there are case reports of thyroid involvement as the first or only manifestation of the disease [95-97]. Reports have described sarcoidosis along with Hashimoto's thyroiditis, Graves' disease, thyroid cancer, Hürthle cell hyperplasia, and painful thyroid nodules [98]. Concurrent sarcoidosis in patients with thyroid cancer has led to false-positive imaging for metastatic disease in cervical lymph nodes [99].

Middle-aged women have been described most frequently to have sarcoid infiltration of the thyroid. These cases typically involve sarcoid with peripheral or intrathoracic lymphadenopathy [100]. A case-control study showed that women with sarcoidosis have a significantly higher prevalence of antithyroid peroxidase antibodies, ultrasound characteristics of thyroid autoimmunity, and both clinical and subclinical hypothyroidism when compared with age-matched controls with a similar dietary iodine status [94].

Pathology — Thyroid sarcoidosis is diagnosed with fine-needle aspiration (FNA) biopsy or thyroidectomy for treatment of goiter demonstrating noncaseating epithelioid granulomas. The histologic features of sarcoidosis of the thyroid are similar to those of sarcoidosis elsewhere and consist of noncaseating granulomas with epithelioid cells, multinucleated giant cells, and lymphocytic infiltration (see "Clinical manifestations and diagnosis of sarcoidosis"). These granulomatous lesions should be differentiated from fungal or mycobacterial infections, Hashimoto's thyroiditis, and foreign body reactions.

Treatment — Patients with sarcoidosis of the thyroid do not usually need treatment unless they have a goiter of sufficient size to cause obstructive symptoms or thyroid dysfunction. The effects of glucocorticoids or external radiation on thyroid enlargement caused by sarcoid goiter are not known. Thyroidectomy is generally performed in patients with obstructive symptoms or other absolute indications for surgery, such as thyrotoxicosis or thyroid cancer. Hypothyroidism, if present, should be treated with thyroid hormone therapy.

SCLERODERMA — Scleroderma (progressive systemic sclerosis) is a connective tissue disorder characterized by sclerosis of the subcutaneous tissue and multiple visceral organs and the presence of autoantibodies to nuclear and other tissue components. (See "Pathogenesis of systemic sclerosis (scleroderma)" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

Clinical manifestations — The cardinal manifestation of scleroderma of the thyroid is diffuse goiter. The goiter is rarely large enough to cause symptomatic compression of vital neck structures, but hypothyroidism and antithyroid peroxidase antibody positivity are relatively common [101].

Pathology — Pathologic examination of the thyroid in patients with scleroderma usually shows fibrosis, even among patients who are euthyroid [102]. The fibrosis is probably due to scleroderma, although it could be a result of coexistent thyroid autoimmune disease since many, but not all, patients, also have serologic evidence of autoimmune thyroiditis.

Treatment — Patients with scleroderma of the thyroid do not need to be treated unless they have hypothyroidism or their goiter leads to local obstructive symptoms. The goiter does not usually respond to T4 (levothyroxine) therapy; as a result, thyroidectomy is occasionally indicated.

SUMMARY AND RECOMMENDATIONS

●Infiltrative thyroid diseases – Infiltrative thyroid diseases are rare and may occur as an isolated abnormality or as a manifestation of generalized disease. Diseases of thyroid infiltration include amyloid goiter, Riedel's thyroiditis, as well as thyroid infiltration occurring in cystinosis, hemochromatosis, Langerhans cell histiocytosis (LCH; histiocytosis X), sarcoidosis, and scleroderma. (See 'Introduction' above.)

●Clinical presentation – Painless, progressive enlargement of the thyroid is the most common presentation of infiltrative thyroid disease but compressive symptoms may occur, depending on the underlying etiology. Some patients may present with solitary or multiple thyroid nodules. Changes in thyroid function tests are less commonly seen, although infiltration of the thyroid can be associated with hypothyroidism. (See 'General approach' above.)

●General approach to evaluation – Thyroid function tests (thyroid-stimulating hormone [TSH] and free thyroxine [T4]) should be measured when thyroid enlargement or nodular thyroid disease is noted on physical examination. Thyroid ultrasonography can be used to assess the morphology of the thyroid. Fine-needle aspiration (FNA) of a suspicious nodule or expanding mass in the thyroid may be considered to further evaluate the variable pathology of this entity. (See 'General approach' above.)

●General approach to management – Patients with hypothyroidism require treatment with thyroid hormone replacement (T4 [levothyroxine]). Surgical intervention is often necessary when there are signs of obstruction from tracheal or esophageal compression. When infiltrative thyroid disease occurs as a manifestation of generalized disease, the underlying disease should be treated. (See 'General approach' above and "Treatment of primary hypothyroidism in adults".)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Stephanie L Lee, MD, PhD, and Sonia Ananthakrishnan, MD, who contributed to an earlier version of this topic review.