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e Art and Science of yroid Surgery in the Age
of Genomics: 100 years aer eodor Kocher
Seza Gulec
Herbert Wertheim College of Medicine, Florida International University/%1)#!61#"1
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Review
Mol Imaging Radionucl Ther 2017;26(Suppl 1):1-9 DOI:10.4274/2017.26.suppl.01
Ad dress for Cor res pon den ce: Seza Gulec, MD, FACS, Florida International University Herbert Wertheim College of Medicine,
Departments of Surgery and Nuclear Medicine, Miami, USA
Phone: (786) 693 08 21 E-mail: sgulec@fiu.edu
1
Seza Gulec, MD, FACS
Florida International University Herbert Wertheim College of Medicine, Departments of Surgery and Nuclear Medicine, Miami, USA
The Art and Science of Thyroid Surgery in the Age of Genomics:
100 years after Theodor Kocher
Genomik Çağında Tiroid Cerrahi Sanat ve Bilimi: Theodor Kocher’den 100 Sene Sonra
Abstract
Cancer is a disorder of the genome. The thyroid cancer genome is being decoded. Recent studies have identified a mutation
or a genetic alteration in 95% of thyroid cancers. The National Cancer Institute initiated the Cancer Genome Atlas project in
2006 to catalogue genetic mutations associated with cancer, using genome sequencing and bioinformatics. The project has
expanded to carry out genomic characterization and sequence analysis of thyroid cancer. The concept of risk stratification
based on traditional parameters will soon vacate their role for clear molecular markers of non-invasive/focal, invasive/
metastatic and systemic stages/phases of neoplastic disorder. A refined classification scheme based on genomics and its
phenotypic expressions will accurately reflect the biologic differences between the different morphologic definitions we use
today. Tumor differentiation/de-differentiation, and clinical behavior of an individual cancer will be defined by molecular
markers, in addition to standard morpho-pathology. Empiricism in science of medicine and surgery has acquired a new
method for testing the appropriate treatment for individual patients; that is molecular pathology, governed by genomics. The
technology is present and rapidly evolving. The surgeons will determine the extent of interventions with molecular evidence
and guidance.
Keywords: Genomics, thyroid cancer, thyroidectomy, radioactive iodine, beta knife
Öz
Tiroid cerrahisinin bilimsel temelleri Theodor Kocher tarafından tanımlandı. Bu ustayı 100 yıl önce uğurladık. Tirod kanseri
cerrahisi ve tiroid kanseri hastalarının tedavisi ile tartışmalar süregelmektedir. Konunun mihengi açıkçası ilk aşama cerrahi
tedavinin boyutudur. Cerrahi tedaviyi izleyen kısa ve uzun dönemde uygulanabilecek tedaviler, yararlanılabilecek tetkik
ve görüntüleme yöntemleri de ilk cerrahi tedavinin çerçevesiyle alakalıdır. Amerikan Tiroid Birliği’nin 2015 basımı tedavi
kılavuzu dahil olmak üzere, geleneksel olarak tiroid kanserinin klinik değerlendirmesi morfolojik öğelere dayalı yapılır. Tümör
büyüklüğü, histolojik varyantlar ve hasta yaşı kriterleri cerrahi ve cerrahi sonrası girişimlerin boyutunu belirler. Kanser genomu
projesi kapsamında tiroid kanseri genom profili aydınlanmaya başladı. Hala birçok bilinmeyen olmakla birlikte bu konuda
bilgi birikimimiz hızla artıyor. İnce iğne biyopsisi materyalinde hastaların kromozom değişiklikleri ve nokta mutasyonları tespit
edilebilmekte, bu genomik değişikliklerin biyolojik anlamları araştırılabiliyor. Bu teknoloji hızla teşhis ve tedavi yönlendirilmesinde
kullanıma giriyor. Bundan böyle tedavi seçimlerinde genomik kılavuz ve yönlendirme kullanılacak. Bu makale cerrahi sanatının
mahir ustalarını ve cerrahi bilimindeki genomik devrimi selamlıyor.
Anahtar kelimeler: Genomik, tiroid kanseri, tiroidektomi, radyoaktif iyot, beta bıçak
©
Copyright 2017 by Turkish Society of Nuclear Medicine
Molecular Imaging and Radionuclide Therapy published by Galenos Yayınevi.
2
Milestones
Theodor Kocher died 100 years ago in 1917. Kocher is
considered the father of thyroid surgery (Figure 1).
He received the 1909 Nobel Prize in Physiology or Medicine
for his work in the physiology, pathology and surgery of
the thyroid. A few weeks before his death, at the age of
76, he made his final appearance before the Swiss Surgical
Congress, reviewing his entire thyroid surgery experience.
Kocher reported on approximately 5.000 operations with
a mortality of about 0.5%. When he started his work in
the 1870s, thyroid surgery was a high-risk procedure, with
an estimated mortality of 75% in 1872. Thyroid operations
were prohibited by the Academy of Medicine in France at
that time. Kocher was appointed to the Chair of Surgery in
Berne, Switzerland, in 1872, at the age of 31, and began his
influential work in thyroid surgery and medicine. His most
acclaimed achievement, his surgical technique, was marked
by meticulous care in dissecting and ligating blood vessels,
and precise dissection within the thyroid capsule (1). William
Halsted’s impression on Kocher’s surgical technique was/
is quite remarkable. Halsted described Kocher’s technique
as “neat and precise, operating in a relatively bloodless
manner, scrupulously removing the entire thyroid gland
doing little damage outside its capsule” (2). Kocher was
the first to describe the devastating complication(s) of total
extirpation of the thyroid gland. He also recognized the
underlying pathophysiologic changes in a diseased gland.
This was, in a sense, a “molecular vision.” He intuitively
contemplated that the growth of goiter nodules was an
early determined event in altered thyroid physiology, and
that the abnormal thyroid tissue was the source of a goiter
recurrence. He conceived the notion of autonomously
growing, focally distributed clusters of follicular cells in
nodular goiter. He, thus, advocated a total thyroidectomy
rather than selective removal of all thyroid nodules. Kocher
had realized that the so-called “subtotal” thyroidectomy,
leaving behind naturally growth-prone tissue, would lead to
goiter recurrence. The concept was called “Innere Chirurgie”
(internal surgery), a scientific surgical philosophy based on
biological considerations. This was the beginning of a new
epoch. The leading minds were Kocher in Berne, Halsted
in Baltimore, and Mikulicz (coined the term) in Krakau (3).
Despite impressive discoveries in surgical anatomy and
physiology, the onco-biology of neoplasia and the clinico-
pathologic characteristics of cancer were poorly understood
at Kocher’s time. Although Kocher had significant studies on
malignant tumors of the thyroid gland, the modern science
for cancer surgery was developed by William Halsted, who
championed a radical treatment approach for breast cancer.
Halsted’s idea was based on the premise that cancer had
a linear, step-wise growth fate and had to be be treated
with total extirpation of the organ along with its lymphatic
drainage network. This was believed to be necessary for
cure, and was adapted by many prominent surgeons.
This classic rationalistic philosophy in surgery dominated
the surgical world for years. Similarly, thyroid surgery for
cancer in the early post-Kocher era, called for an “en-block
resection” or “conventional radical neck dissection,” which
usually sacrificed the sternocleidomastoid muscle, internal
jugular vein, often the accessory nerve and sometimes the
marginal mandibular branch of the facial nerve. This was
all justified in the name of “cure. The core problem with
the rationalistic logical flow is the potential/possible flaw
Seza Gulec. Thyroid Surgery in the Age of Genomics
Mol Imaging Radionucl Ther 2017;26(Suppl 1):1-9
The extirpation of the thyroid gland typifies,
perhaps better than any operation, the
supreme triumph of the surgeon’s art. A
feat which today can be accomplished by
any competent operator without danger of
mishap and which was conceived more than
one thousand years ago might appear an
unlikely competitor for a place in surgery so
exalted.
William Stewart Halsted
Figure 1. Theodor Kocher
3
in the original hypothesis. The entire chain of thoughts/
deductions, then, may lead to incorrect conclusions
(a-priori error). The outcomes, however, need to be tested
independently. (post-priori validation). This is the essence
of evidence-based, data-driving scientific methodology”.
George “Barney” Crile Jr. should be credited as the first
to challenge the radical thought process and action. He
was one of the first surgeons ever to promote the idea
that “the less surgery the better,” and he campaigned
vigorously for the abandonment of the radical operations.
His ideas on thyroid cancer surgery, and later breast cancer
surgery, were briskly opposed at the time, but eventually
succeeded (4). The new surgical vision was reluctantly,
but progressively accepted by the surgical community over
time, and has since, shaped the evolution of the philosophy
of surgical treatment.
Mid-century brought in a major innovation in the
management of thyroid cancer, the radioactive iodine
(RAI) treatment. First used by Samuel Seidlin (5), and
established as a fortitude by Bierwaltes (6), RAI became
an invaluable theranostic agent. The role for RAI in
the management of metastatic differentiated thyroid
cancer (DTC) became indisputable. Its utilization post-
operatively, however, is still a matter of debate. As a guide
to perplexed; RAI treatment is given in 3 distinct settings
with distinct clinical indications (intents). 1) Ablation of
the remnant 2) Adjuvant treatment for residual disease or
occult metastatic disease 3) Therapy for known metastatic
disease. The term “ablation” specifically refers to first-line
RAI treatment following total surgical thyroidectomy. The
specific target of this treatment is normal residual thyroid
tissue- the remnant. The objectives of ablation are three-
folds a) Ablation eradicates all the functioning thyroid
tissue. Thereby, thyroglobulin (Tg) becomes a highly
specific tumor marker. This simply facilitates the post-op
long-term follow-up. b) Ablation wipes out all focal normal
thyroid tissue left in-situ by the surgeon to avoid injury to
laryngeal nerves and parathyroid glands. From surgical
standpoint these small clusters of normal tissue remnants
are inconsequential, however, they appear as focal areas
of RAI uptake on future whole body imaging studies and
can easily be called as metastatic disease. Eradication of
these potential source of misdiagnosis, when surgeon
to imager communication is still on-line, is important.
c) Post-ablation whole-body scan is an excellent extent
of disease evaluation tool. When the post-operative RAI
treatment is contemplated with an adjuvant intent, in
addition to the ablation objectives, RAI is aimed to target
residual disease or occult metastatic disease. When
the intent is adjuvant treatment, the risk stratification
becomes important in the selection of administered
activity of I-131. For remnant ablation purposes only, the
risk stratification has no bearing. The therapeutic effect
of I-131 works through the beta particles, thus, it should
be referred as “beta-knife.” Complete thyroidectomy, in
the strictest sense is only possible with surgical (cold steel
knife) thyroidectomy, followed by I-131 ablation (beta
knife) (Table 1).
The second half of the 20
th
century also witnessed the
birth of neo-empiricism in the acquisition and application of
scientific knowledge in medicine. The established dogmas
for radical surgical treatments were challenged, asking for
proof of efficacy based on outcome data. The new paradigm
was most palpable in the management of breast cancer
and thyroid cancer. The radical versus conservative surgery
argument was relatively easy to settle for breast cancer.
Bernard Fisher in the US and Umberto Veronesi in Italy ran
parallel trials resulting in clear demonstration of equivalency
of lesser surgery over radical operations. The problem with
thyroid cancer, however, remained unsettled. DTC was/is a
more indolent cancer with a much more protracted course.
Clinical trials with required statistical power were very difficult
to perform. The lack of definitive clinical trials unleashed a
never-ending controversy: Total thyroidectomy versus less
than total thyroidectomy. A new, rather ambiguous, lexis for
such operations entered into common use. Sub-total, near-
total thyroidectomy terms subsisted. At least for the sake
of clarification of the nomenclature, there should only be
two standard defining operations: Total thyroidectomy and
lobectomy. Total thyroidectomy is defined as the safe removal
of the thyroid gland with oncologically clean margins. If/
when eradication of all functioning thyroid tissue is the end
point, a cold steel knife is followed by the beta-knife.
Seza Gulec. Thyroid Surgery in the Age of Genomics
Mol Imaging Radionucl Ther 2017;26(Suppl 1):1-9
Table 1. Radioactive iodine ablation objectives
RAI treatment intent Target Objectives
Ablation (First-line) Remnant 1) Increase specificity of Tg monitoring,
2) Complete post-surgical staging
3) Identify/clear ambiguous foci of uptake
Adjuvant treatment (First-line) 1) Remnant,
2) Residual disease,
3) Occult metastatic disease
1) Ablation objectives,
2) Disease control
Therapy (Second-line) 1) Recurrent disease,
2) Metastatic disease
1) Disease control
RAI: Radioactive iodine, Tg: Thyroglobulin
4
The Equipoise
An equipoise is a genuine disagreement among the experts
as to the optimal therapeutic approach in the management
of a particular condition. A true equipoise exists in the initial
treatment of DTC. There are two camps, represented by
two diametrically opposing philosophical thoughts. There
are those aggressively favor/defend the strategy of total
thyroidectomy with radioiodine ablation and periodic Tg
screening for “biochemical evidence of recurrence”. On the
opposite direction there are those taking a conservative stand
and prefer/defend performing thyroid lobectomy, when the
tumor is small and limited to one lobe of the gland. This
stance would automatically rule out post-surgical ablation as
well as “affect” the utility of Tg screening. This approach
relies more on clinical and ultrasound findings for “clinical
evidence of recurrence.” It is a true equipoise, as there is
genuine uncertainty in the expert medical community over
which approach is more beneficial. The option of lobectomy
(pertaining to tumors measuring 1cm or less), was proposed
in the 2009 American Thyroid Association (ATA) guidelines
(7). It became the recommended option for small tumors
in its 2015 edition (8). A more progressive conservatism is
endorsed in the 2010 version of the Japanese guidelines for
the treatment of thyroid tumors. In the Japanese guidelines,
the indications for a lobectomy were extended to tumors as
large as 4 cm, if they are limited to one lobe of the thyroid
with little or no extra-capsular invasion and no gross lymph
node involvement. As for papillary carcinoma less than 1cm,
some Japanese surgeons are proposing that observation
without surgical intervention may be sufficient (9).
It would have been easier to compose a narrative if the history
of thyroid surgery was a linear progression from a radical
operation towards a lesser one. The story, however, is more
confounded, partly due to the particular characteristics of the
disease and perhaps more so due to entrenched positions of
opinionated surgeons and oncologists, the very definition of
equipoise. All respectable institutions, and the thought leaders
in the field have made their contributions to the controversy
(10,11,12,13). Equipoise has become the standard of care in
the initial surgical treatment of thyroid cancer.
Authors on both sides of the debate have pointed out that
not all papillary carcinomas are equally indolent. Some
grow rapidly and progress more aggressively than others
often without obvious histological differences. Histological
variations such as the tall cell variant and columnar cell variant
have been identified, but many unusually malignant strains
cannot be morphologically distinguished as being different
from other examples of papillary carcinoma. Certain well-
DTC will go on to have an aggressive course. They cannot
be histopathologically differentiated from those with typical
indolent course There appears not to have an exact way of
identifying those relatively infrequent differentiated cancers
that are destined to have a more malignant course. Despite
the significant progress in molecular pathology, the clinical
risk factors are currently the only stratification guide used
in thyroid cancer diagnosis and management. Proponents of
total thyroidectomy insist that the increase in complications is
minimal in the hands of an experienced surgeon. Proponents
of lobectomy point out that only one recurrent laryngeal
nerve is at risk when only one lobe of the thyroid is being
resected, thus the theoretical risk of nerve palsy is halved.
Disagreement over the merits of prophylactic central node
dissection has been argued in a similar context. Experience
suggests that the incidence of surgical complications may
not solely be dependent on the proficiency of the surgeon,
but also the extent of surgical procedure performed. So the
debate goes on, “equipoetically”.
The American Thyroid Association Guidelines,
2015
The 2015 ATA guidelines is a 133 page document written in a
dissertation format. The rationale for each recommendation
was discussed, in detail, in a scholarly fashion. The section
on operative approach for a biopsy diagnostic for follicular
cell-derived malignancy (B7, Recommendation 35) defines
three categories.
The guideline committee states that in properly selected
low to intermediate risk patients, the extent of initial
thyroid surgery probably has little impact on disease
specific survival. While recurrence rates can be quite low in
properly selected patients, it is likely that the lowest rates of
recurrence during long term follow-up would be associated
with a total thyroidectomy. However, since salvage therapy
would be quite effective in the few patients that recur after
Seza Gulec. Thyroid Surgery in the Age of Genomics
Mol Imaging Radionucl Ther 2017;26(Suppl 1):1-9
The Japanese Guidelines, 2010
A) It is beyond dispute that patients with the following
characteristics are regarded as high-risk; tumor size
>5 cm, lymph node metastasis >3 cm, lymph node
metastasis extending to the internal jugular vein,
carotid artery, major nerves such as recurrent laryngeal
nerve, and prevertebral fascia, multiple and intensely
swollen lymph node metastasis, extrathyroidal
extension to the trachea and esophageal mucosa and
distant metastasis at diagnosis. Total thyroidectomy
is recommended for patients having one or more of
these characteristics (p.108)
B) Other patients are classified as a “gray-zone”, but
in these patients total thyroidectomy is recommended
if the tumor size is >4 cm, and clinical node metastasis
is detected (regardless of whether it is N1a or N1b)
(p.108)
C) Although further studies with larger patient
numbers and longer follow-up times are required,
observation without immediate surgery for papillary
microcarcinoma without metastasis or invasion can be
considered a reasonable option (p.121).