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Cost-Eectiveness ofProphylactic
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
Surgeries inPreventing Hereditary
Predisposition Syndromes
CharlesSabbagh
4
4.1 Introduction
The aim of cost-effectiveness analysis is to evaluate the cost and health benet of one strategy
compared to another. It helps to dene and illuminate the potential health benets lost when
the best alternative is not selected [1, 2]. Costeffectiveness analysis should include both a societal and healthcare sector perspective. One of the
easier methods to evaluate cost-effectiveness is to
evaluate the cost-per-quality–adjusted life-year
(QALY) [1].
Cost-effectiveness analysis can be useful
in hereditary syndromes in the decision of surveillance versus prophylactic surgery. Costeffectiveness has mainly been evaluated in Lynch
syndrome and BRCA1 syndrome.
4.2 Lynch Syndrome
4.2.1 Prophylactic Surgery inLynch
Syndrome
There are three types of prophylactic surgery for
Lynch syndrome (LS) [3]. The rst is primary
C. Sabbagh (*)
Department of Digestive Surgery, Amiens University
Hospital, Amiens, France
SSPC (Simplication of Surgical Patients Care)
Clinical Research Unit, University of Picardie Jules
Verne, Amiens, France
e-mail: Sabbagh.Charles@chu-amiens.fr
prophylactic surgery. There are no formal indications for primary prophylactic colorectal surgery in LS, as prophylactic colorectal surgery is
not recommended when the patient is free from
colonic lesions [
ectomy at the age of 25 has been predicted to
increase survival by 1.8years compared to endoscopic surveillance [5]. The lack of an indication
explains the lack of cost-effectiveness data for
prophylactic colorectal surgery in LS in the eld
of primary prophylactic surgery.
Primary prophylactic colon surgery can be
proposed for LS patients with endometrial cancer
(EC) requiring a hysterectomy without preservation of the adnexa. Indeed, EC is often referred to
as a “sentinel event” in females with LS because
it is the rst manifestation of LS in more than
one in two women [6], with an earlier age of
onset than in sporadic EC [
signicantly more commonly in patients with
early menarche, nulliparity, and short-term or
no oral contraception (1year) [7]. Women with
LS who develop EC have an increased risk of
developing colorectal cancer. Thus, according to
a previous study based on the Amsterdam criteria, Aarnio etal. (2015) found that the collective
risk (CR) of colorectal cancer 26years after the
development of EC ranged from 40 to 75% [8].
According to a recent registry study that included
127 LS patients with EC, 55% (n = 70) developed a second cancer, more than half (n=40) of
which were colorectal cancer. Indeed, LS women
with EC have a 40-fold higher risk of develop-
4]. Total carcinological col-
6]. EC in LS occurs
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021
O. N. Dilek et al. (eds.), Prophylactic Surgery, https://doi.org/10.1007/978-3-030-66853-2_4
33
34
C. Sabbagh
ing colorectal cancer than women of the general
population [9], which could be the basis for discussion of prophylactic colectomy at the time of
total hysterectomy.
The question of primary prophylactic surgery
in LS is mainly in the context of gynecological
tumors. Given the risk of EC (narrow spectrum)
and ovarian cancer (wide spectrum), gynecological examinations and pelvic ultrasound, with
measurement of the endometrial thickness, are
recommended every year after age 35 or starting
5 years before the rst case of EC in the family. Prophylactic surgery (total hysterectomy with
bilateral salpingo-oophorectomy) should be discussed starting at age 45 or 5years before the rst
case of EC in the family.
The second type of prophylactic surgery is
secondary prophylactic surgery. Most surgical
indications for LS are therefore based on the
treatment of either a colorectal cancer or an endoscopically unresectable dysplasia or adenoma.
Either segmental or total colectomy can be proposed, depending on the location of the lesion.
For rectal lesions, a proctectomy, with or without
sphincter preservation, or total coloproctectomy
can be discussed. In addition to location, the
choice of the technique must take into account
patient factors (age, comorbidities, personal
choice), the morbidity of the procedure, the functional sequelae engendered, the impact on the
quality of life, and, nally, the risk of developing a metachronous lesion. These considerations
are necessary to provide patients with the most
complete information. This decision can be difcult to make and cost-effectiveness analysis can
be useful in such situations.
4.2.2 Cost-Eectiveness Studies
inLynch Syndrome
Several series have evaluated the best prevention
strategies for gynecological cancers in LS. In
2008, Kwon etal. developed a Markov decisionanalytic model to estimate the best strategies in
a cohort of women with LS at risk of endometrial and ovarian cancer [10]. The authors compared ve strategies: no prevention; prophylactic
surgery (hysterectomy and bilateral salpingooophorectomy) at the age of 30years; prophylactic surgery at the age of 40; annual screening with
endometrial biopsy, transvaginal ultrasound, and
CA125 from the age of 30; and nally, annual
screening from the age of 30 until prophylactic
surgery at the age of 40 (dened as the combined
strategy). The authors measured the QALY and
incremental cost-effectiveness ratio (ICER). They
found that the combined strategy provided the
highest net health benet (18.98 QALYs) but had
an ICER of $194,650 per QALY relative to prophylactic surgery at age 40 (the second-best strategy). The authors nally found that the combined
strategy was the most effective gynecological cancer strategy [10]. In 2011, Yang etal. published
another cost-effectiveness analysis of prophylactic surgery versus gynecological surveillance for
women with LS [11]. The authors also designed a
decision-analytic model incorporating key clinical decisions and existing probabilities, costs,
and outcomes from the literature. The aim of
this study was quite different from that of Kwon
et al. (2008), as in this study, the authors compared the health outcomes of prophylactic hysterectomy with bilateral salpingo- oophorectomy
at age 30 versus annual gynecological screening,
versus annual gynecological examinations [11].
The authors found that risk-reducing surgery was
the least expensive option, with a cost of $23,422
per patient for 25.71 QALYs, whereas annual
screening costs $ 68,392 for 25.17 QALYs, and
annual examination without screening, $100,484
for 24.6 QALYs. The conclusion was in favor
of prophylactic surgery, as it leads to the lowest
cost and the highest number of QALYs. The main
limitation of this study was that it only included
one age for prophylactic surgery. The decisionanalytical model was also a limitation relative to
a prospective trial with real women but is inherent to this specic methodology.
As already mentioned, there is no indication of primary colonic prophylactic surgery but
there is an indication for secondary prophylactic
surgery and the main question for which costeffectiveness analysis could be useful is whether
to perform a segmental or total colectomy. In
2019, Jiang etal. published a cost-effectiveness
4 Cost-Eectiveness ofProphylactic Surgeries inPreventing Hereditary Predisposition Syndromes
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35
analysis of total colectomy versus segmental colectomy [12]. The authors performed a Markov
decision tree analysis and compared QALYs following total colectomy or segmental colectomy.
The authors obtained the probabilities, cost, and
utility from the literature. In the base case analysis, a single total colectomy saved 0.67 QALY,
at a cost of $ 17,925 per patient. This led to an
incremental cost-effectiveness ratio of $ 26,624/
QALY for patients undergoing a total colectomy
[12]. Earlier studies have been published on this
topic. In 2010, Maeda etal. published a Markov
model-based study and found that mean survival
was slightly better for total than segmental colectomy for patients younger than 30years of age.
However, the two strategies were approximately
equivalent when QALY was considered, with
21.2 QALYs per patient for total colectomy and
21.5 for segmental colectomy [13]. Nonetheless,
the study by Jiang etal. (2019) is the rst to show
not only the improvement in life expectancy but
also the cost-effectiveness of total colectomy
over segmental colectomy [12].
median age of 30years and are the leading cause
of mortality in patients with familial adenomatous polyposis after prophylactic colorectal surgery [16]. Desmoid tumors are mesenchymal
tumors. They occur preferentially within the
abdomen and are benign (no risk of metastasis)
but are life-threatening because of their potential
for locoregional complications. Other types of
tumors are rare (1–2% of patients) and include
hepatoblastoma (in boys between 6months and
3 years of age), cerebral tumors in children or
adolescents (mainly medulloblastoma, formerly
known as Turcot syndrome), papillary cancer of
the thyroid, and pancreatic cancer. Other possible
lesions are glandular-cystic gastric polyps, which
occur frequently and are benign, and even gastric adenomas and extra- digestive benign lesions,
which are less frequent but herald the occurrence
of colorectal adenomatous polyps, as well as dental anomalies (supernumerary or sunken teeth,
maxillary osteoma), asymptomatic hypertrophy
of the retinal pigmented epithelium, and skin
lesions (epidermoid cysts, lipoma).
4.3 Familial Adenomatous
Polyposis
Patients with familial adenomatous polyposis
can have several hundreds or even thousands of
colorectal polyps, starting during adolescence
and leading to an inevitable risk of colorectal
cancer before the age of 40. These patients can
also develop duodenal adenomas with a 300fold higher risk of developing duodenal adenocarcinoma than the general population [14]. The
severity of duodenal adenomas is currently evaluated using the Spiegelman classication. In 2017,
Sourrouille etal. evaluated the Spiegelman duodenal surveillance score, in particular with respect
to high-grade dysplasia. Multivariable analysis
found that age at the rst endoscopy and modications of the papilla (size and gross aspect) were
independent risk factors associated with highgrade dysplasia [15]. It is therefore necessary to
evaluate the gross aspect of the papilla to appreciate the risk of duodenal dysplasia. Moreover,
desmoid tumors occur in 10–15% of cases at a
4.3.1 Cost-Eectiveness inFamilial
Adenomatous Polyposis
In familial adenomatous polyposis, the goal of
prophylactic surgical treatment is to prevent
death related to colorectal cancer without affecting the quality of life. Of note, one of every four
patients have colorectal cancer at the time of the
operation and one of three develop rectal cancer
during the postoperative surveillance period [17].
There are currently no standardized guidelines or
consensus as to when to operate or which procedure to perform [18]. However, in 2009, the
French National Institution of Cancer (INCA)
published professional recommendations for
prophylactic surgery for patients with a genetic
predisposition for cancer, and in 2017, the French
High Health Authority published recommendations concerning screening and prevention for
high and very high-risk patients. In these recommendations, age, as well as the size, number, and
histology of the polyps, should gure in the indication for prophylactic surgery. In the absence of
36
C. Sabbagh
polyps >5mm and/or those with a villous component, and/or high-grade dysplasia, surgery can
be deferred. Endoscopic surveillance is therefore
fundamental. In certain cases, surgery can be
deferred because of the higher risk of desmoid
tumors than that of colorectal degeneration. In
a recent meta-analysis [19] that included 4625
patients, multivariable analysis found that an age
of under 40, family history, mutations in the APC
gene 3′ of codon 1399, a previous laparotomy,
and female gender were independent risk factors
for developing a desmoid tumor (n= 559, i.e.,
12%). The authors suggested deferring prophylactic colorectal surgery to limit the risk of onset
of desmoid tumors, in particular in women with
attenuated FAP characterized by a mutation of
the APC gene 3′ of codon 1399.
Several elements in the eld of colorectal management could be evaluated by a costeffectiveness analysis, including the age of
resection and the type of resection according
to the type of mutation or surgery in MUTYH
patients. However, there are no currently (June
2020) published cost-effectiveness studies in the
eld of prophylactic colorectal surgery for familial adenomatous polyposis.
In 2009, Greenblatt et al. published a costeffectiveness study of prophylactic surgery for
duodenal cancer. A Markov model was constructed to estimate the life expectancy and cost
of three strategies: pancreaticoduodenectomy
at Spigelman stage III, pancreaticoduodenectomy at Spigelman stage IV, and pancreaticoduodenectomy at cancer diagnosis. The authors
simulated a cohort of 30-year-old familial adenomatous polyposis patients with total colectomies until age 80. They found that prophylactic
surgery at Spigelman stage IV resulted in the
greatest life expectancy. They also found that
surgery at Spigelman stage IV was more expensive than surgery at cancer diagnosis, with an
increased cost of $3200 per QALY gained. The
authors also found that surgery at Spigelman
stage III was not a valid option. This is, up to
now, the only cost- effectiveness study on prophylactic surgery in familial adenomatous polyposis [20].
4.4 Hereditary Breast Cancer
4.4.1 Mutation BRCA1/BRAC2
In 2017, recommendations were published by the
Institut National du Cancer on prophylactic surgery in patients with a BRCA1/2 mutation.
Prophylactic bilateral mastectomy was considered to be the most effective means to prevent
breast cancer for patients without breast cancer
with a BRCA1/2 mutation, despite its mutilating nature. Bilateral mastectomy should thus be
among the proposed treatments for women free
of cancer with a BRCA1/2 mutation. Whether
to proceed with the surgery is the personal decision of the patient after the issues have been presented by an oncogeneticist and a surgeon and a
minimum cooling-off period. Performance of the
surgery is not considered to be urgent. A consultation with a psychologist should be systematically offered to patients as part of this procedure.
The choice of preventive mastectomy must be
approved before it is performed by an oncogenetics multidisciplinary team (MDT). However,
it is not intended that the MDT proposes one
treatment strategy over another. Rather, the
responsibility of specialized MDTs is the treatment and follow-up of the women who choose
risk- reduction surgery. The breast cancer riskreduction surgery itself must be carried out by
surgeons specializing in cancer treatment (expert
opinion). Patients who do not choose this option
should also be informed that they may be able
to reconsider their choice at a later date. Current
data do not allow determination of the optimal
age at which bilateral mastectomy should be
performed. However, given the rarity of breast
cancer before the age of 30, it is not appropriate to offer this procedure before that age, except
in cases of very early-onset breast cancer in the
family. There is no data to specify the age beyond
which the performance of a bilateral mastectomy
would not provide a survival gain. However, over
the age of 65, the benet–risk balance of a breast
cancer risk-reduction surgical strategy should
be evaluated on a case-by-case basis (expert
opinion).
4 Cost-Eectiveness ofProphylactic Surgeries inPreventing Hereditary Predisposition Syndromes
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37
Risk-reduction breast surgery (bi-mastectomy or contralateral) should be proposed to
patients treated for breast cancer. The clinical
relevance must always be balanced with the
cancer prognosis, in particular the probability of
progression of the rst cancer within 3–5years.
Such surgery is not considered to be urgent
within the context of the breast cancer treatment. In cases of cancer with a poor prognosis,
especially if there is a risk of rapid progression within 3–5years, it is recommended to not
consider risk-reduction surgery but to wait to
ensure that the cancer does not develop rapidly.
It should be noted that, given the prognosis of
adnexal cancer (ovaries and tubes), breast cancer risk-reduction surgery is not recommended
for patients who have had adnexal cancer within
the previous 5years.
For the risk of ovarian cancer, adnexectomy
is the recommended risk-reduction strategy for
women with a BRCA mutation who are free of
breast cancer and/or adnexal cancer, given its
proven efcacy in reducing the risk of adnexal
cancer and its benet for survival. The optimal
minimum age cannot be determined and specic issues need to be considered, in particular,
pregnancy and the consequences of hormonal
deprivation.
Adnexectomy is recommended as early as
the age of 40 for women without adnexal cancer, regardless of the BRCA mutation status. This
intervention can be delayed until the age of 45 for
women with BRCA2 mutations. The minimum
age can be rediscussed with patients in specic
cases, such as the occurrence of adnexal cancer at
an earlier age or if the woman requests it.
Several cost-effectiveness studies have been
published concerning prophylactic surgery
in BRAC1/2 women. In 2018, Petelin et al.
published a systematic review covering costeffectiveness and comparative effectiveness of
cancer risk management strategies in BRAC1/2
mutation carriers. A total of 26 economic evaluations and eight comparative effectiveness analyses were included in this study [21]. The biggest
challenge in BRAC1/2 evaluation is that several
situations must be evaluated, such as the risk of
breast and/or ovarian cancer for women with or
without cancer and those who are conrmed or
potential BRCA carriers.
For conrmed BRCA carriers, the authors concluded that risk-reducing salpingo- oophorectomy
and bilateral prophylactic mastectomy were the
strategies associated with the greatest increase
in life expectancy and the dominant strategy in
terms of cost-effectiveness. This strategy leads to
an increase in life expectancy ranging from 0.62
to 9 life years gained relative to other strategies
(no intervention or cancer screening). Moreover,
inclusion of the adverse effects related to riskreducing salpingo- oophorectomy–induced premature surgical menopause did not appear to
affect the results [21].
Among these studies, one concerned a
cost- utility analysis of risk-reducing bilateral
salpingectomy, with or without delayed oophorectomy, as a possible alternative to risk-reducing salpingo- oophorectomy, as this approach
has been suggested to minimize the potential
long-term adverse effects associated with early
risk- reducing salpingo-oophorectomy [22].
Salpingectomy alone and salpingectomy with
delayed oophorectomy were considered costeffective alternatives for BRCA1 carriers, with
a cost of $17,003 to $32,126 per QALY gained.
They were potentially cost-effective for BRCA2
carriers, with a cost of $21,779 to $76,992 per
QALY gained. Cost-effectiveness was highly sensitive to the inutility assigned to salpingectomy.
For conrmed BRCA carriers with breast cancer, contralateral prophylactic mastectomy, with
or without risk-reducing salpingo-oophorectomy,
was the most effective strategy for the management of secondary breast cancer risk in terms of
life years gained, QALYs, and cost-savings relative to breast cancer screening.
For conrmed BRCA carriers with ovarian cancer, bilateral prophylactic mastectomy
was only cost-effective for patients from 40 to
50years of age who were BRCA1 carriers [23].
38
C. Sabbagh
4.5 Conclusion
Cost-effectiveness analyses are useful for prophylactic surgery indications to optimize the indications, the type of surgery, and the best moment to
perform the surgery. However, the available data
is still limited.
References
1. Neumann PJ, Sanders GD.Cost-effectiveness analysis 2.0. N Engl J Med. 2017;376:203–5.
2. Sanders GD, Neumann PJ, Basu A, et al.
Recommendations for conduct, methodological practices, and reporting of cost-effectiveness analyses:
second panel on cost-effectiveness in health and medicine. JAMA. 2016;316:1093–103.
3. Kalady MF, Jarrar A, Leach B, etal. Dening phenotypes and cancer risk in hyperplastic polyposis syndrome. Dis Colon Rectum. 2011;54:164–70.
4. De Jong AE, Morreau H, Van Puijenbroek M, et al.
The role of mismatch repair gene defects in the
development of adenomas in patients with HNPCC.
Gastroenterology. 2004;126:42–8.
5. Kalady MF, Lipman J, McGannon E, Church JM.Risk
of colonic neoplasia after proctectomy for rectal cancer in hereditary nonpolyposis colorectal cancer. Ann
Surg. 2012;255:1121–5.
6. de Vos tot Nederveen Cappel WH, Buskens E, van
Duijvendijk P, et al. Decision analysis in the surgical treatment of colorectal cancer due to a mismatch
repair gene defect. Gut. 2003;52:1752–5.
7. Anele CC, Adegbola SO, Askari A, et al. Risk of
metachronous colorectal cancer following colectomy
in Lynch syndrome: a systematic review and metaanalysis. Color Dis. 2017;19:528–36.
8. Heneghan HM, Martin ST, Winter DC.Segmental vs
extended colectomy in the management of hereditary
nonpolyposis colorectal cancer: a systematic review
and meta-analysis. Color Dis. 2015;17:382–9.
9. Malik SS, Lythgoe MP, McPhail M, Monahan
KJ. Metachronous colorectal cancer following segmental or extended colectomy in Lynch syndrome: a
systematic review and meta-analysis. Familial Cancer.
2018;17(4):557–64.
10. Kwon JS, Sun CC, Peterson SK, et al. Costeffectiveness analysis of prevention strategies for
gynecologic cancers in Lynch syndrome. Cancer.
2008;113:326–35.
11. Yang KY, Caughey AB, Little SE, Cheung MK, Chen
LM.A cost-effectiveness analysis of prophylactic sur-
gery versus gynecologic surveillance for women from
hereditary non-polyposis colorectal cancer (HNPCC)
families. Familial Cancer. 2011;10:535–43.
12. Jiang B, Ofshteyn A, Idrees JJ, etal. Total abdominal colectomy is cost-effective in treating colorectal
cancer in patients with genetically diagnosed Lynch
syndrome. Am J Surg. 2019;218:928–33.
13. Maeda T, Cannom RR, Beart RW Jr, Etzioni
DA. Decision model of segmental compared with
total abdominal colectomy for colon cancer in hereditary nonpolyposis colorectal cancer. J Clin Oncol.
2010;28:1175–80.
14. Bulow S, Bjork J, Christensen IJ, etal. Duodenal adenomatosis in familial adenomatous polyposis. Gut.
2004;53:381–6.
15. Sourrouille I, Lefevre JH, Shields C, etal. Surveillance
of duodenal polyposis in familial adenomatous polyposis: should the Spigelman score be modied? Dis
Colon Rectum. 2017;60:1137–46.
16. Church J, Lynch C, Neary P, LaGuardia L, Elayi E.A
desmoid tumor-staging system separates patients with
intra-abdominal, familial adenomatous polyposisassociated desmoid disease by behavior and prognosis. Dis Colon Rectum. 2008;51:897–901.
17. Smith JC, Schaffer MW, Ballard BR, et al.
Adenocarcinomas after prophylactic surgery for
familial adenomatous polyposis. J Cancer Ther.
2013;4:260–70.
18. Vasen HF, Moslein G, Alonso A, etal. Guidelines for
the clinical management of familial adenomatous polyposis (FAP). Gut. 2008;57:704–13.
19. Sinha A, Tekkis PP, Gibbons DC, Phillips RK, Clark
SK. Risk factors predicting desmoid occurrence in
patients with familial adenomatous polyposis: a metaanalysis. Color Dis. 2011;13:1222–9.
20. Greenblatt WH, Hur C, Knudsen AB, Evans JA,
Chung DC, Gazelle GS.Cost-effectiveness of prophylactic surgery for duodenal cancer in familial adenomatous polyposis. Cancer Epidemiol Biomark Prev.
2009;18:2677–84.
21. Petelin L, Trainer AH, Mitchell G, Liew D, James
PA.Cost-effectiveness and comparative effectiveness
of cancer risk management strategies in BRCA1/2
mutation carriers: a systematic review. Genet Med.
2018;20:1145–56.
22. Kwon JS, Tinker A, Pansegrau G, etal. Prophylactic
salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers. Obstet Gynecol.
2013;121:14–24.
23. Gamble C, Havrilesky LJ, Myers ER, etal. Cost effectiveness of risk-reducing mastectomy versus surveillance in BRCA mutation carriers with a history of
ovarian cancer. Ann Surg Oncol. 2017;24:3116–23.
Prophylactic Thyroidectomy
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XiangDa Dong andRifatLati
5
5.1 Introduction
Cancer is currently the second most common
cause of death in the United States [1]. A subset
of cancers is caused by the presence of genetic
defects leading to instability in the genome [2].
Many hereditary malignancies have been identied through genetic sequencing and linked to
particular coexisting conditions. Knowing that
certain hereditary cancers have a high rate of
penetrance, precautionary measures are needed
to mitigate either the mortality associated with a
disease or the morbidity caused by the disease [2].
In the twenty centuries, the morbidity and mortality of surgical procedures have been reduced dramatically due to advances in surgical techniques
and perioperative care, as well as other medical
advances. Therefore, many prophylactic surgeries are being performed to reduce the incidence
of organ-specic diseases when the morbidity of
surgery is acceptable. Total thyroidectomy represents one of the models for prophylactic surgery
to mitigate the development of surgically treatable thyroid diseases.
X. Da Dong (*)
Department of Surgery, Westchester Medical Center,
NewYork Medical College, Valhalla, NY, USA
e-mail: xiang.dong@wmchealth.org;
R. Lati
Department of Surgery, Westchester Medical Center
and New York Medical College, Valhalla, NY, USA
e-mail: Rifat.Lati@wmchealth.org
In order to proceed with prophylactic operations, several criteria should be met. The knowledge that the predisposing condition warrants
intervention due to risk of cancer development
or signicant morbidity with age need to be conrmed through preoperative workup and genetic
testing. Ideally, a quantiable risk category needs
to be given following the workup. The tests to
determine the population most at risk should be
reproducible and readily available. The ability
to perform the surgery with minimal morbidity
and mortality is a prerequisite for surgery. On
occasion, organ function replacement with exogenous medications is needed such as the case for
post thyroidectomy state. Finally, patients need
to be followed to look for evidence of recurrent
disease [2].
The thyroid gland is one of the organs that can
be safely removed for the purpose of treating cancer with proper hormone replacement afterwards.
Following discovery of thyroxine, thyroidectomy
was attempted initially with variable results.
Currently, thyroidectomy can be performed with
minimal morbidity in expert hands. Therefore,
several conditions that can cause thyroid cancers would lead one to consider the possibility
of thyroidectomy to minimize cancer development [3–6]. In terms of thyroidectomy, this has
been routinely used in MEN2A, MEN2B, and
other types of familial MTCs (FMTC) due to the
RET proto-oncogene defect [7]. This is a particularly worrisome cancer that can be effectively
treated with prophylactic surgery. However, there
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021
O. N. Dilek et al. (eds.), Prophylactic Surgery, https://doi.org/10.1007/978-3-030-66853-2_5
39
40
X. Da Dong and R. Lati
are other genetic conditions such as Cowden
syndrome which can cause less aggressive differentiated thyroid cancers (DTC). Although
prophylactic surgery offers signicant protective
effect, the benets and risks of surgery need to be
weighed prior to intervention. Furthermore, surveillance of thyroid gland for neoplasia is oftentimes easily reproducible without morbidity.
Barriers to the routine performance of prophylactic thyroidectomy are numerous. Availability
of surgical expertise is one of the rst barriers.
Identication of patients at risk based on genetic
lineage is another. Determining the timing of
surgery in pediatric patients will be important as
the patients are at increased risk of surgical complications compared to adults. Furthermore, the
group of patients most at risk for development of
cancer is also the group least capable of making
informed decisions for themselves. Finally, one
of the benets of the Human Genome Project has
been development of pharmacologic agents capable of specic blockade of metabolic pathways
[8]. The development of newer agents capable of
inhibiting the genetic development of cancer is
only now being investigated and may render prophylactic surgeries obsolete in the future.
In this review, we will examine the role of
prophylactic thyroidectomy for a variety of conditions that may trigger cancers in patients. The
various genetic predispositions are examined in
detail in terms of their particular risks. In addition, the age and benet to the patient will be
evaluated for the long-term morbidity and benet
ratio. Consequences of the surgery will be discussed for the patients. Finally, benign conditions
that are not routinely indicated for thyroid surgery are touched upon as well.
5.2 Familial Medullary Thyroid
Cancer
One of the fundamental requirements for prophylactic surgery is the identication of at-risk
patients. This process of identifying at-risk indi-
viduals requires germline testing to ensure that
the risk is present prior to the choice of selecting prophylactic surgery to reduce the risk of
malignancy [9]. Approximately 5–10% of thyroid cancers are MTCs and over 25% of these are
related to hereditary RET gene defect as part of
three autosomal dominant disorders: MEN2A,
MEN2B, and familial FMTC.MTC is a rare type
of neuroendocrine tumor that arises from parafollicular C cells of the thyroid gland. Surgery in
these patients offers a particularly effective means
to control and cure a potentially fatal malignancy.
Unlike colorectal or breast cancers, there are also
no chemotherapeutic means to prevent the development of MTCs. Furthermore, effective means
of detecting precancerous lesions may not be
easily achievable such as in infants with MEN2B
disease. Therefore, prophylactic thyroidectomy
remains the cornerstone of surgical prophylaxis
in these patients.
5.2.1 RET Proto-Oncogene
The RET proto-oncogene was rst identied in
1985 and found to be a transmembrane tyrosine
kinase receptor [9–13]. This gene was localized
to the pericentriomeric region of chromosome
10 (locus 10q11.2) and subsequently referred to
as RET (Rearranged during Transfection) protooncogene [10, 12, 13]. The RET protein is a
tyrosine kinase (TK) receptor that affects growth
and differentiation. The protein comprises an
extracellular domain with both cadherin-like
and cysteine- rich regions. Within the intracellular components, two tyrosine kinase subdomains
are present. Binding of the ligand to the receptor
leads to RET dimerization and subsequent intracellular substrate phosphorylation (Fig.5.1) [10].
The RET proto-oncogene is a gain of function
protein and mutations can lead to oncogenesis
of thyroid parafollicular C cells [14–16]. More
than 100 RET mutations have been reported to
date [14–16]. The specic RET mutation also
has a direct correlation with the phenotype and
Codon 883 and 918 associated with MEN 2B. All others are associated with MEN 2A and FMTC.
5 Prophylactic Thyroidectomy
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Extracellular Domain
(Cysteine rich)
41
Exon: Codon
Exon 10: 609, 611, 618, 620
Exon 11: 630, 634
Transmembrane
Domain
Intracellular Tyrosine
Kinase Domain 1
Intracellular Tyrosine
Kinase Domain 2
Exon 13: 768, 790, 791
Exon 14: 804
Exon 15: 883, 891
Exon 16: 918
Catalytic Core
Fig. 5.1 Schematic diagram of RET proto-oncogene along with the associated exon and codon defect
42
X. Da Dong and R. Lati
aggressiveness of the MTC and other features of
the MEN syndrome. RET protein itself has four
ligands including artemin, persephin, neurturin,
and glial cell line-derived neurotrophic factor
[14–16]. Binding of the ligand leads to subsequent intracellular dimerization. Alternatively,
when there is a germline mutation, the intracellular tyrosine kinase can be constitutively activated.
Mutations in the extracellular domains of
RET frequently is associated with FMTC and
MEN2A. Occasionally, FMTC is considered a
subtype of MEN2A.MEN2A has been subclassied into four variants and includes classic MEN2A,
MEN2A with cutaneous lichen amyloidosis,
MEN2A with Hirschsprung’s disease, and FMTC
[17]. Testing for children who display phenotypic
ndings of either MEN2A or MEN2B should have
directed testing of the most common mutations rst
followed by less common mutations, and subsequent gene sequencing if needed. The follow-up
care for patients following identication of their
mutation will depend on the mutation itself. In
patients with suspected MEN2A, the vast majority
of patients have a missense mutation in the extracellular domain at a single codon [14]. Exons 10
and 11, with codon mutations in 609, 611, 618, 620,
630, and 634, represent the most common types of
mutations [7]. Codon 634 mutation in exon 11 is
also the most common gene variant in MEN2A and
is found in the majority of patients with classic- type
MEN2A [18, 19]. Interestingly, somatic RET mutations that occur with sporadic MTC, which occurs
in 75% of cases, also typically occur in exon 11 at
codon 634. Sporadic MTC, although they can present at any age, is usually later in onset and presents
with presence of thyroid mass and presence of concurrent nodal metastases [9, 20].
When the intracellular TK domains of the
RET gene is involved, development of MTC is
usually earlier in onset although such mutations
are much less common [21]. The intracellular
TK2 domain mutation on exon 16 (codon 918) is
responsible for 95% of MEN2B cases, followed
by exon 15 (codon 883) [16, 21]. These deeper
intracellular mutations often lead to aggressive
early-onset tumors that mandate management
early on. Following identication of patients
with any MTC, all patients should be screened
for familial patterns of inheritance. Newly diagnosed FMTC should also prompt dissemination
of information to related kindreds due to the high
penetrance of cancer (Table5.1).
5.2.2 Current ATA
Recommendations
forScreening
andProphylactic
Thyroidectomy
Patients with newly diagnosed MTC or C cell
hyperplasia frequently require next-generation
sequencing of exons 10, 11, 13, 14, 15, and 16in
order to ascertain their risks both for MTC and
other associated malignancies seen with MEN
syndromes. Once an index patient has been diagnosed with a germline RET mutation, it is also
imperative that their rst-degree relatives be
offered the opportunity to evaluate for the presence of MEN or FMTC syndrome.
Current American Thyroid Association (ATA)
guidelines list the recommended age of surgery for
patients based on the risks of MTC development
with the particular types of mutation (Table5.2).
Table 5.1 Risk of medullary thyroid cancer development based on hereditary condition
Type
MEN 2A Bilateral Yes Pheochromocytoma,
MEN 2B Bilateral Yes/no Pheochromocytoma,
Familial
MTC
Sporadic Unilateral No None 3+
Thyroid
distribution
Bilateral Yes None 1+
Familial
pattern Associated clinical abnormalities
hyperparathyroidism
neurobromatosis
Biological
aggressiveness
2+
4+
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