What I Want from My Endocrine Surgeon? Pre-Lecture Survey

5/3/2019

WHAT I WANT FROM MY ENDOCRINE SURGEON?

DR. VANITHA SINGARAM, MD, FACE ENDOCRINOLOGIST IOWA DIABETES AND ENDOCRINOLOGY CENTER

PRE-LECTURE SURVEY

• 52 YEAR OLD MAN WITH A 5 CM RIGHT THYROID NODULE, FNA REVEALS PAPILLARY THYROID CARCINOMA. NEXT STEP?

A. TOTAL THYROIDECTOMY

B. TOTAL THYROIDECTOMY WITH CENTRAL COMPARTMENT DISSECTION

C. US OR CT NECK D. PET

1 5/3/2019

PRE-LECTURE SURVEY

35 YR. OLD FEMALE WITH HYPERCALCEMIA, PARATHYROID LABS HIGH NORMAL, RECURRENT RENAL CALCULI ( CALCIUM STONES ), 24. HR. URINE CALCIUM 250 MG, SESTAMIBI SCAN DID NOT LOCALIZE AN ADENOMA ? NEXT STEP ? a. MEDICAL SURVEILLANCE b. REPEAT SCAN c. SURGERY PARATHYROID EXPLORATION d. REPEAT 24 HR. URINE CALCIUM TO EVALUATE FOR FAMILIAL HYPOCALCIURIC HYPERCALCEMIA

PRE-LECTURE SURVEY

• 48 YEAR OLD WOMAN WITH 6.3 CM ENHANCING HETEROGENOUS RIGHT ADRENAL MASS. SHE IS OTHERWISE HEALTHY WITH NO HISTORY OF HYPERTENSION OR SYSTEMIC ILLNESS. NEXT STEP? A. CT-GUIDED BIOPSY OF MASS B. RIGHT ADRENALECTOMY C. CHECK SERUM METANEPHRINES D. URINARY VMA E. NO FURTHER INTERVENTION

2 5/3/2019

DISCLAIMERS AND DISCLOSURES

• NO FINANCIAL CONFLICTS OF INTEREST

• NOOFF-LABEL DISCUSSION

OBJECTIVES AND SCOPE

• PROVIDE AN APPROACH TO WORKING UP INCIDENTALLY DISCOVERED ENDOCRINE NODULES

• BRIDGE THE SURGICAL AND THE CLINICAL WORLDS • THYROID NODULES AND DIFFERENTIATED THYROID CANCER

• PRIMARY HYPERPARATHYROIDISM • ADRENAL INCIDENTALOMAS INCLUDING PRIMARY HYPERALDOSTERONISM AND PHEOCHROMOCYTOMA

3 5/3/2019

THYROID INCIDENTALOMAS

• COMMON:

• PREVALENCE ( PALPATION ) : 5 % IN WOMEN, 1 % IN MEN

• SONOGRAPHIC PREVALENCE UP TO 68 %

• INCREASES WITH AGE

• 27% IN < 50 YEAR OLDS

• ~50% OF 50 YEAR OLDS

• MORE COMMON IN WOMEN

• KEY QUESTIONS :

• ARE THEY AFFECTING THYROID FUNCTION? SERUM TSH

• ARE THEY MALIGNANT? NO ROLE FOR SERUM THYROGLOBULIN

Ezzat S. Arch Int Med 1994 Brander A. Radiology 1991

EVALUATION:

• LABS: TSH TO ASSESS FOR HYPERTHYROIDISM

• IF HYPERTHYROID- POSSIBILITY OF A HOT NODULE

• NEXT STEP : I-123 UPTAKE & SCAN +/- REFERRAL TO ENDOCRINOLOGIST TO EVALUATE NEED FOR TREATMENT AND DISCUSS TREATMENT OPTIONS. • IMAGING: HIGH-SENSITIVITY ULTRASONOGRAPHY

• SONOGRAPHIC RISK FACTORS

• HYPOECHOIC NODULES

• IRREGULAR MARGINS

• INCREASED VASCULARITY

• MICROCALCIFICATIONS

Gharib H. Endocrinol Metab Clin N Am 2007

4 5/3/2019

OTHER MODALITIES :

• FDG-PET – FOCAL UPTAKE WITH US CONFIRMED NODULES > 1 CM WARRANT FNA • FDG-PET – DIFFUSE UPTAKE WITH US AND BIOCHEMICAL EVIDENCE OF CHRONIC LYMPHOCYTIC THYROIDITIS DOES NOT WARRANT FNA • CT/MRI: • ONLY IF SUBSTERNAL, NODE MAPPING

• RADIONUCLIDE UPTAKE & SCAN • ONLY IF HYPERTHYROID- TO CONFIRM HOT NODULE • COLD NODULE = MALIGNANCY? • BUT MOST COLD NODULES ARE BENIGN • AND MANY CANCERS DON’T APPEAR COLD ON IMAGING

5 5/3/2019

ULTRASOUND-GUIDED THYROID BIOPSY

• US-GUIDED FNA • GOLD STANDARD • OFFICE BASED • MULTIPLE NODULES: • SONOGRAPHIC SUSPICION

Khoo TK. Endocr Prac 2008 AACE/AME Task Force on Thyroid nodules. Endocr Prac 2006

6 5/3/2019

RESULTS AND IMPLICATIONS

• DIAGNOSTIC

• BENIGN

• ATYPIA OR FOLLICULAR LESION OF UNDETERMINED SIGNIFICANCE

• SUSPICIOUS FOR FOLLICULAR NEOPLASM OR MALIGNANCY

• MALIGNANT

• NONDIAGNOSTIC

Cibas ES. Am J Clin Pathol 2009

ROLE OF MOLECULAR MARKERS

1. AFFIRMA GENE EXPRESSION CLASSIFIER : - MRNA EXPRESSION OF 167 GENES - NPV 95 % IN ATYPIA OF UNKNOWN SIGNIFICANCE/FOLLICULAR LESION OF UNKNOW SIGNIFICANCE, FOLLICULAR NEOPLASM ( BETHESDA III&IV) - PPV 37 % -GOOD ‘RULE OUT’ TEST IN INDETERMINATE NODULES. 2. THYGENX AND THYRAMIR : -GENE MUTATION : BRAF, RAS, RET/PET, PAX8/PPARΓ - NPV 94 %, PPV 74 % 3. THYROSEQ : -GENE MUTATION & FUSION PANEL - NPV 96 %, PPV 88 %, ‘RULE IN’ TEST LONG-TERM OUTCOME DATA INSUFFICIENT AT THIS POINT

7 5/3/2019

THYROID MALIGNANCY

• ONLY 1 IN 20 NODULES IS MALIGNANT

• 1% OF ALL CANCERS • 1975-2009 : INCIDENCE : 4.9 TO 14.3 /100,000 MORTALITY : STABLE 0.5 /100,000

Davies L. JAMA Otolaryngol Head & Neck Surgery 2014

Davies L. JAMA 2006

8 5/3/2019

SUBTYPES

• FOLLICULAR-DERIVED

• DIFFERENTIATED

• 80 % PAPILLARY THYROID CARCINOMA (VARIANTS- TALL CELL, FOLLICULAR, CLEAR CELL)

• 10 %FOLLICULAR THYROID CARCINOMA (HURTHLE CELL)

• 1-2 % UNDIFFERENTIATED/ANAPLASTIC

• 5 -10 % MEDULLARY • RARE – PRIMARY LYMPHOMAS & SARCOMA

PAPILLARY THYROID CARCINOMA

• INCIDENCE 8:100,000 • MICROPTC IN UP TO 30% OF AUTOPSIES

• ~80% OF THYROID CANCERS • 50% ARE ≤ 1 CM • FEMALES > MALES

• RISK FACTORS • RADIATION EXPOSURE • FAMILY HISTORY

Davies L. JAMA 2006 Schlumberger MJ. N Engl J Med 1998

9 5/3/2019

PAPILLARY THYROID CARCINOMA

• COMMONLY MULTICENTRIC- 20-80% OF CASES

• LYMPH NODE METASTASIS

• METS TO REGIONAL NODES UP TO 80%, EVEN IF SMALL, INTRATHYROIDAL

• PRE-OPERATIVE NODAL EVALUATION SHOULD BE UNDERTAKEN!

• U/S TO ASSESS LATERAL COMPARTMENTS

• CT IF LIMITED EXPERIENCE IN U/S

Schlumberger MJ. N Engl J Med 1998 Mazzaferri EL. Am J Med 1994 ATA Guidelines 2006

FOLLICULAR THYROID CARCINOMA

• DISTINGUISHED FROM FOLLICULAR ADENOMAS FROM INVASION OF CAPSULE AND VESSELS

• 10% OF THYROID CANCERS

• LESS FREQUENTLY MULTICENTRIC, NODAL METS

• HEMATOLOGIC METASTASES TO LUNGS, BONES

• SLIGHTLY POORER PROGNOSIS

Schlumberger MJ. N Engl J Med 1998

10 5/3/2019

TREATMENT: 3 STEP PROCESS

• THYROIDECTOMY

• PTC- ROUTINE CENTRAL COMPARTMENT DISSECTION?

• 50% INVOLVEMENT

• THYROID SUPPRESSION THERAPY –LEVOTHYROXINE 1.6MCG/KG & REFER BACK TO ENDOCRINOLOGIST TO ASSESS NEED FOR RAI AND PLAN SURVEILLANCE

• RADIOIODINE REMNANT ABLATION

• LOW RISK : NO RAI, FOLLOW WITH ULTRASOUND AND THYROGLOBULIN LEVELS.

• HIGH RISK : RECOMBINANT TSH STIMULATED REMANANT ABLATION

• NOT BE USED TO ‘CLEAN UP’ INADEQUATE SURGERY

ATA Guidelines. Thyroid 2006 Hay I. Endocr Prac 2007 Mazzaferri EJ. Endocr Prac 2007

SUMMARY

• THYROID NODULES ARE COMMON: - BIOCHEMICAL TESTING : TSH - BASED ON SIZE & CHARACTERISTICS : FNA

• FOR PTC, STRONGLY CONSIDER PRE-OP NODAL IMAGING

• CONSIDER CENTRAL COMPARTMENT DISSECTION FOR SELECT CASES • THYROID HORMONE REPLACEMENT : 1.6 MCG/KG/BODYWEIGHT

• COMMUNICATE/REFER BACK TO ASSESS NEED FOR RAI

11 5/3/2019

PRIMARY HYPERPARATHYROIDISM

• 1% OF ADULT POPULATION

• 2% OR MORE > AGE 55

• 80-85% PARATHYROID ADENOMA

• 10 % MULTI GLAND HYPERPLASIA

• 4 % DOUBLE GLAND ADENOMA

• 1% CARCINOMA

• OVEREXPRESSION OF CYCLIN D1 & DEFICIENCY OF MEN-1

• PARATHYROIDECTOMY IS THE ONLY CURATIVE TREATMENT

DIAGNOSIS

• PERSISTENT HYPERCALCEMIA OR HIGH NORMAL CALCIUM LEVEL

• INAPPROPRIATELY NORMAL OR ELEVATED PARATHYROID LEVELS

• 24 HR. URINE CALCIUM AND CREATININE

• CA/CR < 0.01 SUGGESTS FHH

• PARATHYROID IMAGING DOES NOT AID DIAGNOSIS

12 5/3/2019

IMAGING MODALITIES

• 99MTC-SESTAMIBI SCAN –SENSITIVITY : 88 % ADENOMA, 44 % HYPERPLASIA, 29 % WITH DOUBLE ADENOMA, 33 % CARCINOMA

• HIGH RESOLUTION ULTRASOUND

• SINGLE PHOTON EMISSION CT • NO SUBSTITUTE TO AN EXPERIENCE SURGEON !!!

• MINIMALLY INVASIVE PARATHYROIDECTOMY

• 4 GLAND EXPLORATION IN 20-40 % - NEGATIVE OR EQUIVOCAL SCAN

• INTRA-OPERATIVE PTH LEVELS – GREATER CERTAINTY OF CURE

INDICATIONS FOR SURGERY

• NIH +NIDDK PANEL 2002

1. AGE < 50

2. CANNOT PARTICIPATE IN MEDICAL FOLLOW-UP

3. SERUM CALCIUM > 1MG/DL ABOVE UPPER LIMIT OF NORMAL

4. URINARY CALCIUM >400 MG/24

5. + 30 % DECLINE IN RENAL FUNCTION

6. NEPHROCALCINOSIS, OSTEOPOROSIS, PSYCHONEUROLOGIC DISORDER

13 5/3/2019

ADRENAL INCIDENTALOMAS

• NOT UNCOMMON EITHER!

• 4-10% OF ABDOMINAL SCANNING

• AGE-DEPENDENT

• QUESTIONS

• IS THIS WORRISOME?

• IS THIS AFFECTING THE FUNCTION?

Bovio S. J Endocrinol Invest 2006 Terzolo M. Eur J Endocrinol 2011

“IS THIS WORRISOME?”

• NEED A GOOD RADIOLOGIST! • IMAGING OF CHOICE-TRIPHASIC CT (MRI FOR PHEO) • BENIGN PHENOTYPE: • SIZE <4CM, MARGINS • DENSITY • HOUNSFIELD UNITS <10, >50% WASHOUT • WORRISOME PHENOTYPE • MICROCALCIFICATIONS • ADRENOCORTICAL CARCINOMA • HETEROGENOUS OR CYSTIC CHANGES • NO ROLE FOR CT-GUIDED BIOPSY!

Szolar DH. Radiology 2005

14 5/3/2019

“IS THIS HYPERFUNCTIONING?”

Aldosterone

Cortisol

Androgens

Catecholamines

Bovio S. J Endocrinol Invest 2006 Terzolo M. Eur J Endocrinol 2011

PRIMARY HYPERALDOSTERONISM

• ALDOSTERONE PRIMARILY CONTROLLED BY RENIN-ANGIOTENSIN SYSTEM, NOT ACTH

• OVERPRODUCTION LEADS TO SALT RETENTION AND CLINICAL HYPERTENSION

• MAY SEE HYPOKALEMIA (9-37%) • NOT HYPERNATREMIA

Mulatero P. J Clin Endocrinol Metab 2004

15 5/3/2019

INVESTIGATIONS

• SCREEN: 8 AM ALDOSTERONE:RENIN

• >30:1 & HIGH ABSOLUTE ALDOSTERONE >15

• CONFIRMATION

• ORAL SALT LOADING: URINE NA >200 MG AND URINE ALDOSTERONE >12 IN 24 HOURS

• SALINE INFUSION: 2 LITERS OVER 4 HOURS, SERUM ALDOSTERONE <10

Endocrine Society Clinical Practice Guideline 2008 Giacchetti G. J Hypertens 2006

TREATMENT

• MEDICAL THERAPY

• SPIRONOLACTONE OR EPLERENONE

• HIGHLY EFFECTIVE

• UNILATERAL ADRENALECTOMY

• MUST BE PRECEDED BY ADRENAL VEIN SAMPLING TO CONFIRM UNILATERAL, IPSILATERAL DISEASE

• ALDOSTERONE, CORTISOL SAMPLES TAKEN AND COMPARED

Young WF. Surgery 2004

16 5/3/2019

PHEOCHROMOCYTOMA

• TUMORS OF NEUROENDOCRINE CELLS

• CATECHOLAMINE-PRODUCING

• EPINEPHRINE, NOREPINEPHRINE

• ANNUAL INCIDENCE >0.8 PER 100,000

CLINICAL FEATURES

• CLASSICAL: HEADACHES, DIAPHORESIS, PALPITATIONS

• OTHERS: PAROXYSMAL HYPERTENSION, PALLOR, TREMORS, ANXIETY ATTACKS, ETC

Stein PP. Medicine 1991

17 5/3/2019

HOWEVER:

• 10-49% PRESENT AS INCIDENTAL FINDING

• UPTO57.6% WERE ASYMPTOMATIC

• THE MOST COMMON SIGN WAS HYPERTENSION

• OFTEN SUSTAINED (NOT PAROXYSMAL)

• OFTEN WELL-CONTROLLED WITH MEDICATIONS

• SO, THE CLASSIC TRIAD, IS RARE

• CANNOT RULE OUT PHEO ON BASIS OF HISTORY

Kudva YC. The Endocrinologist 1999 Baguet JP. Eur J Endocrinol 2004 Motta-Ramirez GA. Am K Roentgenol 2005

INVESTIGATIONS: BIOCHEMISTRY

• FRACTIONATED PLASMA METANEPHRINES OR

• 24-HOUR URINE CATECHOLAMINES AND METANEPHRINES

• BEWARE OF INTERFERING MEDICATIONS AND FALSE POSITIVES

• PHEOS >2X ABOVE UPPER LIMIT

• (VMA HAS POOR SENSITIVITY AND SPECIFICITY)

Sawka AM. J Clin Endocrinol Metab 2003 Lenders JW. JAMA 2002

18 5/3/2019

INVESTIGATIONS: IMAGING

• CT

• CYSTIC/HEMORRHAGIC CHANGES

• HYPERINTENSE WITH >20 HU, VASCULAR

• MRI MIGHT BE SUPERIOR TO CT

• HYPERINTENSE ON T2 IMAGES

• MIBG OR PET IF NOT LOCALIZABLE

Baid SK. Ann Intern Med 2009

TREATMENT

• SURGERY, BUT REQUIRES MEDICAL PREPARATION FIRST

• ALPHA BLOCKADE-PHENOXYBENZAMINE 10 MG BID, INCREASING TO GOAL

• PRAZOSIN, DOXAZOSIN FOR LONGTERM • OTHERS: LABETOLOL, NICARDIPINE, • REPEAT BIOCHEMISTRY POST-OP AND ANNUALLY

Amar L. J Clin Endocrinol Metab 2005

19 5/3/2019

OTHER TESTS

• CORTISOL: 1 MG OVERNIGHT DEXAMETHASONE SUPPRESSION TEST

• ANDROGEN: DHEA

IF NONFUNCTIONING:

• IF NO WORRISOME PHENOTYPE, REPEAT IMAGING IN 6 AND 12 MONTHS.

• REPEAT BIOCHEMISTRY FOR ALDOSTERONE AND CATECHOLAMINE ANNUALLY?

Terzolo M. Eur J Endocrinol 2011

20 5/3/2019

SUMMARY

• BIOCHEMICAL TESTING IS MANDATORY FOR ALL ADRENAL INCIDENTALOMAS

• LACK OF SYMPTOMS DOES NOT NEGATE TESTING

• HYPERALDOSTERONISM IS NOT ALWAYS SURGICAL

• MEDICAL PREPARATION IS CRITICAL FOR PHEOCHROMOCYTOMA

POST-LECTURE SURVEY

• 52 YEAR OLD MAN WITH A 5 CM THYROID NODULE, FNA REVEALS PAPILLARY THYROID CARCINOMA. NEXT STEP?

A. THYROIDECTOMY

B. THYROIDECTOMY WITH CENTRAL COMPARTMENT DISSECTION

C. US OR CT NECK D. PET

21 5/3/2019

POST-LECTURE SURVEY

22 5/3/2019

QUESTIONS/DISCUSSION