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Thyroid cancer

Papillary and follicular thyroid


carcinoma:
Controversies in follow-up
Steven B. Porter, MD
PGY-1, Department of Surgery
Team IV Rounds
June 20, 2008
Thyroid cancer

Outline
• Case Presentation
• “Differentiated Thyroid Cancer”
– Papillary Thyroid Carcinoma
– Follicular Thyroid Carcinoma
• Cohort Data
• Analysis of Data
• Summary
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Thyroid cancer

Negative Outline
• No discussion of medullary thyroid ca
• No discussion of MEN2a, MEN2b
• No discussion of surgical technique (as I
haven’t seen surgery on a thyroid since
2005)

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Thyroid cancer

Case presentation
• HPI: M is a 30 yo M referred to endocrine
surgery for a palpable thyroid nodule on
physical exam by PMD. No dysphonia,
dysphagia, odynophagia, change in voice.
No smoking history. Recent cough for a
few weeks. No fevers, chills, weight loss.
No hx of radiation to neck

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Thyroid cancer

Case Presentation cont’d


• PMH: major depressive disorder, sleep apnea
– Meds: desipramine, buproprion
• PSH: left shoulder surgery 1996, pilonidal cyst
excision 2000
• All: NKDA
• FHx: M: Hashimoto’s, F: benign goiter MAunt:
hypothyroidism
• SHx: no tobacco, social etoh, no drugs

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Thyroid cancer

Case Presentation cont’d


• PE
– VS: unable to obtain (afebrile, normotensive)
– Gen: NAD, healthy appearing
– HEENT: palpable ~3 cm nodule in thyroid R lower
lobe
– CV: RRR, no murmurs
– Pulm: CTA b/l, no wheezes
– Abd: SNTND
– Extr: 2+ DP pulses b/l

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Thyroid cancer

Case Presentation cont’d: US and


FNA
US: Hypoechoic nodule in R lower lobe with punctate
calcifications and some cystic degeneration measuring 2.9
x 3.0 x 3.4 cm sagittal. At the extreme R right lower pole, an adjacent
hypoechoic nodule measured 1.2 x 1.6 x 1.4 cm sagittal with irregular margins. In
the mid-R lobe, a cystic nodule measured 0.9 x 1.0 x 0.9 sagittal. A mid-L
complex nodule with isoechoic solid elements measured 0.9 x 1.4 cm sagittal. A
lower L hypoechoic nodule measured 0.7 cm

FNA: Positive for malignant cells. Papillary thyroid carcinoma.


Foamy cells c/w cyst contents and/or cystic degeneration. Scant colloid. Rare
nuclear grooves present. Rare intranuclear inclusions present.

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Thyroid cancer

Case Presentation cont’d


• Hospital Course
– DAS for total thyroidectomy
– Palpable pretracheal and paratracheal lymph
nodes in ORcentral LN dissection, PACU
iCa: 1.11
– POD#1: tolerating diet, afebrile, FROM of
neck, JP d/c’d, iCa: 0.96, 1.0, 1.03
– POD#2: iCa: 1.04, d/c’d to home on vitamin D
and calcium carbonate
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Thyroid cancer

Case Presentation cont’d


• Pathology
– L lateral paratracheal LN: 1/1 met papillary ca
– Lateral paratracheal tissue: 1/3 met papillary ca
– Thyroid gland: well differentiated papillary thyroid ca extensively
involving b/l thyroid lobes and isthmus (largest R lobe tumor
measuring 4.6 cm).
– Tumor extending to perithyroid soft tissue and is <1 mm from
inked specimen surface.
– Lymphovascular invasion identified.
– Background parenchyma shows Hashimoto’s thyroiditis
– 13/17 LN positive for met papillary ca
– AJCC Stage: p T3 N1 Mx

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Thyroid cancer

Case Presentation cont’d


• So how do we follow the patient s/p total
thyroidectomy?
• What are the recommendations for total vs
hemithyroidectomy?
• And what data are these follow-up
algorithms and consensus guidelines based
on?

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Thyroid cancer

The Thyroid Gland

Gray’s Anatomy 11
Thyroid cancer

Background
• 1% of all new malignant disease
• 94% differentiated thyroid carcinoma
– Derive from follicular epithelial cells
• Papillary or follicular thyroid carcinoma
• 5% medullary thyroid carcinoma
– Neuroendocrine tumors
• 1% anaplastic
– Dedifferentiated thyroid carcinoma
Figge J. Epidemiology of thyroid cancer. In: Wartofsky L, ed. Thyroid cancer: a
comprehensive guide to clinical management. Totowa: Humana Press, 1999; 77-83.
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Thyroid cancer

Diagnosis
• In sporadic cancer, patients usually present with a
solitary thyroid nodule
• The initial diagnostic procedure of choice is FNA
– Allows diagnosis of papillary, medullary, anaplastic
cancers
– To distinguish between follicular adenoma and
carcinoma, histological examination is necessary
• False-positive and false-negative rates of FNA are
<5%
Ravetto C, Colombo L, Dottorino ME. Usefulness of fine-needle aspiration in the diagnosis of thyroid
carcinoma: a retrospective study of 37,895 patients. Cancer 2000;90:357-63.
Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: an appraisal. Ann Intern Med
1993;118:282-89. 13
Thyroid cancer

Epidemiology
• F:M ~2:1
• Median age of diagnosis: 45 years
• If iodine deficient area: follicular > papillary
• Risk factors:
– External radiation, especially during childhood
– E.g. Chernobyl disaster
– Inherited polyposis syndromes: FAP, Gardner’s,
Cowden’s

Sherman, SI. Thyroid carcinoma. Lancet 2003;361:501-11.


Figge J. Epidemiology of thyroid cancer. In: Wartofsky L, ed. Thyroid cancer: a comprehensive guide to
clinical management. Totowa: Humana Press, 1999; 77-83.
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Thyroid cancer

Molecular Genetics
• After radiation exposure, RET proto-oncogene
(formerly PTC) rearrangements papillary
carcinoma
• Other factors for papillary carcinoma:
overexpression of TRK, MAPK, DNA
hypermethylation, and activating mutations of
RAS
• For follicular carcinoma: RAS mutations,
chromosomal rearrangements (PAX8 fused to
PPAR-gamma-1)
Fagin JA. Molecular pathogenesis of tumors of thyroid follicular cells. In: Fagin JA, ed. Thyroid Cancer.
Boston: Kluwer, 1998.
Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid
carcinoma [corrected]. Science 2000;289:1357-60. 15
Thyroid cancer

Clinicopathological Staging
• There are >14 staging systems for thyroid
cancer
• Histological subtypes that connote a poor
prognosis:
– Papillary: tall cell, columnar cell variants
– Hurthle cell (oxyphilic cell)
– Follicular: poorly differentiated variants

Sherman SI, Brierley JD, Sperling M, et al. Prospective multicenter study of treatment of thyroid
carcinoma: initial analysis of staging and outcome. Cancer 1998;83:1012-21.
Burman KD, Ringel MD, Wartofsky L. Unusual types of thyroid neoplasms. Endocrinol Metab Clin
North Am 1996;25:49-68. 16
Thyroid cancer

TNM Staging System

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Thyroid cancer

•14 staging systems applied to 589 PTC patients from


1961-2001at one center in Hong Kong
•Evaluated those with best predictive system for cancer-
specific survival
•Cancer-specific survival calculated by Kaplan-Meier
curves and compared with log-rank test
•Top three systems:
•MACIS (Metastases, Age, Completeness of Resection, Invasion, Size)
•TNM (Tumor, Node, Metastasis)
•EORTC (European Organization for Research and Treatment of Cancer)
Lang BH et al. Staging systems for papillary thyroid carcinoma. Ann Surg 2007;245:366-378.
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Thyroid cancer

Papillary Cancer: FNA and histology

FNA showing papillary ca. The malignant cells Blue arrow points to papillary structure.
including the one at the tip of the arrow are very The center is fibrovascular. The cells
loosely arranged covering it are epithelial. The red arrow
shows a similar papillary structure in cross
section.
Images from UConn’s Pathweb 19
http://pathweb.uchc.edu
Thyroid cancer

Papillary Cancer

• Most common thyroid cancer


• Best prognosis: 5% mortality at 20 years if
no evidence of local invasion at diagnosis
• ‘Lateral aberrant thyroid’ – cervical lymph
node infiltrated with metastatic thyroid
cancer

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Thyroid cancer

Papillary Cancer
• Psammoma bodies: laminated calcified spheres, diagnostic of papillary
cancer
• Certain histological variants have higher risk of recurrence: Tall cell,
columnar cell, diffuse sclerosing cell
• Can spread to lung (also bone, liver, brain)
• Very rare conversion to anaplastic type

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Thyroid cancer

Follicular cancer: FNA and histology

FNA showing follicular cells. The follicles are Normal thyroid follicles appear at the lower
composed of small clusters of cells. The right. The follicular adenoma is at the center to
colloid cannot be identified easily in this upper left. This adenoma is a well differentiated
preparation. The nuclei are monotonous neoplasm because it closely resembles normal
without obvious atypia. tissue.

Images from UConn’s Pathweb 22


http://pathweb.uchc.edu
Thyroid cancer

Risk Stratification of Variables Influencing


Cancer Recurrences and Cancer Death
Patient Variables
- Age <15 or >45 yrs
- Family hx of thyroid ca
Tumor Variables
- Tumor >4 cm
- Bilateral disease
- Extrathyroidal extension
- Vascular invasion
- Cervical or mediastinal LN mets
- Certain tumor subtypes (e.g. Hurthle)
- Histologic grade
- Tumors that do not concentrate iodine well
- Distant metastases

Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin
Endocrinol Metab 2001;86:1447-1463. 23
Thyroid cancer

Primary surgical management


• Total thyroidectomy: Pro
– Papillary foci are b/l in 60-85% of patients
– 5-10% recurrence rates for papillary ca after
unilateral surgery for “microcarcinoma”
– Effectiveness of treatment with 131I and f/u with
serum Tg are highest with maximal resection

Katoh R, Sasaki J, Kurihara H, et al. Multiple thyroid involvement (intraglandular metastasis) in papillary
thyroid carcinoma. A clinicopathologic study of 105 consecutive patients. Cancer 1992;70:1585-90.
Silverberg SG, Hutter RVP, Foote FW Jr. Fatal carcinoma of the thyroid: histology, metastases, and
causes of death. Cancer 1970;25:792-802. 24
Thyroid cancer

Primary surgical management


• Total thyroidectomy: Con
– Minimal benefit for more extensive surgery
– Higher risk of hypoparathyroidism
– Higher risk of injury to recurrent laryngeal
nerve
– Tumor multicentricity seems to have little
prognostic significance
– If recurrence, usually those lesions are treatable
Cady B. Papillary carcinoma of the thyroid gland: treatment based on risk definition. Surg Oncol Clin N
Am 1998;7:633-44.

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Thyroid cancer

Consensus Guidelines
• Most concensus guidelines state:
– For papillary ca:
• If > 1 cm, or mets, or extends beyond thyroid, or hx of
irradiation total thyroidectomy
• If < 1 cm and confined to one lobehemithyroidectomy
– For follicular ca:
• Total thyroidectomy unless only suspicion on cytology, then
can proceed with hemithyroidectomy and isthmusectomy with
potential completion thyroidectomy based on histology
British Thyroid Association and Royal College of Physicians. Guidelines for the management of thyroid
cancer in adults. London: Guidelines for the management of thyroid cancer in adults, 2002.
Task Force TC. AACE/AAES medical/surgical guidelines for clinical practice: Management of thyroid
carcinoma. Endocr Pr 2001;7:203-20.
Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and
follicular thyroid cancer. Am J Med 1994;97:418-28. 26
Thyroid cancer

Data to Support Consensus Guidelines

•National Cancer Data Base (1985–1998)


•52,173 patients with surgery for PTC
•Survival estimated by Kaplan-Meier method, compared using log-rank tests
•Cox Proportional Hazards modeling stratified by tumor size used to assess impact of surgical extent
on outcomes
•Results: 43,227 (82.9%) underwent total thyroidectomy, 8946 (17.1%) underwent lobectomy.
• For PTC<1 cm, extent of surgery did not impact recurrence or survival (P = 0.24, P = 0.83)
• For tumors >1 cm, lobectomy resulted in higher risk of recurrence and death (P = 0.04, P =
0.009)
• 1 to 2 cm lesions were examined separately: lobectomy again resulted in a higher risk of
recurrence and death (P = 0.04, P = 0.04).

Bilimoria KY et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg
2007;246:375-384. 27
Thyroid cancer
Data to Support Consensus Guidelines cont’d:
Cumulative Recurrence Rate vs Years of
Follow-Up by Tumor Size

Bilimoria KY et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg
2007;246:375-384. 28
Thyroid cancer
Data to Support Consensus Guidelines cont’d:
Cumulative Recurrence Rate vs Years of
Follow-Up by Extent of Surgery

Bilimoria KY et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg
2007;246:375-384. 29
Thyroid cancer
Data to Support Consensus Guidelines cont’d:
Cumulative Survival Rate vs Years of Follow-
Up by Extent of Surgery

Bilimoria KY et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg
2007;246:375-384. 30
Thyroid cancer

Postoperative 131I adjuvant therapy


• Specific uptake into follicular cells
• Undergoes β-decay, releasing high energy
electronsradiation cytotoxicity
• Also emits γ-rays which are detectable
• (i) destroys residual microscopic foci of ca
• (ii) increases specificity of future scans for
residual ca
• (iii) improves sensitivity of future Tg screen
Maxon HR, Thomas SR, Samaratunga RC. Dosimetric considerations in the radioiodine treatment of
macrometastases and micrometastases from differentiated thyroid cancer. Thyroid 1997;7:183-88.

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Thyroid cancer

Postoperative 131I adjuvant therapy cont’d


• For maximum radioiodine uptake after
thyroidectomy, want TSH >30-50 mU/L
• Stop thyroxine for 4-6 weeksiatrogenic
hypothyroidism
• Because liothyronine has a shorter t1/2, can give until
2 weeks prior to treatment
• Avoid iodinated contrast for CT for 1-3 months prior
to treatment
• These same principles apply to radioiodine scanning
for f/u
Schlumberger M, Tubiana M, et al. Long-term results of treatment of 283 patients with lung and bone
metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab 1986;63:960-67.
Goldman JM Line BR, Aamodt RI, Robbins J. Influence of triiodothyronine withdrawal time on 131I
uptake post-thyroidectomy for thyroid cancer. J Clin Endocrinol Metab 1980;50:734-39.
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Thyroid cancer

Long-term Monitoring: RAI scanning


• 6-12 months after initial ablation
• If negative 90% 10 year relapse-free
survival
• If consecutively negative x2 >95% 10
year relapse-free survival
• Consensus guidelines: surveillance
scanning beyond this period only indicated
if clinical/diagnostic findings occur
Grigsby PW, Baglan K, Siegel BA. Surveillance of patients to detect recurrent thyroid carcinoma. Cancer
1999;85;945-51.
Sherman SI. NCCN practice guidelines for thyroid cancer, version 2001. National Comprehensive Cancer
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Network, 2001.
Thyroid cancer

Long-term Monitoring: Thyroglobulin


• Produced exclusively by thyroid follicular cells
• Used to detect residual, recurrent, or metastatic disease
• Reaches nadir within 3 months post-ablation (upper range
1-2 years)
• Sensitivity of 85-95% for detection of disease during
thyroid hormone withdrawal
• Sensitivity of 50% with TSH suppression or
dedifferentiated tumors

Spencer CA, LoPresti JS, Fatemi S, Nicoloff IT. Detection of residual and recurrent differentiated
thyroid carcinoma by serum thyroglobulin measurement. Thyroid 1999;9:435-41.
Ozata M, Suzuki S, Miyamoto T, Liu RT, Fierro-Renoy F, DeGroot LJ. Serum thyroglobulin in the
follow-up of patients treated with differentiated thyroid cancer. J Clin Endocrinol Metab
1994;79;98-105.
Haugen BR, Pacini F, Feiners C, et al. A comparison of recombinant human thyrotropin and thyroid
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hormone withdawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab
1999;84:3877-85.
Thyroid cancer
Long-term Monitoring:
Thyroglobulin caveats
• Reported Tg concentrations can be falsely lowered by
autoAbs that bind Tg and prevent detection by
immunoassays
• These autoAbs are present in as many as 25% of pts with
thyroid cancer, and 10% of general population
• Methods to detect Tg mRNA are in development though
their utility has been questioned

Mariotti S, Barbesino G, Caturegli P, et al. Assay of thyroglobulin in serum with thyroglobulin


autoantibodies: an unobtainable goal? J Clin Endocrinol Metab 1995;80:468-72.
Spencer CA, LoPresti JS, Faterni S, Nicoloff JT. Detection of residual and recurrent differentiated thyroid
carcinoma by serum thyroglobulin measurement. Thyroid 19999;9:435-41.
Ringel MD, Ladenson PW, Levine MA. Molecular diagnosis of residual and recurrent thyroid cancer by
amplification of thyroglobulin messenger ribonucleic acid in peripheral blood. J Clin Endocrinol
Metab 1998;83:4435-42. 35
Thyroid cancer
Long-term Monitoring:
Combining RAI and Tg
• If negative RI scan and negative Tg level
given elevated TSHcan use rTSH scan
instead of w/d from supplemental T4
• Diagnostic dilemma: Negative RI scan with
positive Tg level
– Advanced thyroid ca can de-differentiate and,
thus, lose the ability to concentrate I
– Usually, other supplemental imaging (US, CT,
PET/CT, thallium MIBI)

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Thyroid cancer
Long-term Monitoring:
What Is At Stake
• 10-yr cancer specific mortality rates for
papillary and follicular thyroid cancer are 7
and 15%, respectively, base on cohort data
on 53,856 patients managed in the US
between 1985 and 1995
• Prevalence of DTC survivors is 300,00 in
USA
• Each needs lifelong surveillance
Ries LAG, Eisener MP, Kosary CL, Hankey BF, Miller BA, Cleeg L, Mariotto A, Fay MP, Feuer EJ,
Edwards BK. 2003 SEER Cancer Statistics Review, 1975-2001. Bethesa, MD: National Cancer
Institute. http://seer.cancer.gov/csr/1975_2001/results_single/sect_25_table.12.pdf
Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856
cases of thyroid carcinoma treated in the US, 1985-1995. Cancer 1998;83:2638-48. 37
Thyroid cancer
Unique Pros, and Side Effects, of
Remnant Ablation
• Persistent disease and tumor stage cannot be identified
shortly after surgery when there is a large thyroid remnant
• Without RA, half of lung metastases in children cannot be
identified
• But:
– Transient loss of taste
– Acute and chronic radiation-induced parotitis
– Sialadenitis with possible xerostomia
– Transient testicular damage
– Side effects tend to be dose-related
Sclumberger M et al. Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective. Eur J
Endocrinol 2004;150:105-112.
Bal CS et al. Is chest x-ray or high-resolution computed tomography scan of the chest sufficient investigation to detect
pulmonary metastasis in pediatric differentiated thyroid cancer? Thyroid 2004; 14:217-225.
Mandel SJ, Mandel L. Radioactive iodicine and the salivary glands. Thyroid 2003;13:265-271. 38
Mazzaferri EL. Gonadal damage from 131I therapy for thyroid cancer. Clin Endocrinol (Oxf) 2002;57:313-314.
Thyroid cancer

The Risk of Late-Tumor Identification


• Persistent tumor not recognized in many studies with 10
year follow-up only
• For example, in one study, 15% of locoregional tumors
and 24% of distant metastases were first identified >2
decades after initial therapy
• Tumor is often present when a baseline Tg < 1 ng/mL rises
>2-5 ng/mL with rhTSH or >5-10 ng/ml with
levothyroxine withdrawal
• Risk of developing tumor <0.5% when no clinical
evidence of tumor combined with TSH-stimulated
undetectable serum Tg and negative neck US
Mazzaferri EL. An overview of thet management of papillary and follicular thyroid carcinoma. Thyroid
1999;9:421-27.
Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L, Haugen BR, Sherman
SI, Coooper DS, Braunstein GD, Lee S, Davis TF, Arafah BM, Ladenson PW, Pinchera A. A
consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients 39
with papillary thyroid carcinoma. J Clin Endocrinol Metab 2003;88:1433-1441.
Thyroid cancer

Tumor recurrence after thyroid surgery and thyroid


hormone tx with and without 131I tx

Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin
Endocrinol Metab 2001;86:1447-1463. 40
Thyroid cancer

Summary
• Most thyroid carcinoma is differentiated type
• US/FNA
• TNM or MACIS for staging
• Total thyroidectomy for most
• Post-surgical radioactive iodine
ablation/remnant ablation
• RxWBS + serum Thyroglobulin

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