https://orcid.org/0000-0002-3843-896X
Abstract
Riedel thyroiditis (RT) is a rare inflammatory autoimmune disease that is often a clinically diagnostic dilemma because of its insidious presentation and nonspecific symptoms.
The aim of the present systematic review and meta-analysis is to clarify the presentation, management, and outcomes of RT.
A systematic search of PubMed/MEDLINE and Web of Science was conducted to identify relevant reports published up to September 2019.
First author, country, patient sex, ethnicity, presentation, biochemical status, duration of symptoms, histology, treatment, follow-up duration, and short- and long-term outcomes.
Data from 212 RT patients were retrieved. The mean age was 47 years with a predominantly female population (81%). Neck swelling (89%), dyspnea (50%), and neck pain (41%) were the most common presenting symptoms. Inflammatory markers were elevated in 70% to 97% and thyroid antibody positivity was present in less than 50%. Up to 82% underwent surgical intervention, with the most common being total thyroidectomy in 34% of individuals. Glucocorticoids were used in 70% of individuals with median duration 3 months. Prognosis was reasonable with 90% having resolution or improvement of symptoms.
This analysis is the largest and most comprehensive to date of RT and provides clinicians with vital information on the common presentation features that may alert to the diagnosis and highlight management options.
Riedel thyroiditis (RT) is a rare inflammatory disorder formally presented by Riedel in 1896, when he described a case of hard, fibrous thyroid mimicking malignancy (1). RT has an estimated incidence of 1.06 cases per 100 000 population with a higher prevalence in women and those between age 30 and 50 years (2).
RT is characterized by fibrosis of the thyroid gland and often the adjacent structures, including the parathyroid glands, skeletal muscle, nerves, blood vessels, as well as the trachea (3). Histologically, the thyroid parenchyma is replaced with dense fibrous tissue with inflammatory cells, predominantly a mixed population of lymphocytes, plasma cells, and eosinophils (4, 5). Although the true etiology of this disorder is unclear, there have been increasing associations with a systemic fibrosis process or autoimmune process such as Hashimoto disease or thyroid disease with immunoglobulin G (IgG)4 elevation (6-8). Indeed, the prevalence of IgG4-positive plasma cells in subsets of RT specimens suggests that these disease processes are linked, and hence the histopathological workup of RT patients could benefit from the inclusion of an IgG4 immunostaining (5).
Presentation and diagnosis are often complex. Individuals often present with a fixed, expanding, painless mass and localized obstructive/compressive symptoms including dyspnea, dysphagia, and hoarseness (2, 3, 5, 9). Owing to the firm nature of the mass, it can sometimes be clinically mistaken for malignancy, including suspicions of anaplastic thyroid cancer, thyroid angiosarcoma, or lymphoma (10-12). Biochemical abnormalities can include hypothyroidism and hypocalcemia (5, 13, 14).
Diagnosis is difficult; hence RT often requires histopathological confirmation. Because of the extensive fibrosis, fine-needle aspirations are usually nondiagnostic and often a surgical open biopsy is required (13). RT is usually confirmed by the presence of a fibroinflammatory process of the thyroid with extension into surrounding tissue. The inflammatory infiltrate must not contain giant cells, lymphoid follicles, oncocytic change or granulomas. Although occlusive phlebitis is often present, synchronous thyroid malignancy must be ruled out, especially the paucicellular variant of anaplastic thyroid carcinoma, the diffuse sclerosing variant of papillary thyroid carcinoma, a solitary fibrous tumor of the thyroid, as well as the nodular sclerosis variant of Hodgkin disease (15).
There is currently no standardized treatment for RT. Surgical intervention is often difficult because typically no tissue planes are discernible macroscopically. As such, risk of complications can be high and surgical intervention can be limited to airway decompression and diagnostic tissue retrieval. There are no randomized controlled trials but the primary treatment is often glucocorticoids or alternative agents that have included tamoxifen, mycophenolate, and rituximab in nonresponsive cases with variable success (5, 16-18). Additionally, treatment of endocrine deficiencies such as levothyroxine replacement therapy for hypothyroidism, and calcium as well as calcitriol therapy for hypoparathyroidism is pertinent. Moreover, screening for thyroid disease with elevated IgG4 (testing of serum levels of IgG4, imaging modalities, and biopsies) could be advocated in subsets of cases (19).
Owing to the rarity of the condition, there are no large case series exploring the presentation and management of RT. The aim of the present systematic review and meta-analysis was thus to clarify the presentation, treatment modalities, and outcomes of this disease.
Methods
Search strategy
A systematic search of PubMed/MEDLINE and Web of Science was conducted to identify relevant reports published up to September 2019 using the following search terms: “Riedel thyroiditis” and the misspelt variant “Reidel thyroiditis.” No limits were placed on language, country, or publication date. Reports were initially screened by title for relevance and then by abstract, with full-text articles of relevant reports reviewed. The reference lists of the retrieved full-text studies were also reviewed to identify additional relevant reports. The articles were reviewed by 2 of the authors (A.Z. and T.B.) and articles were included and excluded with reference to the criteria described in the next section.
Study selection and data extraction
Case reports or case series reporting RT were included. Review articles, editorials, and meeting abstracts were excluded, as were reports that did not demonstrate biopsy evidence of RT. Reports not in the English language were excluded if relevant information could not be extracted. If a single case was described in multiple reports, all reports were reviewed to ensure the maximum details of the case had been obtained.
The following information was extracted from each report: first author, country, patient sex, ethnicity, salient symptoms at presentation, biochemical thyroid status at presentation, thyroid antibody status, inflammatory markers, duration of symptoms, histology, treatment modality, follow-up duration, and short- and long-term outcomes. The use of a quality assessment (eg, the Newcastle-Ottawa Scale; available at www.ohri.ca/programs/clinical_epidemiology/oxford.asp) was considered inappropriate because these instruments had not been developed to study case reports or series. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed (20).
Statistical analysis
Values for the biochemical variables were converted to SI units. For thyroid function tests, values were included only if laboratory references ranges were provided. If normally distributed, mean ± SD was used; otherwise, median and range was used. Statistical significance was defined as P less than .05. All analyses were performed using Rcmdr (R Commander; R package, version 2.4-1; in R version 3.4.2).
Results
The systematic search identified 504 potentially relevant records. After removal of duplicates and screening for eligibility, 149 articles were identified with 212 individuals diagnosed with RT (Fig. 1) (5, 8, 9, 13, 14, 16, 17, 21-162). Records ranged from the year 1925 to 2019.
Flowchart illustrating the procedure for article inclusion and exclusion in a meta-analysis of Riedel thyroiditis. A systematic search of PubMed/MEDLINE and Web of Science up to September 1, 2019, with manual searching of reference lists, identified 149 relevant reports of Riedel thyroiditis.
Patient characteristics
The mean age of a patient presenting with RT was 47 years with the majority being female (81%) (Table 1). The most common ethnicities were Caucasian followed by Asian. Smoking status was often not recorded but the majority for whom data were available were nonsmokers. Prior thyroid status was known in 150 individuals with the majority having known hypothyroidism (46%) or euthyroidism (44%). The remaining had hyperthyroidism (7%), subclinical hypothyroidism (2%), or subclinical hyperthyroidism (1%). Other comorbidities were often not disclosed; however, in those with these data available (99 cases), 80% had no described comorbidity. Of those, diabetes was the most common at 7% of individuals.
Meta-analysis of 212 individuals with Riedel thyroiditis
| Variable | Cases | Total No. of cases with information |
|---|---|---|
| Sex | Male n = 41 (19.3%) Female n = 171 (80.7%) | 212 |
| Age, y | 47 (10.5-81) | 212 |
| Ethnicity | Caucasian n = 55 (56%) Asian n = 32 (33%) African n = 5 (5%) Black n = 2 (2%) Arab n = 2 (2%) Persian n = 2 (2%) | 98 |
| Smoking status | Smokers n = 14 (16%) | 89 |
| Comorbidities | None n = 79 (80%) •Asthma n = 3 (3%) •Diabetes n = 7 (7%) •Cerebrovascular disease n = 1 (1%) •Coronary artery disease n = 1 (1%) •Chronic kidney disease n = 2 (2%) •Hashimoto disease n = 2 (2%) •Graves disease n = 1 (1%) •Multiple sclerosis n = 1 (1%) •Behçet n = 1 (1%) •Thyroid malignancy n = 1 (1%) | 99 |
| Presenting complaint Swelling Dyspnea Neck pain Hoarse voice Stridor Dysphagia | n = 162 (89%) n = 83 (50%) n = 64 (41%) n = 69 (41%) n = 44 (31%) n = 97 (63%) | 182 167 155 166 144 153 |
| Duration of symptoms, mo | 4 (0.1-180) | 128 |
| Prior thyroid status | Hyperthyroidism n = 10 (7%) Hypothyroidism n = 70 (46%) Euthyroidism n = 66 (44%) Subclinical hypothyroidism n = 3 (2%) Subclinical hyperthyroidism n = 1 (1%) | 150 |
| Clinical status at review | Hyperthyroidism n = 23 (11%) Hypothyroidism n = 8 (4%) Euthyroidism n = 49 (23%) Subclinical hypothyroidism n = 13 (6%) Subclinical hyperthyroidism n = 2 (1%) Sick euthyroidism n = 1 (0.5%) | 212 |
| Thyroid peroxidase antibody status | Positive n = 40 (43%) Negative n = 52 (57%) | 92 |
| Thyrotropin receptor stimulating antibody | Positive n = 2 (20%) Negative n = 8 (80%) | 10 |
| Thyroglobulin antibody | Positive n = 17 (27%) Negative n = 45 (73%) | 62 |
| CRP | High n = 18 (72%) | 25 |
| ESR | High n = 31 (97%) | 32 |
| Histology | Fibrous tissue n = 179 (100%) Lymphocyte infiltrate n = 175 (98%) Occlusive phlebitis n = 77 (43%) Concomitant malignancy n = 1 (0.5%) | 179 |
| Size, cm | 3.1 (1-13) | 59 |
| Surgery | No n = 37 (18%) Tracheostomy n = 20 (10%) Isthmectomy n = 13 (6%) Thyroidectomy n = 70 (34%) Hemithyroidectomy n = 25 (12%) Surgery unspecified n = 40 (20%) | 205 |
| Weight of thyroid, g | 70 (7-417) | 23 |
| Tracheal compression | n = 122 (75%) | 162 |
| Size of tracheal compression, mm | 8 (5–20) | 10 |
| Glucocorticoids | n = 121 (70%) | 173 |
| Duration of glucocorticoids, mo | 3 (0.1-60) | 65 |
| Prednisolone | 40 mg/d (0.5-100 mg) Dose duration 3 mo (0.1-60 mo) | 53 |
| Dexamethasone | 10 mg/d: 1 Dose not given: 2 No duration data | 3 |
| Methylprednisolone | 62 mg/d (4-1000) Dose duration 2 mo (0.1-24) | 11 |
| Betamethasone | 5.5 mg/d (3-8) Dose duration 2 results: 4 and 11 mo | 4 |
| Tamoxifen | 20 mg/d (10-40) Dose duration 8 mo (1-48 mo) | 28 |
| Rituximab | 1 g/d IV Dose duration 3 mo | 3 |
| Other treatment | Alfacalcidol (1 μg) n = 1 Azathioprine (40 mg/d, 125 mg/d, and 50 mg 3×/d) n = 4 Cortisone acetate (30 and 100 mg) n = 2 Fluorouracil n = 1 Warfarin n = 2 Mycophenolate mofetil 2 g/d n = 1 | |
| Follow-up duration, mo | 12 (0.1-566) | 120 |
| Follow-up data | Improved n = 154 (90%) Some improvement but not completely n = 5 (3%) -Goiter resolved but ongoing hoarseness -Continued right vocal cord paralysis but resolution of symptoms -Postoperative dysphonia -Residual hoarseness -Ongoing vocal cord palsy No improvement n = 12(7%) -Goiter unchanged n = 6 -Recurrence n = 4 -Death from Riedel thyroid disease n = 2 | 171 |
| Death | 10 (4.7%) | 212 |
| Cause of death | Pneumonia n = 1 (10%) Acute myocardial infarct n = 1 (10%) Riedel progression with systemic fibrosis n = 2 (20%) Secondary hemorrhage from tracheostomy n = 1 (10%) Hydronephrosis n = 1 (10%) Unclear n = 1 (10%) Pneumonia in combination with myxedema n = 1 (10%) Septic shock 15 d after surgical debridement n = 1 (10%) |
| Variable | Cases | Total No. of cases with information |
|---|---|---|
| Sex | Male n = 41 (19.3%) Female n = 171 (80.7%) | 212 |
| Age, y | 47 (10.5-81) | 212 |
| Ethnicity | Caucasian n = 55 (56%) Asian n = 32 (33%) African n = 5 (5%) Black n = 2 (2%) Arab n = 2 (2%) Persian n = 2 (2%) | 98 |
| Smoking status | Smokers n = 14 (16%) | 89 |
| Comorbidities | None n = 79 (80%) •Asthma n = 3 (3%) •Diabetes n = 7 (7%) •Cerebrovascular disease n = 1 (1%) •Coronary artery disease n = 1 (1%) •Chronic kidney disease n = 2 (2%) •Hashimoto disease n = 2 (2%) •Graves disease n = 1 (1%) •Multiple sclerosis n = 1 (1%) •Behçet n = 1 (1%) •Thyroid malignancy n = 1 (1%) | 99 |
| Presenting complaint Swelling Dyspnea Neck pain Hoarse voice Stridor Dysphagia | n = 162 (89%) n = 83 (50%) n = 64 (41%) n = 69 (41%) n = 44 (31%) n = 97 (63%) | 182 167 155 166 144 153 |
| Duration of symptoms, mo | 4 (0.1-180) | 128 |
| Prior thyroid status | Hyperthyroidism n = 10 (7%) Hypothyroidism n = 70 (46%) Euthyroidism n = 66 (44%) Subclinical hypothyroidism n = 3 (2%) Subclinical hyperthyroidism n = 1 (1%) | 150 |
| Clinical status at review | Hyperthyroidism n = 23 (11%) Hypothyroidism n = 8 (4%) Euthyroidism n = 49 (23%) Subclinical hypothyroidism n = 13 (6%) Subclinical hyperthyroidism n = 2 (1%) Sick euthyroidism n = 1 (0.5%) | 212 |
| Thyroid peroxidase antibody status | Positive n = 40 (43%) Negative n = 52 (57%) | 92 |
| Thyrotropin receptor stimulating antibody | Positive n = 2 (20%) Negative n = 8 (80%) | 10 |
| Thyroglobulin antibody | Positive n = 17 (27%) Negative n = 45 (73%) | 62 |
| CRP | High n = 18 (72%) | 25 |
| ESR | High n = 31 (97%) | 32 |
| Histology | Fibrous tissue n = 179 (100%) Lymphocyte infiltrate n = 175 (98%) Occlusive phlebitis n = 77 (43%) Concomitant malignancy n = 1 (0.5%) | 179 |
| Size, cm | 3.1 (1-13) | 59 |
| Surgery | No n = 37 (18%) Tracheostomy n = 20 (10%) Isthmectomy n = 13 (6%) Thyroidectomy n = 70 (34%) Hemithyroidectomy n = 25 (12%) Surgery unspecified n = 40 (20%) | 205 |
| Weight of thyroid, g | 70 (7-417) | 23 |
| Tracheal compression | n = 122 (75%) | 162 |
| Size of tracheal compression, mm | 8 (5–20) | 10 |
| Glucocorticoids | n = 121 (70%) | 173 |
| Duration of glucocorticoids, mo | 3 (0.1-60) | 65 |
| Prednisolone | 40 mg/d (0.5-100 mg) Dose duration 3 mo (0.1-60 mo) | 53 |
| Dexamethasone | 10 mg/d: 1 Dose not given: 2 No duration data | 3 |
| Methylprednisolone | 62 mg/d (4-1000) Dose duration 2 mo (0.1-24) | 11 |
| Betamethasone | 5.5 mg/d (3-8) Dose duration 2 results: 4 and 11 mo | 4 |
| Tamoxifen | 20 mg/d (10-40) Dose duration 8 mo (1-48 mo) | 28 |
| Rituximab | 1 g/d IV Dose duration 3 mo | 3 |
| Other treatment | Alfacalcidol (1 μg) n = 1 Azathioprine (40 mg/d, 125 mg/d, and 50 mg 3×/d) n = 4 Cortisone acetate (30 and 100 mg) n = 2 Fluorouracil n = 1 Warfarin n = 2 Mycophenolate mofetil 2 g/d n = 1 | |
| Follow-up duration, mo | 12 (0.1-566) | 120 |
| Follow-up data | Improved n = 154 (90%) Some improvement but not completely n = 5 (3%) -Goiter resolved but ongoing hoarseness -Continued right vocal cord paralysis but resolution of symptoms -Postoperative dysphonia -Residual hoarseness -Ongoing vocal cord palsy No improvement n = 12(7%) -Goiter unchanged n = 6 -Recurrence n = 4 -Death from Riedel thyroid disease n = 2 | 171 |
| Death | 10 (4.7%) | 212 |
| Cause of death | Pneumonia n = 1 (10%) Acute myocardial infarct n = 1 (10%) Riedel progression with systemic fibrosis n = 2 (20%) Secondary hemorrhage from tracheostomy n = 1 (10%) Hydronephrosis n = 1 (10%) Unclear n = 1 (10%) Pneumonia in combination with myxedema n = 1 (10%) Septic shock 15 d after surgical debridement n = 1 (10%) |
Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IV, intravenous.
Meta-analysis of 212 individuals with Riedel thyroiditis
| Variable | Cases | Total No. of cases with information |
|---|---|---|
| Sex | Male n = 41 (19.3%) Female n = 171 (80.7%) | 212 |
| Age, y | 47 (10.5-81) | 212 |
| Ethnicity | Caucasian n = 55 (56%) Asian n = 32 (33%) African n = 5 (5%) Black n = 2 (2%) Arab n = 2 (2%) Persian n = 2 (2%) | 98 |
| Smoking status | Smokers n = 14 (16%) | 89 |
| Comorbidities | None n = 79 (80%) •Asthma n = 3 (3%) •Diabetes n = 7 (7%) •Cerebrovascular disease n = 1 (1%) •Coronary artery disease n = 1 (1%) •Chronic kidney disease n = 2 (2%) •Hashimoto disease n = 2 (2%) •Graves disease n = 1 (1%) •Multiple sclerosis n = 1 (1%) •Behçet n = 1 (1%) •Thyroid malignancy n = 1 (1%) | 99 |
| Presenting complaint Swelling Dyspnea Neck pain Hoarse voice Stridor Dysphagia | n = 162 (89%) n = 83 (50%) n = 64 (41%) n = 69 (41%) n = 44 (31%) n = 97 (63%) | 182 167 155 166 144 153 |
| Duration of symptoms, mo | 4 (0.1-180) | 128 |
| Prior thyroid status | Hyperthyroidism n = 10 (7%) Hypothyroidism n = 70 (46%) Euthyroidism n = 66 (44%) Subclinical hypothyroidism n = 3 (2%) Subclinical hyperthyroidism n = 1 (1%) | 150 |
| Clinical status at review | Hyperthyroidism n = 23 (11%) Hypothyroidism n = 8 (4%) Euthyroidism n = 49 (23%) Subclinical hypothyroidism n = 13 (6%) Subclinical hyperthyroidism n = 2 (1%) Sick euthyroidism n = 1 (0.5%) | 212 |
| Thyroid peroxidase antibody status | Positive n = 40 (43%) Negative n = 52 (57%) | 92 |
| Thyrotropin receptor stimulating antibody | Positive n = 2 (20%) Negative n = 8 (80%) | 10 |
| Thyroglobulin antibody | Positive n = 17 (27%) Negative n = 45 (73%) | 62 |
| CRP | High n = 18 (72%) | 25 |
| ESR | High n = 31 (97%) | 32 |
| Histology | Fibrous tissue n = 179 (100%) Lymphocyte infiltrate n = 175 (98%) Occlusive phlebitis n = 77 (43%) Concomitant malignancy n = 1 (0.5%) | 179 |
| Size, cm | 3.1 (1-13) | 59 |
| Surgery | No n = 37 (18%) Tracheostomy n = 20 (10%) Isthmectomy n = 13 (6%) Thyroidectomy n = 70 (34%) Hemithyroidectomy n = 25 (12%) Surgery unspecified n = 40 (20%) | 205 |
| Weight of thyroid, g | 70 (7-417) | 23 |
| Tracheal compression | n = 122 (75%) | 162 |
| Size of tracheal compression, mm | 8 (5–20) | 10 |
| Glucocorticoids | n = 121 (70%) | 173 |
| Duration of glucocorticoids, mo | 3 (0.1-60) | 65 |
| Prednisolone | 40 mg/d (0.5-100 mg) Dose duration 3 mo (0.1-60 mo) | 53 |
| Dexamethasone | 10 mg/d: 1 Dose not given: 2 No duration data | 3 |
| Methylprednisolone | 62 mg/d (4-1000) Dose duration 2 mo (0.1-24) | 11 |
| Betamethasone | 5.5 mg/d (3-8) Dose duration 2 results: 4 and 11 mo | 4 |
| Tamoxifen | 20 mg/d (10-40) Dose duration 8 mo (1-48 mo) | 28 |
| Rituximab | 1 g/d IV Dose duration 3 mo | 3 |
| Other treatment | Alfacalcidol (1 μg) n = 1 Azathioprine (40 mg/d, 125 mg/d, and 50 mg 3×/d) n = 4 Cortisone acetate (30 and 100 mg) n = 2 Fluorouracil n = 1 Warfarin n = 2 Mycophenolate mofetil 2 g/d n = 1 | |
| Follow-up duration, mo | 12 (0.1-566) | 120 |
| Follow-up data | Improved n = 154 (90%) Some improvement but not completely n = 5 (3%) -Goiter resolved but ongoing hoarseness -Continued right vocal cord paralysis but resolution of symptoms -Postoperative dysphonia -Residual hoarseness -Ongoing vocal cord palsy No improvement n = 12(7%) -Goiter unchanged n = 6 -Recurrence n = 4 -Death from Riedel thyroid disease n = 2 | 171 |
| Death | 10 (4.7%) | 212 |
| Cause of death | Pneumonia n = 1 (10%) Acute myocardial infarct n = 1 (10%) Riedel progression with systemic fibrosis n = 2 (20%) Secondary hemorrhage from tracheostomy n = 1 (10%) Hydronephrosis n = 1 (10%) Unclear n = 1 (10%) Pneumonia in combination with myxedema n = 1 (10%) Septic shock 15 d after surgical debridement n = 1 (10%) |
| Variable | Cases | Total No. of cases with information |
|---|---|---|
| Sex | Male n = 41 (19.3%) Female n = 171 (80.7%) | 212 |
| Age, y | 47 (10.5-81) | 212 |
| Ethnicity | Caucasian n = 55 (56%) Asian n = 32 (33%) African n = 5 (5%) Black n = 2 (2%) Arab n = 2 (2%) Persian n = 2 (2%) | 98 |
| Smoking status | Smokers n = 14 (16%) | 89 |
| Comorbidities | None n = 79 (80%) •Asthma n = 3 (3%) •Diabetes n = 7 (7%) •Cerebrovascular disease n = 1 (1%) •Coronary artery disease n = 1 (1%) •Chronic kidney disease n = 2 (2%) •Hashimoto disease n = 2 (2%) •Graves disease n = 1 (1%) •Multiple sclerosis n = 1 (1%) •Behçet n = 1 (1%) •Thyroid malignancy n = 1 (1%) | 99 |
| Presenting complaint Swelling Dyspnea Neck pain Hoarse voice Stridor Dysphagia | n = 162 (89%) n = 83 (50%) n = 64 (41%) n = 69 (41%) n = 44 (31%) n = 97 (63%) | 182 167 155 166 144 153 |
| Duration of symptoms, mo | 4 (0.1-180) | 128 |
| Prior thyroid status | Hyperthyroidism n = 10 (7%) Hypothyroidism n = 70 (46%) Euthyroidism n = 66 (44%) Subclinical hypothyroidism n = 3 (2%) Subclinical hyperthyroidism n = 1 (1%) | 150 |
| Clinical status at review | Hyperthyroidism n = 23 (11%) Hypothyroidism n = 8 (4%) Euthyroidism n = 49 (23%) Subclinical hypothyroidism n = 13 (6%) Subclinical hyperthyroidism n = 2 (1%) Sick euthyroidism n = 1 (0.5%) | 212 |
| Thyroid peroxidase antibody status | Positive n = 40 (43%) Negative n = 52 (57%) | 92 |
| Thyrotropin receptor stimulating antibody | Positive n = 2 (20%) Negative n = 8 (80%) | 10 |
| Thyroglobulin antibody | Positive n = 17 (27%) Negative n = 45 (73%) | 62 |
| CRP | High n = 18 (72%) | 25 |
| ESR | High n = 31 (97%) | 32 |
| Histology | Fibrous tissue n = 179 (100%) Lymphocyte infiltrate n = 175 (98%) Occlusive phlebitis n = 77 (43%) Concomitant malignancy n = 1 (0.5%) | 179 |
| Size, cm | 3.1 (1-13) | 59 |
| Surgery | No n = 37 (18%) Tracheostomy n = 20 (10%) Isthmectomy n = 13 (6%) Thyroidectomy n = 70 (34%) Hemithyroidectomy n = 25 (12%) Surgery unspecified n = 40 (20%) | 205 |
| Weight of thyroid, g | 70 (7-417) | 23 |
| Tracheal compression | n = 122 (75%) | 162 |
| Size of tracheal compression, mm | 8 (5–20) | 10 |
| Glucocorticoids | n = 121 (70%) | 173 |
| Duration of glucocorticoids, mo | 3 (0.1-60) | 65 |
| Prednisolone | 40 mg/d (0.5-100 mg) Dose duration 3 mo (0.1-60 mo) | 53 |
| Dexamethasone | 10 mg/d: 1 Dose not given: 2 No duration data | 3 |
| Methylprednisolone | 62 mg/d (4-1000) Dose duration 2 mo (0.1-24) | 11 |
| Betamethasone | 5.5 mg/d (3-8) Dose duration 2 results: 4 and 11 mo | 4 |
| Tamoxifen | 20 mg/d (10-40) Dose duration 8 mo (1-48 mo) | 28 |
| Rituximab | 1 g/d IV Dose duration 3 mo | 3 |
| Other treatment | Alfacalcidol (1 μg) n = 1 Azathioprine (40 mg/d, 125 mg/d, and 50 mg 3×/d) n = 4 Cortisone acetate (30 and 100 mg) n = 2 Fluorouracil n = 1 Warfarin n = 2 Mycophenolate mofetil 2 g/d n = 1 | |
| Follow-up duration, mo | 12 (0.1-566) | 120 |
| Follow-up data | Improved n = 154 (90%) Some improvement but not completely n = 5 (3%) -Goiter resolved but ongoing hoarseness -Continued right vocal cord paralysis but resolution of symptoms -Postoperative dysphonia -Residual hoarseness -Ongoing vocal cord palsy No improvement n = 12(7%) -Goiter unchanged n = 6 -Recurrence n = 4 -Death from Riedel thyroid disease n = 2 | 171 |
| Death | 10 (4.7%) | 212 |
| Cause of death | Pneumonia n = 1 (10%) Acute myocardial infarct n = 1 (10%) Riedel progression with systemic fibrosis n = 2 (20%) Secondary hemorrhage from tracheostomy n = 1 (10%) Hydronephrosis n = 1 (10%) Unclear n = 1 (10%) Pneumonia in combination with myxedema n = 1 (10%) Septic shock 15 d after surgical debridement n = 1 (10%) |
Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IV, intravenous.
Presentation
The most common presenting symptoms were neck swelling (89%), dyspnea (50%), neck pain (41%), and hoarse voice (41%)(Fig. 2) (see Table 1). Obstructive symptoms were common with 31% presenting with stridor and 63% presenting with dysphagia. Symptoms had been present for a median of 4 months before seeking medical attention.
Graph demonstrating the incidence in percentage of common presenting symptoms of individuals with Riedel thyroiditis. Neck swelling was the most common presentation at 89%.
Antibody status
Most individuals did not have antibody positivity. However, antibody data were available for only 92 individuals and in those who had antibodies tested, antithyroid peroxidase antibody was the most common with 43% of patients being positive. Antithyroglobulin positivity was present in 27% of those tested. Thyrotropin receptor stimulating antibody was tested in only 10 individuals with 20% being positive. Biochemical thyroid status at time of presentation was not available for almost half of the included patients. Most commonly, patients were euthyroid (23%).
Inflammatory markers
Inflammatory markers were tested in only a minority but were commonly abnormal (see Table 1). An elevated C-reactive protein was found in 72% and the erythrocyte sedimentation rate was elevated in 97%. Owing to various laboratory reference ranges and often incomplete data provision, median or mean levels could not be calculated.
Size and weight of the thyroid in addition to tracheal compression
Size and weight data of resected thyroid specimens were available for 59 and 23 cases, respectively. The thyroid size at its largest dimension was 3.1 cm (range, 1-13 cm). Weight was 70 g (range, 7-417 g) (see Table 1).
Owing to the large size and fibrosis, tracheal compression was common, with 75% of individuals demonstrating this on radiological imaging with the tracheal size being reduced to 8 mm (range, 5-20 mm) with the standard trachea size being 15 to 20 mm.
Histopathology
In cases in which RT was clinically suspected, confirmation was performed through a surgical biopsy or a total or hemithyroidectomy. Detailed histology data were available in 179 cases with fibrous tissue being present in all samples (100%). Other common findings included lymphocyte infiltrate (98%) and occlusive phlebitis in 43% of cases. Concomitant follicular carcinoma was uncommon, with only one case (0.5%).
Surgical treatment
Treatment included medical management with immunosuppressive agents or decompression through surgical intervention. Often a mixture of both modalities was used. There were 205 cases in which surgical treatment was discussed. Of these, 82% underwent some surgical intervention (see Table 1). In these individuals, the most common intervention was total thyroidectomy (34%). In 20%, the surgical intervention used was unidentified. Other interventions included tracheostomy (10%), isthmectomy (6%), and hemithyroidectomy (12%). Exploration of complications rates was outside the scope of this paper and were not reported widely.
Medical treatment with glucocorticoids
Glucocorticoids were used in 70% of individuals with a duration of 3 months (range, 3 days-60 months) (see Table 1). Prednisone was the most commonly used glucocorticoid, usually at 40 mg orally once daily (range, 0.5-100 mg). The most common duration of prednisolone treatment was 3 months.
Other glucocorticoids included dexamethasone, methylprednisone, and betamethasone. Dexamethasone was used in only 3 cases. The dose used was 10 mg once daily for an unclear duration.
Methylprednisone was the second most commonly used glucocorticoid after prednisone. There were 11 cases (10% cases), with the most common dose being 62 mg once daily. Treatment continued for 2 months (range, 3 days-24 months).
Betamethasone was used in 4 cases with variable dosing of 3 to 8 mg/day. Dose duration was available in only 2 cases and were 4 and 11 months, respectively.
There were 2 cases of cortisone acetate treated at 30 mg and 100 mg, respectively, of which the duration was unclear.
Nonglucocorticoid agents
Nonglucocorticoid agents otherwise used included tamoxifen, rituximab, and azathioprine. Tamoxifen was used in 28 cases (14%) with a median dose of 20 mg once daily (range, 10-40 mg). Duration was 8 months (range, 1-48 months).
Azathioprine was used in 4 cases. Of these, dosages were available in 3 cases at 40 mg once daily, 50 mg 3 times daily, and 125 mg once daily. Rituximab was also used in 3 cases at a dose of 1 g intravenous monthly for 3 months. There was one case using mycophenolate mofetil at 1 g twice daily in combination with prednisone at 100 mg daily of unclear duration.
Follow-up
The majority of cases had a good prognosis following treatment. The median follow-up was 12 months (range, 0.1-566 months) (see Table 1). Of these, 90% had improvement or resolution of their symptoms. In 5 cases, there was some minor improvement but persistent symptoms, usually ongoing persistent hoarseness (13, 36, 84, 135).
In 12 cases (2.7%) there was no improvement with the treatment used (5, 9, 13, 28, 57, 59, 70, 113, 118, 139), with 2 deaths from progression of RT (5, 57). In 6 cases, there was no change in goiter size (9, 13, 28, 113, 118, 139). In 4 cases, there was recurrence of disease (5, 13, 59, 70). The first case was a 39-year-old woman with preexisting hypothyroidism, an enlarged thyroid, and a spiculated, 1.8-cm right apex lung nodule (59). Both the thyroid and pulmonary nodule demonstrated fibroinflammatory process on biopsy. She was treated with prednisone 60 mg once daily with initial resolution of symptoms. However, on tapering, the goiter enlarged, and she was started on tamoxifen. She progressed to have lacrimal enlargement 1-year posttamoxifen. Further follow-up data were not available, but thyroid disease with elevated IgG4 was suspected. The second case was a 25-year-old woman with 4 years of transient dosing of steroids with periods of activation of disease (5). Eventually, she proceeded to thyroidectomy with removal of some lymph nodes because of lymph node biopsy evidence of plasma cell infiltration. Eight years after surgery, and 12 years after initial presentation, the patient still had symptomatic exacerbations, treated with prednisolone for different periods of time. Over the next 22 years, she required azathioprine, mycophenolate, and rituximab because of the limited efficacy of any single agent and ongoing inflammation. The third case was of a 31-year-old man treated with subtotal thyroidectomy and 2 courses of prednisone with an initial good response but later relapse (13). Further details were not provided. The fourth case was of a 35-year-old woman presenting with a partial nasal obstruction. A tan-colored tumor was found of fibrous tissue with scattered plasma infiltrates (70). Seven years later, a left neck mass developed with rapid progression in size and subsequent dysphagia, dyspnea, and dysphonia. She was biochemically euthyroid. Surgical histopathology confirmed RT with involvement of the left recurrent laryngeal nerve. Isthmus and half of the left thyroid lobe was removed because of obscurity of the planes of dissection. She was placed on 2 weeks of steroids and long-term suppressive thyroxine treatment. One year after surgery, the left neck mass recurred with dysphagia with resolution after a short course of steroids.
In 10 cases (5%), the individual died; 5 were potentially related to RT (progression of RT n = 2, myxedema and pneumonia n = 1, septic shock 15 days after surgical debridement n = 1, secondary hemorrhage from tracheostomy n = 1). The 2 deaths from progression of RT included an 81-year-old woman whose initial presentation was of a toxic adenoma treated with the block and replacement method (5). Four years later, she presented with a 55-mm neck mass, dysphagia, and tracheal compression, requiring urgent tracheostomy. Histology confirmed RT and the patient declined surgery. She received betamethasone at 7 mg daily and tamoxifen at 20 mg daily with a mild improvement in size. Steroids was gradually down-titrated and 6 months later while on 2 mg betamethasone, her neck mass significantly grew. She was changed to 60 mg prednisone but 1 month later and 4.5 years from initial presentation she was found dead. The second case involved a 51-year-old man with a large goiter with mediastinal invasion who underwent an isthmectomy but died following progression of his RT (57).
Discussion
The present systematic review identifying 212 cases of Riedel thyroiditis is the largest and most complete review to date. Additionally, to the best of our knowledge, it is the first study to provide quantitative analysis of patient characteristics and outcomes.
Women were more commonly affected, which is similar to the experience from the Mayo Clinic (13). At Mayo, the age group most affected comprised those between age 30 and 50 years, further reflecting the present study with the median age being 47 years. The present meta-analysis also demonstrated that the majority affected were of Caucasian or Asian descent and nonsmokers. Contrastingly, in the Mayo Clinic series, 76% had a smoking history and 48% were current smokers (13). This may be reflective of the changing health practices over time with a general decline in smoking prevalence rates due to public education.
Individuals with RT commonly present with a firm thyroid mass and associated swelling (89% in the present meta-analysis). Owing to the fibrous enlargement of the thyroid gland, compressive symptoms such as dyspnea, dysphagia, hoarseness, and dysphonia were common. In the present meta-analysis, obstructive symptoms of stridor were present in 31% and 63% presented with dysphagia. Tracheal compression was found in 75% on radiological imaging, with the tracheal size being reduced to 8 mm. The clinical course was variable with symptoms before diagnosis ranging from 3 days to 15 years, with a median time of 4 months. This may seem to be a long time, but RT is an uncommon disorder that may delay the diagnosis (5).
Primary hypothyroidism has been demonstrated in 25% to 80% at some stage of the disease process in some studies (9, 13, 163) and this was further supported by our analysis because 46% of individuals had known hypothyroidism preceding the disease process. Hypothyroidism has been postulated to be a consequence of the infiltrate process or due to concomitant Hashimoto thyroiditis (9, 113, 164, 165). Other presentations include thyrotoxicosis due to subacute (de Quervain) thyroiditis or possibly lymphocytic subacute thyroiditis (17, 84). A minority of patients had presented with hyperthyroidism attributed to Graves disease (8, 60). This was difficult to confirm in our meta-analysis because of the paucity of thyrotropin receptor antibody testing, with only a few individuals being tested, but of these 20% were positive.
Regarding the presence of other antibodies, initial reports suggested no direct correlation (14, 118, 164). However, with time and further case reports, thyroid antibody positivity was being increasingly detected with up to a 67% positivity in Schwaegerle et al and a 90% antibody positivity in the Mayo Clinic study (13, 74, 163). Our meta-analysis has further delineated the degree of antibody positivity, with 43% of individuals being antithyroid peroxidase positive and 27% being thyroglobulin antibody positive. Along with antibody positivity, inflammatory markers were typically raised, with 72% of individuals having an elevated C-reactive protein and 97% having an elevated erythrocyte sedimentation rate.
Although clinical history, examination, biochemical makers, and imaging studies can assist in the diagnosis of RT, the diagnosis is confirmed on histology. Histological confirmation is required because RT can often mimic thyroid malignancy in its clinical presentation of a slow-growing firm mass with associated goiter-related compressive symptoms. Imaging and biochemical pathology are not useful in differentiating between the 2 pathologies, except that hypothyroidism may be more prevalent if the infiltrative process in RT involves the entire thyroid (15, 164). Results of fine-needle aspiration are usually nondiagnostic and surgical biopsy is often required. The diagnosis is confirmed with the following (166): 1) a fibroinflammatory process in the thyroid with extension into surrounding tissue; 2) inflammatory infiltrate containing no giant cells, lymphoid follicles, oncocytes, or granulomas; 3) evidence of occlusive phlebitis; and 4) no evidence of thyroid malignancy. In our review, not all biopsy results were available. Detailed histology data were available in 179 cases with fibrous tissue in all samples, lymphocytic infiltrate in 98%, and occlusive phlebitis in 43% of cases. There was evidence of concomitant metastatic thyroid malignancy in one case (2 × 1.5 cm follicular carcinoma) and as such this does not strictly meet the histopathological criteria, but we chose to include this because the thyroid malignancy was not the major part of the thyroid disease and the authors had determined that all other signs were in accordance with RT and not primarily thyroid cancer (103). Based on the occurrence of lymphocytic infiltrate in the majority of the cases, we cannot with certainty exclude that a significant number of patients diagnosed with RT might in fact have been suffering from a fibrous variant of Hashimoto thyroiditis. With a fibrosing variant of Hashimoto thyroiditis, extrathyroidal extension of fibrosis and obliterative phlebitis are absent. Histologically, Hashimoto thyroiditis demonstrates κ-dominant lymphocyte light chains as opposed to λ-dominant in RT, and plasma cell production is more IgG:IgA deviated than in RT (15, 164). In all, these disease entities might be co-occurring to a larger extent than previously thought; alternatively, the true incidence of RT is even lower than presented in the scientific literature. Even so, this also highlights the rather disparate criteria for diagnosing RT from a histopathological standpoint and advocates the need for more stringent criteria rather than just the occurrence of a fibrous process in the thyroid.
There is no consensus regarding the management of RT. Definitive treatment with surgical management is sometimes required in the case of obstructive symptoms. Owing to the obliteration of tissue planes by the fibrotic process, surgical intervention can lead to complications such as hypoparathyroidism and recurrent nerve damage (13). Because of limited data from the case series, it was difficult to explore these complications in our systemic review, which revealed 82% underwent surgical intervention; the most common interventions were total thyroidectomy followed by tracheostomy, hemithyroidectomy, and isthmectomy.
Medical therapy is often the first-line management in the absence of obstructive symptoms. Common therapies include glucocorticoids and tamoxifen, both of which are not validated by randomized controlled trials because of the rarity of the condition (18). Various glucocorticoid doses have been reported (18). In our meta-analysis, 70% of individuals took glucocorticoids for a median duration of 3 months (range, 3 days-60 months), the most common being prednisone at 40 mg daily. It has been claimed that active smokers with more aggressive fibrotic progression often needed repeated courses and longer duration of glucocorticoid therapy compared with nonsmokers (13). Unfortunately, we were unable to explore this correlation because of the paucity of data.
Tamoxifen has also been commonly used because of its anti-inflammatory role through induction of autocrine secretion of transforming growth factor β1 and subsequent inhibition of fibroblastic function (95, 167). Doses of 10 to 40 mg of tamoxifen are often used as reflected by our meta-analysis. Among the 28 patients receiving tamoxifen, the duration was 8 months. Other therapies demonstrated in our review included azathioprine (4 cases), rituximab (3 cases) ,and mycophenolate mofetil (1 case).
The majority of patients improve or remain stable with medical and surgical management. The Mayo Clinic study showed that 86% of patients were stable or improved symptomatically (13). In our meta-analysis, the prognosis was better, with 90% having improvements or resolution to their symptoms with a median follow-up of 12 months. In 5 cases, there was some minor improvement and in 12 cases, there was no improvement with the treatment used. Two individuals died directly from systemic progression of fibrotic disease from their RT (57, 162). Owing to the small numbers, it is difficult to ascertain any clear factors that may have contributed to the poor prognosis.
Although our systematic review and meta-analysis are the largest summary of data on RT to date, it was still limited by a paucity of data and the absence of a control population. A potential bias could be in the reporting of favorable outcomes. Additionally, uniformity in techniques/assays used for biochemical measurements and references ranges was not available, limiting the interpretation of certain data. Also, because of the limited data available, our meta-analysis was unable to focus on the presence of extrathyroidal fibrosis or surgical complications including hypoparathyroidism. In the Mayo series (13), 8 patients had disease occurring in 1 or more extrathyroidal locations, with 4 patients with fibrosing mediastinitis, 3 with retroperitoneal fibrosis, and 1 with orbital fibrosis. Furthermore, our meta-analysis was unable to explore thyroid status at the end of follow-up largely because of the limitation of data available and the likelihood of hypothyroidism due to potential thyroidectomy or progressive fibrotic transition of the thyroid. In the Mayo series, 81% of patients were hypothyroid, 10% were euthyroid, and 5% were hyperthyroid with a diagnosis of Graves disease (13). With the increasing prevalence of fibrosing disease, analysis of the presence of IgG4 would also be of benefit.
Conclusion
RT is a rare diagnosis. The purpose of this systematic review and meta-analysis was to provide information on the common presentation features that may alert to the diagnosis. Findings that increased the likelihood were restrictive or infiltrative symptoms, which may be out of proportion to the size or extent of the demonstrable mass lesion. Surgical intervention may be used as diagnosis or intervention, noting that previous studies have suggested an increased risk of complications from surgical intervention. Medical therapy in RT focuses predominantly on the use of glucocorticoids and tamoxifen with variable duration and dosages used. The long-term outcomes seem favorable.
Abbreviations
Acknowledgments
Financial Support: This work was supported by the Magnus Bergvall Foundation (grant numbers 2017-02138, 2018-02566, and 2019-03149 to H.F.).
Additional Information
Disclosure Summary: The authors have nothing to disclose.
Data Availability: All data generated or analyzed during this study are included in this published article or in the data repositories listed in “References.”
