Thyroid Nodules and Cancer

Anatomy

The thyroid is a bi-lobed shield-shaped organ located anteriorly in the neck that is responsible for the production of thyroid hormones and calcitonin. It has a right and left lobe connected by the isthmus. Each lobe has a superior and inferior lobe.

• Embryology
  • Originates from endodermal tissue from the pharyngeal pouches at the base of the tongue at the foramen cecum
  • Descends the neck anterior to the hyoid bone, larynx and trachea.
  • This median connection remains connected to the base of the tongue as the thyroglossal duct. The thyroglossal duct usually atrophies and disappears
  • The thyroid eventually differentiates into follicular cells and follicles
• Relation of the recurrent laryngeal nerve to the thyroid
  • Travels within the tracheoesophageal groove to the larynx and lie directly posterior to the thyroid
  • They are in close proximity to the inferior thyroid arteries
  • Tremendous variation can occur. This can lead to inadvertent recurrent laryngeal nerve damage

Other thyroid tissue

Thyroid Nodule

A thyroid nodule is a discrete lesion in the thyroid gland that can be palpated on physical exam or seen on ultrasound as distinct from the surrounding parenchyma. It is common neoplasm of thyroid tissue. Most thyroid nodules are benign and subclinical. They are usually discovered on routine examination. Nodules can also be functioning or non-functioning. All non-functioning nodules are more likely to be thyroid cancer and are an absolute indication for FNAC. Lobectomy is the standard of care for thyroid nodules. Nodulectomy is not recommended since there is a high risk of positive margins with malignant nodules.

50% of the general population have a thyroid nodule identifiable on ultrasound. 5% have a palpable nodule.

Definition of terms

• Risk factors
  • Prior exposure to radiation
  • Older age
  • Iodine deficiency
  • Gender
  • Female (4 times more likely to have thyroid nodule than men)
• Patient History
  • Age: nodules in children are malignant in 10-15% of cases. Odds of malignancy increase with age
  • Sex: women are more likely than men to develop malignancy. Thyroid nodules in men are more likely to be malignant
  • Family History: Medullary thyroid cancer can be inherited (MEN-2)
  • Radiation exposure to the head or neck: especially as a child e.g. treating lymphoma
  • Nodule characteristic: firm nodules are more likely to be malignant than soft nodules
  • Cervical lymphadenopathy: suggests malignancy
  • Voice change: suggests malignancy
  • Compressive symptoms: dysphagia, voice changes, hoarseness, shortness of breath, snoring, sleep apnea
• Signs and symptoms
  • Palpable thyroid nodule
  • Hyperthyroid symptoms in functioning nodules
• Physical examination
  • Fixed nodule is more likely to be malignant
  • Palpate level 2 – 5 for lymphadenopathy
  • Pemberton sign: an enlarged thyroid causes a ‘cork’ like effect when the arms are raised obstructing venous return from the head and neck at the thoracic inlet. This leads to congestion of the head and neck.
• Differentials
  • Benign colloid nodule
  • Thyroiditis (pseudo-nodules or nodular hyperplasia from growth of the gland)
  • Benign colloid cyst
  • Benign thyroid tumor (follicular adenoma)
  • Thyroid cancer
• Investigations
  • TSH level: best initial test. Can be functioning and non-functioning nodules. Decreased TSH in non-functioning
  • RAIU Scan: Localize functioning nodules
    • Hyperfunctioning: ‘hot’ nodules (toxic adenoma or TMG). Increased uptake. Benign most of the time.
    • Non-functioning: ‘cold’ nodules. Decreased uptake. 10% are malignant
  • Ultrasound: qualitative information about the gland, nodules and adjacent lymph nodes. Can be performed bed-side
  • Ultrasound- guided Fine Needle Aspirate Cytology (FNAC): most accurate test. Gives the cytology. Can also determine whether the nodule is a cystic.
    • Solid nodules: malignancy, follicular abnormality, Hurthle cells, adenomatous hyperplasia, or indeterminate cytology
    • Cystic nodule: observe
• Features on ultrasound that are suggestive of malignancy
  • Solid nodule (vs cystic nodule)
  • Hypoechoic (vs iso- or hyperechoic)
  • Ill-defined margins (vs well-defined margins)
  • Infiltrative margins
  • Microcalcifications (vs macrocalcifications)
  • Increased blood flow within the nodules (vs peripheral vascularity)
  • Atypical cervical lymph nodes
• Features on ultrasound that are suggestive of an atypical lymph node
  • Solid, mixed/cystic
  • Hypoechogenic
  • Round shape
  • Central hyperecoic line (ilus) absent
• Treatment
  • Thyroid lobectomy (benign nodule > 4 cm)
  • Total or partial thyroidectomy (malignant)
• Indications to operate on a nodule
  • Compressive symptoms in the appropriate clinical setting
  • Bethesda 3 – 4 (of molecular testing is not available or is positive)
  • Bethesda 5 – 6
  • Benign nodule > 4cm (false negative increases up to 13% larger than this, hence the need to excise)
• Indications to operate on a goiter
  • Compression symptoms
  • Substernal growth (there is a risk of further growth which increases the difficulty for future surgical resection and development of compressive symptoms)
  • Nodules > 4 cm or TMNG
  • Suspicious nodules (Bethesda 3 – 6) on FNA
  • Disfigurement or cosmetic concerns (weigh carefully against the risk of complications and need for thyroid hormone replacement)
  • Family history of thyroid cancer or exposure to therapeutic radiation
• Indications to re-biopsy (FNA) a thyroid nodule
  • Suspiscious sonographic features
  • Nodule increases in size (20% increase in diameter with a minimum increase of ≥ 2mm in at least two dimensions)
  • Bethesda 3
• Complications of thyroidectomy
  • Thyroid storm
  • Hemorrhage
  • Hypoparathyroidism
  • Recurrent Laryngeal Nerve Injury

Investigations and when to use them

Bethesda system for reporting Thyroid cytopathology

Thyroid Cancer

Thyroid cancer is the most common endocrine cancer. Thyroid cancer is managed using thyroidectomy with cervical lymph node dissection. Thyroid cancer has a wide range of prognoses. Fortunately, most thyroid cancers are well-differentiated and treatable.

Histological subtypes

• Risk factors
  • History of head and neck radiation in childhood e.g. treatment for lymphoma
  • Exposure to ionising radiation from nuclear radiation (outbreak of thyroid carcinoma in Japan 1940s – 1950s from nuclear radiation)
  • Hereditary: MEN-2 (medullary thyroid cancer + ozempic/GLP-1 RA) or other familial cancer syndromes
  • Age < 20 or > 65
  • Family history of papillary thyroid cancer in two or more first-degree relatives
• Patient History
  • Age < 20 or > 65
  • Rapidly enlarging neck mass
  • Lateral cervical lymphadenopathy
• Signs and symptoms
  • Neck mass or lump (rapidly enlarging)
  • Dysphagia
  • Hoarseness of voice (warrants laryngoscopy or laryngeal ultrasound to evaluate the vocal cords – due to recurrent laryngeal nerve involvement)
  • Difficulty breathing

Papillary Thyroid Carcinoma (PTC)

PTC affects women more than men (3:1) and is prevalent in ages 30 – 50 years old. The cells originate from the thyroid follicular epithelium and biopsy shows a papillary architecture (finger-like formations of the tumor)

• Investigations
  • FNAC: characteristic nuclei
  • Biopsy and histology: Orphan Annie Nuclei (cleared out nuclei) , Psamomma bodies (calcified necrotic tips of the papillae)
  • Thyroid function test: pre-operative workup
  • Ultrasound: evaluate central neck lymph nodes pre-operatively
• Pattern of spread
  • Lymphatic spread to the central level VI first then to lateral nodes at level II – IV
  • Can have skip lesions to lateral nodes without involving central nodes e.g. Level II
  • Rarely involves level I and V nodes
• Treatment
  • Thyroidectomy
    • Total thyroidectomy for tumors ≥ 4 cm, anaplastic thyroid carcinoma
    • Lobectomy for smaller tumors
  • + Neck dissection if there is lymph node involvement
  • Thyroid hormone replacement for patients who have had total thyroidectomy
  • Radioactive Iodine Ablation can be given as an adjuvant for FTC and PTC 2 months after surgery (Thyroglobulin should be checked and below 2ng/ml before giving a dose)
  • Palliative care if the tumor is non-resectable
• Indications for lobectomy
  • Tumor < 4cm
  • No extrathyrodal extension or invasion into adjacent tissue
  • No lymph node involvement
  • No distant metastatic disease
• Indications for total thyroidectomy
  • Tumor > 4 cm
  • Bilateral thyroid nodules
  • Already hypothyroid (and on thyroid hormone replacement)
• Indications for adjuvant radioactive iodine ablation
  • Total thyroidectomy with an intermediate or high risk of recurrence:
    • Positive margins
    • Gross extrathyroidal extension of tumor
    • Large or numerous lymph node involvement
    • Aggressive variants
• Post-operative management
  • Start thyroid hormone replacement (levothyroxine) immediately after surgery for total thyroidectomy
  • TSH and thyroglobulin level 6 weeks after surgery
    • TSH: confirm correct dose of levothyroxine after total thyroidectomy
    • Thyroglobulin: tumor marker. Should be close to zero following total thyroidectomy

Follicular Thyroid Carcinoma (FTC)

FTC is a well differentiated, non-aggressive tumor. It is defined as ‘cancer’ when cells are seen invading the capsule or blood vessels (on histology after surgical excision). Thus diagnosis cannot be definitively made using FNA. Pre-operative workup and management is similar to PTC.

• Pattern of spread
  • Spreads hematogeously to distant sites e.g. lung and bones
  • Can spread lymphatically (10%, less common than PTC)

Medullary Thyroid Carcinoma (MTC)

MTC arises from parafollicular C-cells which secrete calcitonin.

Familial MTC makes up 25% of all MTCs (MEN2A/2B, germline RET mutation). 75% of cases are sporadic (unilateral with somatic RET mutation). Sporadic MTC is common in women aged 50 – 60 years. Familial MTC presents at an earlier age (< 20 years) and is usually multifocal and bilateral.

• Patient History
  • Family History of Thyroid Cancer (for familial MTC)
• Investigations
  • Serum calcitonin and CEA: confirm diagnosis. Serum calcitonin > 100 pg/mL is diagnostic
  • Ultrasound guided FNAC + evaluation of lymph nodes
  • CT scan of the head and neck: for potential distant metastasis if calcitonin level is markedly elevated
  • Calcium and PTH levels: to screen for primary hyperparathyroidism
  • Plasma metanephrines: screen for pheochromocytomas or functional paragangliomas pre-operatively
• Pattern of spreads
  • Distant metastasis to the lung, liver, bones, and rarely, the brain
• Treatment
  • Total thyroidectomy with bilateral central neck dissection
  • Ipsilateral modified radical neck dissection (MRND) can be added for patients with suspicious lateral neck nodes that have been proven with biopsy to be metastases
  • Thyroidectomy at around 5 years for patients with hereditary MTC (through genetic testing)
• Why is central neck dissection performed with no suspicious nodes?
  • 80% of patients with palpable tumors have been found to have central neck disease
• Post-operative care
  • Thyroid hormone replacement
  • Surveillance with serial serum calcitonin and CEA and neck imaging

Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinoma is the most aggressive thyroid cancer. FNA can be used to diagnose.

Median survival is 3 – 6 months. One year mortality is 80%. Most cases are diagnosed at 60 years old.

• Patient History
  • Fast-growing thyroid gland
  • Long-standing goiter that suddenly began to grow
  • Compressive symptoms
• Investigations
  • Ultrasound of the thyroid and cervical lymph nodes
  • CT scan of the head and neck: to determine extent and invasiveness of the tumor
  • PET scan: to evaluate distant metastases
  • Pre-operative laryngoscopy: to assess vocal cord function and screen for direct invasion of the airway
• Treatment
  • Total thyroidectomy if the tumor is confined to the thyroid
  • Palliative care
• Components of palliative care for anaplastic thyroid carcinoma
  • Tracheostomy if there is impending airway obstruction
  • External beam radiation treatment (EBRT)
  • Chemotherapy
• Factors for a more favourable prognosis
  • Age < 60 years
  • Tumor < 7 cm
  • Absence of distant metastasis

Thyroid Lymphoma

Thyroid lymphoma is an extremely rare thyroid neoplasm. Most are B-cell non-Hodgkin lymphomas.

• Patient History
  • Older woman
  • Long-standing Hashimoto’s thyroiditis (increases risk 70 – 80 times)
  • Rapidly enlarging neck mass with associated compressive symptoms
• Signs and symptoms
  • Rapidly enlarging neck mass
  • B-type symptoms: fever, night sweats, and weight loss (10%)
• Investigations
  • FNA or core needle biopsy: biopsy helps to subtype the lymphoma. But FNA is adequate enough to diagnose since there will predominant lymphocytes.
  • Ultrasound of the neck: enlarged thyroid mass and generalized lymphadenopathy
  • PET or CT scan: for distant metastasis
  • Bone marrow biopsy: to exclude bone marrow involvement
• Treatment
  • Tracheal stenting to alleviate tumor compression be
  • Chemotherapy
  • Locoregional radiation