Thyroid nodule natural history, complications and prognosis

Thyroid nodule Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Thyroid nodule from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic study of choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
Chest X Ray
CT
MRI
Echocardiography or Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Thyroid nodule natural history, complications and prognosis On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Thyroid nodule natural history, complications and prognosis All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Thyroid nodule natural history, complications and prognosis
CDC on Thyroid nodule natural history, complications and prognosis
Thyroid nodule natural history, complications and prognosis in the news
Blogs on Thyroid nodule natural history, complications and prognosis
Directions to Hospitals Treating Thyroid nodule
Risk calculators and risk factors for Thyroid nodule natural history, complications and prognosis

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

Overview

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.

Natural History

• 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:
    • Trachea: Dyspnea
    • Esophagus: Dysphagia
    • Carotid artery: Lightheadedness
    • Vagus nerve: Vasovagal syncope
  • 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.

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.
• Common complications of thyroid nodules include:

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 Post hemorrhage inflammation Fibrosis around the nerve	Usually resolve spontaneously Prednisone may shorten the duration
Horner syndrome	Ocular discomfort Conjunctivitis 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 intra-thyroidal lesions toward extra-thyroidal lesions Sudden neck swelling and pain	Spontaneous tearing of the tumor wall and thyroid capsule at a weak point Post radiofrequency ablation massage Strong movement of the neck Delayed bleeding caused by micro vessel 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 ultrasound	May cause hemorrhage in the following structures: Perithyroidal capsule Subcapsular region 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	May be associated with odinophagia	Mass effect of thyroid nodule on the esophagus	Tumor resection
Upper airway obstruction	Dyspnea	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 raioactive iodine(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 corticosteroids
Vasovagal reaction	Bradycardia Hypotension Vomiting	Due to vagus nerve stimulation in nodules adjacent to the common carotid artery and the internal jugular vein	Symptoms usually last a few minutes
Hypothyroidism	Fatigue Cold intolerance Decreased sweating Hypothermia Coarse skin Weight gain	Due to radio-iodine therapy 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

The American Joint Committee on Cancer (AJCC) introduced the TNM staging system for evaluating thyroid cancer prognosis.

A summary of TNM staging system and the related prognosis:

T categories for thyroid cancer (other than anaplastic thyroid cancer)
TX		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.

Stage grouping

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)	The tumor can be any size (any T) and may or may not have spread to nearby lymph nodes (any N). It has not spread to distant sites (M0).	100%
	Stage II (Any T, Any N, M1)	The tumor can be any size (any T) and may or may not have spread to nearby lymph nodes (any N). It has spread to distant sites (M1).
Papillary or follicular (differentiated) thyroid cancer in patients 55 years and older	Stage I (T1, N0, M0)	The tumor is 2 cm or less across and has not grown outside the thyroid (T1). It has not spread to nearby lymph nodes (N0) or distant sites (M0).	100%
	Stage II (T2, N0, M0)	The tumor is more than 2 cm but not larger than 4 cm across and has not grown outside the thyroid (T2). It has not spread to nearby lymph nodes (N0) or distant sites (M0).
	Stage III	One of the following applies: T3, N0, M0: The tumor is larger than 4 cm across or has grown slightly outside the thyroid (T3), but it has not spread to nearby lymph nodes (N0) or distant sites (M0). T1 to T3, N1a, M0: The tumor is any size and may have grown slightly outside the thyroid (T1 to T3). It has spread to lymph nodes around the thyroid in the neck (N1a) but not to other lymph nodes or to distant sites (M0).	93%
	Stage IVA	One of the following applies: T4a, any N, M0: The tumor is any size and has grown beyond the thyroid gland and into nearby tissues of the neck (T4a). It might or might not have spread to nearby lymph nodes (any N). It has not spread to distant sites (M0). T1 to T3, N1b, M0: The tumor is any size and might have grown slightly outside the thyroid gland (T1 to T3). It has spread to certain lymph nodes in the neck (cervical nodes) or to lymph nodes in the upper chest (superior mediastinal nodes) or behind the throat (retropharyngeal nodes) (N1b), but it has not spread to distant sites (M0).	51%
	Stage IVB (T4b, Any N, M0)	The tumor is any size and has grown either back toward the spine or into nearby large blood vessels (T4b). It might or might not have spread to nearby lymph nodes (any N), but it has not spread to distant sites (M0).
	Stage IVC (Any T, Any N, M1)	The tumor is any size and might or might not have grown outside the thyroid (any T). It might or might not have spread to nearby lymph nodes (any N). It has spread to distant sites (M1).
Medullary thyroid cancer	Stage I (T1, N0, M0)	The tumor is 2 cm or less across and has not grown outside the thyroid (T1). It has not spread to nearby lymph nodes (N0) or distant sites (M0).	100%
	Stage II	One of the following applies: T2, N0, M0: The tumor is more than 2 cm but is not larger than 4 cm across and has not grown outside the thyroid (T2). It has not spread to nearby lymph nodes (N0) or distant sites (M0). T3, N0, M0: The tumor is larger than 4 cm or has grown slightly outside the thyroid (T3), but it has not spread to nearby lymph nodes (N0) or distant sites (M0).	98%
	Stage III (T1 to T3, N1a, M0)	The tumor is any size and might have grown slightly outside the thyroid(T1 to T3). It has spread to lymph nodes around the thyroid in the neck (N1a) but not to other lymph nodes or to distant sites (M0).	81%
	Stage IVA	One of the following applies: T4a, any N, M0: The tumor is any size and has grown beyond the thyroid gland and into nearby tissues of the neck (T4a). It might or might not have spread to nearby lymph nodes (any N). It has not spread to distant sites (M0). T1 to T3, N1b, M0: The tumor is any size and might have grown slightly outside the thyroid gland (T1 to T3). It has spread to certain lymph nodes in the neck (cervical nodes) or to lymph nodes in the upper chest (superior mediastinal nodes) or behind the throat (retropharyngeal nodes) (N1b), but it has not spread to distant sites (M0).	28%
	Stage IVB (T4b, Any N, M0)	The tumor is any size and has grown either back toward the spine or into nearby large blood vessels (T4b). It might or might not have spread to nearby lymph nodes (any N), but it has not spread to distant sites (M0).
	Stage IVC (Any T, Any N, M1)	The tumor is any size and might or might not have grown outside the thyroid(any T). It might or might not have spread to nearby lymph nodes (any N). It has spread to distant sites (M1).
Anaplastic (undifferentiated) thyroid cancer	Stage IVA (T4a, Any N, M0)	The tumor is still within the thyroid (T4a). It might or might not have spread to nearby lymph nodes (any N), but it has not spread to distant sites (M0).	7%
	Stage IVB (T4b, Any N, M0)	The tumor has grown outside the thyroid (T4b). It might or might not have spread to nearby lymph nodes (any N), but it has not spread to distant sites (M0).
	Stage IVC (Any T, Any N, M1)	The tumor might or might not have grown outside of the thyroid (any T). It might or might not have spread to nearby lymph nodes (any N). It has spread to distant sites (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

Recurrence risk

• 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