Thyroid nodule natural history, complications and prognosis
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. 
A solitary thyroid nodule can become symptomatic if it grows rapidly due to hemorrhage or malignancies, invades laryngeal nerves, compressing nearby structures, and secretory nodules that produce TSH. Thyroid nodules may be a manifestation of thyroid cancer, that usually develops in the 6th decade of life, and start with symptoms such as weight loss, fatigue, and hoarseness. Without treatment, the patient with benign nodules may remain asymptomatic, while the patients with thyroid neoplasm may develop distant metastasis, which may eventually lead to death. The most common complications of thyroid nodules are hoarseness, horner syndrome, nodule rupture, needle track seeding, hemorrhage/hematoma, dysphagia, upper airway obstruction, pain, skin burn, vasovagal reaction, hypothyroidism, transient thyrotoxicosis, anaphylactic reaction, thromboembolism, and pneumothorax. Benign thyroid nodules have great prognosis, while prognosis of malignant thyroid nodules may be determined based on their type by scoring system of TNM staging.
- Thyroid nodules are mostly asymptomatic. A solitary thyroid nodule can become symptomatic if:
- Grows rapidly due to hemorrhage or malignancies
- Invades laryngeal nerves
- Compress nearby structures including:
- Secretory nodules that produce TSH
A simple thyroid nodule without any complication usually remain asymptomatic, may resolve spontaneously or may progress to other malignant diseases. Thyroid nodules can be a manifestation of thyroid cancer, that usually develops in the 6th decade of life, and start with symptoms such as weight loss, fatigue, and hoarseness.
Without treatment, the patient with benign nodules may remain asymptomatic, while the patients with thyroid neoplasm may develop distant metastasis, which may eventually lead to death.
- Noncancerous thyroid nodules are not life threatening. Many do not require treatment. Follow-up exams are enough. On the other hand, cancerous thyroid nodules can lead to a different variety of complications, depending on the type of cancer.
- Common complications of thyroid nodules include:
|Needle track seeding||
|Upper airway obstruction||
|Pain/sensation of heat||
||Mostly due to:
||May cause pneumothorax due to apical pleural injury in:
The American Joint Committee on Cancer (AJCC) introduced the TNM staging system for evaluating thyroid cancer prognosis.
|T categories for thyroid cancer (other than anaplastic thyroid cancer)|
Primary tumor cannot be assessed.
|T0||No evidence of primary tumor.|
|T1||T1a||The tumor is 1 cm (less than half an inch) across or smaller and has not grown outside the thyroid.|
|T1b||The tumor is larger than 1 cm but not larger than 2 cm across and has not grown outside of the thyroid.|
|T2||The tumor is more than 2 cm but not larger than 4 cm (slightly less than 2 inches) across and has not grown out of the thyroid.|
|T3||The tumor is larger than 4 cm across, or it has just begun to grow into nearby tissues outside the thyroid.|
|T4||T4a||The tumor is any size and has grown extensively beyond the thyroid gland into nearby tissues of the neck, such as the larynx (voice box), trachea (windpipe), esophagus (tube connecting the throat to the stomach), or the nerve to the larynx. This is also called moderately advanced disease.|
|T4b||The tumor is any size and has grown either back toward the spine or into nearby large blood vessels. This is also called very advanced disease.|
|T categories for anaplastic thyroid cancer|
|T4||T4a||The tumor is still within the thyroid.|
|T4b||The tumor has grown outside the thyroid.|
|N categories for thyroid cancer|
|NX||Regional (nearby) lymph nodes cannot be assessed.|
|N1||N0||The cancer has not spread to nearby lymph nodes.|
|N1a||The cancer has spread to lymph nodes around the thyroid in the neck (called pretracheal, paratracheal, and prelaryngeal lymph nodes).|
|N1b||The cancer has spread to other lymph nodes in the neck (called cervical) or to lymph nodes behind the throat (retropharyngeal) or in the upper chest (superior mediastinal).|
|M categories for thyroid cancer|
|MX||Distant metastasis cannot be assessed.|
|M0||There is no distant metastasis.|
|M1||The cancer has spread to other parts of the body, such as distant lymph nodes, internal organs, bones, etc.|
Once thyroid cancer diagnosis is made, the values for T, N, and M should be determined to be combined into stages. Unlike most other cancers, thyroid cancer staging system considers cancer subtype and the patient’s age for determining the prognosis.
Staging of thyroid tumors is the most valid way to determine cancer's prognosis. The best prognostic factor considering thyroid cancer is 5 year survival rate since the diagnosis date. The latest survival statistics were provided by AJCC, based on the staging of thyroid cancer during initial diagnosis phase. These statistics were published in 2010 in the 7th edition of AJCC Cancer Staging Manual.
|Cancer type||Stage||Definition||5 year survival rate|
|Papillary or follicular (differentiated) thyroid cancer in patients younger than 55||Stage I (Any T, Any N, M0)||
|Stage II (Any T, Any N, M1)||
|Papillary or follicular (differentiated) thyroid cancer in patients 55 years and older||Stage I (T1, N0, M0)||
|Stage II (T2, N0, M0)||
|Stage III||One of the following applies:
|Stage IVA||One of the following applies:
|Stage IVB (T4b, Any N, M0)||
|Stage IVC (Any T, Any N, M1)||
|Medullary thyroid cancer||Stage I (T1, N0, M0)||
|Stage II||One of the following applies:
|Stage III (T1 to T3, N1a, M0)||
|Stage IVA||One of the following applies:
|Stage IVB (T4b, Any N, M0)||
|Stage IVC (Any T, Any N, M1)||
|Anaplastic (undifferentiated) thyroid cancer||Stage IVA (T4a, Any N, M0)||
|Stage IVB (T4b, Any N, M0)||
|Stage IVC (Any T, Any N, M1)||
There is no evidence that radiation-associated thyroid cancers are more aggressive than other thyroid cancers.
Recent large prospective studies have confirmed the ability of genetic markers (BRAF, Ras, RET=PTC) and protein markers (galectin-3) to improve preoperative diagnostic accuracy for patients with indeterminate thyroid nodules. Thyroid nodules diagnosed as benign require follow-up because of a low, but not negligible, false-negative rate of up to 5% with FNA. False negative diagnosis may be even higher with nodules>4 cm. While benign nodules may decrease in size, malignant tumors often increase in size, albeit slowly. Morbidity and mortality are increased in patients with distant metastases, but individual prognosis depends upon factors including histology of the primary tumor, distribution and number of sites of metastases (e.g., brain, bone, lung), tumor burden, age at diagnosis of metastases, and 18FDG and radio-active iodine avidity.  Improved survival is associated with responsiveness to surgery and or radio-active iodine. The rate of survival in patients with distant metastases is variable, depending upon the site of metastases. Among patients with small pulmonary metastases but no other metastases outside of the neck, the 10-year survival rate is 30 to 50 percent; even higher survival rates have been reported in patients whose pulmonary metastases were detected only by radio-iodine imaging.
Overall predictive value of thyroid nodule malignancies is low. The most important related clinical features that can be associated with a more accurate malignancy diagnosis include:
- Male sex
- Nodule size (>4 cm)
- Oder patient age
- Cytologic features such as presence of atypia can improve the diagnostic accuracy for malignancy in patients with indeterminate cytology, overall predictive values are still low
|Comparison of carcinomas|
|Thyroid cancer type|
|Follicular carcinoma||Papillary thyroid carcinoma|
|• Peak incidence between ages 40 and 60 years |
• Presence of local clinical symptoms and infiltration into neighboring structures as the main predictive factors
• Rates of disease-free patients are 71% at 5 years and 58% at 10 years
• Gender specificity, with an approximate prevalence of three times more in women than in men
|• Peak incidence between the ages of 30 to 50 yearsm |
• Cancer-related mortality in patients without metastases at presentation who underwent total thyroidectomy, with a median follow-up of 16 years, is around 6 percent 
• Mortality increases progressively with advancing age without a specific age cutoff that stratifies mortality risk
• Persistent or recurrent disease associated with:
•• Nonincidental cancer
•• Lymph node metastases at presentation
•• Bilateral tumor
- Low-risk patients have the following characteristics:
- No local or distant metastases
- Complete resection of all macroscopic tumor
- Lack of tumor invasion to loco-regional tissues or structures
- Non-aggressive tumor histology (e.g., tall cell, insular, columnar cell carcinoma)
- Lack of vascular invasion
- No 131-iodine uptake outside the thyroid bed on the first post treatment whole-body RAI scan
- Intermediate-risk patients have any of the following:
- Microscopic invasion of tumor into the peri-thyroidal soft tissues at initial surgery
- Cervical lymph node metastases
- 131 iodine uptake outside the thyroid bed on the RxWBS done after thyroid remnant ablation
- Tumor with aggressive cell type
- Vascular invasion
- High-risk patients have:
- Macroscopic tumor invasion
- Incomplete tumor resection
- Distant metastases
- Thyroglobulinemia out of proportion to what is seen on the post treatment scan
Other factors associated with a minor increase in the risk of either recurrence or death include:
- Multi-centricity of intrathyroidal tumor
- Bilateral or mediastinal lymph node involvement
- Greater than 10 nodal metastases
- Nodal metastases with extranodal extension
- Male sex
- Delay in primary surgical therapy of more than one year after detection of a thyroid nodule
Mortality and Morbidity
5–20% of patients with distant metastases die from progressive cervical disease. That is the reason why treatment of a specific metastatic area must be considered in light of the patient’s performance status and other sites of disease.
- Poorer prognosis in patients who have large tumors
- Increase in the risk of death of five fold in case of soft-tissue invasion
- Substantial morbidity if there is involvement of the trachea, esophagus, recurrent laryngeal nerves, or the spinal cord
- Poorer prognosis for specific sub-types of papillary thyroid cancers, including:
- Tall cell varient
- Insular varient
- Hobnail variant
- ↑ Wang JF, Wu T, Hu KP, Xu W, Zheng BW, Tong G, Yao ZC, Liu B, Ren J (2017). "Complications Following Radiofrequency Ablation of Benign Thyroid Nodules: A Systematic Review". Chin. Med. J. 130 (11): 1361–1370. doi:10.4103/0366-6999.206347. PMC 5455047. PMID 28524837.
- ↑ Edge SB, Compton CC (2010). "The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM". Ann. Surg. Oncol. 17 (6): 1471–4. doi:10.1245/s10434-010-0985-4. PMID 20180029.
- ↑ Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA (2009). "Medullary thyroid cancer: management guidelines of the American Thyroid Association". Thyroid. 19 (6): 565–612. doi:10.1089/thy.2008.0403. PMID 19469690.
- ↑ Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L (2016). "2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer". Thyroid. 26 (1): 1–133. doi:10.1089/thy.2015.0020. PMC 4739132. PMID 26462967.
- ↑ "Thyroid Cancer Survival Rates, by Type and Stage".
- ↑ Acharya S, Sarafoglou K, LaQuaglia M, Lindsley S, Gerald W, Wollner N, Tan C, Sklar C (2003). "Thyroid neoplasms after therapeutic radiation for malignancies during childhood or adolescence". Cancer. 97 (10): 2397–403. doi:10.1002/cncr.11362. PMID 12733137.
- ↑ Nikiforov YE, Steward DL, Robinson-Smith TM, Haugen BR, Klopper JP, Zhu Z, Fagin JA, Falciglia M, Weber K, Nikiforova MN (2009). "Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules". J. Clin. Endocrinol. Metab. 94 (6): 2092–8. doi:10.1210/jc.2009-0247. PMID 19318445.
- ↑ Franco C, Martínez V, Allamand JP, Medina F, Glasinovic A, Osorio M, Schachter D (2009). "Molecular markers in thyroid fine-needle aspiration biopsy: a prospective study". Appl. Immunohistochem. Mol. Morphol. 17 (3): 211–5. doi:10.1097/PAI.0b013e31818935a9. PMID 19384080.
- ↑ Ylagan LR, Farkas T, Dehner LP (2004). "Fine needle aspiration of the thyroid: a cytohistologic correlation and study of discrepant cases". Thyroid. 14 (1): 35–41. doi:10.1089/105072504322783821. PMID 15009912.
- ↑ Carmeci C, Jeffrey RB, McDougall IR, Nowels KW, Weigel RJ (1998). "Ultrasound-guided fine-needle aspiration biopsy of thyroid masses". Thyroid. 8 (4): 283–9. doi:10.1089/thy.1998.8.283. PMID 9588492.
- ↑ McCoy KL, Jabbour N, Ogilvie JB, Ohori NP, Carty SE, Yim JH (2007). "The incidence of cancer and rate of false-negative cytology in thyroid nodules greater than or equal to 4 cm in size". Surgery. 142 (6): 837–44, discussion 844.e1–3. doi:10.1016/j.surg.2007.08.012. PMID 18063065.
- ↑ Alexander EK, Hurwitz S, Heering JP, Benson CB, Frates MC, Doubilet PM, Cibas ES, Larsen PR, Marqusee E (2003). "Natural history of benign solid and cystic thyroid nodules". Ann. Intern. Med. 138 (4): 315–8. PMID 12585829.
- ↑ Zettinig G, Fueger BJ, Passler C, Kaserer K, Pirich C, Dudczak R, Niederle B (2002). "Long-term follow-up of patients with bone metastases from differentiated thyroid carcinoma -- surgery or conventional therapy?". Clin. Endocrinol. (Oxf). 56 (3): 377–82. PMID 11940050.
- ↑ Pittas AG, Adler M, Fazzari M, Tickoo S, Rosai J, Larson SM, Robbins RJ (2000). "Bone metastases from thyroid carcinoma: clinical characteristics and prognostic variables in one hundred forty-six patients". Thyroid. 10 (3): 261–8. doi:10.1089/thy.2000.10.261. PMID 10779141.
- ↑ Casara D, Rubello D, Saladini G, Masarotto G, Favero A, Girelli ME, Busnardo B (1993). "Different features of pulmonary metastases in differentiated thyroid cancer: natural history and multivariate statistical analysis of prognostic variables". J. Nucl. Med. 34 (10): 1626–31. PMID 8410272.
- ↑ Tuttle RM, Lemar H, Burch HB (1998). "Clinical features associated with an increased risk of thyroid malignancy in patients with follicular neoplasia by fine-needle aspiration". Thyroid. 8 (5): 377–83. doi:10.1089/thy.1998.8.377. PMID 9623727.
- ↑ Tyler DS, Winchester DJ, Caraway NP, Hickey RC, Evans DB (1994). "Indeterminate fine-needle aspiration biopsy of the thyroid: identification of subgroups at high risk for invasive carcinoma". Surgery. 116 (6): 1054–60. PMID 7985087.
- ↑ Kelman AS, Rathan A, Leibowitz J, Burstein DE, Haber RS (2001). "Thyroid cytology and the risk of malignancy in thyroid nodules: importance of nuclear atypia in indeterminate specimens". Thyroid. 11 (3): 271–7. doi:10.1089/105072501750159714. PMID 11327619.
- ↑ Ríos A, Rodríguez JM, Ferri B, Martínez-Barba E, Torregrosa NM, Parrilla P (2015). "Prognostic factors of follicular thyroid carcinoma". Endocrinol Nutr. 62 (1): 11–8. doi:10.1016/j.endonu.2014.06.006. PMID 25156926.
- ↑ Mazzaferri EL, Jhiang SM (1994). "Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer". Am. J. Med. 97 (5): 418–28. PMID 7977430.
- ↑ Pellegriti G, Scollo C, Lumera G, Regalbuto C, Vigneri R, Belfiore A (2004). "Clinical behavior and outcome of papillary thyroid cancers smaller than 1.5 cm in diameter: study of 299 cases". J. Clin. Endocrinol. Metab. 89 (8): 3713–20. doi:10.1210/jc.2003-031982. PMID 15292295.
- ↑ Schlumberger M, Berg G, Cohen O, Duntas L, Jamar F, Jarzab B, Limbert E, Lind P, Pacini F, Reiners C, Sánchez Franco F, Toft A, Wiersinga WM (2004). "Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective". Eur. J. Endocrinol. 150 (2): 105–12. PMID 14763906.
- ↑ Toubeau M, Touzery C, Arveux P, Chaplain G, Vaillant G, Berriolo A, Riedinger JM, Boichot C, Cochet A, Brunotte F (2004). "Predictive value for disease progression of serum thyroglobulin levels measured in the postoperative period and after (131)I ablation therapy in patients with differentiated thyroid cancer". J. Nucl. Med. 45 (6): 988–94. PMID 15181134.
- ↑ Cailleux AF, Baudin E, Travagli JP, Ricard M, Schlumberger M (2000). "Is diagnostic iodine-131 scanning useful after total thyroid ablation for differentiated thyroid cancer?". J. Clin. Endocrinol. Metab. 85 (1): 175–8. doi:10.1210/jcem.85.1.6310. PMID 10634383.
- ↑ Bachelot A, Cailleux AF, Klain M, Baudin E, Ricard M, Bellon N, Caillou B, Travagli JP, Schlumberger M (2002). "Relationship between tumor burden and serum thyroglobulin level in patients with papillary and follicular thyroid carcinoma". Thyroid. 12 (8): 707–11. doi:10.1089/105072502760258686. PMID 12225639.
- ↑ Wenig BM, Thompson LD, Adair CF, Shmookler B, Heffess CS (1998). "Thyroid papillary carcinoma of columnar cell type: a clinicopathologic study of 16 cases". Cancer. 82 (4): 740–53. PMID 9477108.
- ↑ Kim TY, Kim WB, Kim ES, Ryu JS, Yeo JS, Kim SC, Hong SJ, Shong YK (2005). "Serum thyroglobulin levels at the time of 131I remnant ablation just after thyroidectomy are useful for early prediction of clinical recurrence in low-risk patients with differentiated thyroid carcinoma". J. Clin. Endocrinol. Metab. 90 (3): 1440–5. doi:10.1210/jc.2004-1771. PMID 15613412.
- ↑ Lin JD, Chao TC, Hsueh C, Kuo SF (2009). "High recurrent rate of multicentric papillary thyroid carcinoma". Ann. Surg. Oncol. 16 (9): 2609–16. doi:10.1245/s10434-009-0565-7. PMID 19533244.
- ↑ Leboulleux S, Rubino C, Baudin E, Caillou B, Hartl DM, Bidart JM, Travagli JP, Schlumberger M (2005). "Prognostic factors for persistent or recurrent disease of papillary thyroid carcinoma with neck lymph node metastases and/or tumor extension beyond the thyroid capsule at initial diagnosis". J. Clin. Endocrinol. Metab. 90 (10): 5723–9. doi:10.1210/jc.2005-0285. PMID 16030160.
- ↑ Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS (1993). "Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989". Surgery. 114 (6): 1050–7, discussion 1057–8. PMID 8256208.
- ↑ Asioli S, Erickson LA, Sebo TJ, Zhang J, Jin L, Thompson GB, Lloyd RV (2010). "Papillary thyroid carcinoma with prominent hobnail features: a new aggressive variant of moderately differentiated papillary carcinoma. A clinicopathologic, immunohistochemical, and molecular study of eight cases". Am. J. Surg. Pathol. 34 (1): 44–52. doi:10.1097/PAS.0b013e3181c46677. PMID 19956062.
- ↑ Ghossein RA, Leboeuf R, Patel KN, Rivera M, Katabi N, Carlson DL, Tallini G, Shaha A, Singh B, Tuttle RM (2007). "Tall cell variant of papillary thyroid carcinoma without extrathyroid extension: biologic behavior and clinical implications". Thyroid. 17 (7): 655–61. doi:10.1089/thy.2007.0061. PMID 17696836.