IMAGING OF PARATHYROID DISEASE : A GUIDE FOR THE REFERRING PHYSICIAN Maroun Karam MD FACP Professor of Radiology and Nuclear Medicine

Nuclear Imaging of Hyperparathyroidism Parathyroid imaging - The clinical problem - Facts about Tc Sestamibi - When to order scintigraphy ? - Protocol for dual-phase imaging - Radiopharmaceutical - Imaging technique - Dual tracer imaging - Illustrative cases - How does it compare to ultrasound? - How to improve results - Practical recommendations

PREOPERATIVE IMAGING OF PARATHYROID LESIONS . Was rarely performed because 1111. Intraoperative localization by experienced surgeon in 90-95% (Bilateral neck exploration) 2. Recent increase in preoperative imaging because - Not all surgeries are performed by experienced surgeons. - There is increased interest in less invasive surgery - Unilateral neck exploration (UNE) - Minimally invasive parathyroidectomy (MIP) 3. Bilateral neck exploration is still required if there is hyperplasia or suspected multigland disease -Recent survey: less invasive surgery by >50% of surgeons worldwide. 3. If there is, bilateral neck exploration is still required.

PERSISTENT HYPERPARATHYROIDISM Continuation of calcium abnormalities immediately after surgery Was the ONLY indication for scintigraphy before MIP Occurs in 7-10% of all patients who undergo surgery. Causes: - Failure to localize the adenoma (ectopic): frequent - Inadequate resection of multigland disease. - Surgical inexperience. - Metastatic parathyroid carcinoma ( very rare) More frequent in familial syndromes (20-50%)

Some Facts About Tc Sestamibi Not specific for parathyroid tissue. High uptake in cells with increased metabolism and high number of mitochondria (parathyroid and thyroid adenomas), uptake 2.5 times background Limited performance in parathyroid hyperplasia ( 50-60% detection rate ) because hyperplasia is a different disease with fewer active mitochondria ( uptake is 1.2 times background )

TECHNIQUE OF DUAL PHASE IMAGING Easiest to perform and most commonly used Injection of 25 mci of Tc Sestamibi 3. Immediate visualisation of thyroid tissue and abnormal parathyroid tissue Progressive washout of tracer from the thyroid and persistent uptake in abnormal parathyroid glands False positive: thyroid adenoma can be eliminated by the performance of a neck ultrasound or exam prior to nuclear imaging in pts with hyperpara False negative : small or not metabolically active parathyroid adenomas(10%) EQUIVOCAL : DELAYED OR INCOMPLETE WASHOUT FROM THE THYROID MAY NOT ALLOW DETECTION OF ADENOMA .

EASY TEXTBOOK CASE UNFORTUNATELY NOT ALL CASES ARE LIKE THIS ONE

FALSE POSITIVE: Thyroid adenoma FALSE POSITIVE: Thyroid adenoma . It is important to perform a rapid neck EXAM Before sending pt to scintigraphy. If there is a thyroid nodule, info should be put on the request , indicating location of nodule

2 hr planar 10 min planar DELAYED IMAGE EARLY IMAGE VERY SMALL ADENOMA ALMOST A FALSE NEGATIVE IT IS BEST TO HAVE PTH TWICE NORMAL BEFORE REQUESTING IMAGING Most common cause of false negative : small adenomas that are only seen on the early planar images

Identification of a persistent focus requires that The tracer washes out from the thyroid The report will say : On delayed imaging No persistent focus of activity was seen Did you know that the pattern above is one common reason for the reported result ?

WHY DELAYED OR INCOMPLETE THYROID WASHOUT? Preparation consists of a mixture of Tc MIBI and free Tc Residence of MIBI in the thyroid gland is 30-60 min Residence of free Tc is 120- 360 min If percentage of Tc is > 5% incomplete washout can happen preventing detection of parathyroid adenoma Current commercial preps have 10% of free TC . This is adequate for cardiac imaging but is NOT for parathyroid NEED TO INCREASE PURITY OF MIBI COMMERCIAL PREPARATIONS FOR PARATHYROID IMAGING

Purity =90% Delayed image : 2 hrs Early image : 20 min No adenoma identified Early image : 20 min Purity =90%

SAME PT AFTER INCREASING PURITY TO 95%

This pt had a neg study with 90% purity prep at another hospital Repeat Study at AMC with 97% purity Was positive for right lower adenoma

Radiochemical Purity of Current Technetium 99m Sestamibi Commercial Preparations May Not Be Adequate for Dual-phase Parathyroid Imaging. M. Karam, R Dansereau, P Feustel , M Mecca, L Robinson Albany Medical College Department of Radiology Division of Nuclear Medicine “Nuclear medicine Communications”2005 p 1093

HOW IS THE SITUATION DIFFERENT IN LEBANON FROM THE US In the US radiotracers are delivered as individual doses by central pharmacies When we have to do a parathyroid scan we have to indicate it on request The central pharmacy will change the method of preparation to obtain higher purity In Lebanon we don’t have central commercial pharmacies . The nuc med tech prepares the tracer I have learned from R Dansereau PhD how to improve purity and I have taught the tech here

PARATHYROID SCINTIGRAPHY RESULTS Single Gland disease Sens : 90%. FN most often when small or mildly metabolically active adenoma ( SPECT) Multigland disease Sens : overall 60% and related to number of glands 2 glands: 79% 3 glands: 64% 4 glands: 40%

PRIMARY HYPERPARATHYROIDISM -Mostly women and elderly : 1-2/1000 of routine blood screening. Explains significant rise in incidence SPORADIC DISEASE 1. Adenomas or single gland disease: 80-85%* 5 % of adenomas are bilateral 2. Hyperplasia or multigland disease: 15-20%* 3. 15-20% of adenomas are ectopically located (15% in the neck, 2-5% in the chest)MOST ECTOPIC ADENOMAS ARE IN THE NECK AND OUT OF THE US FIELD 4. Only 60% of inferior adenomas are adjacent to inferior pole . 40% of inferior adenomas are ectopic at base of the neck 5. Supernumerous (> 4) glands in 2-5% of the population. FAMILIAL SYNDROMES Associated with multigland disease as a rule. 1. MEN-1 (85-90%) 2. MEN-2 (5-10%) 3. Other. *Histopathologic criteria to distinguish adenoma from hyperplasia are not defined. Adenoma= single gland disease. Hyperplasia=multigland disease.

Non-Primary Hyperparathyroidisnm Secondary ( CRF) : Always hyperplasia Tertiary: -Uncommon. -Occurs after prolonged secondary. -Can be adenoma on hyperplasia

PRACTICAL CONCLUSIONS FOR THE REFERRING PHYSICIAN. 11 Rule out secondary hyperparathyroidism. 2. Rule out thyroid focal pathology. - Exam - Ultrasound - If positive →Info provided on prescription 3. Family history (-) MEN (-) - high likelihood of adenoma ( 85%) - Imaging very helpful -If (+) Consider unilateral neck exploration . 4. Family history (+) or MEN (+) - Bilateral neck exploration is required. -Imaging not necessary unless persistent hyperparathyroidism. 5. Suspect tertiary hyperpara  imaging can be helpful

How to Improve Imaging Results Neck examination before every scan and write down findings on requisition ( thyroid nodules > 1 cm ). If ultrasound performed first , please write results if thyroid nodule on scinti request . It is a must to use pinhole collimator for planar neck images ( improves detection from 60 to 75%) SPECT - improves sensitivity from 75 to 85% - Provides exact location of adenoma allowing smaller incision and shorter operative time ( local anesthesia ? ) SPECT/CT has been shown to be superior to SPECT if the adenoma is extra cervical * Lavely et al J. Nuc Med 48 2007,1084-1089

Bilateral adenoma

WHERE IS THE ADENOMA ? LEFT OR RIGHT ? NEED SPECT IMAGING TO DETERMINE SIDE

RIGHT ANTERIOR PARATHYROID ADENOMA

THE ADENOMA IS IMMEDIATELY BELOW LOWER POLE OF LEFT LOBE

Cervical But ectopic Parathyroid Adenoma , very Difficult to detect By ultrasound

THIS ADENOMA IS INTRATHROIDAL

Superior Mediastinal Adenoma

Only situation where SPECT/CT Found to be superior to SPECT* Mediastinal adenoma Only situation where SPECT/CT Found to be superior to SPECT* * Gayed et al J. Nuc Med, 46, 2005 248-252

SPECT/CT IN PARATHYROID IMAGING WILL BECOME AVAILABLE AT ST GEORGE HOSPITAL IN JUNE 2017

SPECT/CT IN PARATHYROID IMAGING

SPECT/CT IN PARATHYROID IMAGING

DUAL TRACER IMAGING IMPROVES SENSITIVITY FROM 83 TO 87% ONLY substraction Reserved For negative Dual tracer or Imaging of persistent Disease Or if there is a thyroid nodule DUAL TRACER IMAGING IMPROVES SENSITIVITY FROM 83 TO 87% ONLY

DUAL TRACER IMAGING : PROS AND CONS Advantages ; Allows to exclude thyroid pathology as cause of false positive Improves reader confidence Disadvantages 1 . Is time consuming and expensive ( 2 tracers + 2 scintigraphies ) 2 . Requires complete neck immobilization and patient cooperation 3 Neck motion will introduce false positive or false negative findings DUAL TRACER IMAGING IMPROVES SENSITIVITY FROM 83 TO 87% ONLY IF HIGH PURITY AND SPECT ARE USED

Comparative Performance of Parathyroid scan and US Ultrasound: Variable sensitivity depending on series ( 53%-78%) Specificity HIGH at 96% Meta-analysis of US in 1523 cases : Sens 69% Dual Phase imaging of primary sporadic hyperparathyroidism. Sens : 78- 85%, specificity 95% = narrow range of sensitivity if experienced nuclear medicine physician Very wide range of sensitivity for US suggests that it is operator dependent .Opposite true for NM NM results are better overall than best US operator but they also require excellent technique and expert reader ( AUB experience: NM 91%, US 73% on same pts , World J Surg, 2006) Sestamibi nuclear scan is the test of choice for persistent HP because of high incidence of ectopic adenoma. Same reason applies for negative ultrasounds

US vs NM for HP ( 2) All studies show superior performance of NM vs US in ectopic glands (80 vs 25%) Ectopic gland is the most common cause of persistent hyperparathyroidism Almost all studies show both methods are poor for hyperplasia and multigland disease no need for imaging US more convenient to the pt ( brief exam ) if operator is skilled All studies show that accuracy decreases in the presence of thyroid disease Most studies show , that when one is negative, the other is often positive ( combined sens : 95%)

PRACTICAL RECOMMENDATIONS Secondary Hyperparathyroidism (HP) or familial syndromes : Bilateral neck exploration Persistent hyperparathyroidism : Tc Sestamibi scan FIRST because of high likelihood of ectopic disease. If scan negative , can perform intraoperative localization after tracer administration 3. Sporadic primary HP : Start with the imaging method provided by an available expert 4. If starting with NM scan , thorough neck examination, looking for thyroid nodule 5. If thyroid nodule > 1 cm present, make note on requisition of nodule location 6. If first imaging method is negative , proceed to the second. 7. Even in the best hands , sensitivity of ultrasound is lower than NM scan ( ectopic) 8. If both imaging methods are negative, or equivocal bilateral neck exploration

HOW TO IMPROVE SURGICAL RESULTS Intraoperative measurement of PTH before and after resection of lesion* ↓50% or more in value is required (PTH T1/2=2-3min) ↑Sens for detection of multigland disease from 23 to 88% Sens: 98%, Spec: 94% Accuracy: 97% in predicting surgical success. More recent results reported not to be as good *Bergson et al Arch Otol Head Neck Surg 130(1) 2004 87-91

CONCLUSIONS (1) Since MIS , preoperative parathyroid imaging has become necessary. It is best to have a PTH twice normal before imaging unless immediate surgery is necessary because imaging yield increase with high PTH It is important first to establish primary etiology ( or tertiary) If familial syndromes or secondary , NO IMAGING BECAUSE BILATERAL US is very operator dependent but gives OK results in good hands NM is the imaging of choice for persistent hyperpara because most common cause is ectopic adenoma

CONCLUSIONS (2) HIGH purity of preparation is essential . If provided dual tracer imaging is ONLY marginally better than dual phase imaging SPECT has improved results and allows exact localization of adenoma for surgeon ( smaller incision , shorter operative time) SPECT/CT helpful for extra-cervical adenomas Intraoperative PTH has improved surgical results An experienced surgeon remains important