Thyroid nodule natural history, complications and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Natural History

Thyroid nodule is mostly asymptomatic. A solitary thyroid nodule can become symptomatic if:

Grows rapidly due to hemorrhage or malignancies
Invades laryngeal nerves
Compress nearby structures including:
- Trachea: Dyspnea
- Esophagus: Dysphagia
- Carotid artery: Lightheadedness
- Vagus nerve: Vasovagal reflex
Secretory nodules that produce TSH

Thyroid nodules can be a manifestation of thyroid cancer. Thyroid cancer 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 asymptomatic nodule may remain asymptomatic, while the patients with thyroid neoplasm may develop distant metastases, which may eventually lead to death.

Complications

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.

The most important possible complications of thyroid nodules ^[1]

Complication	Features	Cause	Treatment
Hoarseness	Usually transient Patients with recurrent thyroid cancers have a greater risk of permanent hoarseness	Invasion of the laryngeal nerves that controls the vocal cords Radiofrequency ablation(RFA)-induced thermal injury of the recurrent laryngeal nerve or vagus nerve Trauma: Laryngoscopic evaluation Stretching of the nerve over a hematoma Lidocaine injection Posthemorrhage inflammation Fibrosis around the nerve	Usually resolve spontaneously Prednisone may shorten the duration
Horner syndrome	Ocular discomfort Redness of the conjunctiva Ptosis Miosis Anhidrosis of the face	Subsequent thermal injury to middle cervical sympathetic ganglion due to RAI to a nearby ganglion	Usually resolve spontaneously Prednisone may shorten the duration
Nodule rupture	Breakdown of the thyroid capsule and a leak of the fluid from intrathyroidal lesions toward extrathyroidal lesions Sudden neck swelling and pain	Spontaneous tearing of the tumor wall and thyroid capsule at a weak point Post-RFA massage Strong movement of the neck Delayed bleeding caused by microvessel leakage within the nodule, leading to delayed volume expansion and rupture	May resolve spotanously May need antibiotic therapy May need incision and drainage
Needle track seeding	Rare Implantation of tumor cells by contamination when instruments like biopsy needles are used to examine, excise or ablate a tumor Spread of the tumor to nearby structures	After RFA or FNA of thyroid carcinoma
Hemorrhage/hematoma	Usually asymptomatic A rapidly expanding hypo/anechoic signal within the nodular tissue, resulting in gradual enlargement Can be detected by real-time US	May cause hemorrhage in the following structures: Perithyroidal Subcapsular Intranodular during needle insertion May be due to the sudden reduction of intranodular pressure due to fluid evacuation especially in multinodular or complex nodular structures	Drainage if indicated
Dysphagia	Difficulty in swallowing	Mass effect of thyroid nodule on the esophagus	Tumor resection
Upper airway obstruction	Difficulty in breathing	Mass effect of thyroid nodule on the trachea	Tumor resection
Pain/sensation of heat	Pain located generally in the neck Occasionally radiating around toward the head, gonial angle, ear, shoulder, or teeth	During the RAI procedure mostly due to thyroid capsule thermal damage Due to parenchymal edema	Mostly self-limited
Skin burn	First-grade skin burns, which presented with skin color changes and mild pain and discomfort	Due to radioiodine frequency ablation	Topical coticosteroids
Vasovagal reaction	Bradycardia Hypotension Vomiting	Due to vagus nerve stimulation in nodules adjacent to the common carotid and the internal jugular vein	Symptoms usually last a few minutes
Hypothyroidism	Fatigue Cold intolerance Decreased sweating Hypothermia Coarse skin Weight gain	Due to RIA Due to antibody formation prior to any treatment	Levothyroxine
Transient thyrotoxicosis	Thyroid hormone increase TSH decrease	An inflammatory process following needle aspiration of a thyroid cyst Cause thyroiditis and thyrotoxicosis that triggers the release of thyroid hormones	Temporary anti thyroid drugs
Anaphylactic reaction	Rare Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, hypoxemia) Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia, collapse, syncope, incontinence)	Mostly due to: Local anesthetics Rupture of a parasitic cyst, mistaken for a simple cystic thyroid nodule	Epinephrine
Thromboembolism	Rare Mostly present with TIA or stroke	Mostly in elderly especially if known carotid artery atherosclerosis coincides	Anticoagulants
Pneumothorax	Rare Mostly asymptomatic Mostly a self limited situation that resolves spontanously	May cause pneumothorax due to apical pleural injury in: Supraclavicular thyroid nodules Deep-seated thyroid nodules Substernal multinodular goiter	Prednisone

Prognosis

ggg


Prognostic stage groups
Differentiated
When age at diagnosis is...	And T is...	And N is...	And M is...	Then the stage group is...
<55 years	Any T	Any N	M0	I
<55 years	Any T	Any N	M1	II
≥55 years	T1	N0/NX	M0	I
≥55 years	T1	N1	M0	II
≥55 years	T2	N0/NX	M0	I
≥55 years	T2	N1	M0	II
≥55 years	T3a/T3b	Any N	M0	II
≥55 years	T4a	Any N	M0	III
≥55 years	T4b	Any N	M0	IVA
≥55 years	Any T	Any N	M1	IVB
Anaplastic
When T is...	And N is...	And M is...	Then the stage group is...
T1-T3a	N0/NX	M0	IVA
T1-T3a	N1	M0	IVB
T3b	Any N	M0	IVB
T4	Any N	M0	IVB
Any T	Any N	M1	IVC

If left untreated:

[#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3]. Common complications of [disease name] include [complication 1], [complication 2], and [complication 3]. Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

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.^[2]^[3]^[4]

There is no evidence that radiation-associated thyroid cancers are more aggressive than other thyroid cancers.

12733137

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.^[5]^[6] Thyroid nodules diagnosed as benign require follow-up because of a low, but not negligible, false-negative rate of up to 5% with FNA.^[7]^[8] False negative diagnosis may be even higher with nodules >4 cm.^[9] While benign nodules may decrease in size, malignant tumors often increase in size, albeit slowly.^[10] 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 metastasis (e.g., brain, bone, lung), tumor burden, age at diagnosis of metastases, and 18FDG and RAI avidity.^[11] ^[12] Improved survival is associated with responsiveness to surgery and or RAI. 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 radioiodine imaging^[13]

Recurrence risk

Low-risk patients have the following characteristics:^[14]^[15]
- No local or distant metastases
- Complete resction of all macroscopic tumor
- Lack of tumor invasion to locoregional tissues or structures
- Non-aggressive tumor histology (e.g., tall cell, insular, columnar cell carcinoma)
- Lack of vascular invasion
- No 131I uptake outside the thyroid bed on the first post treatment whole-body RAI scan (RxWBS)
Intermediate-risk patients have any of the following:^[16]^[17]^[18]
- Microscopic invasion of tumor into the perithyroidal soft tissues at initial surgery
- Cervical lymph node metastases
- 131I uptake outside the thyroid bed on the RxWBS done after thyroid remnant ablation
- Tumor with aggressive histology
- Vascular invasion

High-risk patients have:^[19]
- 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 are: ^[20]^[21]

Multicentricity 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
The prognosis is poorer in patients who have large tumors^[22]
Soft-tissue invasion increases the risk of death five fold
Substantial morbidity if there is involvement of the trachea, esophagus, recurrent laryngeal nerves, or the spinal cord
Poorer prognosis for specific subtypes of papillary thyroid cancers, including tall cell, insular, and hobnail variants^[23]^[24]

Comparison of most common thyroid nodules with each other:

2

References

↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.

Template:WH Template:WS

[pmid28524837-1] 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.

[pmid9623727-2] 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.

[pmid7985087-3] 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.

[pmid11327619-4] 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.

[pmid19318445-5] 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.

[pmid19384080-6] 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.

[pmid15009912-7] 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.

[pmid9588492-8] 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.

[pmid18063065-9] 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.

[pmid12585829-10] 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.

[pmid11940050-11] 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.

[pmid10779141-12] 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.

[pmid8410272-13] 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.

[pmid14763906-14] 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.

[pmid15181134-15] 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.

[pmid10634383-16] 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.

[pmid12225639-17] 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.

[pmid9477108-18] 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.

[pmid15613412-19] 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.

[pmid19533244-20] 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.

[pmid16030160-21] 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.

[pmid8256208-22] 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.

[pmid19956062-23] 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.

[pmid17696836-24] 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.

[pmid25156926-25] 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.

[pmid7977430-26] 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.

[pmid15292295-27] 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.

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