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WHAT I WANT FROM MY ENDOCRINE SURGEON?

DR. VANITHA SINGARAM, MD, FACEENDOCRINOLOGIST

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 COMPARTMENTDISSECTION

C. US OR CT NECK

D. PET

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PRE-LECTURE SURVEY

35 YR. OLD FEMALE WITH HYPERCALCEMIA, PARATHYROID LABS HIGHNORMAL, RECURRENT RENAL CALCULI ( CALCIUM STONES ), 24. HR. URINE CALCIUM 250 MG, SESTAMIBI SCAN DID NOT LOCALIZE ANADENOMA ? NEXT STEP ?

a. MEDICAL SURVEILLANCE

b. REPEAT SCAN

c. SURGERY PARATHYROID EXPLORATION

d. REPEAT 24 HR. URINE CALCIUM TO EVALUATE FOR FAMILIALHYPOCALCIURIC HYPERCALCEMIA

PRE-LECTURE SURVEY

• 48 YEAR OLD WOMAN WITH 6.3 CM ENHANCINGHETEROGENOUS RIGHT ADRENAL MASS. SHE ISOTHERWISE HEALTHY WITH NO HISTORY OFHYPERTENSION OR SYSTEMIC ILLNESS. NEXT STEP?A. CT-GUIDED BIOPSY OF MASS

B. RIGHT ADRENALECTOMY

C. CHECK SERUM METANEPHRINES

D. URINARY VMAE. NO FURTHER INTERVENTION

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DISCLAIMERS AND DISCLOSURES

• NO FINANCIAL CONFLICTS OF INTEREST

• NO OFF-LABEL DISCUSSION

OBJECTIVES AND SCOPE

• PROVIDE AN APPROACH TO WORKING UPINCIDENTALLY DISCOVERED ENDOCRINE NODULES

• BRIDGE THE SURGICAL AND THE CLINICAL WORLDS

• THYROID NODULES AND DIFFERENTIATED THYROIDCANCER

• PRIMARY HYPERPARATHYROIDISM

• ADRENAL INCIDENTALOMAS INCLUDING PRIMARYHYPERALDOSTERONISM ANDPHEOCHROMOCYTOMA

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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 TOENDOCRINOLOGIST TO EVALUATE NEED FOR TREATMENT ANDDISCUSS TREATMENT OPTIONS.

• IMAGING: HIGH-SENSITIVITY ULTRASONOGRAPHY

• SONOGRAPHIC RISK FACTORS

• HYPOECHOIC NODULES

• IRREGULAR MARGINS

• INCREASED VASCULARITY

• MICROCALCIFICATIONS

Gharib H. Endocrinol Metab Clin N Am 2007

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OTHER MODALITIES :

• FDG-PET – FOCAL UPTAKE WITH US CONFIRMED NODULES > 1 CMWARRANT FNA

• FDG-PET – DIFFUSE UPTAKE WITH US AND BIOCHEMICAL EVIDENCEOF 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

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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

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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

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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

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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

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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 OFCAPSULE 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

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TREATMENT: 3 STEP PROCESS

• THYROIDECTOMY

• PTC- ROUTINE CENTRAL COMPARTMENT DISSECTION?

• 50% INVOLVEMENT

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

• RADIOIODINE REMNANT ABLATION

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

• 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 SELECTCASES

• THYROID HORMONE REPLACEMENT : 1.6 MCG/KG/BODYWEIGHT

• COMMUNICATE/REFER BACK TO ASSESS NEED FOR RAI

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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

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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 EQUIVOCALSCAN

• 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, PSYCHONEUROLOGICDISORDER

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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

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“IS THIS HYPERFUNCTIONING?”

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

Aldosterone

Cortisol

Androgens

Catecholamines

PRIMARY HYPERALDOSTERONISM

• ALDOSTERONE PRIMARILY CONTROLLED BY RENIN-ANGIOTENSINSYSTEM, NOT ACTH

• OVERPRODUCTION LEADS TO SALT RETENTION AND CLINICALHYPERTENSION

• MAY SEE HYPOKALEMIA (9-37%)

• NOT HYPERNATREMIA

Mulatero P. J Clin Endocrinol Metab 2004

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INVESTIGATIONS

• SCREEN: 8 AM ALDOSTERONE:RENIN

• >30:1 & HIGH ABSOLUTE ALDOSTERONE >15

• CONFIRMATION

• ORAL SALT LOADING: URINE NA >200 MG AND URINEALDOSTERONE >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 CONFIRMUNILATERAL, IPSILATERAL DISEASE

• ALDOSTERONE, CORTISOL SAMPLES TAKEN AND COMPARED

Young WF. Surgery 2004

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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

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HOWEVER:

• 10-49% PRESENT AS INCIDENTAL FINDING

• UP TO 57.6% 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

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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 PREPARATIONFIRST

• ALPHA BLOCKADE- PHENOXYBENZAMINE 10 MGBID, INCREASING TO GOAL

• PRAZOSIN, DOXAZOSIN FOR LONGTERM

• OTHERS: LABETOLOL, NICARDIPINE, • REPEAT BIOCHEMISTRY POST-OP AND ANNUALLY

Amar L. J Clin Endocrinol Metab 2005

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OTHER TESTS

• CORTISOL: 1 MG OVERNIGHT DEXAMETHASONESUPPRESSION TEST

• ANDROGEN: DHEA

IF NONFUNCTIONING:

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

• REPEAT BIOCHEMISTRY FOR ALDOSTERONE AND CATECHOLAMINEANNUALLY?

Terzolo M. Eur J Endocrinol 2011

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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 REVEALSPAPILLARY THYROID CARCINOMA. NEXT STEP?

A. THYROIDECTOMY

B. THYROIDECTOMY WITH CENTRAL COMPARTMENT DISSECTION

C. US OR CT NECK

D. PET

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POST-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 HYPOCALCIURICHYPERCALCEMIA

POST-LECTURE SURVEY

• 48 YEAR OLD WOMAN WITH 6.3 CM ENHANCINGHETEROGENOUS RIGHT ADRENAL MASS. SHE ISOTHERWISE HEALTHY WITH NO HISTORY OFHYPERTENSION OR SYSTEMIC ILLNESS. NEXT STEP?A. CT-GUIDED BIOPSY OF MASS

B. RIGHT ADRENALECTOMY

C. CHECK SERUM METANEPHRINES

D. URINARY VMAE. NO FURTHER INTERVENTION

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QUESTIONS/DISCUSSION