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\begin{document}

\title{A critical update on the management of retrosternal goiter}



\author[1]{Cesare Miani}%
\author[2]{Luca Giovanni Locatello}%
\author[2]{Anna Maria Bergamin-Bracale}%
\author[2]{Nicole Caiazza}%
\author[2]{Stefania Rigo}%
\author[3]{Maria Gabriella Rugiu}%
\author[1]{Andrea Zuin}%
\author[4]{RICARD SIMO}%
\affil[1]{Universita degli Studi di Udine}%
\affil[2]{Presidio Ospedaliero Universitario Santa Maria della Misericordia}%
\affil[3]{Azienda sanitaria universitaria Friuli Centrale}%
\affil[4]{Guy's and St Thomas' NHS Foundation Trust Ear Nose and Throat Head and Neck Service}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Retrosternal goiters (RGs) pose several challenges to head
and neck surgeons because of the intricate anatomical relationships with
major vessels and other mediastinal structures. Methods: A scoping
review of the last five years in the PubMed database was conducted and a
total of 105 articles were discussed, along with methodological issues
and future directions in the research on RGs. Results: The surgical
excision of RGs may be accomplished by standard transcervical approach
in the vast majority of cases, yet the potential need for a
transthoracic approach must be always kept in mind. Great expertise in
referral centers is required to maintain an acceptable rate of
postoperative complications, and a thorough diagnostic work-up is
mandatory. Several non-surgical treatments in addition to mini-invasive
approaches have been proposed for RGs. Conclusions: RGs require a
multidisciplinary thyroid team in order to eventually minimize the risk
of complications and avoid extracervical approaches.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Retrosternal goiter (RG), also referred to as intrathoracic or
retrosternal, or cervico-mediastinal goiter, was first described by
Haller in 1794 but it still represents a challenge for inexperienced
head and neck and thoracic surgeons, as well as for
anesthesiologists\textsuperscript{1,2}. Clinically RGs are usually
incidental findings, yet they can present sometimes with
life-threatening dyspnea. They pose many issues in terms of airway
management: because of tracheal deviation, external compression, and
risk of tracheomalacia and cardiovascular collapse, RGs should be
managed only in referral centers where expected difficulties can be
safely managed. In this regard, an accurate preoperative work-up is
mandatory in order to avoid complications and to reduce the need for an
extra-cervical approach. The most recent review available on RG dates
back to some years ago, and since then the evolution of technology has
brought in different innovations, especially in new mini-invasive
techniques such as image-guided ablation or robotic-assisted
transthoracic surgery\textsuperscript{3}.

The present review aims to critically discuss the published evidence in
the last five years on the medical and surgical management of RG, with
particular attention to the need for multidisciplinary management of
these patients.

\textbf{Materials and Methods}

The PRISMA statement
(\emph{https://www.equator-network.org/reporting-guidelines/prisma/})
was followed in the preparation of the present paper, and a modified
PRISMA flowchart is given in \textbf{Figure 1} \textsuperscript{4}. No
institutional review board approval was necessary for the present work.
The PubMed database was used in order to perform the review of the
literature from January 1st 2017 to January 1st 2023. The following
search string was used: ``(intrathoracic OR retrosternal OR
cervico-mediastinal OR substernal) AND (goiter OR goitre)''. All the
pertinent articles were included after careful reading of the titles and
abstracts. Full texts of the included articles were then retrieved by
the first author (LGL) and quantitative and qualitative data were
synthesized accordingly. Papers reporting surgical outcomes of RG mixed
with other thyroid disorders (Reason 1); studies other than original
articles or reviews or case series/reports (Reason 2), or written in
languages other than English or French, or Italian were excluded (Reason
3).

The search strategy retrieved a total of 172 articles and, after
applying the selection criteria, a total of 98 articles were ultimately
analyzed. Additionally, a further 7 articles were retrieved and included
in the discussion after checking through the reference lists of the
relevant studies. Quantitative and qualitative data regarding surgical
outcomes were summarized and systematically reported in tables.

\textbf{Definition, Classification, and Pathogenesis of RG}

From an etymological point of view, RG must at least partially be
located in the mediastinum, but a myriad of factors affects this
seemingly simple definition: a clinical versus a radiological
evaluation, the extension of the head at the time of examination, the
proportion of thyroid mass that is required to extend into the thoracic
cavity, just to name a few. As of today, we still haven't found a
commonly accepted definition of RG which suffers from an ``identity
crisis''\textsuperscript{2}, and a historical overview of the over ten
definitions available has just been published\textsuperscript{5}.
Notably, Rios et al. analyzed the various criteria to define RGs and
they found none to be clinically meaningful\textsuperscript{6}. The most
recent (and somehow broadest) definition comes from the 2020 American
Association of Endocrine Surgeons (AAES) guidelines, where ``if a
mediastinal extension is present, meaning that the gland extends
caudally past the sternal notch on physical examination, computer
tomography (CT) imaging, or at the time of surgery'' it can be
considered as a true RG\textsuperscript{7}. Since an authoritative
international consensus has not been reached, the most recent literature
is still heavily affected by these heterogeneous definitions
(see\textbf{Table 1} ), and this represents an enormous obstacle for
comparing surgical outcomes.

RGs can be variously defined according to their extension and
relationships with anatomical structures of the mediastinum: the most
recent classification divides them into a Type I RG (extending
anteriorly to the trachea and RLN), a Type II RG (where at least a part
of the mass extends posteriorly to the mediastinal vessels, the trachea,
and the RLN), and a Type III (purely mediastinal) RG\textsuperscript{8}.
Unfortunately, a formal correlation of these classifications with
surgical outcomes has not been performed. We must remember that over
99\% of RGs are secondary (type I and II), \emph{i.e.} they represent an
inferior extension of the normal thyroid gland, and they are
vascularized by branches of superior and inferior thyroid arteries.
Instead, primary (type III) RGs are clearly separated from the
orthotopic cervical thyroid, they receive arterial branches from
intrathoracic arteries, and they are usually incidental
findings\textsuperscript{9}. In these cases, a missed gland can be
diagnosed only when postoperative TSH levels remain unchanged or a
(functional) imaging of the chest is performed\textsuperscript{10--13}.
From an embryological point of view, type III RG is explained by an
erroneous migration of the two median and lateral anlagen from the
pharyngeal pouch and the ultimobranchial body, as it was recently
reviewed by Rico and Lung\textsuperscript{14}. Migration of the median
anlage may also lead to a presternal goiter, and in 2019 the seventh
case worldwide was reported\textsuperscript{15}. Sometimes, after
subtotal thyroidectomy, patients may present with only a residual
central mediastinal mass shifting the trachea laterally
(``pseudo-primary RG'')\textsuperscript{16--18}. This may also happen
decades after the initial surgery and it may mimic other mediastinal or
pulmonary pathologies, such as paraganglioma or adenocarcinoma of the
lung\textsuperscript{19,20}.

Regarding the pathogenesis of RG, no recent study has ever explored if
there are different molecular mutations in RG compared to
non-intrathoracic goiters. The issue remains unsolved and anatomical and
functional factors (no limitations downwards encountered by the
expanding gland, traction forces associated with swallowing, a negative
intrathoracic pressure during inspiration), and gravity itself has been
called into question\textsuperscript{21}. A 1939's study by Crile
proposed that patients with a short neck and hypertrophic cervical
muscles might theoretically favor the retrosternal expansion of the
goiter\textsuperscript{22}, but no formal anthropometric study exists to
corroborate this assumption. In the end, and besides the simple time
during which a goiter has been allowed to grow undisturbed, risk factors
for the development of RGs remain still unexplored.

\textbf{Clinical Presentation}

A chronic and slowly progressive airway compression is the usual
presentation of RG, and this can last many years in areas where iodine
deficiency is endemic\textsuperscript{23}. A choking sensation
exacerbated by the supine position, globus, wheezing, and
exercise-induced dyspnea (both mistaken for asthma), or dysphagia are
the symptoms most commonly reported by patients, that on the other hand
are asymptomatic at presentation in over one-third of
cases\textsuperscript{5}. Mechanisms of dyspnea are believed to be
direct extrinsic tracheal compression, dysfunction of the recurrent
laryngeal nerve, and lung atelectasis\textsuperscript{24}. Instead, in
less than 5 \% of cases the clinical presentation of RG may be acute:
spontaneous hemorrhagic enlargement of RG may occur during
pregnancy\textsuperscript{25,26} or for unclear
reasons\textsuperscript{27,28}, acute asphyxia and cardiac arrest have
been described\textsuperscript{29,30}, and some authors have
hypothesized a direct phrenic nerve compression by the RG as the main
cause of these dramatic scenarios\textsuperscript{31}.

Rarer presentation may be constituted by thyrotoxicosis or symptoms of
superior vena cava syndrome (facial plethora and congestion, upper neck
cyanosis, or a positive Pemberton's sign with facial flushing and
engorgement of superficial jugular veins upon raising the
arms)\textsuperscript{5}. While it had been previously reported that
this syndrome was more often associated with malignancy, this remains
unproven\textsuperscript{21}. Isolated dysphagia is also possible in
case of goiter growing only in the retro-esophageal
plane\textsuperscript{32,33}, while the only presenting symptom may also
be represented by oropharyngeal bleeding because of pharyngolaryngeal
``downhill'' (\emph{i.e} ., without venous portal hypertension)
varices\textsuperscript{34}. Furthermore lower and upper extremities
edema\textsuperscript{35}, pericardial effusion, chylothorax, or
hemoptysis because of tracheal varices have been also
described\textsuperscript{21}.

\textbf{Diagnostic Work-up and Anesthesiologic Considerations}

The diagnostic workup of a goiter begins with simple palpation of the
neck and performing an ultrasound. Regarding the former, Pattashanee and
colleagues have shown that clinical examination in modified Rose's
position (\emph{i.e.} , supine, a roll under the shoulders, and by
hyperextending the neck) has an excellent sensitivity (98\%) and a
variable specificity (46.7-91.1\%) to identify substernal
extension\textsuperscript{36}. Another interesting result is that, in
the absence of the Pemberton's sign, the probability of getting a false
positive finding of a substernal extension was only 4\%, and this is
quite relevant in the context of low-income countries where the
availability of CT scan is scarce\textsuperscript{3633}, an 89\%
sensitivity and 87\% specificity for any degree of tracheal narrowing
were registered (AUC = 0.90)\textsuperscript{37}.

CT scan of the neck and thorax remains the gold standard for a full
assessment and classification of RG because it evaluates the dimensions,
the morphology, and the relationships to the adjacent mediastinal
anatomical structures (\textbf{Figure 2} ). It is usually performed with
the aid of intravenous iodine contrast agents, despite a theoretical
more than a real risk of precipitate thyrotoxicosis (Jod-Basedow
phenomenon)\textsuperscript{5,21}. Some authors have proposed a simple
yet not validated rule-of-thumb: if the RG remains cranial to the aortic
arch in the sagittal plane of CT performed while the patients maintain a
full neck extension, then sternotomy is usually not
necessary\textsuperscript{38}. Classical predictors of the need for
sternotomy are based on the craniocaudal length of the retrosternal
extension, the ratio between the retrosternal portion and the diameter
of the upper thoracic inlet (so-called ``iceberg'' or ``cone-shaped
RG''), and the anterior or posterior relationships with major
vessels\textsuperscript{2,393} had a negative predictive value for the
extra-cervical approach of 100\%\textsuperscript{40}. Volume was
manually outlined on axial sections by two radiologists, but interrater
agreement and kappa coefficients were not calculated thus leaving doubts
on the applicability of this technique. The value of imaging in the
prediction of an exclusive transcervical approach to RG will be
discussed further in the next sections.

CT scan lets a clear assessment of both tracheal deviation and extrinsic
compression, which are both reasons why airway management is usually
labeled as difficult in RG patients, and a very low threshold for
endoscopic-assisted awake intubation is kept by anesthesiologists. This
fear mostly derives from anecdotal evidence of extreme RG where
emergency tracheostomy\textsuperscript{29}, or the need for a pediatric
flexible bronchoscope were necessary\textsuperscript{41}. In the most
extreme case, the application of extracorporeal membrane oxygenation
(ECMO) before the induction of general anesthesia has been described
with success\textsuperscript{42,43}. Actual evidence instead dispels the
myth of a difficult airway, in the absence of classical risk factors
(mouth opening less than 4 cm, a thyromental distance less than 6 cm,
Mallampati Class III or higher, etc.)\textsuperscript{39}. In a 2020
paper, 22 cases of ``giant'' type I RG (defined as trespassing the
aortic arch on CT scan), with a mean maximum diameter of 114.2 \selectlanguage{ngerman}± 19.5 mm
were all successfully intubated with standard laryngoscopy or awake
tracheal intubation (for 5 patients, 22\%) using flexible
bronchoscopy\textsuperscript{44}. A larger multi-institutional series
from the USA, confirmed that direct laryngoscopy or videolaryngoscopy
techniques were sufficient in 162 patients (90.5\%), while transnasal of
transoral fiberoptic was intubation used for the remaining 17
patients\textsuperscript{45}. The authors did not give a clear-cut
definition of RG, yet they performed a multivariate analysis where the
body mass index was the only factor to positively correlate with the
number of attempted intubations\textsuperscript{45}.

\textbf{Non-surgical management of RG}

When surgery is not indicated or it is not feasible because of the
patient's general status, frailty, or comorbidities, a wait-and-see
approach or medical treatment of RG may be
proposed\textsuperscript{5,21}. In the most recent literature, no new
studies regarding levothyroxine supplementation or radioiodine treatment
have been published. For both options many drawbacks are present (missed
malignancy, risk of thyrotoxicosis or of an increase airway obstruction)
and only with the advantage of a slow and modest size reduction at
best\textsuperscript{21}. Instead minimal-invasive techniques such as
transcervical microwave ablation (TcMA), transcervical radiofrequency
ablation (TcRfA), or selective embolization of the thyroid arteries
(SETA), whose preliminary reports date back to the 2000s, are being
further explored.

Ultrasound-guided microwave TCA of RG combined with ethanol injection
was reported as an effective and safe treatment for solitary nodular RG,
especially for patients who are ineligible or unwilling to receive
surgical treatment \textsuperscript{46,47}. A first preliminary
experience was presented by Cui et al in 2018 on 10 patients a mean
volume reduction ratio (VRR) of around 67\% was reported after one
month, while no local (pain, hematoma, etc.) or functional
(thyrotoxicosis crisis, changes in TSH, etc.) adverse events were
reported\textsuperscript{46}. In a subsequent prospective study from the
same hospital involving 72 patients (mean age 47.8 years) and with a
mean follow-up of 23.9 months, TCA yielded a mean VRR of 83.12 ± 12.74
\% (range: 52.01--100\%) after one year; 57 patients (79.2\%) showed a
total regression of the intrathoracic extension (by CT scan) while 8
patients (11.1\%) needed a second procedure because of ``regrowth of
unsatisfactory reduction''. 4.2\% (3/72). Two patients complained of
temporary neck pain/discomfort, while there was a case of postprocedural
dysphonia, which resolved spontaneously after 1 month, for an overall
complication rate of 4.2\%\textsuperscript{47}.

It should be noticed that in both studies, a significant reduction in
terms of RG-associated signs and symptoms (\emph{i.e.} , neck
circumference and a VAS scale measuring pain, shortness of breath,
positional dyspnea, dysphagia, and dysphonia) was obtained, despite the
fact that the procedure focused only on the largest retrosternal
nodule\textsuperscript{46,47}.

TcRfA is another option and Chiang et al. recently showed a VRR of
75.5\% (p\textless{}0.001) in a series of 16 RGs\textsuperscript{48}. In
this series, only 4 (25\%) patients showed complete regression of the
substernal portion of the goiter, while there was a case of temporary
hoarseness and a case of subcutaneous/focal mediastinal hematoma, which
was managed conservatively (complication rate 12.5\%). Nonetheless, all
the patients reported significantly lower cosmetic and symptom scores on
the VAS scale at 6 months\textsuperscript{48}.

Regarding the SETA procedure, a small Italian series of 10 patients
reported complete success in reducing the thyroid function and RG
dimensions but no formal endpoints were used, and follow-up time was not
reported. In addition, all patients developed transient thyrotoxicosis
requiring corticosteroids, antibiotics, and methimazole, while one
patient (10\%) had right vocal cord fixation lasting around 6
months\textsuperscript{49}. Yilmaz and coworkers instead presented their
experience with SETA in 56 goiters, and among them 47 were considered
``intrathoracic''\textsuperscript{50}. The procedure was conducted
successfully in 145 out of the 146 thyroid arteries and complications
occurred in 27 patients (48\%), but if we eliminate a case of
intraoperative blurry vision, one case of groin hematoma, and 23 cases
of hyperthyroidism (since it is a predictable effect because of the
necrosis of the gland), only 3 (5\%) patients developed temporary
hoarseness. Notably, after 6 months, the mean thyroid volume was reduced
from 147.0 mL to 62.6 mL, while the mean retrosternal extension was
reduced from 31.7 mm to 15.9 mm (P \textless{} .001). Quality of life
was measured by the popular ThyPRO tool and the mean scores improved
from 155.4 to 70.4 (P \textless{} .001)\textsuperscript{50}. These
authors also reported that one patient died of myocardial infarction two
weeks after SETA, and a possible causative effect cannot be excluded.
Despite the absence of a comparative study, SETA is reported to be
applicable irrespective of the goiter dimensions but this does not fit
the preprocedural reported mean dimensions of the nodules (80.2 ± 46.7
mL for SETA\textsuperscript{50}, versus 76.10 ± 50.56 mL for
TcMA\textsuperscript{47}).

In summary, all these non-surgical approaches have many advantages (no
reported risk of iatrogenic hypothyroidism or hypoparathyroidism; they
are a day or one-day procedures for ablation and SETA, respectively;
they can be performed even in very fragile patients, etc.) but they
retain the fundamental limit of not permitting any histological
evaluation of the RG, even though at least one\textsuperscript{50}, or
two\textsuperscript{47} consecutive non-malignant (up to Bethesda
category 3) fine-needle core biopsies were required as an inclusion
criterion. The clinical experience remains however limited and, most
importantly, the lack of a head-to-head comparison between standard
surgical resection and these techniques remains their central limit.

\textbf{Indications and Classical surgical approaches to RG}

Classical indications for surgically removing a simple/non-toxic goiter
date back to the beginning of the twentieth century: relief from
compression symptoms, prevention of or suspicion of an associated
malignancy, or for cosmetic purposes\textsuperscript{51}. Unfortunately,
these criteria are somehow vague and, because ultimately the surgeon is
the sole responsible for the outcomes of thyroidectomy, in 2018 a
``Choosing wisely'' initiative from Germany proposed more reproducible
criteria: compression symptoms (dyspnea, stridor, dysphagia) must be
directly attributable to goiter while a reasonable suspicion of
malignancy must be documented (\emph{i.e.} , TI-RADS category 4c/ 5, Tir
3 or higher class at FNAC in the presence of risk factors for thyroid
cancer, basal calcitonin serum level increase \textgreater{}26 pmol/L in
women and 60 pmol/L in men, cN+ status at ultrasound). In the absence of
the above, surgery may also be indicated for ``prevention of
complications'' that may derive from a \emph{progressive} RG (defined as
tracheal compression \textgreater{}35\%, superior vena cava
syndrome)''\textsuperscript{52--54}. Again the progression must be
documented but the very natural history of untreated RG is still poorly
understood\textsuperscript{2}.

An exhaustive explanation to the patient and their caregivers is the key
to surgical success\textsuperscript{3}. A detailed technical overview of
the classical surgical approaches to RG has been recently given by
Uludag et al and it will briefly be discussed here\textsuperscript{39}.
A Kocher incision, ligation of the superior and inferior vascular
peduncles, and digital dissection remain the standard surgical steps,
but resection of the pre-laryngeal musculature is often necessary for
delivering large goiters. A 2022 study has for the first time evaluated
its consequences on vocal and swallowing function: by using
patient-reported impairment scores, a prospective head-to-head study of
34 patients revealed no significant differences when strap muscles are
transected or not\textsuperscript{55}.

In 2021, the International Neural Monitoring Study Group (INMSG)
published the most important study of surgical anatomy since the
introduction of intraoperative neuromonitoring (IONM). The authors have
meticulously evaluated the course and anatomical relationships of 1000
RLNs: strikingly, among other findings, it emerged that in 50\% of cases
of RG (versus 30\% in standard thyroidectomies), the RLN was fixed,
splayed, or entrapped at the level of the capsule of the thyroid, thus
rendering at high risk for loss of signal\textsuperscript{56}. IONM is
thus mandatory for every RG operation and, in the case of ``giant'' RG,
many authors suggest the upfront use of a transcervical medial approach,
which implies the separation of the isthmus and dissection of Berry's
ligament in a layered fashion along the trachea and towards the RLN. In
a series from the USA, successful identification of the RLN was reported
to be 84\% with this approach and postoperative vocal cord dysfunction
(assessed by flexible laryngoscopy) was null\textsuperscript{57}. A very
high rate (17\%) of postoperative hematoma was reported, yet the authors
declared that revision in the operative room was deemed necessary only
for one patient\textsuperscript{57}. Another larger case series from
Greece declared instead no postoperative bleeding, and a permanent RLN
damage rate comparable with classic lateral
approaches\textsuperscript{58}.

Regarding the extent of the resection, even in the most recent series
total thyroidectomy is the preferred strategy for RG, which however can
harbor one or more foci of malignancy in up to 40\% of
cases\textsuperscript{21}. When the intrathoracic part is well
lateralized, or there are anatomical constraints or technical issues
during the dissection, a subtotal resection or a simple
hemithyroidectomy may help relieve the compression symptoms while
minimizing the postoperative complications. New technologies are being
exploited also in this type of operation: in 2018, some authors have
proposed a microdebrider-assisted intracapsular reduction thyroidectomy
on a small series of 26 patients. According to the proponents, a
standard sinus suction debrider may morcellate the intracapsular part of
the RG, it has no effect on the risk of major bleeding, and may avoid
the need for sternotomy in selected patients\textsuperscript{59}.
Instead, recent retrospective papers on transoral endoscopic
thyroidectomy vestibular approach (TOETVA) or transoral robotic
thyroidectomy (TORT) consider RG as an exclusion criterion because of
intrinsic limitations in terms of surgical exposure\textsuperscript{60}.

\textbf{Current Indications for combined surgical approaches to RG}

Several goiter-related and patient-related factors must be considered in
the surgical plan. The former are usually evaluated by neck and chest
imaging, and as already mentioned patients are deemed at high risk for
an extra-cervical approach when: RG extends below the aortic arch, it
has multiple or separate mediastinal compartments, it has an ``iceberg''
or conical shape (\emph{i.e.} , it extends to both sides of the thorax
or it has a diameter that is larger than the upper thoracic
inlet)\textsuperscript{3,21,38,61}. Some authors believe that in
presence of possible malignancy, sternotomy may be favored, but there is
no consensus on this point\textsuperscript{62}. In extreme cases, RG may
be strictly adherent to the pericardium\textsuperscript{63}, or it can
even invade it: in these exceedingly rare cases of intrapericardial RG,
sternotomy and the availability of a cardiopulmonary bypass are
essential\textsuperscript{64}. Instead, patient-related features that
may favor an extracervical approach include a history of previous
thyroid or thoracic surgery, previous irradiation in the neck or chest
areas, preoperative dysfunction of the vocal cords, coagulopathies, or
platelet disorders (\emph{e.g.} , Bernard-Soulier
syndrome)\textsuperscript{2,21,65}.

The most important study that has corroborated these factors was
published in 2019: in a cohort of 237 RGs where 29 (12.2\%) required
sternotomy, on multivariate logistic regression analysis, extension
below the aortic arch (OR 10.84), an iceberg shape (OR 59.30), and
previous neck surgery (OR 4.83) were all significantly associated with
an extra-cervical approach\textsuperscript{66}. For the sake of
completeness, another group has suggested the presence of an
inflammatory component in the excised RG as a predictor for sternotomy
(only on univariate analysis and in a small series)\textsuperscript{67},
while in another series of 109 RGs, only the part extending beyond the
sternal notch into the mediastinum would predict sternotomy (univariate
only, odds ratio 3.43, confidence interval 1.65-6.41), with a
sensitivity of 94\% and specificity of 86.5\% when it is more than 5
cm\textsuperscript{68}. Unmeasurable aspects such as the surgeon's
expertise do however exist since there are case series where RG cases
below the aortic arch or in the posterior mediastinum were reported to
be completely excised through a purely transcervical
approach\textsuperscript{69}.

Complete sternotomy is the gold standard access for RG but less
extensive approaches have been devised, namely partial or split
sternotomy\textsuperscript{70}, manubriotomy\textsuperscript{71},
anterolateral or posterolateral thoracotomy, the hemi-clamshell approach
(partial median sternotomy plus an anterolateral
thoracotomy)\textsuperscript{72}, and they are all technically described
in the work of Uludag et al\textsuperscript{39}. Endoscopic-assisted
approaches are another option but in the last years, video-assisted
mediastinoscopy has lost its interest in favor of thoracoscopic
approaches\textsuperscript{3,73}. For example, the subxiphoid
thoracoscopic approach is a novel alternative proposed by a Chinese
group for median RGs\textsuperscript{74}. Robotic-assisted procedures
are being also actively explored but they are always combined with a
transcervical incision\textsuperscript{75--77}.

Interestingly, in the 2016 American Thyroid Association (ATA) Statement
on Remote-Access Thyroid Surgery (RATS), the substernal extension was
considered a contraindication, but the latest papers seem to overcome
this limit. A RATS by an axillo-thoracic endoscopic approach has been
applied on very selected patients with RG\textsuperscript{78}. The
excellent view of the surgical field provided by high-definition cameras
is obviously very helpful in the identification of critical
neurovascular structures (RLN and phrenic nerves, etc.) but, at present,
all these approaches remain preliminary and a formal comparison with
standard techniques is lacking. Finally and in very rare cases, a
straightforward indication for combined approaches to RG is given by a
coexisting thoracic condition: for instance, a minimally invasive
transcervical and robotic transthoracic approach has been described for
RG and concurrent thymoma\textsuperscript{79}, or RG excision and aortic
valve replacement were performed through a mini-J
sternotomy\textsuperscript{80}.

\textbf{Complications associated with surgery for RG}

The presence of RG is historically known to carry a higher risk of
finding a malignancy and of the development of postoperative
complications (hematoma, transient/permanent hypoparathyroidism, and RLN
dysfunction) compared to cervical goiters\textsuperscript{81}. The most
recent evidence has further confirmed these findings: for example, in a
cohort of 1500 RLNs at risk, substernal extension and a thyroid volume
\textgreater{}100 mL were the only significant factors for postoperative
transient or permanent VC paralysis\textsuperscript{82}. In the IONM
era, a study extracting 42341 operations from the UK Thyroid database
found that RG was an independent factor (OR= 1.36, 95\%CI 1.05- 1.77)
that predicted the risk of RN injury, along with revision surgery and
patient age.\textsuperscript{83} A recent anatomical study has revealed
that iatrogenic lesions of the RNL after RGs' resections are more
frequent on the right side in comparison to the left one because of the
known anatomical and embryological differences in the development of the
RLN on either side of the neck\textsuperscript{84}.

Regarding postoperative hematoma formation, male sex, the use of
preoperative anticoagulant therapy or postoperative subcutaneous
heparin, and the presence of RG (38 cases) were all significant
predictors in a group of 6900 thyroidectomies\textsuperscript{85}.
Instead, RG was not a significant risk factor in another series of 5900
operations, including a total of 148 RGs (2.5\%)\textsuperscript{86}.
Both series, unfortunately, did not provide a definition of RG nor how
the extension was determined. On the contrary, another analysis of the
aforementioned UK registry (n= 53838 entries) revealed in multivariable
analysis that male sex, increasing age, redo surgery, RG (whenever
having an ``extension to the thoracic inlet or below''), and total
thyroidectomy were all correlated with an increased risk of reoperation
for bleeding; interestingly, surgeon monthly thyroidectomy rate
correlated with a decreased risk\textsuperscript{87}.

The presence of RG is linked with a major risk of developing clinical
symptoms of hypocalcemia (OR 10.26)\textsuperscript{88}. A recent study
published by Chen et al. provides evidence that there are predictive
factors for this adverse event. This meta-analysis includes 23 studies
and identifies twelve significant risk factors for postoperative
hypocalcemia. In particular, hypoparathyroidism (OR 5.58), total
thyroidectomy (OR 3.59), hypomagnesemia (OR 2.85), and preoperative
vitamin D deficiency (OR 2.32), were those most associated with
hypocalcemia\textsuperscript{89}. In another observational study, RG and
its extension beyond the carina showed a statistically significant
higher risk for transient (less than one year) hypocalcemia (relative
risk = 1.76) after total thyroidectomy\textsuperscript{90}.

Van Slycke and colleagues reported that the higher risk of postoperative
complication is influenced by the surgical approach chosen: out of 95
thyroidectomies performed for RGs, eighty patients (84\%) were operated
by cervicotomy and 15 (16\%) by cervicosternotomy. The latter group had
a higher risk of temporary recurrent laryngeal nerve palsy (21\%)
compared to cervicotomy (4\%) and standard thyroidectomy (3\%); also,
the risk of temporary hypocalcemia after cervicosternotomy was higher
than with transcervical approaches \textsuperscript{62}. In addition,
another study highlights how postoperative complications associated with
RG surgical removal are low in the hands of experienced, high-volume
thyroid surgeons, regardless of transcervical or transthoracic
approach\textsuperscript{91}. Instead, the presence of RG was
statistically significant for being an independent predictor of any
complication (OR 2.1), when controlling for age, BMI, gender, and
race\textsuperscript{91}.

Tracheomalacia remains the most dreadful complication in the case of
large RGs, despite its incidence seems to be very
low\textsuperscript{92}. In a series of 40 patients subjected to
thyroidectomy with sternotomy, tracheomalacia was reported in 3 cases,
in absence of any patient- or thyroid-related factor significantly
associated with its development: one patient required tracheal resection
with anastomosis, and two patients required
tracheostomy\textsuperscript{92}. In another paper, 17 cases of
tracheomalacia out of 106 cases were reported, probably caused by
long-standing tracheal compression from RG: this study suggested that
prolonged intubation was sufficient to resolve airways collapse without
tracheal reconstruction in all cases\textsuperscript{93}. Zuo et al.
reported how tracheomalacia could be successfully managed
intraoperatively by suspending the trachea to the overlying skin with
Prolene stitches, despite the fact that they didn't exhibit either the
exact number of patients affected or the long-term
outcomes\textsuperscript{94}. Despite all the aforementioned
complications, RG was not considered a contraindication for outpatient
surgery: in a recent national survey conducted by the American
Association of Endocrine Surgeons, the diagnosis of RG had no or minimal
effect on same-day discharge\textsuperscript{95}.

The main issue in the analysis of the complications of surgery for RGs
remains the non-standard definitions and characterizations. For
instance, postoperative vocal cord dysfunction may be diagnosed by using
a mirror\textsuperscript{52}, flexible laryngoscopy\textsuperscript{57},
or a mixture of both\textsuperscript{82}. The timing of what constitutes
a ``permanent'' hypocalcemia changes (after 6\textsuperscript{57},
versus after 12 months\textsuperscript{53}); the same is true for
hematoma/seroma that should be considered only when needing revision
surgery according to some but not all the authors. To overcome these
limitations, the use of the Clavien-Dindo system may be a solution:
proposed in 1992 and revised in 2004, it appears reliable as a
compelling tool for quality assessment in surgery worldwide. This
classification system was reported as simple, reproducible, logical,
useful, and comprehensive\textsuperscript{96} and it is beginning to be
implemented also in thyroid surgery\textsuperscript{97}.

\textbf{Conclusions}

RG is not an uncommon encounter for head and neck surgeons. Its
management requires a long-standing experience in the classical
transcervical approach that may be sufficient in over 90\% of treated
cases. Despite a growing body of publications, we still have no shared
definition of RG and this continues to bring in heterogeneity in the
literature because it hampers a formal comparison and synthesis of the
results. We believe that reaching an international consensus among head
and neck and endocrine surgeons on the very definition and
classification/grading of RG is a priority in order to seriously compare
outcomes by data pooling and to increase the evidence in this field. A
second priority is the definition of the natural course of this
condition since it is likely in the near future that we will face more
and more incidental RG as the use of neck imaging is becoming
widespread.

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\textbf{List of Figures}

\textbf{Figure 1.} A modified PRISMA flowchart for selection and
inclusion of the relevant studies in the present review.

\textbf{Figure 2.} High resolution CT sequences highlighting a bulky
goiter extended in the retrosternal mediastinum. A-B: axial scans; C:
sagittal scan; D: coronal scan. A mild tracheal compression could be
noticed ().

\textbf{List of Tables}

\textbf{Table 1.} An overview of the most recent publications reporting
surgical outcomes for transcervical and/or combined approaches for
retrosternal goiter. CT, computed tomography; CXR, chest
x-ray/radiograph; HEM, hemorrhage; HT, hemithyroidectomy; MRI, magnetic
resonance imaging; NA, not available; PHC, permanent hypocalcemia;
PRLNP, permanent recurrent laryngeal nerve palsy; RG, retrosternal
goiter; TransTx, sternotomy; STT, subtotal thyroidectomy; TransCx,
transcervical; TRACH, tracheomalacia; TT, total thyroidectomy, US,
ultrasound.

\textbf{Hosted file}

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