1. Management of Medullary Thyroid Carcinoma
An update for Surgeons
Dr Tsang Man For
Tseung Kwan O Hospital

2. Introduction
Medullary thyroid cancer is first described as a specific entity in 1959
Surgical management has been standardized over past decade
Breakthrough in understanding of MTC since discovery of somatic RET mutation association and understanding of MEN associations.
Controversies remain in
Diagnostic pathways
Adjuvant
Medullary thyroid cancer is first described as a specific entity in 1959
Surgical management has been standardized over past decade
However controversies remain in diagnosis and adjuvant treatment
The presentation today is to give an updated review on the management

3. Content Controversies in Optimal imaging for MTC
Routine Calcitonin Measurement
FNA Calcitonin assay
Role of Pentagastrin
Optimal imaging for MTC
Update on adjuvant for MTC
The Future
I will first focus on several controversies regarding calcitonin and pentagastrin
Then I will talk about optimal imaging
I will review on adjuvant treatment

4. Routine Calcitonin Measurement
Controversies in
Routine Calcitonin Measurement
Medullary thyroid carcinoma has a poor prognosis
Calcitonin is very useful in diagnosis and in subsequent follow up
Whether it is indicated to have routline calcitonin for all thyroid nodules for early detection
It is controversial

5. Controversies in Routine Calcitonin Measurement
2006
European Thyroid association ✔
American Thyroid Association ✖
In 2006 the european thyroid association published a conensus statement on workup of thyroid nodules
It recommends routeline measurement of serum calcitonion
At that time, The ATA declined ? RREFUSE to recommend for or against this approach

6. More sensitive than FNAC
What is the rationale behind?
European Consensus believe routine serum calcitonin measurement can detect unsuspected medullary thyroid carcinoma with a frequency of 1 in 200 thyroid nodules, with a better sensitivity than FNAC
It can improve the clinical outcome.
Several european prosective studies of thyroid nodules have demonstrated that routine measurement of serum Calcitonin allows the detection of unsuspected medullary thyroid carcinoma with a frequency of 1 in 200–300 thyroid nodules, with better sensitivity than FNAC, and that routine Ct screening improves the outcome. Therefore serum Ct measurement is recommended in the initial diagnostic evaluation of thyroid nodules
Routine calcitonin can detect unsuspected MTC with a frequency 1 in 200 thyroid nodules
More sensitive than FNAC
European Journal of Endocrinology (2006)

7. Regarding the issue : Sensitivity ? Specificity? Assay performance?
However ATA is more conservative at that time
Regarding the sensitivity, specificity, assay performance, and cost effectiveness.
Also, most studies at that time rely on pentagastrin stimulation testing to increase specificity and this drug is not available in the United States
Therefore the panel cannot recommend either for or against the routine measurement of calcitonin
Regarding the issue :
Sensitivity ?
Specificity?
Assay performance?
Cost effectiveness?
The American Thyroid Association Guidelines Taskforce 2006

8. Controversies in Routine Calcitonin Measurement
What about now? ?

9. Controversies in Routine Calcitonin Measurement
Latest ATA 2015 suggests that if screening is done, a calcitonin > 100pg/mL should be considered suspicious for MTC and requires intervention
Most recent ETA guidelines advocate calcitonin screening only in the presence of clinical risk factors
How about the latest situation?
The ATA seems become more aggressive
It recommends that if serum calcitonin is taken and the level is greater than 100 pg/mL, medullary cancer is likely present.
Then further workup should be initiated
For the ETA, it seems to have taken a step back from its 2006 position, it now suggest calcitonin screening only in the presence of clinical risk factors
- When MTC is highly suspcious
- Family history of MTC

10. Conclusion
Routine Calcitonin for all patients presented with thyroid nodules ?
Controversial
Tends to support routine calcitonin screening in patients with risk factors
Effective screening test should meet certain criteria
High sensitivity and high specificity
Allows early detection of disease and translates into lower morbidity and mortality
Needs to be cost effective
Routeline CT screening for MTC doesnt meet all these criterias
As a conclusion Whether routine calcitonin measurement is indicated for all patients presented with thyroid nodules, it is still controversial.
It tends to support routine calcitonin screening in patients with risk factors

11. Calcitonin Assay for FNA Specimen
Controversies in
Calcitonin Assay for FNA Specimen
Besides calcitonin, FNAC is another important diagnotic method for MTC

12. Calcitonin assay for FNA specimen
Boi et al demonstrated that
cytology alone yields sensitivity of 62% and specificity 80%
calcitonin assay of the FNA washout fluid can raise sensitivity and specificity of FNA to 100% for MTC
However from Journal clinical endocrinology in 2007.
the the sensitivity and specificity of cytology alone is just 62 and 80 % respectively
calcitonin assay of the FNA washout can increase the s + s to 100%
Boi F, et al. calcitonin measurement in wash-out fluid from fine needle aspiration of neck masses in
patients with primary and metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab 2007;
92:2115-8

13. Calcitonin assay for FNA specimen
USG-guided Calcitonin FNA was the best tool to identify primary MTC and Local-regional / node metastases in MTC operated subjects.
This may have important implications in the management of MTC

14. “Washout Calcitonin can play a role in diagnosing primary and metastatic MTC.”
“The procedure is easy, cost effective, and should be used in patients undergoing FNA with elevated Serum Calcitonin.”
Anothert sytudy concerning Calcitonin Fine needle aspiration wash out for MTC
It is conductred in 2012 in Italy
It shows that washout calcitonin is easy, cost effective and should be used in patient undergoing FNA with elevated Serum Calcitonin. It can play a role in diagnosing primary and metastatic MTC.
Calcitonin measurement in washout of the needle after aspiration (WO-Ct) has been rarely evaluated. Here we analyzed the role of WO-Ct in a series of subjects who underwent fine needle aspiration (FNA) with suspicious medullary thyroid cancer (MTC). Twenty-one patients referred following elevated serum calcitonin (S-Ct) or suspicious MTC by cytology. All patients underwent re-evaluation of S-Ct, FNA, and measurement of WO-Ct. S-Ct and WO-Ct were assessed by chemiluminescence assay (IMMULITE 2000, Diagnostic Products Corporation, USA). S-Ct showed elevated value in six subjects (mean ± pg/ml), of which three cases were cytologically classified as Class 5. WO-Ct obtained in this group (304.0 ± pg/ml) was no different from S-Ct. After surgery MTC was confirmed in all patients. In the other 15 patients MTC was excluded by cytology or histology. Two subjects had moderately skewed S-Ct with nonmedullary histology. In the remaining 13 patients S-Ct resulted normal (6.2 ± 5.6 pg/ml) and WO-Ct low (2.9 ± 2.2 pg/ml). Significant (two-tailed P < 0.05, r(2) = 0.27, 95% confidence interval = ) correlation was found between S-Ct and WO-Ct in nonmedullary patients but not in MTC patients. This study showed that WO-Ct can play a role in diagnosing primary and metastatic MTC. The procedure is easy, cost effective, and should be used in patients undergoing FNA with elevated S-Ct. Further studies and guidelines for the method are needed to use this technique in clinical routine. Until this any institute should use itself cut-off.

15. Conclusion
Calcitonin assay sensitivity and specificity of FNA specimen
Whether it is a routine procedure for all cases of suspected MTC, further studies and guidelines are needed

16. Suspected MTC + normal Calcitonin?

17. Role of Pentagastrin Controversies in After talking about calcitonin
What about if a patient is susoicious to havew MTYC but the calcinin normalir just. Alittlt bit elevated

18. Role of Pentagastrin Synthetic polypeptide
Stimulate calcitonin release
Useful in cases of suspected MTC that are not associated with elevated calcitonin
Calcitonin is a tumor marker for MTC.
But not all MTC is associated with elevated calcitonin
Pentagastrin has a role in diagnosis of MTC
Pentagastrin is a synthetic polypeptide
It stimulates the secretion of gastric acid, pepsin, and intrinsic factor
Pentagastrin stimulation test
Stimulate calcitonin release parafollicular cell C-cells
Useful in cases of suspected MTC that are not associated with elevated calcitonin
Pentagastrin is a synthetic polypeptide that has effects like gastrin when given parenterally.[2] It stimulates the secretion of gastric acid, pepsin, and intrinsic factor, and has been used as a diagnostic aid as the pentagastrin-stimulated calcitonin test.
Pentagastrin binds to the cholecystokinin-B receptor, which is expressed widely in the brain. Activation of these receptors activates the phospholipase C second messenger system. When given intravenously it may cause panic attacks.[3]
MTC is commonly associated with an elevated calcitonin level, but an elevated level may not always be obvious. The pentagastrin-stimulated calcitonin test is useful in cases of suspected MTC that are not associated with elevated calcitonin. In these patients, injecting pentagastrin will cause calcitonin levels to rise significantly above the normal or basal range.[1]
Pentagastrin's IUPAC chemical name is "N-((1,1-dimethylethoxy)carbonyl)-beta-alanyl-L-tryptophyl-L-methionyl-L-alpha-aspartyl-L-phenylalaninamide".

19. Role of Pentagastrin
Allows for the appropriate selection of patient for surgery
A study performed by Daniels in 2010 to evaluate on pentagastrin stimulation test
It can stimulates calcitonin secretion from tumors and allows for the appropriate selection of patient for surgery
Pentagastrin is not available in US and Canada
Daniels GH. Screening for medullary thyroid carcinoma with serum calcitonin measurements in patients with thyroid nodules in United States and Canada Thyroid Nov;21(11): doi: /thy Epub 2011 Sep 21.

20. Because pentagasgtrin is not wildly avilable in different countries
It leads to the introduction of high dose calcium stimulation test
The study performed in Italy in 2012
The data demonstrates High dose calcium test is a potent and well tolerated procedure and it is much cheaper than Pg stimulation test
It suggest that it can replace Pg stimulation test
High-dose Ca test is a reliable and potent test for the diagnosis of MTC.
It is also cheaper

21. Conclusion
Pentagastrin stimulation test maybe useful in case of modest serum calcitonin elevation
?Calcium stimulation test can replace Pentagastrin stimulation test
Whetheer ?Calcium stimulation test can replace Pentagastrin stimulation test
Further study is needed

22. Optimal Imaging for MTC
When MTC is confirmed

23. Optimal imaging for MTC
ATA guidelines 2015
USG
CT / MRI indicated when diagnosis is uncertain, local LN are involved, or when preoperative calcitonin is greater than 500pg/mL
PET CT scan is not recommended to detect distant metastasis
After MTC is being confirmed
We should provide approprioate imaging
USG neck to look for cervical LN
If preop calcitonin > 400, or when diagnosis is uncertain, CT/MRT is indicated
SRS is suggested to evaluate for distant metastasis
In the latest ATA guideline in 2015
There is not much difference regarding the optimal imaging for MTC.
PET Ct scan is not recommended to detect the presence of distant metastases.
Ultrasound examination of the neck should be performed in all patients with MTC. Contrast-enhanced CT of the neck and chest, three-phase contrast-enhanced multi-detector liver CT, or contrast-enhanced MRI of the liver, and axial MRI and bone scintigraphy are recommended in patients with extensive neck disease and signs or symptoms of regional or distant metastases, and in all patients with a serum Ctn level greater than 500 pg/mL. Grade C Recommendatio
PET CT are less sensitive in detecting metastases, compared to other imaging procedures
The American Thyroid Association Guidelines 2009

24. Because most medullary thyroid cancers express somatostatin receptors
Whether somatostatin receptor scintigraphy (SRS) is useful in detecting metastases in children and aldolescent with MTC.
It is the study conducted in 2012.
It shows that SRS appears less sensitive than conventional imaging
It cannot detect the full extend of the metastatic disease
at detecting the full extent of metastatic disease in children and adolescents with hereditary MTC.”
It is not able to identified sites of tumor competely and it fails to visualize small sites of tumor or liver and lung metastases
Its role is limited in evaluation of metastatic disease in pediatric MTC patients
Therefore SRS does not appear useful for initial evaluation.
It is reserved for occult recurrent disease that cannot be detected by conventional cross sectional imaging.
SRS appears less sensitive than conventional imaging at detecting the full extent of metastatic disease in children and adolescents with hereditary MTC.

25. Optimal imaging for MTC
SRS does not appear useful for initial evaluation.
Its use should be reserved for occult recurrent disease that cannot be detected by conventional cross sectional imaging.
Therefore SRS does not appear useful for initial evaluation.
It is reserved for occult recurrent disease that cannot be detected by conventional cross sectional imaging.

26. Conclusion USG neck ✔ CT / MRI ✔ PET CT scan ✖ SRS ? USG CT MRT
PET CT NO
SRS – reserved for occult recurrent disease

27. Update on adjuvant Treatment for MTC
External beam RT
TACE
Palliative resection
Tyrosin kinase inhibitor
Finally I will talk on the adjuvant therapy
Surgery is the mainstay of treatment in MTC But adjuvant therapy plays a part for local advanced disease and metastatic disease
Regarding treatment
Surgery is the mainstay of treatment for medullary thyroid carcinoma
But adjuvant plays a part in case of local advanced or metastastic diseases

28. External beam RT
It has been shown to increase 10 year rates of control from 52 % to 86 % in a review of 73 patients.
External beam RT is when initial surgery cannot be curative.
A study conducted in 1996 to evaluate the role of external beam radiation therapy for MTC
It shows that in high risk patients - microscopic residual disease, extrathyroid extension vasion, or lymph node involvement, the 10 year control rate was 86% at with postoperative external beam radiation and its 52% for those without external beam RT
To optimize local/regional tumor control, we therefore continue to advise external beam radiation in patients at high risk of local/regional relapse.
Brierley J1, Tsang R, Simpson WJ, Gospodarowicz M, Sutcliffe S, Panzarella T. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid Aug;6(4):

29. TACE
A study of 12 patients that used doxorubicin followed by foam embolization demonstrated partial radiographic tumor response with a median of 17 months in 42 parent and stabilization for a median of 24 months in another 42 percent of those enrolled
The use of Systemic chemotherapy is limited for MTC
In case of metastatic MTC with liver metastasis, TACE can be an treatment option
It is a study conducted in 2006 to evaluate the effect of liver transarterial chemoembolization (TACE) in MTC patients with liver metastases.
It shows partial tumor response for liver metastasis.
TACE should be considered for treating MTC patients with progressive and predominant liver metastasis
TACE can be considered in patients with MTC with progressive and predominant liver metastasis
Fromigué J1, De Baere T, Baudin E, Dromain C, Leboulleux S, Schlumberger M. Chemoembolization for liver metastases from medullary thyroid carcinoma.
J Clin Endocrinol Metab Jul;91(7): Epub 2006 Apr 11.

30. Surgical resection
Palliative re-operative resection can relief of symptoms with minimal operative mortality and morbidity
Many patient with metastatic disease develop symptoms secondary to tumor persistence or progression.
palliative reoperative resection of symptomatic lesions can provide symptom relief with minimal operative mortality and morbidity.
Therefore, in selected case of metastatic MTC lesions, palliative reoperative resection should be considered
Chen H el al. Effective long-term palliation of symptomatic, incurable metastatic medullary thyroid cancer by operative resection. Ann Surg Jun;227(6):

31. Tyrosin kinase inhibitor
Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC.
Wells et al. J Clin Oncol Jan 10;30(2): Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.
Prolong Free survival
Statistically significant advantages for vandetanib were seen for prolong free survival, objective response rate, disease control rate, and biochemical response
Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC.
Tyrosin kinase inhitbitor is one of adjuvant treatment for MTC
Vandetanib, a once-daily oral inhibitor of RET tyrosin kinase
PATIENTS AND METHODS:
Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments.
RESULTS:
Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%).
CONCLUSION:
Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT ).

32. Conclusion External beam RT ✔ TACE ✔ Palliative resection ✔
Tyrosin kinase inhibitor ✔

33. For the future

34. Tumor Vaccines Anti CEA antibody
Understanding the cellular pathways in MTC is key to develop new pharmacologic targets for treatment.
Pathways downstream from RET tyrosine kinase have been targeted for investigation of future systemic therapies for MTC
It is likely that combination of agents that attack RET tyrosine kinase and multiple downstream targets will improve effectiveness

35. Key points Routine calcitonin measurement ?
Calcitonin assay FNA washout ?
Pentagastrin stimulation test ?
Calcium stimulation test ?
PET CT X / SRS ?
External beam RT / TACE / Palliative resection / Tyrosine kinase inhibitor ✔
Tumor vaccine / Anti CEA antibody
To conclude my presentation
Whether Routine calcitonin measurement is indicatded for all thyroid nodules, it is controversial. But there is a trend to have calcitonin screening on patients with risk factors
For the calcitionin assay FNA wash out, pentagastrin and Ca + test, more study and standardied protocols shoule be made before we can apply to our clinical practicde
Routine Calcitonin measurement – No definite answer, current trend is selective calcitonin measurement with the presence of clinical risk factors
PET CT X metastasis
SRS is reserved for recurrent occult disease
Calcitonin / pentagastrin / Ca + test in HK?
Controversial ? Cost effective ? Availbility ? Expensive ? Laboratory may not support
Reserved for borderline cases?
Role of Ca + test not yet well defined
-> can be reserved for borderline case
How to do the stimulation test
Prevalance? Need more evidence?
SRS – limitation + indications -> Controversial

36. How can u perform Calcitonin assay
How can u perform Calcitonin assay? We perform FNA for a thyroid nodule, the needle is washed with saline solution and wash out is submittedf for calcitonin measruement
FNA on thyroid nodules how to do -> Before doing the procedure, check the indicaitons, make sure patients understand the indications and risks of procedure. Localise and immoboloise the lesion with one hand, clean with skin with alcohol swab, advance the needle into the lesions at 30deg to skin, the needle is moving forth and back within the lesion with aspiration. Then withdraw the needle and prepare the smear.
Cut off points? - Different laboratories have different cut off points in the assay.
different laboratories
Screening calcitonon?
The prevalence of MTC is low, around 0.5% of the population with thyroid nodules.
-> Cost effectiveness
Risk of false-positive results.
Presence of secondary C-cell hyperplasia
omeprazole, β-blockers,
How to perform Ca + test
Inject IV calcium gluconate + Serial measurement ionfusion
NO standardized protocol -> Different protocols, no data on standardized cut offs.
Ca is known to increase cardiac contractility and it could lead to hypertensive peaks. 
How prevalence it is in European - ?????
Whether Pentagastrin is available in US now? or in HK? –NoT available
When to use pentagastrin? In case of highly suspicious of MTC with normal calcition.
C cell hyperplasia? – two types – neoplastic – premagliant – asso MEN syndrome / reactive type – asso hypercalcemia
When will u use Ca+ test – Becoz it is a potent test and it is cheaper than pentagastrin and pentagastrin is not widely available. However A standardized protocol with standardized cut off is need for this test to be used in clinical setting
Which one u choose ? Ca + or pentagastrin +
There is no standardize protocol for Ca + test
Pentagastrin test is not avilablde in many different countries
There is no definite answer
U mention PET Scan not distant metastasis , why?
Can RAI for MTC – NO why?
Can TSH Suppression therapy – No why?
How will this presentation make u change in ur clinical practice
Because MTC is a rare disease
Whenm patient present to me with thyroid nodule, I will not routine take calcitonin for all thyroid nodules unless the patient has family history of MTC or FNAC showed suspicious of MTC.
For the Ca + test / pentagastrin + test, more study is need.
Will u do the Calcitonin assay for all patients? No – its not widely available. And a definite cut off point should be standardized before we can use in clinical practice.