thyroid papillary and follicular ca -

8/9/2019 Thyroid Papillary and Follicular CA -

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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


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Outline Case Presentation

Differentiated Thyroid Cancer Papillary Thyroid Carcinoma

Follicular Thyroid Carcinoma

Cohort Data

Analysis of Data

Summary


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Negative Outline No discussion of medullary thyroid ca

No discussion of MEN2a, MEN2b No discussion of surgical technique (as I

havent seen surgery on a thyroid since

2005)


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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 hxof radiation to neck


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Case Presentation contd PMH: major depressive disorder, sleep apnea

Meds: desipramine, buproprion

PSH: left shoulder surgery 1996, pilonidal cystexcision 2000

All: NKDA

FHx: M: Hashimotos, F: benign goiter MAunt:hypothyroidism

SHx: no tobacco, social etoh, no drugs


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Case Presentation contd 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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Case Presentation contd: US

and FNAUS: 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 adjacenthypoechoic 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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Case Presentation contd Hospital Course

DAS for total thyroidectomy

Palpable pretracheal and paratracheal lymphnodes in ORcentral LN dissection, PACU iCa:1.11

POD#1: tolerating diet, afebrile, FROM of

neck, JP d/cd, iCa: 0.96, 1.0, 1.03 POD#2: iCa: 1.04, d/cd to home on vitamin D

and calcium carbonate


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Case Presentation contd 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 extensivelyinvolving b/l thyroid lobes and isthmus (largest R lobe tumormeasuring 4.6 cm).

Tumor extending to perithyroid soft tissue and is


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Case Presentation contd 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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The Thyroid Gland

Grays Anatomy


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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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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, anaplasticcancers

To distinguish between follicular adenoma and

carcinoma, histological examination is necessary

False-positive and false-negative rates of FNA are


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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, Gardners,

Cowdens

Sherman, SI. Thyroid carcinoma. Lancet2003;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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Molecular Genetics

After radiation exposure, RET proto-oncogene(formerly PTC) rearrangementspapillarycarcinoma

Other factors for papillary carcinoma:overexpression of TRK, MAPK, DNAhypermethylation, and activating mutations ofRAS

For follicular carcinoma: RAS mutations,chromosomal rearrangements (PAX8 fused toPPAR-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.


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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. Cancer1998;83:1012-21.

Burman KD, Ringel MD, Wartofsky L. Unusual types of thyroid neoplasms. Endocrinol Metab

Clin North Am 1996;25:49-68.


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TNM Staging System


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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 Surg2007;245:366-378.


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Papillary Cancer: FNA and histology

FNA showing papillary ca. The malignant cells

including the one at the tip of the arrow are very

loosely arranged

Images from UConns Pathweb

http://pathweb.uchc.edu

Blue arrow points to papillary structure.

The center is fibrovascular. The cells

covering it are epithelial. The red arrow

shows a similar papillary structure in cross

section.


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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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Papillary Cancer

Psammoma bodies: laminated calcified spheres, diagnostic of papillarycancer

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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Follicular cancer: FNA and histology

Images from UConns Pathweb

http://pathweb.uchc.edu

FNA showing follicular cells. The follicles are

composed of small clusters of cells. The colloid

cannot be identified easily in this preparation.

The nuclei are monotonous without obvious

atypia.

Normal thyroid follicles appear at the lower

right. The follicular adenoma is at the center to

upper left. This adenoma is a well differentiated

neoplasm because it closely resembles normal

tissue.


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Risk Stratification of Variables Influencing

Cancer Recurrences and Cancer Death

Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer.J Clin

Endocrinol Metab 2001;86:1447-1463.

Patient Variables

- Age 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


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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. Cancer1970;25:792-802.


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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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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 lobehemithyroidectomy

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 Pr2001;7:203-20.

Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary

and follicular thyroid cancer.Am J Med1994;97:418-28.


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Data to Support Consensus Guidelines

Bilimoria KY et al. Extent of surgery affects survival for papillary thyroid cancer.Ann Surg

2007;246:375-384.

National Cancer Data Base (19851998)

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 PTC1 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).


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Data to Support Consensus Guidelines contd:

Cumulative Recurrence Rate vs Years of

Follow-Up by Tumor Size


2007;246:375-384.


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Cumulative Recurrence Rate vs Years of

Follow-Up by Extent of Surgery


2007;246:375-384.


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Cumulative Survival Rate vs Years of Follow-

Up by Extent of Surgery


2007;246:375-384.


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Postoperative 131I adjuvant therapy

Specific uptake into follicular cells

Undergoes -decay, releasing high energyelectronsradiation cytotoxicity

Also emits -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.

Thyroid1997;7:183-88.


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Postoperative 131I adjuvant therapy contd

For maximum radioiodine uptake afterthyroidectomy, want TSH >30-50 mU/L

Stop thyroxine for 4-6 weeksiatrogenichypothyroidism

Because liothyronine has a shorter t1/2, can giveuntil 2 weeks prior to treatment

Avoid iodinated contrast for CT for 1-3 monthsprior to treatment

These same principles apply to radioiodinescanning 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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Long-term Monitoring: RAI scanning

6-12 months after initial ablation

If negative 90% 10 year relapse-freesurvival

If consecutively negative x2 >95% 10 yearrelapse-free survival

Consensus guidelines: surveillance scanning

beyond this period only indicated ifclinical/diagnostic findings occur

Grigsby PW, Baglan K, Siegel BA. Surveillance of patients to detect recurrent thyroid carcinoma.

Cancer1999;85;945-51.

Sherman SI. NCCN practice guidelines for thyroid cancer, version 2001. National

Comprehensive Cancer Network, 2001.


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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 range1-2 years)

Sensitivity of 85-95% for detection of disease duringthyroid hormone withdrawal

Sensitivity of 50% with TSH suppression ordedifferentiated tumors

Spencer CA, LoPresti JS, Fatemi S, Nicoloff IT. Detection of residual and recurrent differentiated

thyroid carcinoma by serum thyroglobulin measurement. Thyroid1999;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 hormone withdawal for the detection of thyroid remnant or cancer. J Clin EndocrinolMetab 1999;84:3877-85.


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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. Thyroid19999;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.


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Combining RAI and Tg If negative RI scan and negative Tg level

given elevated TSHcan use rTSH scaninstead of w/d from supplemental T4

Diagnostic dilemma: Negative RI scan withpositive 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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What Is At Stake 10-yr cancer specific mortality rates for

papillary and follicular thyroid cancer are 7and 15%, respectively, base on cohort data

on 53,856 patients managed in the USbetween 1985 and 1995

Prevalence of DTC survivors is 300,00 inUSA

Each needs lifelong surveillanceRies 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. Cancer1998;83:2638-48.


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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 Europeanperspective. Eur J Endocrinol2004;150:105-112.

Bal CS et al. Is chest x-ray or high-resolution computed tomography scan of the chest sufficient investigation todetect pulmonary metastasis in pediatric differentiated thyroid cancer? Thyroid2004; 14:217-225.

Mandel SJ, Mandel L. Radioactive iodicine and the salivary glands. Thyroid2003;13:265-271.

Mazzaferri EL. Gonadal damage from 131I therapy for thyroid cancer. Clin Endocrinol(Oxf) 2002;57:313-314.


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The Risk of Late-Tumor Identification

Persistent tumor not recognized in many studies with 10year follow-up only

For example, in one study, 15% of locoregional tumorsand 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 withlevothyroxine withdrawal

Risk of developing tumor


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Tumor recurrence after thyroid surgery and thyroid

hormone tx with and without

131

I tx

Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer.J Clin

Endocrinol Metab 2001;86:1447-1463.


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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

thyroid papillary and follicular ca -

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