The evaluation and management of thyroid nodules

Ryan Hungerford, MD, ECNU Providence Medical Center May 3 rd , 2011

Marie de Medici By Peter Paul Rubens, 1622 Goiter considered fashionable

Thyroid glands are beautiful

• • In 1656, Thomas Wharton, English physician and anatomist, is credited with naming the thyroid gland: “glandulae thyroideae”… – whose purpose is to beautify the neck…particularly in females to whom for this reason a larger gland has been assigned.”

Well, maybe some goiters aren’t quite as attractive!

Thyroid Nodules

• • • • • •

Benign (92-96%)

Adenomas (Follicular or Hurthle cell) Focal thyroiditis Thyroid, parathyroid, or thyroglossal cysts Thyroid hemiagenesis Postsurgical or postradioiodine remnant hyperplasia Rare: teratoma, lipoma, hemangioma • • •

Malignant (4-8%)

Well-differentiated (96%) – – – Papillary Follicular (includes Hürthle) Medullary Undifferentiated (3%) – Anaplastic Miscellaneous (1%) – Lymphoma, SCC, metastatic carcinoma, etc.

Thyroid cancer

• • • In general, thyroid cancer is a slow-growing, treatable, often curable, disease with a low mortality rate* – ~98% 10-year mortality for PTC Unfortunately, recurrences are common and a non negligible number of patients will experience: – Progressive disease with regional spread to cervical or mediastinal lymph nodes – Pulmonary or skeletal metastases – – Cerebral metastases Death (often from respiratory failure) In 2010: – 44,670 people were diagnosed with thyroid cancer – 1,690 people died *does not apply to poorly-differentiated cancer, such as anaplastic thyroid ca

Thyroid cancer incidence is rising

1,2 • •

1975

Incidence – 4.85 cases per 100,000 Mortality – 0.55 deaths per 100,000 • •

2007

Incidence – 11.99 cases per 100,000 Mortality – 0.47 deaths per 100,000 2.4 fold increase in thyroid cancer incidence 1 Davies. JAMA 2006;295:2164.

2 NCI Surveillance, Epidemiology and End Results (SEER)

RED = rising incidence Data from the National Program of Cancer Registries (NPCR) and National Cancer Institute using SEER database.

Conclusions: the increased incidence of thyroid cancer is due to “overdiagnosis” of subclinical disease 49% of the increased incidence attributable to small (<1cm) papillary thyroid cancers 1 Davies. JAMA 2006;295:2164.

There is more to this story…

• If the higher incidence is exclusively attributable to detection… • then it would be expected that only the number of patients with smaller tumors and early-stage disease would be increasing.

Larger, more aggressive tumors: Incidence also rising

• • • •

Morris study (Am J Surg 2009)

SEER database since 1983 Tumors >4cm – – All showing rising incidence About 5% annual % ↑ Extrathyroidal extension – – 0.8 per 100,000 (1983) 1.7 per 100,000 (2006) Lymph node mets – 1.0 per 100,000 (1983) – 2.9 per 100,000 (2006) • • •

Chen study (Cancer 2009)

SEER database since 1983 Increased incidence in localized, regional and distant stage tumors Rates of distant mets have risen from 4% to 9% Increasing thyroid cancer incidence not just “overdiagnosis” of subclinical disease!

<1cm 1.0-2.9cm

3.0-3.9cm

>4cm Female Male Chen. Cancer 2009;115:3801.

<1cm 1.0-2.9cm

3.0-3.9cm

>4cm

Thyroid nodules: epidemiology

• • • In the United States, 4 to 7% of the adult population have a palpable thyroid nodule – ~100-150 million Americans have thyroid nodules (u/s + P) – 300,000 new nodules identified in 2010!

– Incidental discovery increasing 1 carotid u/s,

PET

2 with widespread use of CT, MRI, More common in women, and increased incidence with age – If you are a 60 y/o female, there is a 50% chance you have a thyroid nodule – By some estimates, it is more common to have a nodule than to not have a nodule!

Only 1 of 20 clinically identified nodules is malignant 1 Am J Neuroradiol 1997;18:1423.

2 J Nuc Med 2006;47:609.

Case #1: “They found a nodule in my thyroid gland”

• • • • 50 year old female presents for evaluation of neck pain following whiplash from a car accident CT scan of the neck was performed Radiology report: – “Right thyroid lobe contains an ill defined nodule which is inadequately evaluated by this examination. Malignancy cannot be ruled out and a dedicated US study is recommended.” Now what?

Basic approach to a thyroid nodule

1. History 2. Physical 3. Neck Ultrasound 4. TSH 5. Decision to FNA based upon above data

• • • •

Perform a good history Emphasis: thyroid cancer risk factors

Relevant family history – First degree relative with thyroid cancer • The “sister factor” Especially a sibling (6x ↑ risk) or a sister if you are female (11x ↑ risk) – Family history of multiple endocrine neoplasia (MEN) 2, Carney complex, Cowden’s syndrome Age and gender – Male gender and extremes of age (<14 or >70) associated with ↑ risk of malignancy Radiation exposure – History of childhood head and neck irradiation (acne, tonsils, thymus, tinea capitis, etc.) 1 – History of BM transplantation with whole body irradiation – Exposure to ionizing radiation from fallout (in childhood or adolescence), i.e. Chernobyl Relevant symptoms – Rapid growth of nodule (if palpable) or palpable cervical lymph nodes – Hoarseness – The three “Ds”: dysphagia, dyspnea, dysphonia – Symptoms of thyrotoxicosis (palpitations, tremor, etc.) more s/o toxic nodule 1

Otolaryngol Head Neck

Surg 1996;115:403.

Prevalence of malignancy in relation to patients' age in years increased prevalence in patients at the extremes of age Boelaert, K. et al. J Clin Endocrinol Metab 2006;91:4295-4301

Nuclear fallout

• • • Chernobyl, 1986 Estimated that 60% of nuclear fallout landed in Belarus Thyroid cancer incidence rose dramatically, remains elevated to present day

>6,000 cases of thyroid cancer diagnosed as of 2005 among children/adolescents exposed in Belarus, Ukraine, Russia The developing thyroid gland is very sensitive to radiation Chernobyl incident

USA Today, April 26 th , 2011

Perform a focused physical examination emphasis: lymph nodes

• • • Examine neck for palpable nodule(s) and enlarged cervical lymph nodes – Particular concern if fixed, hard mass Palpation vs. ultrasound – ~40% of nodules >2cm are MISSED – by palpation!

1 Using ultrasound, about 15% of patients will have an additional non-palpable nodule >1cm, and 15% will have no nodule at all!

2 For most patients with known or suspected thyroid nodules, the physical examination is not particularly useful!

1 Brander et al. J Clin Ultrasound 1992;20:37.

2 Tan GH et al. Arch Intern Med 1995;155:2418.

Covered so far….

1. History 2. Physical 3. Neck Ultrasound 4. TSH 5. Decision to FNA based upon above data

ATA thyroid cancer guidelines 2009;Thyroid;19:1167.

Screening ultrasound not appropriate for fatigue, hypothyroidism, or elevated TPO antibodies AACE/AME/ETA Thyroid Nodule Guidelines, Endocr Pract. 2010;16(Suppl 1)

Nodule features by Ultrasound

• • • • • •

More likely benign

Iso- or Hyperechoic Smooth borders Halo Uninterrupted Peripheral or “eggshell” calcifications Low vascularity Soft (elastic) • • • • • • •

More likely malignant

Hypoechoic Irregular borders No halo Microcalcifications tall>wide High vascularity Hard (not elastic) There is no single pathognomic finding that confirms malignancy or benignity.

Normal thyroid gland

Normal thyroid

Colloid artifact Benign cyst

Well-defined borders

Irregular borders

Microcalcifications

Microcalcifications Hypoechoic

Taller than wide

Hypoechoic

Hypervascular

PTH dropped from 310  40 after removal Not a cyst! This is a parathyroid adenoma

Nodule features by Ultrasound

• • • • • •

More likely benign

Hyperechoic Smooth borders Halo Uninterrupted Peripheral or “eggshell” calcifications Low vascularity Soft (elastic) • • • • • • •

More likely malignant

Hypoechoic Irregular borders No halo Microcalcifications tall>wide High vascularity Hard (not elastic)

Ultrasound Elastography

• • • • Malignant lesions are associated with changes in the mechanical properties of a tissue Elastography is a dynamic technique that uses ultrasound to provide an estimation of tissue stiffness by measuring the degree of distortion under the application of an external force Has been used to differentiate cancer from benign lesions in prostate, breast, pancreas, LNs Now being applied to thyroid nodules

92 consecutive patients who underwent surgery for solitary thyroid nodules -all underwent standard thyroid ultrasound, standard risk assessment -Elastography was performed for all nodules -nodules “scored” based on how “ELASTIC” they are Rago. J Clin Endocrinol Metab 2007;92:2917-2922.

Elasto study findings

• • • • 92 cases, all proceeded to surgery, known histologic diagnosis – 34% malignant – 66% benign Elastography – Score 1-2 identified in 49 patients: all benign – Score 3 identified in 13 patient: 1 malignancy, 12 benign – Score 4-5 identified in 30 patients: all malignant Conclusions – If your thyroid nodule is very elastic (score 1-2), it is most likely benign – If your thyroid nodule is very firm (score 4-5), it is most likely cancer Elastography is of tremendous clinical value, particularly when added to other standard US sonographic features – Limitations: can’t be used on cystic/solid nodules or calcified nodules Rago. J Clin Endocrinol Metab 2007;92:2917-2922.

Elastic: Score 1 Hard: Score 5

• • • •

Should I do any lab testing for a thyroid nodule?

TSH for everybody!

– If low, don’t biopsy! (To be reviewed in next few slides) TPO and TG antibodies usually NOT necessary – But, TPO abs may help determine the explanation for other sonographic findings (ex: Hashimoto’s) – – – ↑ TG abs associated with thyroid cancer, hypothesis: thyroid inflammation is tumorigenic or abnormal TG expressed by tumor cells triggers immune response Calcitonin Elevated in Medullary Thyroid Cancer (3-5% of thyroid malignancies) and C-cell hyperplasia •

A serum TSH is indicated in all patients

American Thyroid Association (2009) guidelines: recommendation I • • Always measured if family history of MTC or MEN2 Thyroglobulin – Not useful, no relationship to thyroid malignancy – Universal consensus among all professional societies (ATA, AACE, AME, ETA) – Do NOT measure!

AACE/AME/ETA Thyroid Nodule Guidelines, Endocr Pract. 2010;16(Suppl 1).

ATA guidelines for management of thyroid nodules and thyroid cancer, Thyroid, 2009;19(11):1167.

Why is the TSH so useful?

• It helps determine if the nodule is likely to be a “toxic” adenoma – These are autonomous, hyperfunctioning nodules, aka “hot” nodules – They are [almost] always benign! – Thus, FNA is usually

*

unnecessary – If the TSH is low, patient should be sent for a radionuclide study first and/or referred to endo Important: thyroid uptake and scan is not appropriate for MOST patients with thyroid nodules!

*if nodule is smaller (<1.5 or so) with suspicious features, FNA may still be indicated

Does TSH correlate with risk of malignancy in a patient with a nodule?

• • • Prospective study of 1,183 patients with palpable thyroid enlargement All had FNA and/or surgery TSH measured at presentation, then compared to FNA and/or surgical findings Boelaert K. J Clin Endocrinol Metab 2006;91(11):4295.

Risk of thyroid cancer increases as TSH rises Boelaert, K. et al

. J Clin Endocrinol Metab

2006;91:4295-4301

Estimated probability of malignancy in 40 y/o female with a solitary thyroid nodule Why?

TSH 0.3 0.5

Risk of cancer_ 8% 8.4% 1.0

9.4% 3.0

5.0

6.0

14.6% 21.9% 26.4% Boelaert, K. et al

. J Clin Endocrinol Metab

2006;91:4295-4301

Test: true or false?

• • • The larger the nodule, the more likely it is to be cancer.

A patient with a solitary nodule is more likely to have cancer than a patient with multiple nodules (multinodular goiter).

Treatment with levothyroxine will shrink thyroid nodules.

Nodule features by Ultrasound

• • • • • •

More likely benign

Hyperechoic or isoechoic Halo Uninterrupted Peripheral or “eggshell” calcifications Low vascularity Soft/elastic • • • • • • •

More likely malignant

Hypoechoic Irregular borders No halo Microcalcifications tall>wide High vascularity Hard/not elastic

Malignancy rate was not lower (was actually higher) in nodules <1cm 520 consecutive thyroid nodules evaluated from 2003-2006. Group 1: subcentimeter nodules (N=247) Group 2: supracentimeter nodules (N=273) Ultrasound and FNA for all patients; malignant or suspicious  surgery Berker. Thyroid 2008;18:603-608.

Size does not predict risk of malignancy

US guided FNA in 402 pts with non-palpable nodules Nodule



10 mm Nodule >10 mm 9.1% cancer 7.0% cancer

Papini E et al. J Clin Endocrinol Metab 2002:87:1941-1946

Cohort

Cancer risk: Solitary vs Multiple

n McCall et al (1986 U.S.) Cochand-Priolett et al (1994 France) Sachmechi et al (2000 U.S.) Marqusee et al (2000 U.S.) Papini et al (2002 Italy) Deandrea et al (2002 Italy) Frates et al (2006 U.S.) 442 132 443 156 494 420 1,985 US US US Imaging modality Scan/Hx Scan/US NM Scan US FNA Palpation

Cancer risk

Single

17

as %

Multiple

13 US guided Palpation 13 8 14 10 US guided US guided US guided US guided 7 9 6 14.8

14.9

9 6 7

Levothyroxine to shrink nodules

• • • • Systematic review of 6 highest quality RCT evaluating the efficacy of LT4 suppressive therapy (>50% vol reduction) 5 of 6 studies: no statistically significant benefit, though a trend toward nodule volume reduction was seen

The use of LT4 to

It is possible that a subgroup of patients, not

shrink thyroid nodules

characteristics, could benefit

has fallen out of favor

Must consider potential skeletal and cardiac risks of TSH suppression Gharib. N Engl J Med 1987;317:70.

Castro. J Clin Endocrinol Metab 2002;87:4154. Gharib. Ann Intern Med 1998;128:386.

Post test

• • • The larger the nodule, the more likely it is to be cancer. False A patient with a solitary nodule is more likely to have cancer than a patient with multiple nodules (multinodular goiter). False Treatment with levothyroxine will shrink thyroid nodules. False

Fine needle aspiration (FNA)

• Most accurate, cost-effective means to assess

The objective of the FNA

• • – – – Specificity ~85% or higher Note: false negatives (FNA positive for malignancy, but negative histologic findings) do occur (~5%), but are relatively uncommon In general, FNA findings are very reliable

• • •

The biopsy (FNA): How it’s done

Simple in-office procedure – Some use local anesthesia (1% Lidocaine), I do not – Patient prepped with alcohol (“clean,” not sterile, procedure) – – Usually 25-27g needle, perpendicular or parallel approach 2 passes, sometimes 3-4, more usually does not ↑ diagnostic yield Most patients report minimal or no pain – Bruising, bleeding rare (can be done on coumadin) – Infection almost unheard of (case reports outside U.S.) – Patient can go home or back to work, call if swelling Post-procedure – Aspirate smeared on slides, sent to pathology – Some endocrinologists stain slides (Diff-Quik) and assess adequacy by light microscopy prior to sending slides to pathology, and repeat the procedure if insufficient cellular material – I do this for every FNA

Pathology Findings

• • • • Benign (~65-70%) Indeterminate (~10-20%) – Atypia or follicular lesion “of undetermined significance” – Follicular or Hürthle cell neoplasm Malignant or suspicious for malignancy (~5%) Non-diagnostic (aka insufficient) (10-15%) Gharib, Papini. Endocrinol Metab Clin North Am 2007;36:707.

When should FNA be performed?

• • • • >5mm if high risk history (regardless of sonographic features) – Family history of thyroid cancer, especially MTC – Calcitonin >100pg/mL – – History of external beam irradiation or ionizing radiation to the neck as a child or adolescent clinical risk factors and sonographic – 18 features of the nodule and cervical 1-2cm depending on presence or absence of suspicious sonographic

lymph nodes

≥2cm if spongiform, >50% cystic, no suspicious sonographic features A couple exceptions: – NEVER if purely cystic, regardless of size – ALWAYS if abnormal cervical lymph nodes

ATA guidelines for management of thyroid nodules and thyroid cancer, Thyroid, 2009;19(11):1167.

Important conclusions: The decision to perform FNA can NOT be made without a focused medical history and can NOT be made without high quality ultrasonography with lymph node evaluation.

AACE/AME/ETA Thyroid Nodule Guidelines, Endocr Pract. 2010;16(Suppl 1)

Lymph node evaluation

• • • Presence of malignant-appearing lymph nodes dramatically alters FNA threshold Many sonographers are not comfortable with detailed LN evaluations, it is not currently part of the sonographer training curriculum If pathologic LNs are identified, this changes the surgery!

Thyroid, 2009;19(11):1167.

ECNU

• • “Endocrine Certification in Neck Ultrasound” Recognized by the American Institute of Ultrasound in Medicine (AIUM), the preeminent national accreditation body for u/s practices

Why can’t we just FNA all nodules?

• • • Diagnostic possibilities from FNA – Non-diagnostic (insufficient) – Benign – Indeterminate, follicular neoplasm – Malignant or suspicious for cancer When FNA is performed, depending on quality of cytology, there is a 10-30% chance that the patient will be sent for surgery The majority of “indeterminate” cytology findings turn out to be benign by histology Massive numbers of people would be subjected to surgery, most unnecessarily

The future is now (2011)

• • • Genetic mutations associated with thyroid cancer have been identified – BRAF V600E , RAS, RET/PTC, Pax8-PPARɣ, galectin-3 – Presence or absence provides useful information regarding malignancy risk – American Thyroid Association: “may be considered” for indeterminate cytology on FNA 1 – Just not enough data for a stronger recommendation – Until now – We can test for all of these mutations from DNA and RNA isolated from a single FNA pass, have results back in a week 2 Molecular analysis – High-dimensionality genomic data 3 – mRNA expression analysis used to measure 200,000+ transcripts from thyroid nodule samples – Potential to classify a nodule “benign” with high certainty (96% NPV!!) – Confirmatory studies underway, available in 3 states currently, but should be available soon 4 Clinical applicability – Use of these advanced tests in those individuals found to have indeterminate FNA findings, thus allowing greater certainty in determining if nodule is benign – Could save thousands of people from unnecessary surgery 1 ATA thyroid nodule guidelines, 2009.

2 www.asuragen.com

3 Chudova. J Clin Endocrinol Metab 2010;95:1-9.

4 www.veracyte.com

Back to case #1

• • • • 50 y/o female Incidental discovery of nodule on CT scan A neck ultrasound is performed This is what is found

2.1 cm nodule clear borders isoechoic, halo Biopsy?

Not enough info!

Now biopsy?

Don’t forget about the Hx/PE/TSH

• • • • History – Palpitations for 3 months – Weight loss of 8 lbs – Slight tremor of hands, feels anxious Exam – palpable R thyroid mass, no lymphadenopathy TSH 0.05

Now what?

Send patient for

123

I scan!

Case #2: incidental nodule by CT

• • • • • History – No fam hx of thyroid ca, MEN2 – – No history of neck irradiation Patient can’t feel nodule Exam – You feel nothing TSH 1.9

Ultrasound – Solid nodule, measures 1.1cm

– Isoechoic, + halo, minimal blood flow – Normal-appearing lymph nodes Now biopsy?

NO. This nodule can be followed.

Case #3: incidental nodule by CT

• • • • History – Sister has thyroid cancer – No history of neck irradiation – Patient can’t feel nodule Exam – You feel nothing TSH 1.9

Ultrasound – Solid nodule, measures 1.1cm

– Isoechoic, + halo, minimal blood flow – Abnormal lymph node (see next slide)

Case #3: incidental nodule by CT

Now biopsy?

YES! This is a high risk patient.

*FNA decision would have been different without all the data!

Summary: thyroid nodule workup

Thyroid nodule identified by palpation or imaging History, physical, TSH TSH normal or high Diagnostic US TSH low Non functioning I-123 scan Hyper functioning Evaluate and treat for hyperthyroidism Follow No Suspicious sonographic features and/or high risk history?

Yes FNA

Summary

• • • • • Thyroid cancer incidence is rising nationally and in Oregon, for uncertain reasons Thyroid cancer is generally a treatable disease with an excellent prognosis All known or suspected thyroid nodules require a high quality U/S with lymph node assessment Serum TSH, family history, and sonographic lymph node assessment are vital components to proper w/u Most nodules do not need FNA, it depends on above risk factors, time is on your side!

Thank you!

Further questions?

• • 541-776-2003 (office) 801-540-1523 (cell) • • Please call with questions!

For this topic or other endocrine topics