Management of differenciated thyroid cancer (ESCO 2019)

Concept, epidemiology, etiology, clinical picture, diagnosis and prognosis of Differenciated Thyroid Cancer are taken for granted. There are quite a lot of book chapters and reviews about that. 

The article we comment is this and appeared in Annals of Oncology in September 2019. 

In the next post we review management of advanced disease. 

 

 

First of all, staging. It will give us the prognosis i.e. death risk:

• TNM (TNM 8 staging system):
• T1: a: <= 1 cm: b: 1-2 cm.
  
• T2: 2-4 cm
• T3: 
• a: > 4 cm limited to thyroid
• b: gross extrathyroidal extension invading strap muscles
  
• T4: 
• a: macroscopic extrathyroidal extension: soft tissues, larynx, trachea, oesophagus, recurrent nerve.
  
• b: prevertebral fascia, carotid artery or mediastinal vessel
• N0: no nodes
  
• N1a: nodes in level VI (pre- or paratrachear, delphian or prelaringeal) or VII (superior mediastinum)
  
• N1b: nodes in levels I-V.
  
• M0: no metastasis
  
• M1: metastasis
• Stage 
• <55:
• I: M0
• II: M1 
• >=55:
• I: T1-T2 (N0M0)
  
• II: T3 or N1
  
• III: T4a
  
• IVa: T4b
  
• IVb: M1

Secondly, Surgical Management: 

•  Unifocal papillary microcarcinonas (T1aN0M0): 
• Surveillance has been proposed with US every 6-12 m and surgery if nodes or >3mm growth is seen. Younger age is risk factor for operation. 
• Surgery is the alternative for rest of cases (for type of operation, read below). If history of neck radiation, TC family history, or aggressive cytology, surgery (TT) is proposed.
  
• Rest of T1 through T4a: 
• Total thyroidectomy (Standard therapy).
• In low risk T1-T2N0 low-quality evidence (bias-prone large database studies) shows that lobectomy gets similar survival but slightly higher local recurrence. In any case, TT is always proposed:
• As initial surgery if posterior or adyacent to trachea
• After lobectomy if postoperatively we find aggressive histotype, vascular invasion, T3, N1 or residual tumor (R1)
•  Prophylactic central neck dissection (CND):
• In low risk tumors T1-T2 no high quality evidence (HQE) exists for or against it in terms of survival. Advantages are better staging and possible lower local recurrence. 
• T3-T4a CND improves regional control. 
• T4b: no surgery, consider external beam radiotherapy (EBRT)
• N1a: TT+- therapeutic CND
• N1b: TT+- therapeutic CND +- therapeutic compartment oriented lateral neck dissection (LND)

Third: Risk Stratification for prediction of persistent or recurrent disease:

• Low (<5%):
• NIFTP (<1%)
• PTC (1-6%): all of them:
• T: no remnants, no local invasion, no aggressive histotype, Braf V600E if <1cm, no vascular invasion
• N: Clinical N0 or pathological N1 with <5 nodes< 2 mm each 
• M: no metastasis, no RAI foci outside thyroid bed
• FTC (2-3%): intrathyroidal, well diferenciated, no or <4 foci of vascular invasion, capsular invasion.
  
• Intermediate (5-20%):
• PTC: 
• Microscopic ETE (8%)
• Symptoms (10%)
• Braf V600E if <4 cm (10%)
• Aggressive hystology (15%):
• tall
• columnar
• hobnail
• diffuse sclerosant
• squamous
• solid/trabecular
  
• Vascular invasion (15-30%)
• Extrathyroid neck foci in 1st WBS
• Clinical N1 or pathological >5 nodes < 30 mm (20%)
  
• Multifocal + ETE + Braf V600E (20%)
• FTC:
• Clinical N1 or pathological >5 nodes < 30 mm (20%)
• Extrathyroid neck foci in 1st WBS
• High (>20%):
• PTC:
• Gross ETE (30%)
• Nodes >3 cm (30%)
• Extranodal extension (40%)
• Braf V600E + TERT (40%)
• Tg suggesting metastasis (100%)
  
• Incomplete resection (100%)
• Metastasis (100%)
• FTC:
• Vascular invasion >4 foci (30-55%)
• Tg suggesting metastasis (100%)
  
• Incomplete resection (100%)
• Metastasis (100%)

Fourth: consider RAI therapy:

• No residual disease (remnant ablation, adjuvant):
• Low risk:
• T1aN0: no RAI
• Other low risk: no consensus, no HQE for or against. If given, 30 mCi with rTSH is proposed. 
• Intermediate risk: also no consensus, if given, RAI 30-100 mCi with rTSH or withdrawal. 
• High risk: consensus RAI >100 mCi with rTSH (better QoL) or withdrawal (recommended if distant metastasis). 
• Residual disease (therapeutic, incomplete surgery or methastasis): 100-200 mCi, with withdrawal:
• Refractory: no more treatment:
• no uptake in WBS
• no uptake after RAI therapy
• some MTS uptake, other not
• RECIST progression after RAI
• *other (controversial): aggressive histology, positive PET, persistance after several treatment courses
  
• No refractory: repeat every 6-12 months until 600 mCi reached.

Fifth: evaluate response to treatment. It'll depend on serum thyroglobulin (Tg) and image:

• Serum Tg
• Undetectable levels have high negative predictive value, but detectable have low positive PV, they can be false positive.
• Always measure antiTg Ab. If positive, false negative or, more rarely, false positive value is possible and Tg level is unreliable.
• Almost 60% of TT with no RAI have Tg<0,2 ng/mL, which indicates absence of disease. If detectable, serial measurement is mandatory. 
• Neck US: useful in PCT, in FTC only to explore thyroid bed. 
• Whole Body Scan (WBS). Low sensibility 27-55%, high specificity, better with spect. Indicated when suspected residual disease. 
• 18F-PET: More sensitive less specific than WBS, indicated in agressive WBS- tumors. Prognostic marker, but no indicator of tumor growth. 
• CT: for neck and chest. Contrast for neck and mediastinum, not for lungs. Delay RAI 6 weeks if contrast. 
• MRI: for liver, bones and brain. 

This way response to treatment can be classified in 4 groups:

•  Excellent: 
• TT+RRA: no image + Tg<0,2 ng/mL or stTg<1 + negative TgAb
• TT alone: no image + Tg<0,2 ng/mL or stTg<1 + negative TgAb
• Lobectomy: no image + stable Tg + negative TgAb
  
• Indeterminate:
• TT+RRA: nsp image, or nsp thyroid bed uptake on thyroid bed, or Tg0,2-1 ng/mL, stTg 1-10 or stable or declining TgAb with no image
• TT alone: nsp image, or Tg 0,2-5 ng/mL, or stable or declining TgAb with no image
  
• Lobectomy: nsp image
• BQ incomplete:
• TT+RRA: no image + Tg >1 or stTg>10 ng/mL or rising TgAb
  
• TT alone: no image + Tg >5 or rising Tg on stable TSH or rising TgAb
  
• Lobectomy: Rising Tg on stable TSH or rising TgAb
  
• Structural incomplete:
• Positive image regardless of Tg or TgAb

Sixth: follow-up strategy, it'll depend on 4 variables: 1.-Histotype, 2.- Initial treatment (surgery, RAI); 3.- Recurrence risk; and 4.- Response to treatment.

After initial therapy (surgery +- RAI), measure Tg(+Ab) + neck US at 6-18 months:

• In low risk PTC + negative image, intermediate risk PTC + excellent response, or (although based in LQE) low risk FTC + excellent response:
• 12-24 month serum Tg
• TSH range 0,5-2 mcU/mL
• Neck US based on serum TG
• In low and intermediate risk PTC + indeterminate or BQ incomplete response (i.e. negative image):
• serum Tg + neck US every 6-12 months, if rising Tg perform conventional image
• TSH level 0,1-0,5 in intermediate risk. 
• In high risk PTC, poorly-differenciated TC and invasive FTC with negative image (excellent, indeterminate or incomplete response): Tg every 6-12 m, perform image if detectable Tg or of high risk even with negative Tg (for risk of dedifferentiation)
  
• Structural incomplete response (positive image): local or systemic therapy.