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Prophylactic Thyroidectomy in Multiple
Endocrine Neoplasia 2 (MEN2)
patients with the C634Y mutation
PRESENTED BY: Dr. Aryan
A LONG-TERM FOLLOW-UP IN A LARGE SINGLE-CENTER COHORT
2
Introduction
Germinal mutation in RET proto-oncogene
Preneoplastic stage of C cell hyperplasia, later progresses to
Medullary Thyroid Carcinoma (MTC)
ATA recommends CND at calcitonin levels >40pg/mL and based on
basal calcitonin levels
C634Y mutation (less common) present a more indolent clinical
course.
C634R:more aggressive course.
3
Objective of the Study
to analyze the long-term results of a large cohort of
MEN2 patients with the C634Y mutation who had
undergone prophylactic thyroidectomy in a tertiary
referral hospital, and to analyze the results in terms
of age and Ct levels.
4
Study Population
110 MEN2 patients (carriers of the C634Y mutation) who
had undergone a prophylactic thyroidectomy
Treated between the years 1983 and 2016 at the Virgen de
la Arrixaca University Hospital (Murcia, Spain)
5
Inclusion Criteria
1. asymptomatic at the time of diagnosis, absence of thyroid
disease according to clinical and radiological criteria
2. normal result in the neck examination and no signs of thyroid
nodules or lymphadenopathy
3. with a neck ultrasound showing a normal thyroid gland or with
nodules <5mm and the absence of suspicious nodes
6
Exclusion Criteria
1. Patients who presented with clinical and/or radiological
disease preoperatively
2. Patients with a follow up time of less than a year.
7
Plans for Follow up
Postsurgical complications (hypoparathyroidism and/or permanent recurrent
lesion) determined.
Periodic examinations of Ct levels were taken after surgery
Follow-up examinations carried out at 1 month after surgery and every 6
months thereafter
Later, changed to an annual follow-up
Disease considered to be cured when the patient had Ct levels within a
normal range in most recent consultation.
8
Statistical tools
SPSS 21.0
Chi Square Test and Fisher’s Exact Test
Test for Normality:
Kolmogorov-Smirnov Test
If rejected, Mann-Whitney’s U Test was used
Statistically significant variables (p < 0.05) in the bivariate
analysis taken to calculate the partial correlations
9
Results
From the year 1983 to 2015, total of 50 patients were
recorded with criteria for prophylactic thyroidectomy
Patient's mean age was 12 ± 9 years, with a range of
4-42 years; half of them being males (n=25)
26% of the patients were treated for
pheochromocytoma and one patient was treated for
hyperparathyroidism
10
Development of MTC according to
age, gender and Ct levels
CCH (n=22) MTC (n=28) p-value
Age at the time of
the thyroidectomy
7 ± 3 years 15 ± 10 years <0.001
Normal Ct levels
(n=36)
19 (53%) 17 (47%) 0.045
Above Normal
Levels (n=14)
3 (21%) 11 (79%)
11
Partial correlation analysis
Controlled By Correlation p-value
Ct levels Age-MTC 0.407 0.004
Age Ct levels-MTC 0.027 0.856
12
Logistic regression analysis
Variables Regression
Coefficient
Standard Error Odds Ratio p-value
Age 0.328 0.109 1.388 (1.049-
1.525)
0.003
Ct levels -0.187 1.026 0.829 (0.928-
19.589)
0.855
Constant -2.821 0.969 0.060 0.004
13
Follow up
Mean follow-up time of the patients was 16 ± 6 years,
with a range of 1-24 years.
During the follow-up no case of recurrence was found,
and all patients have been cured with a survival rate of
100%.
14
Discussion
Once MTC has developed, tumor sizes of >1 cm affect the
disease-free rate and can lead to a higher recurrence rate with
nodal metastasis
Recommendations that prophylactic thyroidectomy be
carried out in these patients before the age of 5
High risk: C634F/G/R/S/W/Y and A883F
15
Age is a factor related to progression from CCH to MTC and
to the presence of metastasis and disease persistence or
recurrence
Recommendations for adults?
Criterion for prophylactic thyroidectomy that the ATA puts forward
seems questionable
Usually being recommended according to Ct levels
16
Literature review
Elisei et al. prefered to carry out thyroidectomy when levels of bCt
increase, regardless of age
Machens et al. reported that when bCt rises, there is the possibility of
the patient having MTC with nodal metastasis
Dralle et al. considered the recommendation of CND in cases >10
years
More recent studies have revealed the importance of Ct levels in the
evolution of the disease, regardless of the mutation and age
17
Critical analysis
Did the study address a clearly focused issue?
Population: Multiple Endocrine Neoplasia (MEN 2) patients
Intervention: prophylactic thyroidectomy
Outcome: Follow Up for development of CCH, MTC and Ct levels
Was the cohort recruited in an acceptable way?
The data was from single center but included diverse
population characteristics
Was the exposure accurately measured to minimize bias?
Prophylactic thyroidectomy was performed in the subset of the
sample population
Have the authors identified all important confounding
factors? Have they taken account of the confounding
factors in the design and/or analysis?
Statistical analysis partial correlation for controlling the
confounding variable
Do you believe the results?
The results are believable
Can the results be applied to the local population?
The recommendations can be used in our population too
What are the implications of this study for practice?
Although gene mutation studies can be difficult to conduct for
every case, prophylactic thyroidectomy for established case,
ideally before the age of 5 can offer the best prognosis.
Limitations
Single-centre study
Possibility of unintentional selection bias could not
be fully excluded
Conclusion
Performing prophylactic thyroidectomy in MEN2A
patients with the C634Y mutation allows us to cure the
disease without causing any long-term complications.
Our results support that an age of <5 years should be
considered as a criterion for prophylactic thyroidectomy
in these patients.
23
References
Febrero B, et al., Prophylactic thyroidectomy in multiple endocrine
neoplasia 2 (MEN2) patients with the C634Y mutation: A long-term
follow-up in a large single-center cohort, European Journal of Surgical
Oncology https://doi.org/10.1016/j.ejso.2018.09.002
Lips CJ, Landsvater RM, H€oppener JW, et al. Clinical screening as
compared with DNA analysis in families with multiple endocrine
neoplasia type 2A. N Engl J Med 1994;331:828e35.
Niederle B, Sebag F, Brauckhoff M. Timing and extent thyroid surgery for
gene carriers of hereditary C cell disease-a consensus statement of the
European Society of Endocrine Surgeons (ESES). Langenbeck's Arch Surg
2014;399:185e97.
24
Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-
oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2.
International RET mutation consortium analysis. J Am Med Assoc 1996;276:1575e9.
Wells SA, Chi DD, Toshima K, et al. Predictive DNA testing and prophylactic thyroidectomy
in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 1994;220:237e50.
Machens A, Dralle H. Prophylactic thyroidectomy in RET carriers at risk for hereditary
medullary thyroid cancer. Thyroid 2009;19:551e4.
Lips CJ, Landsvater RM, H€oppener JW, et al. Clinical screening as compared with DNA
analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med
1994;331:828e35.
25
26

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Journal Club: Prophylactic Thyroidectomy in Multiple Endocrine Neoplasia 2

  • 1. Prophylactic Thyroidectomy in Multiple Endocrine Neoplasia 2 (MEN2) patients with the C634Y mutation PRESENTED BY: Dr. Aryan A LONG-TERM FOLLOW-UP IN A LARGE SINGLE-CENTER COHORT
  • 2. 2
  • 3. Introduction Germinal mutation in RET proto-oncogene Preneoplastic stage of C cell hyperplasia, later progresses to Medullary Thyroid Carcinoma (MTC) ATA recommends CND at calcitonin levels >40pg/mL and based on basal calcitonin levels C634Y mutation (less common) present a more indolent clinical course. C634R:more aggressive course. 3
  • 4. Objective of the Study to analyze the long-term results of a large cohort of MEN2 patients with the C634Y mutation who had undergone prophylactic thyroidectomy in a tertiary referral hospital, and to analyze the results in terms of age and Ct levels. 4
  • 5. Study Population 110 MEN2 patients (carriers of the C634Y mutation) who had undergone a prophylactic thyroidectomy Treated between the years 1983 and 2016 at the Virgen de la Arrixaca University Hospital (Murcia, Spain) 5
  • 6. Inclusion Criteria 1. asymptomatic at the time of diagnosis, absence of thyroid disease according to clinical and radiological criteria 2. normal result in the neck examination and no signs of thyroid nodules or lymphadenopathy 3. with a neck ultrasound showing a normal thyroid gland or with nodules <5mm and the absence of suspicious nodes 6
  • 7. Exclusion Criteria 1. Patients who presented with clinical and/or radiological disease preoperatively 2. Patients with a follow up time of less than a year. 7
  • 8. Plans for Follow up Postsurgical complications (hypoparathyroidism and/or permanent recurrent lesion) determined. Periodic examinations of Ct levels were taken after surgery Follow-up examinations carried out at 1 month after surgery and every 6 months thereafter Later, changed to an annual follow-up Disease considered to be cured when the patient had Ct levels within a normal range in most recent consultation. 8
  • 9. Statistical tools SPSS 21.0 Chi Square Test and Fisher’s Exact Test Test for Normality: Kolmogorov-Smirnov Test If rejected, Mann-Whitney’s U Test was used Statistically significant variables (p < 0.05) in the bivariate analysis taken to calculate the partial correlations 9
  • 10. Results From the year 1983 to 2015, total of 50 patients were recorded with criteria for prophylactic thyroidectomy Patient's mean age was 12 ± 9 years, with a range of 4-42 years; half of them being males (n=25) 26% of the patients were treated for pheochromocytoma and one patient was treated for hyperparathyroidism 10
  • 11. Development of MTC according to age, gender and Ct levels CCH (n=22) MTC (n=28) p-value Age at the time of the thyroidectomy 7 ± 3 years 15 ± 10 years <0.001 Normal Ct levels (n=36) 19 (53%) 17 (47%) 0.045 Above Normal Levels (n=14) 3 (21%) 11 (79%) 11
  • 12. Partial correlation analysis Controlled By Correlation p-value Ct levels Age-MTC 0.407 0.004 Age Ct levels-MTC 0.027 0.856 12
  • 13. Logistic regression analysis Variables Regression Coefficient Standard Error Odds Ratio p-value Age 0.328 0.109 1.388 (1.049- 1.525) 0.003 Ct levels -0.187 1.026 0.829 (0.928- 19.589) 0.855 Constant -2.821 0.969 0.060 0.004 13
  • 14. Follow up Mean follow-up time of the patients was 16 ± 6 years, with a range of 1-24 years. During the follow-up no case of recurrence was found, and all patients have been cured with a survival rate of 100%. 14
  • 15. Discussion Once MTC has developed, tumor sizes of >1 cm affect the disease-free rate and can lead to a higher recurrence rate with nodal metastasis Recommendations that prophylactic thyroidectomy be carried out in these patients before the age of 5 High risk: C634F/G/R/S/W/Y and A883F 15
  • 16. Age is a factor related to progression from CCH to MTC and to the presence of metastasis and disease persistence or recurrence Recommendations for adults? Criterion for prophylactic thyroidectomy that the ATA puts forward seems questionable Usually being recommended according to Ct levels 16
  • 17. Literature review Elisei et al. prefered to carry out thyroidectomy when levels of bCt increase, regardless of age Machens et al. reported that when bCt rises, there is the possibility of the patient having MTC with nodal metastasis Dralle et al. considered the recommendation of CND in cases >10 years More recent studies have revealed the importance of Ct levels in the evolution of the disease, regardless of the mutation and age 17
  • 18. Critical analysis Did the study address a clearly focused issue? Population: Multiple Endocrine Neoplasia (MEN 2) patients Intervention: prophylactic thyroidectomy Outcome: Follow Up for development of CCH, MTC and Ct levels
  • 19. Was the cohort recruited in an acceptable way? The data was from single center but included diverse population characteristics Was the exposure accurately measured to minimize bias? Prophylactic thyroidectomy was performed in the subset of the sample population
  • 20. Have the authors identified all important confounding factors? Have they taken account of the confounding factors in the design and/or analysis? Statistical analysis partial correlation for controlling the confounding variable
  • 21. Do you believe the results? The results are believable Can the results be applied to the local population? The recommendations can be used in our population too What are the implications of this study for practice? Although gene mutation studies can be difficult to conduct for every case, prophylactic thyroidectomy for established case, ideally before the age of 5 can offer the best prognosis.
  • 22. Limitations Single-centre study Possibility of unintentional selection bias could not be fully excluded
  • 23. Conclusion Performing prophylactic thyroidectomy in MEN2A patients with the C634Y mutation allows us to cure the disease without causing any long-term complications. Our results support that an age of <5 years should be considered as a criterion for prophylactic thyroidectomy in these patients. 23
  • 24. References Febrero B, et al., Prophylactic thyroidectomy in multiple endocrine neoplasia 2 (MEN2) patients with the C634Y mutation: A long-term follow-up in a large single-center cohort, European Journal of Surgical Oncology https://doi.org/10.1016/j.ejso.2018.09.002 Lips CJ, Landsvater RM, H€oppener JW, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994;331:828e35. Niederle B, Sebag F, Brauckhoff M. Timing and extent thyroid surgery for gene carriers of hereditary C cell disease-a consensus statement of the European Society of Endocrine Surgeons (ESES). Langenbeck's Arch Surg 2014;399:185e97. 24
  • 25. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto- oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. J Am Med Assoc 1996;276:1575e9. Wells SA, Chi DD, Toshima K, et al. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 1994;220:237e50. Machens A, Dralle H. Prophylactic thyroidectomy in RET carriers at risk for hereditary medullary thyroid cancer. Thyroid 2009;19:551e4. Lips CJ, Landsvater RM, H€oppener JW, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 1994;331:828e35. 25
  • 26. 26