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Differentiated thyroid cancer

Sub-section: Thyroid Section: Endocrine

Definition

General Principles

  • Treatment options
    • Conservative management
    • Surgery
    • TSH suppression
    • Radioactive iodine treatment
  • Similar principles for persistent/recurrent disease
  • Radiation and systemic chemo play a role in a few cases
  • Future therapies of targets tyrosine kinase inhibitors may be useful for metastatic DTC that is refractory to RAI
  • Principles
    • Remove primary tumour and clinically significant cervical nodes
    • Minimise treatment related morbidity
    • Accurately stage the disease
    • Facilitate post-op RAI therapy if appropriate
    • Permit accurate long-term surveillance
    • Minimise risk of recurrence or metastasis

Conservative management

  • For small papillary microcarcinoma, with no clinically evident metastasis, in an easily accessible area – you can consider active surveillance.
  • This is useful for patients who’s co-morbidities confer a higher surgical risk, or who short remaining life-span.
  • Contra-indications to conservative management include previous head and neck radiation, familial thyroid cancer syndrome, or evidence of nodal metastasis.

Thyroid Resection

Upfront strategy

  • Thyroid Resection - PTC
  • Consider Hemithyroidectomy if:
    • < 1cm (some debate could be up to 4cm)
    • Well-differentiated
    • Unifocal
    • No local invasion
  • Total Thyroidectomy if any of

    • 4cm

    • High risk patients - Previous head/neck radiation/ Familial PTC
    • Suspicious contralateral lesions
    • Evidence of cervical LN mets
    • Multifocal Papillary Microcarcinoma
      • Definition: Size < 1cm
        • < 5 foci – Hemithyroidectomy

        • 5 foci – Total Thyroidectomy Size

  • <1cm (T1a)
    • Hemithyroidectomy or conservative management.
  • 1-4cm, without extra-nodal extension and lymph node negative (T1b – T2, No)
    • Either a hemithyroidectomy or total thyroidectomy
    • Factors which would make you do a total thyroidectomy vs lobectomy
      • Need to consider the likelihood of there being residual disease in the other lobe i.e. other suspicious nodules.
      • What you think the likelihood of needing radioactive iodine is (you can’t give radioactive iodine if there is a residual hemi-thyroid)
  • Tumours >4cm in size
    • Total thyroidectomy NB: it is uncommon to have a tumour >4cm without lymph node involvement.
  • Any tumour size with extrathyroidal extension (T3+), lymph node metastasis, or distant metastasis
    • Total thyroidectomy
  • High risk patients (Previous head/neck radiation and Familial PTC
    • Total thyroidectomy

Indications for subsequent completion thyroidectomy

  • If initially thought to be well differentiated cancer
    • Poorly differentiated high grade carcinoma
    • Lymphatic or vascular invasion.
    • Multifocal disease
  • If Bethesda III or IV lesion and no indication for Total Thyroidectomy
    • Completion Total Thyroidectomy if confirmed on histology
    • Except if < 1cm (or maybe <4cm), unifocal, minimally invasive, intrathyroid, node neg

Follicular thyroid cancer surgical treatment

  • You often won’t know it’s a follicular cancer pre-operatively.
    • You will often be operating on a FNA results reporting a “follicular lesion of uncertain significance” (Bethesda III or IV lesion)
  • You will often be doing a diagnostic lobectomy
  • The management of T1-T2 tumours is the same as papillary thyroid cancer.
    • <1cm leave
    • 1-4cm discuss

    • 4cm completion thyroidectomy

Lymph Node Dissection

Therapeutic LN dissection

  • Do if exam or USS evidence of pathologic nodes (central or lateral)
  • Therapeutic central-compartment (level VI) neck dissection for patients with clinically involved central nodes should accompany total thyroidectomy to provide clearance of disease from the central neck.
  • Therapeutic lateral neck compartmental lymph node dissection should be performed for patients with biopsy-proven metastatic lateral cervical lymphadenopathy

Prophylactic LN dissection - PTC only

  • Consider central (level VI) dissection if
    • Tumour > 4cm +/- extrathyroidal extension (T3 or T4)
    • Clinically involved lateral nodes
    • High risk patients (Previous head/neck radiation, Familial PTC)
  • Arguments
    • For prophylactic central neck dissection
      • Low morbidity if done in the hands of an experienced surgeon
      • Gives more accurate staging (thus helps determine need for radioactive iodine).
      • May reduce the need for re-operative surgery – there is a trial that looked at tumours >1cm, and found that there was 4x lower risk of re-operative surgery for recurrence in patients who had a routine central neck dissection
      • Might lower post-op thyroglobulin levels which means it is more useful for monitoring.
    • Against
      • Most metastasis are micro-metastatic
        • Removal of these occult foci does not clearly influence survival and they would likely be treated by radioactive iodine.
  • Prophylactic lateral neck dissection not recommended

Radioactive Iodine Therapy (I131)

Overview

  • Indications/Purposes
    • Ablation of remnant thyroid tissue to facilitate detection of later recurrence by imaging and Tg
    • Adjuvant therapy targeting occult metastatic disease
    • Primary treatment of known persistent disease
    • Not effective for Hurthle cell differentiated follicular cancer – only about 15% of these tumours will take up iodine.
  • Pre-treatment considerations
    • Need low iodine stores
      • 1-2/52 low iodine diet to make cells iodine avid
        • Avoid iodine loads
        • Amiodarone – can interfere with RAI therapy for months to years
        • Contrast CT has high load - can mean delay to therapy for up to 3 months
    • Need high TSH levels (stimulates RAI uptake)
      • Aim for levels > 30IU/L
      • Can withdraw thyroid hormone
        • W/H levothyroxine for 3-4/52 prior
      • Can also give thyrogen, recombinant human TSH (rhTSH)
        • Avoids hypothyroidism
          • Using rTSH/thyrogen is easier for the patient - it can be given just before the RAI
        • Evidence early but caution with intermediate/high risk Ca’s (can stimulate mets etc)

Indications

  • Indicated for differentiated thyroid cancers (papillary and follicular)
  • Three reasons
    • Remnant ablation
    • Adjuvant treatment
    • Treatment of known disease
  • Based on risk
    • High risk - give
    • Intermediate risk - consider
    • Low risk - do not give

Summary of ATA risk

  • Low risk – Papillary thyroid cancer confined to thyroid
  • Intermediate risk – Low regional mеtаѕtaѕes, worrisome histologies, extrathyroidal extension, or vascular invasion
  • High risk – High regional mеtаѕtaѕes, Gross extrathyroidal extension, distant mеtаѕtases, or postoperative serum Tg suggestive of distant mеtаѕtases

Low risk tumour

  • Tumour <4cm
  • No vascular invasion
  • Not high grade
  • Not a worrisome subtype.
  • <5 lymph nodes which are micro metastatic (<2mm).

Intermediate risk tumour

  • Tumour > 4cm
  • Microscopic invasion into peri-thyroidal tissue
  • Tumour with aggressive histology - tall cell, insular, Hurthle cell carcinoma etc.
  • Clinical N1 or >5 pathologic N1 with all involved lymph nodes <3 cm in largest dimension

High risk tumour

  • Risk
    • Gross extra-thyroidal extension
    • Pathologic N1 with any metastatic lymph node ≥3 cm in largest dimension
    • Multiple lymph nodes >3cm
    • Follicular thyroid cancer with extensive vascular invasion (>4 foci)
  • Remnant disease
    • R1
    • Any evidence of distant metastatic disease.
    • Thyroglobulin level suggestive of metastatic disease.

  • High risk disease:
    • Metastatic disease (M1)
    • Gross extrathyroidal extension (T4)
  • Consider if intermediate risk (and generally favoured in):
    • Tumour > 4cm (T3)
    • Microscopic extrathyroidal extension or
    • Positive central (N1a), lateral or mediastinal LNs (N1b)
    • Adverse histological subtype (Tall cell) or vascular invasion
  • Not routinely recommended if low risk
    • 1 - 4cm, intrathyroidal, no nodes or mets

AMES risk calculator

  • AMES
    • Age
    • Metastases
    • Extrathyroidal invasion
    • Size
  • Gives low risk or high risk

Dose

Remnant ablation

  • Is typically 30mCi
  • Primary goal is destruction of remnant thyroidal tissue to facilitate staging and follow up studies.
  • There is controversy regarding the role of remnant ablation - this is something which is generally only offered to patients with low risk tumours, which, generally don’t benefit from radioactive iodine treatment anyway.

Adjuvant therapy

  • Is typically 75mCi
  • to treat any suspected but not proven disease (in moderate or high risk patients). 

Therapeutic

  • Is typically 150mCi
  • patients with known residual or recurrent disease (biochemically or structurally)

Contraindications

  • Pregnancy – Crosses placenta and causes Cretinism
  • Breast-feeding
    • Lactating breast will take up radioiodine
    • Need to stop feeding 6-8/52 prior to Rx (or consider dopamine agonist at later time)

Complications

  • Sialadenitis
  • Neck oedema
  • Tumour haemorrhage/oedema
  • Risk of secondary malignancies
    • Salivary or breast (have Na/I symporter)
    • Urinary or GIT (RAI excreted from here)
    • Reduce by giving laxatives and encourage hydration to clear RAI
  • Leukaemia
  • Myelodysplastic syndromes
  • Need to advise to stay 6 feet away from others for 24hrs

Follow up

  • Post RAI imaging should occur 2-8 days after RAI is given.
  • You will be able to observe WHERE the RAI has been taken up - which will thus confirm metastatic disease sites and thus help with staging.
  • If a metastatic site doesn’t take up radio-iodide on this scan - then it is not responsive to RAI and treatment should not be repeated.

TSH Suppression

  • Differentiated Thyroid Ca express TSH-R
    • TSH still works as growth factor
  • Give supra-physiologic dose of Thyroxine
    • Balance between risk of malignancy and hyperthyroid symptoms
  • Aim
    • High Risk
      • Aim TSH < 0.1 mU/L
    • Intermediate Risk
      • Aim TSH 0.1-0.5 mU/L
    • Low Risk
      • No suppression
      • Aim TSH 0.5-2.0 mU/L
  • Long term consequences of TSH suppression
    • Arrhythmias/AF
    • Development of osteopenia/osteoporosis

Follow up

Thyroglobulin

  • Check serum Tg levels 4-6 weeks post-op
  • Normal should be:
    • Total thyroidectomy + ablation
      • Nonstimulated Tg <0.2 ng/mL
      • TSH-stimulated Tg <1 ng/mL
    • Total thyroidectomy
      •  Nonstimulated Tg <0.2 ng/mL
      • TSH-stimulated Tg <2 ng/mL
    • Lobectomy
      • Serum Tg level <30 ng/mL
  • Stimulating vs non-stimulation
    • Most patients will be on thyroxine (TSH suppressed)
    • Patients can be given rhTSH or thyroxine stopped (TSH stimulated) to increase the level of Tg
      • Stimulated Tg values are useful to document an excellent response to therapy or to identify the presence of persistent/recurrent disease
      • With the newer, more sensitive Tg assays stimulation may not be required

Dynamic risk stratification

  • Reassessment of response to therapy at each visit
    • Based on
      • Neck USS
      • TSH
      • Thyroglobulin
  • Classifications
    • Excellent response to treatment
      • Negative imaging (USS or radio-iodide scan)
      • Non-stimulated thyroglobulin < 0.2
      • Stimulated thyroglobulin level < 1.
    • Indeterminate response
      • Non-specific signs on imaging (USS or radio-iodide scan)
      • Non-stimulated thyroglobulin level which is detectable but < 1
      • Stimulated thyroglobulin level which is detectable but < 10.
    • Biochemical incomplete response
      • Negative imaging
      • Non-stimulated thyroglobulin level > 1
      • Stimulated thyroglobulin level > 10.
      • Rising anti-thyroglobulin anti-bodies after treatment.
    • Structurally incomplete response
      • Residual disease on USS or radio-iodide scan
      • With or without elevated thyroglobulin levels.

Surveillance

  • Usually follow up appointment to check wound
  • Check TFT and baseline thyroglobulin at 6-8 weeks post-op
  • Neck USS
    • 6–12-month intervals
  • TSH + Thyroglobulin
    • Every 3-6 months
    • NB: Also measure anti-Tg levels as antibody will interfere with assay
  • If concerns on USS or biochemically, perform
    • Diagnostic whole body radioiodine scan
    • Consider CT, MRI, PET-CT

Recurrence

  • Minimal disease
    • Re-operative an option
    • If on going uptake on radioiodine scanning then RAI can be given
      • Disease that is FDG-PET avid tends to not respond to RAI
  • Extensive disease
    • Radioiodine, if scans demonstrate uptake.
    • Systemic chemotherapy (eg, kinase inhibitors).
    • External radiotherapy.
    • Percutaneous ethanol injection of cervical nodal metastases.
    • Radiofrequency ablation of cervical, osseous, and pulmonary metastases – This is an alternative for patients who are poor surgical candidates and whose metastases do not concentrate radioiodine, but expertise in this treatment modality is not widely available.
    • Palliative embolization of bone metastases – Palliative embolization may reduce symptoms or be used prior to surgery.

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