12 liu thyroid nodule mgmt - ucsf cme liu thyroid... · 2016. 3. 28. · ata2015 thyroid2016&...

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2015 ATA Management Guidelines Thyroid Nodules & Differen=ated Thyroid Cancer

Focused Case Based Discussion

Chienying Liu MD

Disclosure

•  None •  Adult guidelines should not be applied to children < 18-‐20 yo

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Year 1975 1980 1985 1990 1995 1999 2003 2007

5-‐Year RelaJve Survival 92.3% 92.8% 92.5% 95.5% 95.8% 96.8% 97.3% 97.9%

New Cases, Deaths and 5-Year Relative Survival

SEER Cancer StaJsJcs Factsheets: Thyroid Cancer. NaJonal Cancer InsJtute. Bethesda, MD, hTp://seer.cancer.gov/staUacts/html/thyro.html

Increase mostly due to small PTC 50% < 1cm 30% 1-‐2 cm

Thyroid Cancer ‘Epidemic’ in Korea

15 x

NEJM 2014

Most Common Cancer In Korea

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Thyroid Cancer-‐Autopsy Studies

•  6-‐11% in most studies •  In US

•  6.2%, 5 to 10.5mm, 46% multifocal, 14% LN metastases •  1020 autopsies

•  In Finland – Occult PTC: 2-‐3 mm secJon •  101 consecutive autopsies >40 yo •  35.6% (43.3% in men and 27.1% in women) •  77% < 1 mm •  93 autopies younger than 40 •  14% •  27% between 18-40 yo •  Tumor size 0.05-2 mm (mean 0.2mm)

Lang et al, Am J Clin Pathol 1988 Franssila et al Cancer 1985 and 1986

A large reservoir of subclinical diseases Many cases uncovered through imaging

THYROID NODULE/THYROID CANCER

•  Guidelines •  1996: ATA published treatment guidelines on thyroid nodules and cancer •  2006: ATA established a task force to develop guidelines – evidence based

medicine •  2009: Revised guidelines because of rapid growth in the literature on this topic

•  Introduced risk stratification for recurrence: low, intermediate, high for recurrences

•  2015: Updated and expanded from 2009 •  Added 21 recommendations and amended 21 prior recommendations

•  Controversies exist •  Lack of high quality randomized controlled trials

Thyroid January 2016 101 rec/21 new rec

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Schematic diagram of a follicular cell, illustrating the steps involved in thyroid hormone synthesis. Park S M , and Chatterjee V K K J Med Genet 2005;42:379-389

©2005 by BMJ Publishing Group Ltd

Thyroid Physiology 101

•  Normal thyroid cells more iodine avid

•  To use RAI in DTC → remove most of the normal thyroid tissue

•  Therapeutic

•  Diagnostic/Surveillance scanning •  Especially when iodine scan was the

primary modality for surveillance

Thyroglobulin-‐ Tg

•  ½ life 1-‐3 days (Carole Spencer: 3 days)

•  The nadir achieved by 3-‐4 weeks ager surgery

•  1ng/mL =1 gram of thyroid Jssue when euthyroid

•  Post op Tg can be helpful •  Thyroid remnant + neoplastic thyroid tissue (if any)

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Factors to Consider When Interpre=ng Tg •  TSH

•  TSH stimulates Tg synthesis •  Stimulated Tg the most sensitive way of detecting recurrences

•  Interfering AB •  Tg AB – most common (20-30%) - falsely lower Tg •  Heterophile AB – Uncommon - falsely elevate Tg (need to ask Lab to run test )

•  FuncJonal sensiJvity •  1st generation assays: functional sensitivity: 0.5 to 1

•  May fail to detect early tumor recurrence and will only be positive after TSH stimulation

•  2nd generation assays: functional sensitivity: 0.05 to 0.1 (UCSF, Quest, Labcorp) •  Tg < 0.1 correlates with rh TSH stimulated Tg (<2) well (total thyroidectomy and remnant ablation)

•  Any injury or inflammatory process

Case

•  76 yo woman found to have a FDG avid 9mm nodule on PET-‐CT for surveillance of breast cancer

•  PMH also significant for lung cancer, in remission

•  U/S showed mulJple non-‐suspicious nodules and a suspicious 9 mm nodule

•  TSH normal

•  Biopsy?

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ATA Guidelines 2015 Thyroid 2016

ATA 2015 Guidelines Thyroid 2016

FNA can be considered at the lower cutoffs in the presence of known clinical risk factors -‐  Unusual symptoms, childhood radiaJon exposure, familial thyroid cancer syndrome

Surveillance can be considered in selected paJents who met the cutoffs for FNA -‐  Very low risk nodules, paJents with comorbidiJes

Vary Your Cutoffs Based on Individual paJent’s Risk or ComorbidiJes

ATA 2015 Thyroid 2016

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FDG Avid Thyroid Nodules

•  FDG avid nodules – 35% risk of malignancy •  Biopsy if ≥ 1 cm

Our paJent •  FNA: PTC

Strong RecommendaJon, Moderate Quality Evidence

ATA 2015, Thyroid 2016

Ultrasound Evalua=on

•  Lymph node evaluaJon should be included •  In all patients with thyroid nodules

•  Lymphadenopathy will change management


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Ultrasound Surveillance & Follow Up

•  Benign nodules do grow •  Suspicious ultrasound paTerns more important than growth

•  Missed cancers frequently have suspicious ultrasound features •  On repeat biopsies, higher malignancy rates in nodules with suspicious

ultrasound findings (17-20%) than in nodules that grew in size (1.3-1.4%)

Ultrasound Surveillance & Follow Up Ultrasound PaUern FNA benign If No FNA High Suspicion

Repeat US and FNA in 12 m (Strong/Moderate-‐Quality)

Repeat US 6-‐12 m (Weak/Low-‐Quality)

Low to Intermediate Suspicion

•  Repeat US at 12-‐24 m •  FNA if growth or new suspicious features

(Weak/Low-‐Quality)

Repeat US 12-‐24 m (Weak/Low-‐Quality)

Very Low Suspicion •  UJlity of repeaJng US unclear

•  When repeat, repeat > 24 m (Weak/Low-‐Quality)

> 1cm •  UJlity of repeaJng US unclear •  If repeat US, should be > 24 m (No recommendaJon, In sufficient evidence)

< 1 cm •  RouJne US not needed •  If repeated US, should be > 24 m (Weak/Low-‐Quality) ATA 2015 Guidelines

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Management of Benign Nodules RecommendaJon 25 •  “RouJne TSH suppression in iodine sufficient populaJon is

not recommended” RecommendaJon 26 •  Adequate iodine intake for pts with benign solid or mostly

solid nodules •  “If inadequate dietary intake is found or suspected, a daily

supplement (containing 150 mcg iodine) is recommended RecommendaJon 27 •  “Benign growing nodules should be monitored” •  “AsymptomaJc nodules should be monitored without

intervenJon” RecommendaJon 29 •  “There are no data to guide recommendaJons on the use of

thyroid hormone therapy in paJents with growing nodules that are benign on cytology”

•  Strong recommenda=on, High-‐quality evidence

•  Strong recommenda=on, Moderate-‐quality evidence

•  Strong recommenda=on, Low-‐quality evidence

•  No recommenda=on, Insufficient evidence


Case •  76 yo woman

•  9 mm PTC

•  No lymph nodes on ultrasound or PET-CT

•  What do you recommend •  Total thyroidectomy •  Lobectomy

•  Active surveillance


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Ac=ve Surveillance – A Feasible Op=on

•  Low risk papillary microcarcinoma < 1 cm

•  No evidence of local invasion •  No metastasis •  No cytologic (or molecular) evidence

of aggressiveness

•  High surgical risk •  Short life span •  Concurrent medical issues that

need to be addressed first

Ito et al 1235 pts: Mean f/u 60 m (18-‐227 m) Tumor enlargement 5% 5 yrs 8% 10 yrs Lymph node metastasis 1.7% 5 yrs 3.8% 10 yrs Clinical progression (>12mm or nodal met)

3.9% 5 yrs 6.8% 10 yrs Predictors: Younger age and larger size

Sugitani et al 230 pts; Mean f/u 60 m (1-‐17 yrs) Tumor enlargement 7% Lymph node metastasis 1%

•  No death •  Salvage surgery effecJve

•  only 1 case of recurrence ager delayed surgery

For PTMC

Ac=ve Surveillance Ito et al. Thyroid 2014

Miyauchi A. Would J Surgery 2016

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Miyauchi A. World J Surgery 2016

Proper Pa=ent Selec=on for Ac=ve Surveillance

Tumors •  NOT adjacent to the trachea or the

posterior surface of the lobe •  NOT high grade cytology from FNA •  NO nodal metastasis

AcJve Surveillance •  Appropriate for low risk PTMC

•  Low rates of progression, esp in older pts •  Small sub-‐cm high suspicious nodules

Case •  64 yo woman with mulJple sclerosis

was found to have a leg 2.5 cm thyroid nodule. FNA ‘ atypical’

•  US: no clinical nodes & 2 small 5 mm nodules in the right lobe, without suspicious features

•  IntraoperaJve findings -‐ no invasion, no nodal disease

•  Lobectomy -‐ Final pathology showed a 2.3 cm papillary thyroid cancer

•  Should she undergo compleJon thyroidectomy?

•  Will this improve outcomes? •  Is lobectomy sufficient?

•  Will she benefit from RAI?

•  Can you monitor her without completion

thyroidectomy

•  What does she want?

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2009 Guidelines

•  RECOMMENDATION 26 •  For paJents with thyroid cancer >1 cm, the iniJal surgical •  procedure should be a near-‐total or total thyroidectomy •  unless there are contraindicaJons to this surgery

Lobectomy – An Op=on for T1-‐T2 RecommendaJon 35 •  Total/near Total for cancer > 4 cm, gross extrathyroidal invasion, distant or clinical regional nodal metastases

•  Cancer >1 cm and <4 cm without extrathyroidal extension, and without clinical evidence of any lymph node metastases (cN0), the iniJal surgical procedure can be near-‐total or total thyroidectomy or lobectomy


Prior guidelines – total/near total thyroidectomy for tumors >1 cm

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Studies Database Pa=ents Overall Survival -‐10 yr DSS Recurrence

Bilimoria et al 1985-‐1998 Median f/u 6 yr

NaJonal Cancer PTC all sizes

Total: 43227 Lobe: 8946

Total: 98.4% Lobe: 97.1% P< 0.05

Total:7.7% Lobe: 9.8% P< 0.05

No adjustment for co-‐morbidiJes & ETE, mulJfocality, resecJon

Adam et al 1998-‐2006 Mean f/u 6.8 yr

NaJonal Cancer PTC 1-‐4 cm

Total: 54926 Lobe: 6849

Same 1-‐2 cm and 2.1-‐4 cm

Adjusted for co-‐morbidiJes+ complexiJes

Barney et al 1983-‐2002 Median f/u 6.7 yr

SEER PTC/FTC

Total: 12598 Lobe: 3266

Total: 90.4% Lobe: 90.8%

Total: 96.8% Lobe: 98.6%

Adjusted for TNM, age, sex, surgery, RAI use

Mendelsohn et al 1998-‐2001 Mean f/u 9 yr

SEER PTC

Total: 16760 Lobe: 5964

Total:90.8% Lobe: 89.4%

Total: 97.5% Lobe: 98.4%

Adjusted for variables and tumor size

Nixon et al 1986-‐2005 Median f/u 8yr

SKMCC Total 528 Lobe 361

Total: 92% Lobe: 93%

Total 98% Lobe 100%

6% -‐ immediate compleJon 4% -‐ compleJon later

Vaisman et al Median f/u 5yr

SKMCC No RAI

Total 72 Lobe 217

Total: 2.3% -‐recur (level VI) Lobe: 4.2% -‐recur (contra-‐ lobe) Tg not helpful/ T4 not used if TSH nl

Matsuzu et al 1986-‐1995 Median f/u 17.6yr

Japan Ito hospital

Lobe+ipsilat (VI + II-‐V) 1088

25 yrs: 95.2%

25 yrs recurrence free survival 93.5% lobe, 90.6% nodes, 93.6% dist TSH suppression in most

JCEM 2015

No Difference in OS, unadjusted or adjusted, for various sizes

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Lobectomy – An Op=on for T1-‐T2 RecommendaJon 35

•  Cancer >1 cm and <4 cm without extrathyroidal extension, and without clinical evidence of any lymph node metastases (cN0), the iniJal surgical procedure can be near-‐total or total thyroidectomy or lobectomy

No impact on survival Recurrences usually easily detected and appropriately treated Lower complicaJon rates (7.6% vs 14.5%)

Thyroid 2016

Case •  64 yo woman with mulJple sclerosis

was found to have a leg 2.5 cm thyroid nodule. FNA ‘ atypical’

•  US: no clinical nodes & 2 small 5 mm nodules on the right without suspicious features

•  IntraoperaJve findings no invasion, no nodal disease


•  Should you perform compleJon thyroidectomy?


•  Will she benefit from RAI? •  Will RAI lower the risk of

recurrence?

•  Can you monitor her without completion thyroidectomy?


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TNM STAGING

TNM Staging

Age < 45 yo Age > 45 yo

Stage I Any T, any N T 1 0-‐2cm (T1a ≤ 1 cm, T1b 1-‐2 cm) Stage 2 Distant metastasis T 2 2-‐4 cm Stage 3 T 3 > 4 cm

T 3 Minimal/microscopic ETE N 1a Central neck node involvement

Stage 4 T 4 Invasion of adjacent =ssues M1 Distant metastases N 1b Lymph node other than central neck (medias=nal or lateral)

•  AJCC TNM – most widely used •  Predicts mortality

INITIAL RISK STRATIFICATION Low Intermediate High

•  No mets, all macroscopic tumor resected

•  No ETE •  No aggressive histology •  No vascular invasion •  No uptake outside of thyroid bed if I131 given

•  Uptake outside of thyroid bed locally

•  Microscopic ETE •  Aggressive histology •  Vascular invasion •  N1

•  Gross ETE •  Incomplete tumor resecJon

•  Distant metastases •  >> Tg out of proporJon

•  Clinical N1 or >5 pathologic N1 with all involved lymph nodes <3 cm in largest dimension*

•  MulJfocal papillary microcarcinoma with ETE and BRAFV600E mutated (if known)*

•  Clinical N0 or ≤5 pathologic N1 micrometastases (<0.2 cm in largest dimension)*

•  Intrathyroidal encapsulated follicular variant PTC*

•  Minimally invasive FTC* •  Microscopic PTC even with BRAF +*

•  Pathologic N1 >3 cm in largest dimension*

•  FTC, widely invasive (≥ 4 vessels)*

*New risk factors ATA 2015 Guidelines

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Thyroid 2012

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Thyroid 2016

RAI use •  PaJents already at very low risk – no

addiJonal benefits •  PaJents at high risk – likely to see

benefits •  PaJents in the intermediate group, esp

lower intermediate risk – mixed data

Radioac=ve Iodine Use In DTC

•  Treatment of residual cancer/metastaJc foci •  RAI is clearly indicated

•  Adjuvant

•  Treat potential but unproven microscopic disease to improve outcomes

•  Remnant ablaJon •  Rid of the remnant tissue, and to improve outcomes? •  Facilitate follow up using whole body iodine scanning as the modality for

surveillance

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Remnant Abla=on – Long Standing Debate •  RAI was first used for DTC treatment in 1940s

•  Remnant ablaJon to ‘complete thyroidectomy’ or ‘wipe the slate clean’ started in 1960s

•  Remnant ablaJon was demonstrated to have survival/recurrence benefits by 1980s

•  But benefits quesJoned due to opposing data

Hay ID . J Surg Oncol. 2006

ATA Recurrence Risk TNM staging

Tumor Descrip=on

Evidence of RAI for DSS

Evidence of RAI for recurrence

RAI indicated?

Low Risk/T1aN0M0 ≤ 1 cm No No No

Low Risk T1a-‐T2N0M0

1-‐4 cm No ConflicJng observaJonal

Not Rou=ne -‐ Consider -‐vascular invasion -‐aggressive pathology

Low to Intermediate T3N0M0

> 4 cm ConflicJng ConflicJng observaJonal

Consider -‐ Advancing age

Microscopic ETE of any size

No ConflicJng observaJonal

Consider, ‘generally favored’ -‐ Small tumors may not require RAI

Low to Intermediate T1-‐3N1aM0

Central nodal mets

No, except for >45yo (NTCCTSG stage III)

ConflicJng observaJonal

Consider, ‘generally favored’ -‐  Advancing age -‐  Large nodes and Inc # of nodes -‐  Extranodal extension Not clearly indicated -‐ ≤5 and microscopic (<2mm)

Low to Intermediate T1-‐3N1bM

Lateral & MediasJnal nodal mets

No, except for >45yo

ConflicJng observaJonal

Consider, ‘generally favored’ -‐  Advancing age -‐  Large nodes and Inc # of nodes -‐  Extranodal extension

High Risk T4 or M1

Gross ETE Distant mets

Yes ObservaJonal

Yes ObservaJonal

Yes

Thyroid 2016

ATA Intermediate Risk

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Post op Evalua=on in Clinical Decision for RAI •  Post op Tg

•  Post op Tg of 5-10ng/mL – predicts likelihood of having iodine avid disease outside of thyroid bed (nodes or distant mets)

•  Low Post op Tg can be reassuring •  The lower the better •  < 1ng/mL may be reassuring

•  Even in intermediate risk patients •  Cannot rule out small volume disease

•  Uncertainties regarding best cutoffs

•  Neck ultrasound •  In conjunction with postop Tg

•  Iodine scan •  I123

•  Low dose I131

Age

•  Tumor size •  Adverse histologies:

•  Degree of extra-‐thyroidal invasion

•  Vascular invasion

Lymph node status -‐  number, size, locaJon PostoperaJve Tg

Integra=on of Mul=ple Factors

RAI in Low and Low to Intermediate Risk PaJents

Response to Initial Treatment

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Prospec=ve Randomized Trials

•  French Study •  Estimabl2 (Differentiated Thyroid Cancer: Is There a Need for

Radioiodine Ablation in Low Risk Patients)

•  English Study •  The IoN study – Is Ablative Radio-iodine Necessary for Low Risk

Differentiated Thyroid Cancer Patients

•  Will have patients with selected N1 disease

Case •  64 yo woman with mulJple sclerosis was

found to have a leg 2.5 cm thyroid nodule. FNA ‘ atypical’


•  IntraoperaJve findings no invasion, no nodal disease


•  No ETE •  No lymphovascular invasion •  No nodes


•  Will this improve outcomes? •  Is lobectomy sufficient


•  Can you monitor her without a completion thyroidectomy?

•  Older days: iodine WBS •  Nowadays: Serial Tg + Neck U/S


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Low Risk PaJents Lobectomy Only Monitoring Strategies

•  Tg •  Neck ultrasound •  Keep TSH 0.5-‐2mIU/L


Case •  64 yo woman with mulJple sclerosis was

found to have a leg thyroid nodule. FNA ‘atypical’


•  IntraoperaJve findings: no invasion, no nodal disease


•  No ETE •  No lymphovascular invasion •  No nodes




•  Can you monitor her without a completion thyroidectomy


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Risk of Hypothyroidism Aher Lobectomy •  Meta-‐analysis (JCEM 2013) of 32 studies: 22%

•  4 studies: 12% sublinical hypothyroid and 4% clinical hypothyroidism •  Risk Factors: Higher TSH levels, TPO positivity, and evidence of thyroiditis on surgical

pathology

•  Meta-‐analysis of 32 studies (ORL 2013): •  Mean TSH 1.94 to 3.15 µIU/l for postop hypothyroidism •  Mean TSH 1.10 to 1.95 µIU/l for postop euthyroidism •  TSH < 1 unlikely to develop hypothyroidism

•  Stoll et al Surgery 2009 -‐34 months follow up, TSH upper normal 4.82 •  13.5% patients with TSH levels <1.5 µIU/ml •  20.5% of patients with a TSH between 1.51 – 2.50 µIU/ml •  41.3% of patients with a TSH >2.5 µIU/ml

Unclear How Many Can Maintain TSH below 2?

Assessing Response to Therapy

•  IniJal staging system and risk straJficaJon system •  Provide important information and insight •  Guide early therapeutic decisions

•  But - static, single point estimate

•  Response to therapy •  Risk of recurrence and disease specific mortality can change depending

on the response

•  Allows for individualized and ongoing management •  Improves PVE (proportional variance explained)

•  < 30% to 62-84% Thyroid 2016

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Response to Therapy – Classifica=on and Clinical Implica=ons (Aher Total Thyroidectomy and RAI)

Category Response

Defini=on Clinical outcome Management Tg Imaging

Excellent Neg Neg •  1-‐4% recurrence •  < 1 % DS mortality

•  ↓ Intensity/Freq of F/U •  ↓ TSH suppression

Biochemical Incomplete

Uns=mulated ≥ 1 S=mulated > 10 Rising Tg AB

•  30% resolved spontaneously •  20% NED aher more treatment •  20% -‐> structure disease •  < 1% DS mortality

•  Con=nuous observa=on •  TSH suppression •  Addi=onal inves=ga=on if

needed, and possibly treatment

Structure Incomplete

Structural or func=onal

•  50-‐85% persistent disease aher more treatment

•  11% DS mortality

•  Con=nuous observa=on •  TSH suppression •  Addi=onal treatment

Indeterminate Uns=mulated < 1 S=mulated < 10

Nonspecific findings

•  15-‐20% -‐> structure disease •  < 1% DS mortality

•  Con=nuous observa=on •  Serial imaging

ATA 2015 Guidelines/Thyroid 2016

Thyroid Hormone Suppression Risk Adapted & Response Adapted Management

Ini=al

•  Low Risk (Total thyroidectomy) •  0.5-2.0 mU/L If NED

•  0.1-0.5 mU/L

•  Low Risk (Lobectomy) •  0.5-2.0 mU/L

•  Intermediate Risk •  0.1-0.5 mU/L

•  High Risk •  < 0.1 mU/L

•  0.1-0.5 mU/L x 5 years if no dz

Long Term


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Paradigm Shih In Management of Thyroid Cancer •  Risk adapted management

•  Surgery, RAI use, degree of TSH suppression, and follow up •  Allows for more individualized approach

•  Many subclinical cases of low risk, low to intermediate risk thyroid cancer uncovered through imaging

•  Avoid overtreatment in this population but treat appropriately in those high risk patients •  Candidates appropriate for acJve surveillance

•  Lowest progression rates seen in older patients •  The opJon of lobectomy is likely to stay as an opJon for low risk tumors •  Tg and neck ultrasound have changed how we monitor our paJents

•  No need for more aggressive therapy to facilitate surveillance •  RAI use has conJnued to be controversial in the low and low intermediate risk paJents

•  Greatest benefits are likely observed in higher risk patients

12 liu thyroid nodule mgmt - ucsf cme liu thyroid... · 2016. 3. 28. · ata2015 thyroid2016&...

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