Papillary and follicular thyroid carcinoma: Controversies in followup

1
Papillary and follicular thyroid
carcinomaControversies in follow-up

• Steven B. Porter, MD
• PGY-1, Department of Surgery
• Team IV Rounds
• June 20, 2008

2
Outline

• Case Presentation
• Differentiated Thyroid Cancer
• Papillary Thyroid Carcinoma
• Follicular Thyroid Carcinoma
• Cohort Data
• Analysis of Data
• Summary

3
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)

4
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

5
Case Presentation contd

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

6
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

7
Case Presentation contd 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.
8
Case Presentation contd

• Hospital Course
• DAS for total thyroidectomy
• Palpable pretracheal and paratracheal lymph nodes
  in OR?central LN dissection, PACU iCa 1.11
• POD1 tolerating diet, afebrile, FROM of neck,
  JP d/cd, iCa 0.96, 1.0, 1.03
• POD2 iCa 1.04, d/cd to home on vitamin D and
  calcium carbonate

9
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 extensively involving b/l thyroid
  lobes and isthmus (largest R lobe tumor measuring
  4.6 cm).
• Tumor extending to perithyroid soft tissue and is
  lt1 mm from inked specimen surface.
• Lymphovascular invasion identified.
• Background parenchyma shows Hashimotos
  thyroiditis
• 13/17 LN positive for met papillary ca
• AJCC Stage p T3 N1 Mx

10
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?

11
The Thyroid Gland
Grays Anatomy
12
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.
13
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 lt5

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 200090357-63. Gharib H,
Goellner JR. Fine-needle aspiration biopsy of the
thyroid an appraisal. Ann Intern Med
1993118282-89.
14
Epidemiology

• FM 21
• Median age of diagnosis 45 years
• If iodine deficient area follicular gt papillary
• Risk factors
• External radiation, especially during childhood
• E.g. Chernobyl disaster
• Inherited polyposis syndromes FAP, Gardners,
  Cowdens

Sherman, SI. Thyroid carcinoma. Lancet
2003361501-11. Figge J. Epidemiology of thyroid
cancer. In Wartofsky L, ed. Thyroid cancer a
comprehensive guide to clinical management.
Totowa Humana Press, 1999 77-83.
15
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 20002891357-60.
16
Clinicopathological Staging

• There are gt14 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 1998831012-21. Burman KD,
Ringel MD, Wartofsky L. Unusual types of thyroid
neoplasms. Endocrinol Metab Clin North Am
19962549-68.
17
TNM Staging System
18

• 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 2007245366-378.
19
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
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.
Images from UConns Pathweb http//pathweb.uchc.ed
u
20
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

21
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

22
Follicular cancer FNA and histology
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.
Images from UConns Pathweb http//pathweb.uchc.ed
u
23
Risk Stratification of Variables Influencing
Cancer Recurrences and Cancer Death
Patient Variables - Age lt15 or gt45 yrs - Family
hx of thyroid ca Tumor Variables - Tumor gt4
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
2001861447-1463.
24
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 1992701585-90. Silverberg SG,
Hutter RVP, Foote FW Jr. Fatal carcinoma of the
thyroid histology, metastases, and causes of
death. Cancer 197025792-802.
25
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 19987633-44.
26
Consensus Guidelines

• Most concensus guidelines state
• For papillary ca
• If gt 1 cm, or mets, or extends beyond thyroid, or
  hx of irradiation? total thyroidectomy
• If lt 1 cm and confined to one lobe?hemithyroidecto
  my
• 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 20017203-20. Mazzaf
erri EL, Jhiang SM. Long-term impact of initial
surgical and medical therapy on papillary and
follicular thyroid cancer. Am J Med
199497418-28.
27
Data to Support Consensus Guidelines

• 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 PTClt1 cm, extent of surgery did not impact
  recurrence or survival (P 0.24, P 0.83)
• For tumors gt1 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
2007246375-384.
28
Data to Support Consensus Guidelines
contdCumulative 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
2007246375-384.
29
Data to Support Consensus Guidelines
contdCumulative 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
2007246375-384.
30
Data to Support Consensus Guidelines
contdCumulative 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
2007246375-384.
31
Postoperative 131I adjuvant therapy

• Specific uptake into follicular cells
• Undergoes ß-decay, releasing high energy
  electrons?radiation 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. Thyroid
19977183-88.
32
Postoperative 131I adjuvant therapy contd

• For maximum radioiodine uptake after
  thyroidectomy, want TSH gt30-50 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
198663960-67. 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
198050734-39.
33
Long-term Monitoring RAI scanning

• 6-12 months after initial ablation
• If negative? 90 10 year relapse-free survival
• If consecutively negative x2? gt95 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 199985945-51. Sherman SI. NCCN practice
guidelines for thyroid cancer, version 2001.
National Comprehensive Cancer Network, 2001.
34
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
19999435-41. 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 19947998-105. 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 Endocrinol Metab 1999843877-85.
35
Long-term MonitoringThyroglobulin 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 199580468-72. Spen
cer CA, LoPresti JS, Faterni S, Nicoloff JT.
Detection of residual and recurrent
differentiated thyroid carcinoma by serum
thyroglobulin measurement. Thyroid
199999435-41. 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 1998834435-42.
36
Long-term MonitoringCombining 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)

37
Long-term MonitoringWhat 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/re
sults_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 1998832638-48.
38
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
2004150105-112. 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 14217-225. Mandel
SJ, Mandel L. Radioactive iodicine and the
salivary glands. Thyroid 200313265-271. Mazzafer
ri EL. Gonadal damage from 131I therapy for
thyroid cancer. Clin Endocrinol (Oxf)
200257313-314.
39
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 gt2 decades after initial therapy
• Tumor is often present when a baseline Tg lt 1
  ng/mL rises gt2-5 ng/mL with rhTSH or gt5-10 ng/ml
  with levothyroxine withdrawal
• Risk of developing tumor lt0.5 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 19999421-27. 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 with papillary thyroid carcinoma. J Clin
Endocrinol Metab 2003881433-1441.
40
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
2001861447-1463.
41
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