Papillary Thyroid CA

E. A., 57 year old female, married, Filipino from Sampaloc, Manila came in January 15, 2010 at CD-OPD for follow up

History of Present Illness

1983 - 1985 Gradually enlarging L anterior neck mass, approx 3-4 cm Denies weight loss, hoarseness, dysphagia Consult sought, FNAB done: normal results L lobectomy Normal histopathology results

Jan - Feb 2008

Noticed another nodule near previous surgical site Still asymptomatic Consult sought, thyroid function tests: normal Thyroid UTZ: numerous lymph nodes FNAB: Cancer Completion thyroidectomy Histopath: Metastatic Papillary Carcinoma

Surgical Pathology Report

Specimen: R thyroid gland, LN 2,3,4,5 Operation Performed: Thyroidectomy Pathologic Diagnosis: Completion Thyroidectomy s/p Left Lobectomy No residual carcinoma, Right lobe Metastatic Papillary Carcinoma in eleven (11) out of twenty nine (29) cervical lymph nodes, Level 2,3,4 and 5

History of Present Illness

Mar 2008 150mCi RAI ablation therapy DxWBS: functioning thyroid tissues, L: 3.8 x 1.7cm, R: 1.4 x 1.2; B lung mets? Levothyroxine 100mcg/OD TSH: 0.26 (0.27-3.75 uIU/mL)

Sept 2008

UTZ: multiple nodules, R 5, L 3 Thyroglobulin: 21.84 ng/mL Anti-TG: <13 IU/mL US FNAB: (-) for malignant cells 3mCi DxWBS: higher than background activity in the neck area, (-) lungs 150mCi TxRAI Levothyroxine 150 mcg/OD DxWBS: L neck: 1.8x1.3 negative distant mets

Nov-Dec 2008

Scintigraphic report
Detailed imaging of the anterior neck shows an irregularly shaped, elongated focus of activity in the L thyroidal bed measuring approximately 3.8x1.7cm. A circumscribed focus of activity is likewise noted in the R thyroidal bed measuring 1.4 x 1.2 cm and another faint blush in its superolateral aspect. Whole body imaging shows faint, diffuse tracer uptake in both lung fields. The rest of the body shows physiologic tracer accumulation in the oro/nasopharyngeal area, salivary glands, liver and urinary bladder. IMPRESSION: S/P THYROIDECTOMY, S/P RAI ABLATION THERAPY FUNCTIONING THYROID TISSUES IN THE NECK AS DESCRIBED FAINT TRACER ACTIVITY IN BOTH LUNG FIELDS SUSPICIOUS FOR DISTANT FUNCTIONING THYROID METASTASIS.

History of Present Illness

Mar 2008 150mCi RAI ablation therapy DxWBS: functioning thyroid tissues, L: 3.8 x 1.7cm, R: 1.4 x 1.2; B lung mets? Levothyroxine 100mcg/OD TSH: 0.26 (0.27-3.75 uIU/mL)

Sept 2008

UTZ: multiple nodules, R 5, L 3 Thyroglobulin: 21.84 ng/mL Anti-TG: <13 IU/mL US FNAB: (-) for malignant cells 3mCi DxWBS: higher than background activity in the neck area, (-) lungs 150mCi TxRAI Levothyroxine 150 mcg/OD DxWBS: L neck: 1.8x1.3 negative distant mets

Nov-Dec 2008

Ultrasound Report
9/9/98 Both lobes of the thyroid gland are not visualized consistent with history of total thyroidectomy Multiples nodules seen in both sides of the neck measuring
Right:
2.0x0.4x0.7cm 0.8x0.2x0.4cm 1.0x0.2x0.5cm 1.4x0.4x1.0cm 0.9x0.4x0.5cm

-Left:
1.0x0.1x0.4cm 0.6x0.4x1.7cm 0.9x0.4x0.5cm

History of Present Illness

Mar 2008 150mCi RAI ablation therapy DxWBS: functioning thyroid tissues, L: 3.8 x 1.7cm, R: 1.4 x 1.2; B lung mets? Levothyroxine 100mcg/OD TSH: 0.26 (0.27-3.75 uIU/mL)

Sept 2008

UTZ: multiple nodules, R 5, L 3 Thyroglobulin: 21.84 ng/mL Anti-Tg: <13 IU/mL US FNAB: (-) for malignant cells 3mCi DxWBS: higher than background activity in the neck area, (-) lungs 150mCi TxRAI DxWBS: L neck: 1.8x1.3 negative distant mets Levothyroxine 150 mcg/OD

Nov-Dec 2008

History of Present Illness

Mar 2009 TSH: 0.09 UTZ of neck: 1.4 x 0.8cm supraclavicular nodule L Levothyroxine 150 mcg OD

Nov 2009

UTZ of neck: 0.8cm hypoechoic nodule, L Levothyroxine 150mcg OD

Jan 2010

Presents at OPD for follow up TSH: 0.01

Past Medical / Social Histories

Past Medical History:
(-) HPN, DM, asthma (-) prior head/neck external radiation

Social History:
Non smoker, non alcoholic beverage drinker

Family History
Family history:
(-) HPN, DM, CA

OB/Gyn history:
G3P3 (3-0-0-3) all NSD Menarche: 14 y/o Menopause at 54 y/o

Review of Systems

Physical Examination
Conscious, coherent, ambulatory
BP: 110/70 CR: 82/min, regular RR: 16/min T: 37.4C BMI: 21 kg/m2

HEENT:
Pink palpebral conjunctiva, anicteric sclerae, EOMs full and equal, (-) exophthalmos, (-) lid lag Non hyperemic pharyngeal wall, tonsils not enlarged 10cm incisional scar anterior neck area, thyroid non palpable, no palpable cervical, submandibular, supraclavicular lymph nodes

Physical Examination
Breasts:
Symmetrical, no masses, no axillary lymph nodes palpable

Chest/lungs:
Symmetrical chest expansion, no retractions, clear breath sounds

Cardiovascular:
Adynamic precordium, AB at 5th LICS, MCL, no murmurs, no heaves, no thrills

Abdomen:
Flabby, soft, normoactive bowel sounds, no organomegaly

Extremities:
Pulses full and equal, no edema

Salient features
E. A. 57 y/o female 25 year hx: L lobectomy 2 to thyroid nodule (approx 3-4 cm, apparent benign histopath) 2 year hx: Metastatic Papillary CA with multilevel Lymph node metastasis 2x Tx RAI 150mCi (March, Dec 2008) On TSH suppresion with Levothyroxine 100mcg OD UTZ finding of hypoechoic nodule, L

Assessment
Recurrent Papillary Thyroid CA with Lymph node metastasis

Plan
Discontinue Levothyroxine x 3 weeks Repeat TSH if > 30uIU/mL do repeat Tg, anti-Tg Ab

Discussion
Our patient presented 25 years ago with a benign nodule managed by L thyroid lobectomy, however 23 years later subsequently developed CA with multiple lymph node metastasis on the ipsilateral neck. Absent/lacking: EBM principles Clinical practice guidelines Prognostication Surgical, Medical treatment Poor long term follow up

 What are the present guidelines for patients presenting with asymptomatic thyroid nodules?
American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi (AACE/AME, 2006) European Thyroid Association (2008) American Thyroid Association (2006, revised 2009)

Discussion
Palpable thyroid nodules:
5% women, 1% in men

High resolution US:

9-17% randomly selected individuals

Clinical dilemma: identify nodules at risk for carcinoma

Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11. p1176

Nodules requiring evaluation

>1 cm (greater potential to be clinically significant) <1 cm but: suspicious US findings, lymphadenopathy, hx of irradiation, hx of thyroid CA FDG-PET nodules (33% risk of malignancy)

Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11. p1176

Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11.

 History
External irradiation during childhood Familial history of medullary CA Age <20 or >60 yr Male sex

Physical examination
Rapidly growing Firm, hard, painful Fixed to soft tissue Local symptoms Lymphadenopathy Dysphagia, hoarseness

Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11.

UTZ findings suggestive of CA

Nodule hypoechogenicity Increased intranodular vascularity Irregular infiltrative margins Microcalcifications Absent halo Shape taller than the width measured in the transverse dimension

>95%

50-75%

15-25%

 Non diagnostic:
Fail to meet specified criteria
At least 6 follicular cell groups Each containing 10-15 cells derived from at least two aspirates of the nodule

Thyroid nodules: Recommendation

Measure serum TSH in the initial evaluation. Thyroid sonography should be performed in all patients with known or suspected thyroid nodules. FNA is the procedure of choice in the evaluation of thyroid nodules. US guidance for FNA is recommended for those nodules that are nonpalpable, predominantly cystic, or located posteriorly in the thyroid lobe.
Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11.

Thyroid nodules: Recommendation

It is recommended that all benign thyroid nodules be followed with serial US examinations 6 18 months after the initial FNA.

Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11.

Papillary CA
85-90% of all thyroid carcinomas Occur at any age, highest in the 3rd and 4th decades Good prognosis and <10% mortality Invade lymphatic vessels Venous invasion and distant metastasis are rare and account for 5% to 7% of cases
Pacini, F, DeGroot, L. Principles of Endocrinology. Chapter 109. Thyroid Neoplasia

How is Papillary Thyroid CA managed according to the Revised ATA Guidelines?

Goals of Initial Therapy

To remove the primary tumor, disease that has extended beyond the thyroid capsule, and involved cervical lymph nodes. To minimize treatment-related morbidity. To permit accurate staging of the disease. To facilitate postoperative treatment with radioactive iodine, where appropriate. To permit accurate long-term surveillance for disease recurrence. To minimize the risk of disease recurrence and metastatic spread.
Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11.

Algorithm for initial therapy for DTC

Preoperative Staging; Neck US

Surgery, (Lobectomy; Total, Near Total; Completion) +/- Lymph Node Dissection

Post operative Staging: AJCC/IUCC TMN +/- RAI Remnant Ablation, PostTxRAI WBS TSH Suppresion Therapy

Pre operative Neck Ultrasound

Identifies 20-31% of lymph node mets, potentially altering surgical approach Sonographic features suggestive of abnormal metastatic lymph nodes:
loss of the fatty hilus a rounded rather than oval shape hypoechogenicity cystic change calcifications peripheral vascularity

Algorithm for initial therapy for DTC

Preoperative Staging; Neck US

Surgery, (Lobectomy; Total, Near Total; Completion) +/- Lymph Node Dissection

Post operative Staging: AJCC/IUCC TMN +/- RAI Remnant Ablation, PostTxRAI WBS TSH Suppresion Therapy

Surgery
Hemithyroidectomy/Lobectomy Near-Total Thyroidectomy (all thyroid tissue, leaving <1g near the recurrent laryngeal nerve) Total Thyroidectomy

Hemi/Lobectomy: Indeterminate- solitary Malignant, suspicious PTC (<1cm, low-risk,unifocal, intrathyroidal)

>95%

50-75%

15-25%

Surgery
Hemithyroidectomy/Lobectomy Near-Total Thyroidectomy (all thyroid tissue, leaving <1g near the recurrent laryngeal nerve) Total Thyroidectomy

Lymph Node Dissection

Regional lymph node metastases are present at diagnosis in 20-90% of PTC. Associated with poor outcome
All cause survival at 14 years was 82% for PTC without lymph node and 79% with lymph node metastases

Recommended in:
Those with clinically involved central/lateral lymph nodes Advanced primary tumors (>2cm)

Algorithm for initial therapy for DTC

Preoperative Staging; Neck US

Surgery, (Lobectomy; Total, Near Total; Completion) +/- Lymph Node Dissection

Post operative Staging: AJCC/IUCC TMN +/- RAI Remnant Ablation, PostTxRAI WBS TSH Suppresion Therapy

Post operative staging

Permits prognostication Tailor decisions regarding adjunctive therapy (RAI, TSH suppresion) Frequency and intensity of follow up Accurate communication among healthcare professionals

Post operative staging

CAEORTC, AGES, AMES, U of C, MACIS, OSU, MSKCC and NTCTCS systems No scheme has demonstrated clear superiority Recommendation:
AJCC/UICC Staging:
Utility in predicting disease mortality Requirement for cancer registries

AJCC Cancer Staging Manual. 6th Edition. 2002

AJCC Cancer Staging Manual. 6th Edition. 2002

Algorithm for initial therapy for DTC

Preoperative Staging; Neck US

Surgery, (Lobectomy; Total, Near Total; Completion) +/- Lymph Node Dissection

Post operative Staging: AJCC/IUCC TMN +/- RAI Remnant Ablation, PostTxRAI WBS TSH Suppresion Therapy

Postoperative RAI remnant ablation

Facilitates early detection of recurrence based on serum Tg and/or RAI WBS Facilitates initial staging by identifying previously undiagnosed disease Potential tumoricidal effect on persistent thyroid CA cells at risk for recurrence Recommendation:
Known distant metastases, gross extrathyroidal extension, >4cm, documented lymph node mets

Risk stratification
Low risk:
1) no local or distant metastases 2) all macroscopic tumor has been resected 3) there is no tumor invasion of locoregional tissues or structures 4) the tumor does not have aggressive histology (e.g., tall cell, insular, columnar cell carcinoma) or vascular invasion 5) and, if 131I is given, there is no 131I uptake outside the thyroid bed on the first posttreatment whole-body RAI scan
Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11.

Risk stratification
Intermediate-risk patients have any of the following:
1) microscopic invasion of tumor into the perithyroidal soft tissues at initial surgery 2) cervical lymph node metastases or 131I uptake outside the thyroid bed on the RxWBS done after thyroid remnant ablation 3) tumor with aggressive histology or vascular invasion
Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11.

Risk stratification
High-risk patients:
1) macroscopic tumor invasion 2) incomplete tumor resection 3) distant metastases 4) thyroglobulinemia out of proportion to what is seen on the posttreatment scan

Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11.

Algorithm for initial therapy for DTC

Preoperative Staging; Neck US

Surgery, (Lobectomy; Total, Near Total; Completion) +/- Lymph Node Dissection

Post operative Staging: AJCC/IUCC TMN +/- RAI Remnant Ablation, PostTxRAI WBS TSH Supression Therapy

TSH suppresion
Decrease the risk of recurrence Recommendation:
High risk, intermediate risk: <0.1 mU/L Low risk: 0.1-0.5mU/L

Adverse effects:
Exacerbation of angina, AF, osteoporosis

TSH suppresion
Decrease the risk of recurrence Recommendation:
High risk, intermediate risk: <0.1 mU/L Low risk: 0.1-0.5mU/L

Adverse effects:
Exacerbation of angina, AF, osteoporosis

What are the clinical risk factors associated with cervical lymph node recurrence after initial therapy (surgery, RAI, TSH suppresion)?

Risk factors for recurrence

Tumor size >2cm Extrathyroid tumor spread High T stage Lymph node metastasis at time of presentation

Baek, SK et. Al. Clinical Risk Factors Associated with Cervical Lymph Node Recurrence in Papillary Thyroid Carcinoma. Thyroid. 00.00, 2009 Links, TP et al. Life expectancy in differentiated thyroid cancer: a novel approach to survival analysis. Endocrine-Related Cancer. 12. 2005

How is long term management of patients s/p total thyroidectomy s/p TxRAI and on TSH suppression accomplished?

Long term management

Accurate surveillance for possible recurrence
Tests with high negative predictive value to identify low from high risk patients

Provide for early recognition of recurrent disease for effective treatment Serum Tg, anti Tg Ab and Neck US surveillance

Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11.

Tg, anti-Tg Ab
Important modality to monitor patients for recurrent/residual disease especially after total/near total thyroidectomy. Every 6-12 months Achieves highest sensitivity following thyroid hormone withdrawal (THW) or rhTSH stimulation. Serum Tg of >2 ng/mL is highly sensitive in identifying persistent tumor. Tg, Anti-Tg Ab should be taken together
Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11.

 Serum Tg level below 1.0 ng/ml at the first postsurgical evaluation during L-T4 withdrawal was an accurate predictor of no relapse.

Pellegriti, G. et al. Clinical Behavious and Outcome of Papillary Thyroid Cancers Smaller than 1.5 in diameter: Study of 299 Cases. The Journal of Clinical Endocrinology and Metabolism. 89(8):3713-3720

 The positive predictive value of the initial rhTSH-Tg greater than 2ng/ml was 80%, and the negative predictive value was 98%.

Kloos, R.T. and E.L. Mazzaferri, A Single rh Human Thyrothropin Stimulated Serum Thyroglobulin Measurement Predicts Differentiated Thyroid Carcinoma Metastases Three to Five Years Later. J Clin Endocrinol Metab, 2005. 90(9): p. 504757.

Neck Ultrasound
Highly sensitive in the detecting cervical LN metastasis Able to identify metastasis even when Tg levels are undetectable

Frasoldati, A. et al. Diagnosis of Neck Recurrences in Patients with Differentiated Thyroid Carcinoma. Cancer. 91.1.pp 90-96

Long term management

TSH suppresion to levels below 0.1 mU/L recommended specially to those with persistent disease.

Cooper, DS. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. Vol 19.No 11.

In our patient who has persistent L nodal disease, what is the best intervention?
1. surgical excision of locoregional disease in potentially curable patients, 2. I131 therapy for RAI-avid disease, 3. external beam radiation, 4. watchful waiting 5. with patients with stable or slowly progressive asymptomatic 6. disease, and experimental trials, especially for patients with significantly progressive macroscopic refractory disease.

 Surgical removal of recurrent lymph node disease successfully prevent further recurrence in 62% of the patients and can convert 41% of the patients to an undetectable stimulated Tg postoperatively.

Sippel, R. et al. Controversies in the Surgical Management of Newly Diagnosed and Recurrent/Residual Thyroid Cancer.Thyroid.19. 18, 1373-1380