Thyroid cancer

Subtypes

Arising from follicular epithelial cells
- DTC: Differentiated thyroid cancer (arise from thyroid follicular epithelial cells and generally retain the ability to organify iodine) - vast majority
  - PTC: Papillary thyroid cancer
  - FTC: Follicular thyroid cancer
    - HCC: Hurthle Cell Carcinoma
- PDTC: Poorly-differentiated thyroid cancer
- ATC: Anaplastic thyroid cancer
Arising from parafollicular C cells
- MTC: Medullary thyroid cancer

Epidemiology

Women (3:1)
Tripled in incidence past three decades, but no change to mortality overall - primarily insignificant microPTC as discussed below

Presentation

Typically asymptomatic
5% have palpable mass
Pain is suggestive of thyroiditis or acute bleeding into a benign cyst, but can also suggest MTC/primary thyroid lymphoma/ATC
Local invasive features - voice change, coughing, dysphagia
Cervical lymphadenopathy

Pathophysiology of DTC

Papillary thyroid cancer (differentiated)

- Epidemiology
  - Women 3:1
  - Peak incidence 30-50yo
  - 84% of all thyroid cancer, and rising incidence (almost tripled over past 30 years)
    - Much of the rising incidence can be explained by increasingly sensitive testing, and advent of micro PTC (lesions <1cm)
- Risk factors
  - Particularly associated with ionising radiation to head and neck, especially during youth
    - Even a single CXR increases risk, in dose-dependent fashion
  - Family history DTC - familial non-MTC
  - Gardner, Werner and Cowden syndromes, and Carney complex
  - Obesity
  - Flame-retardant chemicals
- Pathophysiology
  - Disseminates via lymphatics, to cervical lymph nodes in central and lateral compartments
  - Distant metastases can occur to lung and bone
  - Histopathology
    - Solid, whitish
    - Complex, branching papillae with pseudo-inclusions
    - Orphan Annie nuclei
    - Nuclear inclusions/grooves
    - Psammoma bodies - calcifications
  - Molecular genetics
    - 60% have BRAFV600E - poor prognostic indicator, especially if TERT is also present - but does allow targeted immunologic therapy e.g. dabrafenib, trametinib
    - 10% have RAS mutations
  - Variants: (all rare)
    - Follicular variant of papillary cancer (fvPTC)
      - Well-defined follicles with minimal papillary projections
      - Described as either encapsulated or invasive (unencapsulated)
        Encapsulated fvPTC seems to be quite indolent - in 2016, renamed to 'non-invasive follicular thyroid neoplasm with papillary-like nuclear features' (NIFTP)
        
        Unencapsulated form behaves more like regular PTC
    - Worse prognosis:
      - Tall cell
      - Hobnail
      - Diffuse sclerosing
      - Columnar

Follicular thyroid cancer (differentiated)

- Epidemiology
  - 11% of all thyroid cancer
  - Peak incidence 40-60yo
  - Female 3:1
- Risk factors
  - Main risk is iodine deficiency
  - Cowden syndrome, Carney complex, Werner syndrome
  - Family history DTC - familial non-MTC
  - Obesity
- Pathophysiology
  - Cytological features are quire variable - FNA will be reported as follicular neoplasm, Hurthle cell neoplasm, or follicular lesion of undetermined significance - but to actually diagnose FTC you need to show invasive nature (vascular or capsule invasion)
  - Molecular genetics
    - RAS mutations 30-40% (NRAS -> HRAS -> KRAS)
    - PAX8/PPARy fusion 20-30%
  - Diagnostic lobectomy is often required, with subsequent completion thyroidectomy if cancer is confirmed.
  - Risk of cancer increased in follicular/Hurthle cell neoplasms >4cm, so up-front total thyroidectomy may be preferred in these cases
  - Frozen section not useful for intra-operative diagnosis of FTC
  - Spreads haematogenously to lungs, liver, brain and bone, with <10% having regional lymph nodes
  - Hurthle cell carcinoma is generally considered to be a subtype of FTC
    - Distinguished from FTC by presence of oxyphilic Hurthle (or oncocytic) cells - characteristic cellular enlargement with abundant eosinophilic granular cytoplasm, due to an increased number of mitochondria
    - Distinct and more aggressive behaviour
    - Peak incidence 50-70yo
    - Metastasises via both blood and lymph, present at diagnosis in 20% of patients
    - 38% are RAI-avid, which is less than other DTCs

Investigation and management of DTC

Workup

- USS thyroid with lymph node mapping of bilateral central and lateral neck lymph nodes +/- FNA of suspicious nodes
  - Thyroglobulin washings from the FNA is reasonably specific for metastatic disease in DTC
- CT for staging if indicated: bulky and/or fixed disease on exam, disease extending into the chest or posteriorly, extra-thyroidal extension
- Consider gastroscopy, laryngoscopy, etc if concern for spread clinically
- PET not generally used

Staging

Differentiated and anaplastic thyroid carcinoma TNM staging AJCC UICC 8th edition

Primary tumor (T)
Papillary, follicular, poorly differentiated, Hürthle cell and anaplastic thyroid carcinoma
T category	T criteria
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor ≤2 cm in greatest dimension limited to the thyroid
T1a	Tumor ≤1 cm in greatest dimension limited to the thyroid
T1b	Tumor >1 cm but ≤2 cm in greatest dimension limited to the thyroid
T2	Tumor >2 cm but ≤4 cm in greatest dimension limited to the thyroid
T3	Tumor >4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles
T3a	Tumor >4 cm limited to the thyroid
T3b	Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size
T4	Includes gross extrathyroidal extension beyond the strap muscles
T4a	Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size
T4b	Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumor of any size
NOTE: All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest tumor determines the classification).
Regional lymph nodes (N)
N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No evidence of locoregional lymph node metastasis
N0a	One or more cytologically or histologically confirmed benign lymph nodes
N0b	No radiologic or clinical evidence of locoregional lymph node metastasis
N1	Metastasis to regional nodes
N1a	Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.
N1b	Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes
Distant metastasis (M)
M category	M criteria
M0	No distant metastasis
M1	Distant metastasis
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

High-risk features
- Need to know these as they should get radio-iodine
- See separate topic

Choice of operation

- Thyroidectomy favoured in many situations
  - Resect primary tumour and involved nodes
  - Provide accurate staging
  - Minimise risk of recurrence
  - Resect undiagnosed contralateral disease
  - Allow giving radio-iodine
- There are arguments for just doing a lobectomy in certain situations
  - Acceptable in lesions 1-4cm, without extra-thyroidal extension or metastases
  - Lobectomy (or surveillance) is best choice in lesions <1cm
- Indications for total thyroidectomy:
  - Tumour >4cm
  - Gross extra-thyroidal extension
  - Evidence of metastatic disease
  - Radiation-induced DTC
  - Familial non-medullary thyroid cancer
  - Multifocal bilateral DTC
- Management of lymph nodes (controversial)
  - Local disease only (N0): thyroidectomy, and indication for neck dissection is relative
    - Consider prophylactic central neck dissection when:
      - High-risk patients with cT3-4N0 PTC and clinically involved lateral neck nodes
      - Information would be helpful in guiding therapy
      - Intra-op evidence of nodal involvement
      - Can make an argument for doing it routinely to allow staging
    - Therapeutic central neck dissection: If N1 or clinical suspicion of nodal disease, or large primary tumours, central neck dissection indicated (level VI: extends laterally to medial aspect of carotid arteries laterally, hyoid bone superiorly and sternal notch inferiorly)
  - Lateral neck dissection: If lateral neck nodes are positive clinically, on ultrasound, or intra-operatively, modified radical neck dissection may be necessary, but should always be confirmed with tissue first. Dissection of levels IIA to VB offers lowest recurrence, although some surgeons omit some levels in some cases. Always do a central dissection if doing lateral.

Adjuvant therapy

- TSH suppression
- RAI
- Radiotherapy
- See separate topic

Surveillance

- See separate topic

Non-operative management

- Indications (acceptable as an option)
  - Unilateral PTC <1cm (although some even suggesting as high as 1.5cm now)
  - Unpalatable for many patients, better uptake in Japan
- Protocol
  - Once or twice yearly USS
- Outcomes
  - 16% of tumours grew by 3mm or more in 10 years
  - 3.4% had cervical nodal metastases at 10 years
  - 2.5% of patients >60yo progressed to any form of clinical disease at 10 years
  - 23% of younger patients progressed to clinical disease at 10 years
    - No detectable negative perioperative or oncologic consequences from delayed surgery
  - Lots of large studies currently evaluating safety of this approach

Prognosis

- Very good
- 10 year OS 90%
- More likely to die from something else, over a 30 year time-frame
- Disease-specific survival

I	98-100%
II	85-95%
III	60-70%
IV	<50%

- See table under 'surveillance' for estimating risk of recurrence

Medullary thyroid cancer

Pathophysiology

- Originates from calcitonin-producing C cells in thyroid
- Only accounts for 2% of adult thyroid cancer
- With palpable disease, 70% have nodal mets
- Usually more aggressive than differentiated cancer
- (differentiated in a sense, but not grouped with the other differentiated cancers)
- Metastasises to liver, mediastinum, lungs and bone

Genetic basis

- RET proto-oncogene - need to test for this in all patients, as 25% of cases are associated in an autosomal dominant fashion
  - MEN 2A: MTC in 100%, phaeo in 40%, PHPT in 30%
  - MEN 2B: early onset aggressive MTC in 100%, phaeo in 40%, characteristic physical features (marfinoid, GIT features)
  - Familial MTC: only MTC

Presentation

- Sporadic
  - Usually 30-50yo
  - Palpable neck mass from primary or secondary lymph node
  - Often arises in the superior lateral thyroid lobe
- Hereditary
  - 10-30yo or even younger
  - Often multifocal
- Can present with diarrhoea, flushing and weight loss (due to high calcitonin)
- Can get paraneoplastic syndromes from high CEA, ACTH, chromogranin, or somatostatin, which are rarely produced

Workup

- Definitively diagnosed by FNA - stromal amyloid without thyroid follicular cells
- Genetic testing for RET
- USS - most useful modality
  - Can do FNA same time
  - Lateral neck looking for mets
- Serum calcitonin and CEA (baseline tumour markers, evaluate extent of disease)
  - Calcitonin >500pg/mL suspicious for metastases
  - Differential diagnosis for high calcitonin - autoimmune thyroiditis, HPT, lung cancer, age <3.
  - CEA reflects degree of de-differentiation
- Additional imaging if TMs up, nodal disease present, serum calcitonin > 500pg/mL, or other sign of mets
  - Chest CT, liver CT/MRI, bone scintigraphy and axial MRI
- Biochemical testing for phaeo and PHPT - PTH, calcium and serum metanephrines
- It seems PET is sometimes done

Medullary thyroid carcinoma TNM staging AJCC UICC 8th edition

Primary tumor (T)
T category	T criteria
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor ≤2 cm in greatest dimension limited to the thyroid
T1a	Tumor ≤1 cm in greatest dimension limited to the thyroid
T1b	Tumor >1 cm but ≤2 cm in greatest dimension limited to the thyroid
T2	Tumor >2 cm but <4 cm in greatest dimension limited to the thyroid
T3	Tumor ≥4 cm or with extrathyroidal extension
T3a	Tumor ≥4 cm in greatest dimension limited to the thyroid
T3b	Tumor of any size with gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid or omohyoid muscles)
T4	Advanced disease
T4a	Moderately advanced disease. Tumor of any size with gross extrathyroidal extension into the nearby tissues of the neck, including subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve.
T4b	Very advanced disease. Tumor of any size with extension toward the spine or into nearby large blood vessels, gross extrathyroidal extension invading the prevertebral fascia, or encasing the carotid artery or mediastinal vessels.
Regional lymph nodes (N)
N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No evidence of locoregional lymph node metastasis
N0a	One or more cytologically or histologically confirmed benign lymph nodes
N0b	No radiologic or clinical evidence of locoregional lymph node metastasis
N1	Metastasis to regional nodes
N1a	Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.
N1b	Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes
Distant metastasis (M)
M category	M criteria
M0	No distant metastasis
M1	Distant metastasis
Prognostic stage groups
When T is...	And N is...	And M is...	Then the stage group is...
T1	N0	M0	I
T2	N0	M0	II
T3	N0	M0	II
T1-3	N1a	M0	III
T4a	Any N	M0	IVA
T1-3	N1b	M0	IVA
T4b	Any N	M0	IVB
Any T	Any N	M1	IVC

Treatment

- Neoadjuvant therapy
  - Consider for those with significant burden of metastatic disease
- Clinically evident disease
  - Must differentiate between sporadic and inherited from the start!
    - If phaeo is also present, do adrenalectomy first
    - If MEN2A is present check for PHPT and do a four-gland exploration simultaneously (enlarged parathyroids should be resected, even if eucalcaemic)
    - If RET is positive, guidelines dictate when prophylactic thyroidectomy should take place based on genotype
    - If MEN2B is present, prophylactic total thyroidectomy and bilateral central neck dissection should be performed <1yo
  - Needs total thyroidectomy + bilateral central neck dissection even if N0. Lateral neck dissection performed for biopsy-proven lateral neck disease or high suspicion of lateral neck disease based on high serum calcitonin (number not really fixed, some say 250, some say 500, make an overall risk stratification).
- Offer prophylactic total thyroidectomy to those with RET
  - Aim to do it before central neck dissection is required
  - Timing depends largely on specific RET mutation
- Adjuvant therapy
  - Traditional systemic chemotherapy is ineffective
  - Tyrosine kinase receptor therapies can be useful - vandetanib
  - EBRT to neck and mediastinum for those with incompletely resected or high risk tumours (although no benefit to overall survival)

Follow-up

- Start regular calcitonin/CEA 3 months post-op
  - Negative/normal: 2x six-monthly tests, then annually
  - Elevated: imaging workup for persistent or recurrent disease

Prognosis

- 50% overall disease recurrence
- 80% 10-year survival overall
- N0: 5 year survival 95%
- N1: 5 year survival 75%
- M1: 5 year survival 35%

Anaplastic thyroid cancer (undifferentiated)

Background
- Only accounts for 1% of thyroid cancers
- Highly lethal undifferentiated cancer that causes more than half of all deaths from thyroid cancer
- Usually metastatic at presentation
- Prognosis 2-6 months
Risk factors
- Mean age at diagnosis 65yo
- Female 2:1
- History MNG
- Previous thyroidectomy
Pathophysiology
- Follicular cell origin, de-differentiated
- Possibly arises from DTC, especially PTC (30% have PTC found too)
- Mixed patterns of spindled, pleomorphic giant, and squamoid cells with mitotic figures, atypical mitoses, and extensive necrosis (can be sarcomatoid, giant cell, epithelial subtype)
- Typically do not secrete or stain for Tg
Presentation
- Rapidly enlarging neck mass
- Neck pain, dyspnoea, cough, hoarseness, dysphagia
- >50% have cervical lymphadenopathy
- 15-50% have distant metastases (skin, liver, kidneys, pancreas, heart, adrenals)
Workup
- FNA (95% accuracy for malignancy, 90% specifically for ATC)
- Neck USS
- CT of neck and mediastinum
- PET is recommended - intensely PET-avid
Staging
- All ATCs are considered stage IV disease
Treatment
- Mainstays of treatment are CTX and RTX
- RAI typically not indicated
- No survival benefit to surgical debulking
- Indications for surgery
  - Open biopsy if FNA is insufficient to differentiate ATC from thyroid lymphoma
  - Tracheostomy in patients with advanced disease
  - Complete tumour resection in the rare cases of those who are discovered to have ATC confined to thyroid
- Chemoradiotherapy - doxorubicin, docetaxel, cisplatin
- Involve palliative care early
Prognosis
- Nearly 100% disease-specific mortality
- Median survival with no mets is 6 months

Other rare thyroid cancers

Thyroid lymphoma (undifferentiated)

- 1% of thyroid cancers
- Hashimoto's thyroiditis predisposes towards it
- Most common subtype is NHL B-cell
- Overall survival 50-70%
- Quite rapidly progressive
- Chemotherapy and radiation are mainstays, no benefit to surgery

Thyroid sarcoma

Metastases to thyroid gland

Pre-op evaluation

Assessment for obstructive/mass effect symptoms
Voice changes - pre-op laryngoscopy essential if voice changes or previous neck/throat surgery
If medullary cancer, ask about hypercalcitonaemia symptoms (flushing, diarrhoea)
Assess for presence of carotid bruit - can make lateral retraction of arteries more dangerous intra-operatively
Bloods - TSH, calcium.
USS to stage lateral neck lymph node basins, with FNA of any abnormal node