Pediatric Versus Adult Papillary Thyroid Carcinoma: Different Diseases Requiring Different Surgical Approaches-Juniper publishers
Juniper publishers-Journal of Head Neck
Introduction
Differentiated thyroid carcinoma is rare in young age
and represents 0.5% to 3.0% of childhood carcinomas: the incidence
increases with age, and peak incidence is observed between 15 and 19
years of age [1]. Even at large referral centers, only few pediatric
thyroid cancers are treated every year; it may take ≥30 years for a
major center to collect a series of 100 children and adolescents with
thyroid cancer [2]. Papillary thyroid cancer (PTC), the most common type
of differentiated thyroid cancer, spreads predominantly via the
lymphatics to the local draining lymph nodes: cervical lymph node
involvement in 60% to 80% of cases and lung metastases at diagnosis in
20% of cases [3]. Since pediatric thyroid cancer is such a rare disease,
treatment recommendations have been based on expert opinion and
retrospective data collected from different practices over decades
[4-6]. Given the paucity of evidence-based pediatric data, guidelines
for adult thyroid cancer occasionally have been generalized to children,
treating them “just like little adults.” Such extrapolations may not be
warranted, in particular when it comes to postoperative morbidity after
thyroidectomy [7].
Traditionally, in most institutions, the therapy for
pediatric and adolescence PTC has been the same as for adults, aimed to
the eradication of all clinical and subclinical neoplastic foci both at
thyroid and lymph-node level. The reasons for such an approach were
- To have a better progression-free survival and overall survival,
- To detect subclinical metastases by radioactive iodine (RAI) scintigraphic scan and treat them by RAI ablation,
- To make the value of serum thyroglobulin level a very sensitive marker of post-treatment relapse, and
- To avoid possible dedifferentiation of occult neoplastic microfoci over time [8]. PTC in children and adolescents is treated in similar fashion as that in adults, primarily because of rarity of disease in pediatric population and lack of availability of pediatric PTC treatment guidelines [9].
As well as in adults, the treatment of PTC is based
on the combination of three therapeutic modalities: surgery, hormone
replacement with levothyroxine, and radioiodine treatment. Surgery
ranges from lobectomy to total thyroidectomy accompanied by different
cervical lymphadenectomies. Latest guidelines recommend total
thyroidectomy, mainly for tumors larger than 1 cm associated with
cervical dissection of central or lateral compartment block if lymph
node metastases are seen in preoperative imaging or during the surgery
[10,11]. The main surgical complications include persist enthypo
parathyroidism and laryngeal nerve damage that may cause a wide spectrum
of clinical consequences: from hoarseness to total vocal cord
paralysis, with need for definitive tracheotomy [12]. Thus, most
societies recommend radioiodine ablation in the vast majority
of patients under 45 years old but none of them make specific
recommendations for children and adolescents [10,13].
In contrast to adults, pediatric PTC has some distinctive
differences such as
- Larger primary tumor at the time of diagnosis,
- High prevalence of neck lymph nodes and distant metastases (DM) at the time of diagnosis,
- The high risk of recurrences [13], and
- Multifocality [14,15]. Nevertheless, advanced pediatric cancers are more likely to respond to therapy and have a better prognosis compared to their adult counterparts [16].
The unusual association between the aggressive presentation
of pediatric PTC and its favorable prognosis is behind the
controversy regarding its most appropriate initial management,
particularly when it comes to choose between total thyroidectomy
and thyroid lobectomy. Despite its seemingly aggressive biologic
behavior, pediatric PTC is considered a favorable prognosis
cancer.
An important difference between thyroid carcinoma in
pediatric and adult age is related to the high prevalence of
expression of sodium-iodide transporter (NIS) in metastatic
focus found in children [17]. In the absence of stimulation of
thyroid-stimulating hormone (TSH), the expression of NIS is
undetectable in 65% of papillary tumors in patients under 20
years of age [18]. In contrast, the expression of NIS is absent or
negligible in 90% of differentiated carcinomas in adults [19].
The greater expression of NIS in the pediatric population results
in greater responsiveness to radioiodine treatment and better
prognosis. In young patients, the recurrence risk increases in
patients that do not express the protein NIS when compared
to those that express it. Thus, the degree of NIS expression
correlates with radioiodine avidity by metastases and lower
clinical recurrence rates [20]. The management of patients
with PTC consisted basically of primary surgery followed by
evaluation for RAI treatment. Criteria for RAI ablation in patients
with PTC was tumor size >1cm, lymph node metastasis (LNM),
presence of extra thyroid extension, macroscopic postoperative
residual disease in the neck, and/or DM [21,22].
Another important difference between PTC in
pediatric
and adult age was represented by a very high sensitivity shown
by pediatric PTC to hormonal manipulation consisting of
L-thyroxine administration at TSH-suppressive doses that can
inhibit normal and neoplastic proliferation, thus preventing
cancer progression and relapse. These findings, together with
the significant morbidity of radical surgery and RAI therapy, led
to the proposal by several groups for a conservative approach
for pediatric PTC, not aimed at the eradication of all clinical and
subclinical neoplastic foci by surgery plus RAI therapy, but rather
the removal of only the grossly detectable disease, followed
by TSH-suppressive hormone therapy to control subclinical
disease, and reserving more aggressive approaches to selected
cases. All these results highlight the extremely high sensitivity
to hormonal manipulation that can control subclinical disease
and prevent the occurrence of clinical relapse. This sensitivity
to hormonal manipulation seems to represent an important
biological difference with respect to adult PTC.
All these observations are in keeping with the proposal
made by Cady et al. [23] on clinical grounds and supported by
genetic findings that thyroid carcinomas in children and adults
are different diseases and not merely different stages in a single
disease, with specific prognosis and therapy needs [23,24]. Thus,
the category of microcarcinoma (including tumors with less than
1cm), commonly used in adults, should be avoided in children,
since a 1cm tumor constitutes a very important finding in this
age group. Regarding the molecular biology of these tumors,
apparently RET-PTC rearrangements occur in childhood more
frequently than in adults, especially in the radiation-related
tumors [25].
The prognosis remains excellent with a low rate of
mortality even in advanced stages [26], but local recurrence
is more frequent than in adults, leading to reoperation [27].
Predictive factors of recurrence remain incompletely known,
although some factors have been suggested from retrospective
studies [15,28,29]. They include young age (<16 years), lymph
node involvement or DM at diagnosis, and histopathologic
characteristics (mainly the diffuse sclerosing papillary variant,
which is frequent in children) [30]. Among them, nodal status is
considered one of the most statistically significant predictors for
an adverse prognosis in young patients [31-33].
The American Thyroid Association (ATA) guidelines for
pediatric PTC doesn’t recommend prophylactic lymph node
dissection (LND) in children clinically negative for LNM due to
the higher rates of complications as recurrent laryngeal nerve
injury and hypocalcemia, which ranges from 1-4% even in
experienced hands [34-38]. Moreover for ATA, in patients with
pre-operative evidence of central and/or lateral neck metastasis,
a therapeutic LND should be performed. For this kind of
patients, LND is associated with a decreased risk of persistent/
recurrent locoregional disease as well as the potential to
increase the efficacy of RAI ablation for distant metastases
[39,40]. According with ATA, Borson-Chazot et al. [41] suggest
a lymph node dissection with the addition of RAI ablation, in
presence of palpable cervical lymph nodes at diagnosis because
it is associated with more invasive forms of malignancy and is a
predictive factor of recurrence.
Tumors with diffuse sclerosing variant are more
common
in younger patients between 15 and 30 years of age according
to Koo et al. [30]. In their study pediatric patients with diffuse
sclerosing variant had a higher incidence of bilateral thyroid
involvement, extrathyroidal extension, lymph node involvement
and recurrence. Also for Lloyd et al. [42], the diffuse sclerosing
variant tumors are characterized by diffuse involvement of the
thyroid (both lobes are typically involved), lymph node and lung
metastasis, but the tumors do not usually lead to the demise of
the patient.
Recently, indications for an optimal surgical management
have been proposed [15,43]: patients with tumor smaller
than 2cm, limited to one lobe, no lymph node involvement and
absence of distant metastasis can be treated with conservative
surgery. In absence of these parameters, radical surgery should
be performed.
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