Special Surgery 3. Malignant Diseases of the Thyroid Gland and Treatment

I. General Diagnostic Approach

Clinical Suspicion

• Most thyroid cancers present as a thyroid nodule
• Most patients are euthyroid
• Suspicious history:

• Childhood or adolescent neck irradiation
• Family history of thyroid cancer or MEN2
• Rapid growth, especially in elderly patient
• Previous thyroid nodule with new hard fixation

• Suspicious symptoms/signs:

• Firm/hard nodule
• Fixed nodule, irregular surface
• Cervical lymphadenopathy
• Hoarseness → recurrent laryngeal nerve paresis until proven otherwise
• Dysphagia, dyspnea, stridor → local invasion/compression

Physical Examination

• Inspection and palpation of thyroid gland
• Stand behind the patient and ask the patient to swallow
• Assess:

• Size, consistency, tenderness
• Solitary vs multinodular
• Mobility with swallowing
• Fixation to surrounding tissues
• Cervical lymph nodes: central and lateral neck

• Indirect/fiberoptic laryngoscopy if hoarseness, previous neck surgery or planned thyroid cancer surgery

Laboratory Tests

• TSH first-line test
• Free T4/T3 if TSH abnormal

• Hyperthyroidism: increased T3/T4, decreased TSH
• Hypothyroidism: decreased T3/T4, increased TSH in primary hypothyroidism

• Calcitonin and CEA → important in suspected/confirmed medullary thyroid carcinoma
• Thyroglobulin is not useful for primary diagnosis of a nodule
• Thyroglobulin becomes useful after thyroidectomy for differentiated thyroid cancer follow-up

Imaging

1. Neck Ultrasound

• First-line imaging for thyroid nodules
• Assesses thyroid morphology and cervical lymph nodes
• Distinguishes solid, cystic and mixed nodules
• Suspicious ultrasound features:

• Hypoechoic solid nodule
• Microcalcifications
• Irregular/infiltrative border
• Taller-than-wide shape
• Extrathyroidal extension
• Absent halo sign
• Suspicious cervical lymph nodes: cystic change, microcalcification, rounded shape, loss of hilum

• Suspicious nodule or lymph node → ultrasound-guided FNAB

2. Scintigraphy

• Main indication: low TSH / suspected autonomous nodule
• Hot nodule → autonomous hormone production; malignancy risk is low but not zero
• Cold nodule → non-functioning tissue; may be cyst, adenoma or cancer → evaluate by ultrasound/FNAB
• Diffuse homogeneous uptake → Graves-Basedow disease pattern

3. CT / MRI / PET-CT

• Not routine for every thyroid nodule
• Use if advanced disease suspected:

• Retrosternal extension
• Tracheal/esophageal invasion
• Bulky nodal disease
• Distant metastasis
• Anaplastic carcinoma staging

Fine Needle Aspiration Biopsy (FNAB)

• Gold standard initial cytological test for suspicious thyroid nodules
• Prefer ultrasound-guided FNAB
• Can diagnose papillary carcinoma, medullary carcinoma, anaplastic carcinoma and many metastases
• Limitation: follicular adenoma vs follicular carcinoma cannot be reliably distinguished by cytology alone
• Follicular carcinoma diagnosis requires capsular and/or vascular invasion on histology

II. Differentiated Thyroid Cancer: Papillary and Follicular

Basic Concept

• Differentiated thyroid cancers arise from follicular epithelial cells
• Main types:

1. Papillary thyroid carcinoma
2. Follicular thyroid carcinoma
3. Hurthle cell carcinoma is usually handled as an oncocytic differentiated thyroid carcinoma

• Usually iodine-avid → may respond to radioiodine therapy
• TSH can stimulate residual tumor cells → levothyroxine replacement and risk-adapted TSH suppression

Papillary Thyroid Carcinoma

Epidemiology and Etiology

• Most common thyroid cancer, about 80%
• May occur at any age
• Female predominance
• Associated with previous ionizing radiation exposure
• Common molecular alterations: RET/PTC rearrangement, NTRK fusion, BRAF mutation

Clinical and Pathology Features

• Often slow-growing
• Can be solitary, multifocal or bilateral
• Firm thyroid nodule or cervical lymph node metastasis
• May be well-circumscribed/encapsulated or infiltrative
• Microscopy:

• Branching papillae with fibrovascular/fibrous stroma
• Orphan Annie eye nuclei
• Nuclear grooves and intranuclear inclusions
• Psammoma bodies

• Metastasis: mainly lymphatic → cervical lymph nodes
• Prognosis: excellent, especially in young patients and localized disease

Treatment

• Surgery is the primary treatment
• Lobectomy can be enough for small, unifocal, intrathyroidal, low-risk tumors
• Total/near-total thyroidectomy if:

• Large tumor
• Multifocal or bilateral disease
• Extrathyroidal extension
• Clinically significant nodal metastasis
• Distant metastasis
• Need for radioiodine therapy/follow-up with thyroglobulin

• Clinically involved lymph nodes → compartment-oriented lymph node dissection
• Central neck dissection if central nodal disease is present
• Lateral neck dissection if proven lateral nodal metastasis
• Radioiodine ablation/therapy (I-131) → residual tissue, nodal/distant iodine-avid disease or higher-risk cases
• Levothyroxine after total thyroidectomy:

• Hormone replacement
• Risk-adapted TSH suppression

Follicular Thyroid Carcinoma

Epidemiology and Etiology

• Second most common thyroid cancer, about 10-15%
• Derived from follicular epithelial cells
• More common in women
• Peak age: 40-60 years
• Increased incidence in iodine-deficient areas

Clinical and Pathology Features

• Usually slow-growing firm thyroid nodule
• Often solitary
• Microscopy: follicular pattern similar to normal thyroid tissue
• Key diagnostic criterion: capsular and/or vascular invasion
• FNAB cannot reliably distinguish follicular adenoma from carcinoma
• Metastasis: hematogenous

• Lung
• Bone
• Liver

• Prognosis: good, but generally worse than papillary carcinoma

Treatment

• Diagnostic lobectomy may be needed first for follicular neoplasm
• Total thyroidectomy is usually preferred for widely invasive, large or higher-risk carcinoma
• Completion thyroidectomy if carcinoma diagnosed after lobectomy and risk profile indicates it
• Lymph node dissection only for clinically involved nodes; routine nodal spread is less common than in papillary carcinoma
• Radioiodine therapy for iodine-avid residual/metastatic or higher-risk disease
• Levothyroxine replacement + risk-adapted TSH suppression

III. Medullary Thyroid Carcinoma

Definition and Etiology

• Neuroendocrine thyroid cancer
• Derived from parafollicular C cells
• C cells secrete calcitonin
• Can be sporadic or hereditary
• Hereditary forms are associated with RET mutation and MEN2 syndromes

• MEN2A: MTC + pheochromocytoma + primary hyperparathyroidism
• MEN2B: MTC + pheochromocytoma + mucosal neuromas/marfanoid habitus

Clinical and Pathology Features

• Firm thyroid nodule or cervical lymphadenopathy
• May be multifocal/bilateral in hereditary disease
• Calcitonin excess may cause diarrhea/flushing in advanced disease
• Hypocalcemia is not a typical presenting feature despite calcitonin secretion
• Microscopy:

• Neuroendocrine tumor pattern
• Amyloid deposition from calcitonin-derived material

• Tumor markers: calcitonin and CEA
• Metastasis: early lymph node spread; distant spread to liver, lung, bone, brain
• Prognosis: worse than differentiated thyroid cancer; depends strongly on stage

Diagnosis

• FNAB cytology can suggest MTC
• Serum calcitonin and CEA support diagnosis and establish baseline
• Genetic testing for RET mutation in all patients with MTC
• If RET-positive/familial:

• Screen family members
• Search for pheochromocytoma before thyroid surgery
• Assess calcium/PTH for hyperparathyroidism in MEN2A

Treatment

• Total thyroidectomy is standard
• Central neck lymph node dissection is usually performed
• Lateral neck dissection if lateral nodal metastasis is proven/suspected or calcitonin burden suggests it
• No radioiodine therapy → C-cell tumor does not take up iodine
• Levothyroxine after thyroidectomy:

• Hormone replacement only
• No TSH-suppression oncological effect in MTC

• Advanced/metastatic disease → targeted systemic therapy may be used in specialist oncology setting
• Follow-up: calcitonin and CEA levels + neck ultrasound/imaging as indicated

IV. Anaplastic Thyroid Carcinoma and Follow-Up Principles

Anaplastic Thyroid Carcinoma

Basic Features

• Very rare, aggressive, undifferentiated thyroid cancer
• Usually arises from follicular epithelial origin by dedifferentiation
• More common in elderly patients and women
• Often presents with rapid neck enlargement
• Prognosis: very poor

Clinical Features

• Rapidly enlarging hard neck mass
• Local invasion:

• Dysphagia
• Dyspnea
• Stridor
• Hoarseness
• Pain
• Skin fixation or ulceration

• Microscopy: highly pleomorphic, poorly differentiated/anaplastic cells
• Metastasis: early hematogenous and nodal spread

• Lung
• Bone
• Brain

Diagnosis and Staging

• Urgent tissue diagnosis: FNAB/core biopsy
• Rapid multidisciplinary evaluation
• Assess airway immediately
• CT/MRI neck and mediastinum to assess tracheal, esophageal and vascular invasion
• Chest/whole-body imaging for metastases
• Molecular testing if systemic targeted therapy is considered

Treatment

• Airway management is often the first priority
• Tracheostomy only if needed for airway compromise; not routine prophylactically
• Most cases are unresectable at diagnosis because of local invasion/metastasis
• If resectable and patient fit → surgery aiming for R0/R1 resection + adjuvant radiotherapy/systemic therapy
• If unresectable/metastatic → radiotherapy, chemotherapy, targeted therapy or immunotherapy in selected cases
• Palliative care and goals-of-care discussion are essential early
• Not responsive to radioiodine
• Levothyroxine replacement only if thyroidectomy performed; no useful TSH-suppression effect

Postoperative and Long-Term Management

1. Differentiated Thyroid Cancer: PTC / FTC

• Levothyroxine after thyroidectomy:

• Replaces missing thyroid hormone
• Suppresses TSH according to recurrence risk and response to therapy

• Radioiodine ablation/therapy only if indicated by risk and iodine avidity
• Follow-up:

• Neck ultrasound
• Serum thyroglobulin
• Anti-thyroglobulin antibodies because they can interfere with thyroglobulin interpretation
• Diagnostic radioiodine scan mainly for selected intermediate/high-risk or suspected recurrent disease

2. Medullary Thyroid Carcinoma

• Follow calcitonin and CEA
• Persistent or rising calcitonin/CEA → residual, recurrent or metastatic disease until proven otherwise
• RET mutation result guides family screening and MEN2 management
• No thyroglobulin follow-up and no radioiodine therapy

3. Main Surgical Complications to Mention

• Bleeding/neck hematoma → airway emergency
• Recurrent laryngeal nerve injury → hoarseness, vocal cord palsy
• External branch of superior laryngeal nerve injury → weak high-pitched voice
• Hypoparathyroidism/hypocalcemia after total thyroidectomy or central neck dissection
• Wound infection is uncommon but possible
• Need for lifelong levothyroxine after total thyroidectomy