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”2, and a historical overview of the over ten
definitions available has just been published5.
Notably, Rios et al. analyzed the various criteria to define RGs and
they found none to be clinically meaningful6. 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 RG7. Since an authoritative
international consensus has not been reached, the most recent literature
is still heavily affected by these heterogeneous definitions (seeTable 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) RG8.
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), 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
findings9. In these cases, a missed gland can be
diagnosed only when postoperative TSH levels remain unchanged or a
(functional) imaging of the chest is performed10–13.
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 Lung14. Migration of the median
anlage may also lead to a presternal goiter, and in 2019 the seventh
case worldwide was reported15. Sometimes, after
subtotal thyroidectomy, patients may present with only a residual
central mediastinal mass shifting the trachea laterally
(“pseudo-primary RG”)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
lung19,20.
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 question21. 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
goiter22, 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.