Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma
Postoperative Surveillance of Differentiated Thyroid Carcinoma
Transcript of Postoperative Surveillance of Differentiated Thyroid Carcinoma
Postoperative Surveillance of
Differentiated Thyroid
Carcinoma
Mitchell E. Tublin, M.D.
Vice Chair & Professor of Radiology
Section Chief: Abdominal Imaging
University of Pittsburgh
School of Medicine
Postoperative Surveillance of
DTC….and some observations
from a recovering cynic
Mitchell E. Tublin, M.D.
Vice Chair & Professor of Radiology
Section Chief: Abdominal Imaging
University of Pittsburgh
School of Medicine
Thyroid carcinoma: “epidemic”
• 2014 ACS estimate:
– 63K new cases (2009: 37K)
– 1,890 deaths, 0.3% of all cancer deaths (CA Cancer J Clin, 2014, Cancer Statistics, 2014)
• Majority are differentiated thyroid carcinoma
– Papillary cancer 80%
– Follicular cancer 11%
• Most slow growing and respond to tx
Thyroid carcinoma: recurrence basics
• Typically indolent tumor
• 5 year survival rate: 97.3%
• Tumor may present decades after initial presentation
• ↑ risk of recurrence, mortality if > 45, advanced tumor at initial presentation
Differentiated thyroid cancer
• Surveillance approaches for DTC rapidly
evolving in context of recent thyroid
carcinoma “epidemic”, improvements in
imaging, and molecular diagnostics
• ATA guidelines: 2006, 2009, 2015
Sono surveillance of DTC: My
world view
• I’m a sono advocate, I like scanning but I’m a
natural cynic
• Use of sono as primary modality for detection of
regional recurrence highlighted in recent (non-
radiology) literature
• Central role in 2015 ATA guidelines
• Imaging has outpaced understanding of biology
• Intervention often patient (and RVU) driven
DTC Surveillance:
controversies
• Which modality and when (it’s
still not all ultrasound…..)
• What criteria
• How report
• Should we care?
DTC surveillance: it’s all
about thyroglobulin
• Thyroglobulin
– Produced exclusively by follicular cells
– Should be undetectable after
thyroidectomy and successful ablation
– Elevated Tg indirect evidence of residual
functioning thyroid tissue or tumor
– Sensitivity of Tg 85-95% with L-T4
withdrawal or rhTSH stimulation
Thyroglobulin
• Very high negative predictive value
• False negatives may occur:
–Anti Tg Ab
–Absent or abnormal Tg production
by dedifferentiated metastases
131 (123)I Whole Body Scan
• Traditional strategy:
– Surveillance 131I whole body scan and
serum Tg post thyroidectomy and
ablation
• WBS utility discounted in 2009, 2015 ATA
guidelines
• Limited additional benefit if stimulated
thyroglobulin undetectable (and sono - )
Pacini, J Clin Endo & Metab, 2002
131 I Whole Body Scan
• 2009/2015 ATA guidelines
– Surveillance WBS not advocated for low
risk pts (no locoregional dz, favorable
histology) with neg Tg/sono
– Surveillance Dx WBS (1123 or low dose
I132) may be useful for intermediate or
high risk pts
131 I Whole Body Scan
• Still used if TG +, cervical US –
• With elevated Tg, 131I WBS localizes
recurrence in:
– 50 – 60% papillary carcinoma
– 64 – 67% follicular carcinoma
• Anatomic detail limited
131 I Whole Body Scan
• Potential causes for false negative WBS
– Insufficient TSH stimulation
– Iodine contamination
– Low volume tumor
– Dedifferentiated tumor
• Absence of 131I uptake in metastatic disease
may be a predictor of poor outcome
Fluorine-18-fluorodeoxyglucose
(FDG) PET
• Long accepted utility in Tg positive, WBS negthyroid cancer
– Sensitivity 60 - 94%
– Specificity 25 – 90%
• Recommended threshold Tg > 10 µg/L
• Increased FDG uptake and loss of 131I uptake may reflect dedifferentiation and more aggressive tumor (flip-flop phenomenon)
• Limited spatial resolution
• False positives (physiologic activity, inflammation)
Combined CT-PET
• Advantages
– Spatial localization
– Increased specificity (physiologic uptake)
• ATA 2015: FDG-PET / CT-PET synonymous
• Potential indications beyond Tg +, WBS – dz
– Initial staging & f/u of high risk pts with poorly differentiated dz
– Selection tool for pts unlikely to respond to 131I ablation
PET-CT Study Patients Sensitivity Specificity
Nahas et al. 33 66% 100%
Palmedo et al. 40 95% 91%
Iagaru et al. 76 88.6 89.3
Finkelstein et al. 65 98% 81%
Shammas et al. 61 68.4% 82.4%
Kim et al. 20 90%
Freudenberg et al. 36 96% 100%
UPitt (Ferris) 123 82.1% 89.7%
CT-PET: Literature
Thyroid cancerCT: 160 mAs; 130 KVp; pitch 1.6; 5 mm slices PET: 7 mCi FDG; 3 x 10 min; 3.4 mm slices
78 year-old male. Thyroid cancer
in 1993. Elevated thyroglobulin.
Negative 131I study. Four lesions identified on PET/CT
PET/CT scannerUniversity of Pittsburgh
131I scan
Thyroid cancer surveillance
• CT
– Useful for distant (lung) metastases
– Limited role for regional recurrence
• Size only useful criteria for nodal dz
• Anatomy may be obscured without IV contrast
• MRI
– Local dz, FSE T2, neck coil
– 1cm size threshold, high T2 signal (n = 26)
• Sensitivity 95% Specificity 51%
• PPV 84% NPV 78% Accuracy 83%
– Interobserver variability
Gross, Laryngoscope, 2001
Ultrasound
• Premier modality for thyroid imaging,
nodule identification, characterization (?)
and bx
• Optimum technique critical for imaging of
local-regional recurrence
– High frequency probe (10-14 MHz)
– Compound imagining
• Operative hx, zone classification
• Physician scanning crucial
Ultrasound
• Combination of rhTSH-stimulated Tg and sonography most sensitive for monitoring differentiated thyroid ca regional recurrence in recent large series (n = 340)
Sens Spec
Sono 70 97.5131I WBS 20 100
Stim Tg 78.2 100
Sono/Tg 96.2 100
Pacini, J Clin Endocrinol Metab, 2003
Ultrasound: Lymph node
diagnositc criteria
• Grey scale
– Size
– Shape
– Internal architecture
• Color (power) Doppler
– Vascularity
– Pattern
Grey scale: malignant cervical
lymph nodes
• Size
– “large” (threshold dependent upon station)
• Short axis measurement
– Increased specificity with ↑ threshold
– ROC thresholds: 5mm (submental) → 9mm (submand)
Ying, JIUM,1998
• Clustering
• Shape
– Round (short axis/long axis ratio > .5)
Grey scale: malignant cervical
lymph nodes
• Internal architecture
– Hypoechoic
– Effaced echogenic hilum
• Unique features of papillary carcinoma
– Cystic
– Microcalcifications
Doppler: malignant cervical
lymph nodes
• Vascular pattern
– Capsular vessels
– “Low” resistive index (<.8)
– Issues
• Operator, parameter, dependent
• Interobserver variability
• Overlap
Ultrasound: Lymph node
diagnostic criteria
• Combination of criteria improves sensitivity/specificity
– Ability of sono to depict internal grey scale and Doppler architecture increases accuracy relative to CT
– Comparison of sono and CT for differentiation of malignant and benign cervical lymph nodes in H/N SCCA (n = 62)
Sensitivity Specificity
CT .68 .82
Sono/doppler .78 .96Sumi, AJR 2001
• Ultrasound guided FNAC still crucial
Ultrasound: ATA 2015 triage
(recommendation # 65)
• Cervical ultrasound q 6-12 mos, and then “periodically” depending on Tgand risk level
• FNA of suspicious nodes > 8-10 mm short axis
• Tg aspirate recommended to ↑ yield
• “Cervical metastases may occasionally be detected at neck US even with undetectable Tg” (ATA 2009)
CS 211666020
• 28 y.o. female, total thyroidectomy, selective
bilateral neck dissection for multifocal, node
positive pap ca
• Completion ablation, right neck dissection 4/02
for recurrence
• Tg 226, neg WBS 8/02, 131I tx
• 2/03 Tg 73.5 / 10/03 Tg 100.5
• WBS neg, CT/PET: small left supraclav node,
mild thymic FDG uptake
• Ultrasound performed prior to resection
SM 163526819
• 30 y.o female, s/p thyroidectomy for tall cell variant papillary carcinoma 3 yrs prior
• 131I ablation x 2
• rhTSH 151
• WBS neg
• CT/PET
– 2 subcm right paratracheal nodules
– Diffuse left paratracheal uptake ? brown fat. “Correlation with Tg level and prior CT recommended.”
MP 050446785
• 45 y.o male, post thyroidectomy, Left RND
for papillary carcinoma
• 131I ablation
• Persistent elevated Tg despite selective
node dissection WBS: mild uptake within
thyroid bed
• MRI: small left level 6 node
• Level 6 dissection (metastatic pap ca)
Differentiated thyroid cancer
• Subclinical nodal metastases probably present
in high percentage of patients with DTC
– No value of prophylactic lymph node
dissection in 57 patients despite high
incidence (90%) of nodal metastases
– 55% of nodal metastases < 5mm (Noguchi,
Cancer, 1970)
And it’s accelerating: Morris, Sikora, Tosteson, Davies. The increasing incidence of thyroid cancer:
the influence of access to care. Thyroid, Nov 2013.
Thyroid-Cancer Incidence and Related Mortality in South Korea,
1993–2011
Ahn HS et al. N Engl J Med 2014;371:1765-1767.
• 50 fold increase incidence, 1993-2011
• Most common CA dx (> 40K, 2011)
Penetration of Thyroid-Cancer Screening (2008–2009) and Incidence of
Thyroid Cancer (2009) in the 16 Administrative Regions of South Korea
Ahn HS et al. N Engl J Med 2014;371:1765-1767.
Ultrasound surveillance of DTC:
practical impact
• Increased incidence of thyroid carcinoma and improved detection of recurrent or residualdisease largely due to ultrasound
• Aggressive surveillance advocated – yearly Tg and neck ultrasound
• Repeated nodal dissections for low volume locoregional recurrence/residual often performed
– Patient anxiety
– $$$$$
Ultrasound surveillance of DTC:
practical impact
• ? Improved survival with aggressive
surveillance and tx of typically indolent tumor
• The cynic:
– “First, do no harm”
– “Don’t ask, don’t tell”
– “What you don’t know won’t hurt you”
– “Turn the machines off”
Cronan, “Thyroid Nodules: Is it time to
turn of the US machines?” Radiology,
2008
34 y.o. female: 3.6 cm tall cell variant, post
thyroidectomy/ablation, 3 yrs prior. Tg 19.
FNA: 7 mm L6 pap ca nodal recurrence.
Difficult resection despite sono localization.
The real (but unspoken) debate
Should we do any postoperative surveillance at all????
Answer: yes, but…
Ultrasound surveillance of DTC:
practical impact
• Biologic variability
• Small subset of even “nano” papillary
carcinoma may be aggressive
Kuffner : Microfoci of papillary carcinoma are
frequent and can be metastatic. Retrospective
analysis of a cohort of patients from the University
of Pittsburgh Thyroid Cancer Database
Surveillance of DTC: observations from a
recovering cynic
• We’re learning and adapting
• Machines still on, but improved pathology lexicon, molecular diagnostics, risk stratification, radiology/endocrinology decision trees must be making a difference
• I’m seeing it locally
UPMC Multidisciplinary Thyroid Clinic
• Paradox
• RVU centric: intervention driven
• Marketing bonanza
• Broad Western PA referral base
• Volume originally not an issue
• Stated goal: rational utilization of resources for indolent dz
UPMC Multidisciplinary Thyroid Clinic
• High volume practice early on
• A great clinical model: expertise leveraged
• Victim of our own success
• Tailored clinical pathways, built upon high impact,
collaborative research
• Volume down….a lot• 43% ↓ total FNAs since 2010 (1400 – 800)
• Clinic largely dissolved: many of original core
have left
• Radiology (me) no longer physically on site: tele-
sonography
De-escalating management of patients
with thyroid nodules and cancer
• Fewer FNAs (ATA, and increasingly ACR
TIRADS)
• Molecular diagnostics (Thryoseq 1,2,3)
• Fewer diagnostic lobectomies
• Fewer completion thyroidectomy
• More conservative staging
• Active surveillance for small PTC
• Cancer nomenclature revision
• Encapsulated follicular variant of PTC → Non-
invasive follicular thyroid neoplasm with
papillary-like nuclear features (NIFTP)
2015 ATA Risk of Structural Disease Recurrence
Low Risk
Intermediate Risk
High Risk
FTC, extensive vascular invasion (≈ 30-55%)
pT4a gross ETE (≈ 30-40%)
pN1, any LN > 3 cm (≈ 30%)
BRAF mutated, not intrathyroidal (≈ 10-40%)
PTC, vascular invasion (≈ 15-30%)
Clinical N1 (≈20%)
pN1, > 5 LN involved (≈20%)
BRAF mutated, intrathyroidal, < 4 cm (≈10%)
pT3 minor ETE (≈ 3-8%)
pN1, all LN < 0.2 cm (≈5%)
pN1, < 5 LN involved (≈5%)
Intrathyroidal 2-4 cm PTC (≈ 5%)
Multifocal PMC (≈ 4-6%)
Minimally invasive FTC (≈ 2-3%)
BRAF wild type, intrathyroidal, < 4 cm (≈ 1-2%)
BRAF mutated, intrathyroidal unifocal PMC (≈ 1%)
Intrathyroidal, encapsulated, FV-PTC (≈ 1-2%)
Unifocal PMC (≈ 1-2%)Slide courtesy of
Steven Hodak, MD
Molecular Signature
BRAF+TERT, RAS+TERT
Multiple driver mutations
(eg. NRAS and PIK3CA or TP53)
TERT
ALK fusions
NTRK1 fusions
NTRK3 fusions
BRAF V600E
RET/PTC
RAS
BRAF K601E
PAX8/PPARG
RAS-like
mutations
BRAF
V600E- like
mutations
Molecular markers for cancer risk stratification
High RiskGross extrathyroidal extension,
incomplete tumor resection, distant metastases,
or lymph node >3cm
Intermediate RiskAggressive histology, minor extrathyroidal extension,
vascular invasion,
or > 5 involved lymph nodes (0.2-3 cm)
Low RiskIntrathyroidal DTC
≤ 5 LN micrometastases (< 0.2 cm)
Risk of Structural Disease Recurrence
(In patients without structurally identifiable disease after initial therapy)
PTC, >1 cm, TERT mutated ± BRAF mutated* (>40%)
PTC, extrathyroidal, BRAF mutated* (≈ 10-40%)
Intrathyroidal PTC, < 4 cm, BRAF mutated* (≈10%)
Intrathyroidal, < 4 cm, BRAF wild type* (≈ 1-2%)
Intrathyroidal unifocal PTMC, BRAF mutated*, (≈ 1-2%)
FTC, extensive vascular invasion (≈ 30-55%)
pT4a gross ETE (≈ 30-40%)
pN1 with extranodal extension, >3 LN involved (≈ 40%)
pN1, any LN > 3 cm (≈ 30%)
PTC, vascular invasion (≈ 15-30%)
Clinical N1 (≈20%)
pN1, > 5 LN involved (≈20%)
pT3 minor ETE (≈ 3-8%)
pN1, all LN < 0.2 cm (≈5%)
pN1, ≤ 5 LN involved (≈5%)
Intrathyroidal PTC, 2-4 cm (≈ 5%)
Multifocal PMC (≈ 4-6%)
pN1 without extranodal extension, ≤ 3 LN involved (2%)
Minimally invasive FTC (≈ 2-3%)
Unifocal PMC (≈ 1-2%)
Intrathyroidal, encapsulated, FV-PTC (≈1-2%)
NIFTP (<1%)
Haugen BR et al. Thyroid. 2016, 26:1-133
❑ A distinct class of thyroid tumors:• Clonal process driven by distinct oncogenic mutations (RAS and
RAS-like gene mutations) • Non-invasive, follicular-patterned, moderately to well developed
nuclear features of PTC (nuclear score 2-3)• Highly favorable outcome (<1% risk of recurrence in 15 y)
❑ Recommended new terminology:
“Non-Invasive Follicular Thyroid neoplasm with Papillary-like nuclear features“ (NIFTP)
Nikiforov et al. JAMA Oncology 2016; 2:1023-9.
Molecular Markers Predict Cancer Risk
n=1510
1. Yip L Ann Surg 2015; 262: 519
2. Song YS Cancer 2016; 122: 1370
p<0.001
DTC, n=1510
High Risk for Recurrence2Markers of Low and
Intermediate Recurrence
Risk1
DTC, n=551
p<0.001
Bethesda III-IV
Cytology
N/A
Observation Lobectomy
Test result
Probability of Cancer or NIFTP
Tumor type, risk of recurrence
Patient management
3-4% 40-80%
NIFTP or low-risk cancer
Active surveillance
<10%
ThyroSeq GC
Positive: RAS-like
mutations,CNA, GEA
Negative: no mutations
Currently Negative:
LR mutations
NIFTP or low-risk cancer
Total thyroidor lobectomy
95-100%
Positive: BRAF-like mutations
Intermediate-risk cancer
Total thyroid+/- LND
98-100%
Positive: HR mutation
High-risk cancer
MTC, PT, Non-FCL
28% 6% 2%7%55%
2%
Nikiforov YE et al. Real world experience with ThyroSeq v3 Genomic Classifier in thyroid nodules with indeterminate
cytology: Results of testing of the first 3,734 consecutive samples. American Association of Clinical Endocrinologists
Annual meeting 2018
Patient Management Informed by Molecular Testing
Conclusions
• Increased incidence of thyroid carcinoma over
past thirty years largely due to imaging
• DTC usually indolent dz, but local recurrence or
detection of previously unrecognized tumor may
occur long after initial presentation
• TG and ultrasound currently best combination for
regional surveillance
• Sensitivity/specificity of sono improved when
multiple discriminatory criteria used; FNAC still
necessary
Conclusions
• Impact of intensive surveillance/tx difficult
to assess…but it’s probably not good
• Improvements in imaging have to now
outpaced our understanding of DTC tumor
biology
• More rational approach needed, and it will
be driven by recent advances in molecular
diagnostics (and insurers)