Hürthle cell carcinoma: current perspectives
OncoTargets and Therapy
Hürthle cell carcinoma: current perspectives
Sara Ahmadi 2
Michael Stang 1
Xiaoyin “Sara” Jiang 0
Julie Ann Sosa 1 3 4
0 Department of Pathology, Duke University Medical Center
1 Section of endocrine Surgery, Department of Surgery
2 Division of endocrinology, Department of Medicine
3 Duke Clinical Research institute, Duke University Medical Center , Durham, NC , USA
4 Duke Cancer institute
Hürthle cell carcinoma (HCC) can present either as a minimally invasive or as a widely invasive tumor. HCC generally has a more aggressive clinical behavior compared with the other differentiated thyroid cancers, and it is associated with a higher rate of distant metastases. Minimally invasive HCC demonstrates much less aggressive behavior; lesions ,4 cm can be treated with thyroid lobectomy alone, and without radioactive iodine (RAI). HCC has been observed to be less iodine-avid compared with other differentiated thyroid cancers; however, recent data have demonstrated improved survival with RAI use in patients with HCC .2 cm and those with nodal and distant metastases. Patients with localized iodine-resistant disease who are not candidates for a wait-and-watch approach can be treated with localized therapies. Systemic therapy is reserved for patients with progressive, widely metastatic HCC.
HCC was first described by Ewing in 1928; it represents
only 3% of all thyroid cancers6 and is currently classified
as a variant of follicular carcinoma according to the World
Health Organization (WHO).7 However, recent data have
called into question whether HCC is indeed a variant of
w u follicular carcinoma or a distinct entity with a different
//:ww loan mutational profile, unique pathologic signature, and clinical
ttsph rrsep behavior. A recent study of 27 Hürthle cell tumor samples
rom oF (8 Hürthle cell adenomas, 9 minimally invasive HCCs, and
ded 10 widely invasive HCCs) used mass spectrometry-based
lao genotyping to interrogate hot spot point mutations in the
ndow most common thyroid oncogenes, and real-time polymerase
yp chain reaction was used to assess for common oncogenic
rhea fusions.8 Transcriptomes for widely invasive HCC were
ndT compared with follicular carcinoma expression array profiles
tsa obtained from the Gene Expression Omnibus. The authors
raeg reported only 11% RAS mutations and no Pax8-PPARγ
rearcoT rangements in HCC tumor samples; in contrast, follicular
O carcinomas had a 45% RAS mutation rate and rearrangements
of Pax8-PPARγ in 25%–60% of cases. This study also showed
that the chromosomal copy number profiles of HCCs were
distinct from follicular carcinomas, as large regions of gain
on chromosomes 5, 7, 12, and 17 are observed in HCC, but
they are not seen in follicular carcinoma.
HCC is subdivided based on histology into either
minimally invasive or widely invasive subgroups. Minimally
invasive carcinomas are fully encapsulated tumors with
microscopically identifiable foci of capsular or vascular
invasion (,4 foci), in contradistinction to widely invasive
tumors, which have extensive vascular invasion (.4 foci)
and extrathyroidal invasion. However, there is a lack of
consensus in the literature, as some centers consider
encapsulated tumors with only microscopic capsular invasion to
be minimally invasive HCCs, whereas encapsulated tumors
with minimal vascular invasion (,4 foci) are classified
separately. Patients with a minimally invasive encapsulated HCC
(microscopic capsular invasion with no vascular invasion)
often experience a good prognosis.9
Studies have reported that HCC with focal vascular
invasion (,4 foci) can also be associated with less
aggressive behavior similar to that of HCCs with minimal
capsular invasion and no vascular invasion. In a retrospective
single-institutional study by Xu et al, the experience of
276 patients with encapsulated differentiated thyroid cancers
(224 encapsulated papillary thyroid cancers, 34 encapsulated
follicular carcinomas, and 16 encapsulated HCCs) showed
that extensive vascular invasion ($4 foci of vascular
invasion) is an independent predictor of recurrence in patients
with encapsulated differentiated thyroid cancers; indeed, the
risk of recurrence was 42% in patients with extensive vascular
invasion compared to 1% in patients with no vascular
invasion or focal vascular invasion (,4 sites).10 In a
retrospective, single-institution study of 50 patients with encapsulated
HCC, Ghossein et al also reported that the pathologic finding
of .4 foci of vascular invasion is the most powerful
predictor of recurrence and compromised recurrence-free survival
(P,0.001) among patients with encapsulated HCC. In this
study, patients with no vascular invasion or ,4 foci of
vascular invasion had 100% recurrence-free survival at 5 years
compared to 20% recurrence-free survival among patients
with .4 foci of vascular invasion.11
Factors other than vascular invasion have been reported
to be associated with overall survival in patients with HCC.
Goffredo et al identified 3,311 patients .18 years of age with
a diagnosis of HCC and 59,585 patients with papillary and
follicular thyroid cancers from the Surveillance,
Epidemiology and End Result (SEER) database from 1988 to 2009 and
determined that older age, larger tumor size, extrathyroidal
tumor extension, and not undergoing surgery were
independently associated with reduced overall survival among
patients with HCC. HCC was more common in older men,
and it appeared to be more aggressive compared to other
differentiated thyroid cancers.12 In another study, Chindris et al
identified 173 patients with HCC between 2001 and 2012;
male gender and American Joint Committee on Cancer TNM
(AJCC-TNM) Stages III–IV were independent risk factors
for recurrence or death among patients with widely invasive
HCC. The cumulative risk of recurrence or death within
5 years of diagnosis was 91% in men with Stages III–IV
disease compared to 74% in women with the same stages
of disease; the 5-year cumulative probability of recurrence
or death in patients with AJCC-TNM Stages I–II was 0%
among women compared to 17% among men.13
One of the fundamental obstacles to expedited treatment
is our inability to establish the diagnosis of HCC
preoperatively, either radiologically or with cytology based on
fine needle aspiration (FNA). In the absence of identifiable
invasive or metastatic disease on imaging studies, it is
usually impossible to distinguish between a benign Hürthle cell
process or neoplasm and HCC; for this reason, histologic
evaluation based on a surgical specimen is generally
necessary. Ultrasound alone is unable to distinguish HCC from
other histologic variants, as it can clinically demonstrate a
spectrum of sonographic findings from hypoechogenicity to
hyperechogenicity14 (Figure 4).
FNA diagnosis of a Hürthle cell neoplasm (HCN) can
typically be classified as a follicular lesion (FLUS) or atypia
of undetermined significance (AUS) with Hürthle cell
features (AUS/FLUS/Hürthle cell lesion of undetermined
significance [HLUS], Bethesda III). Both benign and
malignant oncocytic lesions can demonstrate marked cytologic
atypia, complicating the process of diagnosis on biopsy alone
(Figure 5). Overall, the projected risk of malignancy for
this diagnostic category is 5%–15%. A cytologic diagnosis
of suspicious for HCN (Bethesda IV) carries a projected
15%–30% risk of malignancy.15 However, the true risk of
malignancy for each Bethesda diagnostic cytologic category
varies by institution, and such institutional data should be
examined regularly and made available to clinicians.16,17
In patients with a cytologic finding of a HLUS, possible
management strategies include repeat ultrasound-guided
FNA (potentially paired with molecular testing) and close
surveillance if the molecular testing is reassuring, or surgical
excision for the purpose of definitive diagnosis. In patients
with FNA cytology demonstrating a HCN, diagnostic
surgical excision should be performed if molecular testing is not
done or if it is inconclusive.9
Several studies have examined clinical variables that
may be more indicative of malignancy in patients with FNA
results that are suspicious for a HCN (Bethesda IV). In a 2010
retrospective single-institution study, Kim et al reviewed
LEFT SAG MID
1 L 3.28 cm
1 L 1.88 cm
clinical features, preoperative imaging, and pathology reports
of 57 patients with an FNA cytology consistent with HCN
who underwent thyroidectomy. This study reported that on
multi-logistic regression, patients with nodules .1.5 cm
have a higher risk of being associated with a thyroid
malignancy compared to those with nodules ,1.5 cm (odds ratio
8.00; 95% confidence interval [CI] 1.92–33.37). This is
even more pronounced in older patients, as the predicted
probability of malignancy in patients .45 years of age with
a tumor .1.5 cm reached 65% in this study.18 It should
be noted that this study examined the risk of any thyroid
malignancy and included 9 papillary carcinomas and
7 follicular carcinomas in addition to 10 HCCs. A similar
retrospective single-institution study by Giorgadze et al
reviewed 169 FNAs that were associated with a cytologic
diagnosis of a HCN and reported that the overall risk of
thyroid malignancy was 55% for nodules $2 cm compared
to 45% for nodules ,2 cm (P,0.0001). Malignancy risk
was also higher in older patients, as 82% of nodules among
patients .40 years of age represented a thyroid cancer vs
18% in those ,40 years of age (P,0.0001).19 Again, the
specificity of these findings for HCC is limited, as this study
included 53 cases of HCC, 19 cases of papillary carcinoma,
3 follicular carcinomas, and 1 medullary carcinoma.
Examination of factors related specifically to the
likelihood of HCC is limited, as many of the studies examining
this question have been small, single-institution, retrospective
reviews. A 1998 study by Chen et al found that nodule size is
the most significant predictor of malignancy. Of 57 patients
examined, 20 had HCC, and their tumors were significantly
larger (4.0±0.4 cm) than those with Hürthle cell adenomas
(2.4±0.2 cm).20 A summary of similar studies is presented
in Table 1. Tumor size consistently has been shown to be
associated with the increased probability that an HCN on
FNA will prove to be a HCC. It should be noted that most
of these studies were done prior to formalization of FNA
cytology criteria according to the Bethesda schema, and it
is unclear as to how these findings would translate into the
current Bethesda lexicon. More robust data are needed before
clear criteria can be defined for establishing the likelihood
of HCC in the preoperative setting.
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Molecular marker analysis in thyroid cytology has been
studied predominantly in thyroid nodules with indeterminate
cytology. The 3 commercial tests for which the most data are
available in validation trials are the Afirma Gene Expression
Classifier (GEC, mRNA expression of 167 genes),21 a 7-gene
panel of genetic mutation and rearrangement testing,22 and a
newer multiplexed next-generation sequencing (NGS) panel
examining .400 known drivers of oncogenesis in thyroid
Alexander et al employed the GEC to evaluate 265
nodules with Bethesda III, IV, and V cytology results over
19 months in a prospective, multicenter blinded study.
All thyroid nodules were $1 cm, and all study subjects
had corresponding histological specimens along with fine
needle biopsies. The negative predictive value (NPV) and
positive predictive value (PPV) of the GEC were 95% and
38%, respectively, for aspirates classified as AUS or FLUS
(Bethesda III), and 94% and 37% for aspirates classified
as follicular neoplasm/HCN or suspicious for follicular
neoplasm (Bethesda IV). However, of the 21 patients with
Hürthle cell adenomas in this study, 17 (81%) were
classified as “suspicious” on the GEC. In this setting, use of the
GEC in Hürthle cell lesions may well be associated with
a relatively high false-positive result rate.21 McIver et al
employed the GEC to evaluate 60 nodules that were reported
to be either suspicious for follicular neoplasm/HCN or AUS/
FLUS in patients who were not at high risk for malignancy
(no history of head and neck irradiation, no family history
of thyroid cancer, no prior history of thyroid cancer, and no
worrisome imaging characteristics). There were 31 patients
with cytologies suspicious for follicular neoplasm/HCN who
underwent surgery; 27 of these patients had suspicious GEC
results, and 4 were found to be malignant. PPV and NPV
of the GEC were 15% and 75%, respectively, for aspirates
classified as suspicious for follicular neoplasm/Hürthle call
neoplasm.23 In another study, Brauner et al studied 72 patients
with cytologies suspicious for HCN or AUS/FLUS with a
predominance of Hürthle cells who underwent GEC
testing between 2010 and 2014. Forty-five (63%) GEC results
were classified as suspicious for malignancy; 43 (96%)
of these patients underwent surgery, and 6 (14%) were
found to be malignant.24 Similarly, Lastra et al found that
only 15% (2 of 13) of patients with a cytology suspicious
for HCN and suspicious GEC harbored a malignancy.25
Wu et al also found an increased rate of “suspicious”
GEC results in nodules with Hürthle cell predominance
(77.4% vs 50.5% for nodules without Hürthle cell
predominance, P,0.01), but there was no difference in the rate of
malignancy (25.8% vs 25.3%).26 Together, these data raise
concern that there is an increased rate of suspicious GEC
results in Hürthle cell lesions despite there being a relatively
low risk of malignancy on surgical histology.
Nikiforov et al studied a panel of common thyroid
cancer mutations, including BRAFV600E, NRAS, HRAS, and
KRAS, as well as RET/PTC and Pax8/PPARγ
rearrangements, in 1,056 consecutive thyroid FNA samples with
Bethesda III, IV, and V cytology results and reported a PPV
of 87%–95%. The NPV of the same mutational panel was
86% for Bethesda IV cytology and 94% for Bethesda III
cytology.22 However, there were only 11 follicular
carcinomas in the study cohort, and the published results did not
specify whether any of these were oncocytic in nature and
consistent with a HCC. Mutations were detected in only 5 of
11 follicular carcinoma samples (4 RAS and 1 Pax8-PPARγ),
yielding a sensitivity of 45% for this histology subgroup. As
RAS mutations are less common (and Pax8-PPARγ
mutations nonexistent) in HCC compared to follicular carcinoma,8
it would follow that this limited mutation panel testing is less
reliable in detecting HCC.
More recently, Nikiforov et al applied NGS
technology to greatly expand the simultaneous testing of thyroid
cancer-related genetic markers (ThyroSeq V2) in thyroid
FNA samples. In a series of 143 nodules (39 malignant) with
the cytologic diagnosis of follicular neoplasm/suspicious
for follicular neoplasm, the test performance yielded a 90%
sensitivity, 93% specificity, 96% NPV, and 83% PPV27 for
detection of any thyroid malignancy based on final surgical
pathology. The study included only 3 HCC cases, of which 2
had a mutation detected, and the lesion with a false-negative
result was reported as a minimally invasive HCC. Therefore,
use of molecular testing in the evaluation of thyroid nodules
with Hürthle cell cytologic features should be understood
to have limitations, as HCC has had a limited
representation in most clinical studies. Molecular testing should not
replace clinical judgment and consideration should be given
to the pretest probability of malignancy based on clinical
risk factors, ultrasound imaging, and cytologic findings in
interpreting the results of any molecular marker testing of
Stratification of risk
HCC is currently designated by the WHO as a
histopathologic variant of follicular carcinoma, and this is echoed in the
American Thyroid Association (ATA) and National
Comprehensive Cancer Network (NCCN) treatment guidelines,
with HCC following the same risk stratification as that of
follicular carcinoma. For the ATA, intrathyroidal encapsulated
tumors with minor capsular or vascular invasion (,4 foci)
or #5 metastatic lymph nodes where the foci of metastases
are ,0.2 cm are considered to be low risk. Intermediate
risk of recurrence is defined by vascular invasion, minimal
extrathyroidal extension, or .5 metastatic lymph nodes
(0.2–3 cm). High-risk patients include those with macroscopic
extrathyroidal extension, incomplete tumor resection, distant
metastases, or metastatic lymph nodes .3 cm.9 The NCCN
guidelines for HCC (Version 1.2016) describe minimal
vascular invasion as a few microscopic foci (#4) of invasion in
an intrathyroidal HCC. The NCCN guidelines assign these
patients to a low-risk group.28
.79 Surgical management of HCC
/yb The mainstay of treatment for all differentiated thyroid
can.com cers is surgical resection, and HCC is no exception. Indeed,
rsse . due to the relatively reduced avidity of HCC for radioactive
.vdoep lsyeon iodine (RAI) and the resultant compromised efficacy of
treatw u ment, the completeness of surgical resection is of paramount
/ww lan importance. Since it is impossible to make the cytologic
tsp rse diagnosis of HCC preoperatively, the 2 key decision points
trohm ropF in surgical management are that of planning the initial extent
fd of surgery and whether further surgical resection (completion
dea thyroidectomy) is warranted once the diagnosis of HCC is
lonw histologically confirmed.
yod In general, thyroid surgery is approached with preference
repa for diagnostic thyroid lobectomy unless clinical features
hT prompt considering removal of the entire thyroid gland at
and the primary surgery. A personal history of craniocervical
trsge radiation does not increase the risk of HCC; however, it is
oaT an independent risk factor for developing papillary thyroid
cnO cancer, and significant exposure (particularly in childhood
or adolescence) warrants upfront total thyroidectomy.9 Other
clinical considerations that would prompt initial total
thyroidectomy include presence of dominant contralateral nodules
or preexisting diminished hormone production necessitating
As previously discussed, the predominant clinical feature
associated with an increased risk of HCC in those patients
with indeterminate Hürthle cell findings on FNA is the size
of the nodule (Table 1). A nodule $4 cm is associated with
an increased risk of HCC, and the ATA guidelines
accordingly prescribe upfront total thyroidectomy.
A thorough history and physical examination are critical
in the initial evaluation of patients with the potential
diagnosis of HCC, since dysphagia, dyspnea, and voice change
as well as the physical examination finding of a palpable
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hard, immobile mass are concerning for an invasive
process. Preoperatively, these patients need laryngoscopy to
evaluate vocal cord function and the integrity of the recurrent
laryngeal nerves. Cross-sectional imaging such as computed
tomography (CT) and magnetic resonance imaging (MRI)
is essential in patients with a suspicion for locally advanced
disease, including concern for invasion of the aerodigestive
tract and/or major vessels of the neck, as it can visualize
deeper anatomic compartments not readily imaged by
ultrasound. In the past, clinicians were advised against CT
performed with intravenous contrast, as the iodine load was felt
to delay treatment with RAI; however, more recent studies
have clarified adequate clearance of this iodine, with return
of urinary iodine levels to baseline within 1 month for most
patients with normal renal function.29
HCC is classified as a variant of follicular carcinoma;
as a result, many believe that it spreads hematogenously,
with rare lymph node metastasis as is the case for follicular
carcinoma.30 However, several studies have documented
lymph node metastasis in 5.3%–13% of HCC cases.12,13,31,32
Therefore, the finding of a HCN should prompt thorough
ultrasound evaluation of all compartments of the neck prior
to surgery. In a study of 39 cases of HCC, 3 (8%) were found
to have lymph node metastasis at presentation (1 ipsilateral
central compartment, 2 ipsilateral central and lateral neck
compartments) and warranted neck dissections.31 All 3 cases
of node-positive disease were associated with a primary
tumor .5 cm in size. Another study examining 173 HCCs
treated from 2001 to 2012 found a 9.2% incidence of
nodepositive disease; all cases were associated with a widely
invasive or poorly differentiated phenotype.13 Seven of 173 cases
(4.0%) were limited to the central compartment, while 9
(5.2%) involved the lateral compartments. The largest study
to date examined 3,311 cases of HCC, with documentation of
node-positive disease in 5.3%.12 Implications of this study are
limited, since only 73.9% of patients had any lymph nodes
Once an HCC is histologically confirmed following
diagnostic thyroid lobectomy, consideration should be given to
performing a completion thyroidectomy. Minimally invasive
HCC is considered to be at a low risk of recurrence by both
the ATA and NCCN guidelines, and is very often treated
with lobectomy alone. In one of the large clinical studies
examining outcome for minimally invasive HCC, all 39 cases
(100%) were found to be without evidence of recurrence
or disease-specific mortality, with a median follow-up of
69.8 months.13 However, most patients were indeed treated
with either total thyroidectomy or lobectomy followed by
completion thyroidectomy. Of 23 patients with minimally
invasive HCC treated over 60 years, none experienced a
recurrence or succumbed to their disease.32 The majority
(88%) of patients with minimally invasive HCC were
managed conservatively with thyroid lobectomy alone.
Thyroid cancers ,1 cm usually do not prompt aggressive
surgical treatment or completion thyroidectomy. However,
it is important to note that not all sub-centimeter thyroid
cancers have the same excellent prognosis. Hürthle cell
histology is reported to be an independent risk factor for
reduced survival even among tumors that are ,1 cm.
Studying 564 cases of follicular carcinomas (N=371) and HCCs
(N=193) ,1 cm compared to 22,174 cases of papillary
thyroid microcarcinomas from the SEER database between
1988 and 2009, Kuo et al reported that follicular and Hürthle
cell histologies remain independent risk factors for reduced
10-year disease-specific survival even after adjustment for
patient age, type of surgery, RAI treatment, extrathyroidal
extension, and nodal and distant metastases (hazard ratio 5.3,
95% CI 2.78–10.10).33
In cases of widely invasive HCC, the risk of recurrence
is 73%, and therefore, they should be placed in the ATA
intermediate- or high-risk categories, prompting adjuvant
treatment with RAI.32 For these patients, completion
thyroidectomy is mandated.
Differentiated thyroid cancer cells express the
thyroidstimulating hormone (TSH) receptor and respond to TSH
by promoting cell division and tumor growth. Employing
supra-physiological doses of levothyroxine can suppress TSH
levels, potentially decreasing the risk of recurrence.9 The goal
for the degree of TSH suppression following surgery is
determined by the patient’s overall risk of recurrence,
incorporating the patient’s response to therapy as well as any comorbid
conditions that could be associated with an increased risk of
complications with prolonged TSH suppression. Completely
resected minimally invasive HCC is categorized by both the
ATA and NCCN as being at low risk of recurrence, and it
does not require TSH-suppressive therapy; serum TSH may
be kept within the low-normal reference range (0.5–2 mU/L).
In patients with structurally incomplete response to therapy,
serum TSH should be kept at ,0.1 mU/L indefinitely, unless
there is a contraindication. In patients with an incomplete
biochemical response to therapy and those with high-risk HCC
and an excellent or indeterminate response to therapy, TSH
should be maintained at between 0.1 and 0.5 mU/L, taking
into account thyroglobulin levels, trends in those levels over
time, and the risks of TSH suppression.9
Overall, treatment with RAI is not routinely recommended
in patients at a low risk of recurrence; it should be reserved
for patients at an intermediate or high risk of recurrence.
Examining the utility of RAI in minimally invasive follicular
carcinoma and HCC, Goffredo et al identified 617 minimally
invasive follicular carcinomas in the National Cancer Data
Base (NCDB); 333 had only capsular invasion, and 284 had
minor vascular invasion with or without focal capsular
invasion. They found that 75% of the minimally invasive
follicular carcinoma group with only capsular invasion underwent
total thyroidectomy, and 52.6% received RAI; in comparison,
72.9% of the minimally invasive follicular carcinoma group
with only vascular invasion underwent total thyroidectomy,
and 62.1% received RAI. These findings demonstrate that
US health care providers have been managing minimally
invasive follicular carcinoma more aggressively than
suggested by guidelines, which could be due to the absence
of consensus across pathologists, experts, and guidelines
regarding criteria for the diagnosis of minimally invasive
There is controversy with regard to RAI avidity of HCC
and the effect of RAI treatment on survival of patients with
HCC. Most studies that have evaluated the efficacy of RAI
for HCC are small, retrospective, single-institutional series,
likely due to the rarity of HCC.
In an old study, Lopez-Penabad et al reviewed 127 patients
with HCN (89 patients with HCC and 38 patients with Hürthle
cell adenoma) who were treated from 1944 to 1955 and
reported 38% RAI avidity in patients with HCC. This study
showed that RAI therapy is associated with survival benefit
in patients with HCC when it is used primarily for ablation
rather than when residual disease is believed to be present.35
In a retrospective single-institution study, Besic et al reviewed
16 patients with HCC and distant metastases; all these
patients underwent thyroid hormone withdrawal. Scanning
demonstrated uptake (range 0.1%–12%) in 11 of 16 patients
(69%).36 In another study, Besic et al evaluated 30 HCC
patients with distant metastases and reported RAI uptake in
metastases in 16 of 30 patients (53%), with uptake of $0.5%
in 9 of 30 patients (30%).37 At a nationwide level, Jillard
et al identified 1,909 patients with HCC who underwent
total thyroidectomy in the NCDB between 1998 and 2006.
Patients were included if they had AJCC-TNM pT1 tumors
with N1or M1 disease, and pT2–4 tumors with any N or M
disease status. This study showed an association between
use of adjuvant RAI and improved survival among patients
with HCC. Five- and 10-year survival for patients with
tumors measuring 2–4 cm who received RAI were improved
compared with those who did not receive RAI (97.8% and
87.8% vs 94.1% and 71.9%, respectively; P,0.001).
Fiveand 10-year survival were also improved for patients with
tumors .4 cm who received RAI compared to those who
did not receive RAI (82.3% and 77.6% vs 62.3% and 56.9%,
respectively; P,0.001). Therefore, the authors concluded that
RAI is indicated in HCC patients who have tumors .2 cm
and and/or nodal and distant metastases (Figure 6).38
External beam radiation therapy (EBRT) is another treatment
option in patients with clinically evident gross
extrathyroidal extension that is incompletely resected. However, it is
important to balance the potential benefit of radiation with
.vdoep lsyeon stenosis, esophageal stricture, osteonecrosis, fibrosis, and
potential complications, including dental decay, tracheal
xerostomia.39 Intensity-modulated radiation therapy (IMRT)
uses 3-dimensional (3D) CT to map the tumor and also
computerizes dose calculations. It allows higher radiation
doses to be delivered to the tumor and minimizes the dose
received by surrounding tissues.40 In a study using the
NCDB, 106,374 patients with differentiated thyroid cancer
were evaluated; they included patients .18 years of age,
without distant metastases, who underwent cervical
radiation therapy to assess the impact of IMRT vs 3D-conformal
radiotherapy (3D-CT). Although not statistically significant,
comparison of overall survival between patients undergoing
60 80 100
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IMRT vs 3D-CT demonstrated a hazard ratio of 0.67 (95% CI
0.4–1.1; P=0.115) and trend toward improved overall
survival with IMRT.41
The role of radiation as an adjuvant therapy in patients
who have had complete resection of all locally invasive
disease is controversial.42–46 In the absence of persistent gross
residual disease, radiation is usually reserved for older patients
(.50 years) with tumors that are more likely to be
iodinerefractory (including HCC) and who are at high risk of early
cervical recurrence not amenable to surgical resection.
Radiation is seldom recommended as an adjuvant therapy in young
patients, and especially those with iodine-avid tumors.
Directed therapy for distant metastasis
Targeted therapies in patients with advanced thyroid cancer
are valuable tools to address malignant foci that arise in
critical locations and that are at high risk of causing
significant morbidity or mortality secondary to tumor infiltration
or compression of vital structures if they are not treated
expeditiously.9 Such critical locations include the brain,
spine, and bone (at risk of pathological fracture). Cervical and
mediastinal disease places key airway structures (eg, trachea,
larynx, major bronchi), as well as the digestive tract and great
vessels, at risk. These lesions may require treatment prior to
RAI therapy to prevent morbidity related to swelling that can
occur in some of these metastatic foci. The choice of specific
targeted therapy is dependent on tumor size and location,
patient preference, and discussion between all members of the
transdisciplinary disease management team. Frequently, this
communication is best accomplished in a multidisciplinary
tumor board setting.
The risk of bone metastases is likely increased in HCC
patients. Bone metastases in patients with differentiated
thyroid cancer including HCC are associated with significant
morbidity, including pain and pathologic fracture.47 Surgery
is the preferred treatment option for bone metastases that are
associated with structural instability or that are in critical
locations. A retrospective study of 109 patients with bone
metastases from thyroid cancer (71% with follicular
carcinoma) reported that complete resection of bone metastases in
young patients is associated with a significant improvement
in survival.48 Radiotherapy plays an important role in
treatment of bone lesions, since it can be used in isolation or to
complement surgery in cases of incomplete resection.9 In a
retrospective study of 32 patients with metastatic HCC, Besic
et al reported that the effect of EBRT on bone metastases
lasted from 13 to 165 months (median, 93 months).37 Another
treatment option is embolization of tumor vasculature;
this can be used for pain control, and it can also be used in a
neoadjuvant fashion prior to surgical resection, as these bony
metastases tend to be vascular and prone to intraoperative
bleeding. Radiofrequency ablation has also been reported to
reduce pain from thyroid cancer skeletal metastases.48–51
Localized therapies can also be effective treatment
options for HCC that involves the respiratory tract and
airways. Options include bronchoscopy with laser therapy for
intraluminal disease, endo-bronchial stenting to maintain
patency of airways that are compressed or the subject of
local invasion, surgical resection of the metastatic lesion,
and focused EBRT.
Overall, brain metastases are uncommon; they are usually
found in the setting of widespread metastatic disease and are
associated with a very poor overall prognosis. High-dose
glucocorticoids are usually recommended to decrease the
surrounding edema once brain metastases are identified.
Surgical resection is the preferred treatment option, unless
the lesions are very small and/or mutifocal. Stereotactic
radiation can be effective if ,3–5 small lesions are present,
and whole-brain radiation is required when there are
Some patients with widely metastatic HCC can survive for
many years with only minimal disease progression, and they
can remain relatively asymptomatic; thus, it is important to
identify which patients will likely benefit from a
wait-andwatch approach vs systemic therapy. Factors related to the
tumor, patient comorbidities, patients’ tolerance of
treatmentrelated morbidity and its impact on quality of life, and patient
preference, all should be incorporated into these complex
management decisions. It is unusual to initiate systemic
therapy for lesions that are ,1 cm; however, not all metastatic
lesions .1 cm require systemic therapy. Systemic therapy
should be initiated sooner if metastatic lesions are in
locations where continued growth would result in compromise of
critical surrounding structures. Systemic therapy should be
likely considered in the following cases: when patients have
symptoms of weight loss, muscle wasting, or fatigue, or other
constitutional symptoms attributable to their significant
disease burden; when the rate of progression of structural disease
is rapid enough that the disease is likely to cause morbidity;
or when additional metastatic foci are identified.
Currently, sorafenib and lenvatinib are the only US Food
and Drug Administration-approved multi-kinase inhibitors
available for RAI-refractory differentiated thyroid cancer.
Due to the relatively small number of such cases, there are
no published studies examining outcomes of systemic therapy
specifically for HCC. However, most published studies do
report the response rate of HCC to treatment. A prospective
randomized trial of lenvatinib vs placebo in the treatment
of RAI-refractory thyroid cancer included 70 HCC cases
(lenvatinib N=48, placebo N=22). Lenvatinib demonstrated
a progression-free survival hazard ratio of 0.22 (95% CI
0.10–0.51) in favor of treatment when compared to placebo.57
The DECISION trial was a multicenter, randomized,
doubleblind, placebo-controlled Phase III trial of sorafenib in 417
RAI-refractory thyroid cancers; it included 74 HCC cases.
The precise hazard ratio and CI for HCC were not published
as part of the DECISION trial; however, sorafenib was
reported to be associated with overall progression-free
survival advantage among the subset of patients with HCC.58
Vandetanib has also been studied in a European Phase II
trial in RAI-refractory differentiated thyroid cancer.
Unfortunately, the study included only 2 patients categorized as
having follicular carcinoma with oncocytic features, and both
were randomized to the placebo control group.59 A
multicenter, open-label, single-arm, Phase II study of axitinib in
52 advanced thyroid cancers included 8 HCCs, of which 2
demonstrated a partial response to treatment.60 There are
currently several studies with active recruitment exploring the
role of small-molecule inhibitors for iodine-refractory
differentiated thyroid cancer, including HCC. Based on Category
2A evidence, the NCCN guidelines recommend that
axitinib, everolimus, pazopanib, and sunitinib be considered in
patients with advanced HCC if clinical trials are not available
or appropriate.61 In general, these small-molecule inhibitors
can sometimes provide progression-free survival advantages
with a side-effect profile that is tolerable in properly selected
patients. However, they have not been shown to improve
either disease-specific or overall survival, and specific drug
activity in HCC is unlikely to be known due to the very small
number of HCC cases included in most trials.
Prognosis and follow-up
HCC is associated with more aggressive clinical behavior
compared to other differentiated thyroid cancers; for
example, it is more often seen with a higher rate of distant
metastases.12,33,35,62,63 In a retrospective study of 32 patients
with metastatic HCC, Besic et al reported estimated 5- and
10-year disease-specific survival rates of 81% and 60%,
During initial follow-up of patients with HCC, serum
thyroglobulin/thyroglobulin antibody (Tg/Tg Ab) levels on
levothyroxine therapy should be measured every 6–12 months.
In the ATA high-risk patients, more frequent measurements
may be appropriate. Time intervals between serum Tg/Tg
Ab measurement in the ATA low- to intermediate-risk HCC
risk of recurrence and unique response to therapy.9 RAI
scanning has a high false-negative rate in patients with HCC
due to the lack of iodine avidity in a majority of patients;
therefore, it is not recommended as the principle imaging
modality for surveillance.13 The ATA guidelines
recommend that fluorine-18-fluorodeoxyglucose positron emission
tomography (FDG PET) be considered in patients with
highrisk differentiated thyroid cancers, and those cancers with
elevated Tg levels and negative RAI scans. FDG PET may be
.vdoep lsyeon considered as part of initial staging in patients with invasive
HCC.9 Multiple studies have shown a high sensitivity of FDG
PET for HCC. In a retrospective single-institution study of
44 patients with HCC, Pryma et al reported a sensitivity of
95.8% and specificity of 95% for FDG PET scans in patients
with HCC.64 In a study of 12 patients with HCC, Lowe et al
found that FDG PET had a sensitivity of 92%; they also
noticed that half of the PET scans detected tumors not seen
on conventional imaging, which resulted in a change in
disease staging and management.65 In a retrospective study
of 17 HCC patients, Plotkin et al reported a sensitivity of
92%, specificity of 80%, PPV of 92%, and NPV of 80% for
FDG PET/CT for identification of HCC.66
Cross-sectional imaging including CT and MRI of the
neck and chest should be considered in the setting of bulky
recurrent cervical disease, when potential aerodigestive tract
invasion requires complete assessment, and in high-risk HCC
patients with concern for lung metastases. Cross-sectional
imaging of other organs including the brain, skeleton, and
abdomen should be considered in high-risk HCC patients with
elevated serum Tg and negative neck and chest imaging, and
patients who have symptoms referable to those organs.9
There remains significant controversy with regard to optimal
management of patients with HCC; it is more pronounced
than the management of other forms of differentiated thyroid
cancer, likely due to the relative rarity of the disease and scant
high-quality evidence. Large multi-institutional studies are
needed; until that time, utilization of national and nationwide
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patients can be lengthened to 12–24 months. The ATA
highdata to assemble an adequate number of cases to inform valid
risk HCC patients and all patients with biochemically or
conclusions will need to serve as a surrogate. Important
structurally incomplete or indeterminate response to therapy
questions that are outstanding include identification of the
should have Tg/Tg Ab levels measured every 6–12 months
effect of minimal vascular invasion (1–4 foci) on the risk of
for several years.9
recurrence and survival among patients with HCC, as well as
Cervical ultrasound to evaluate the thyroid bed, central,
measurement of the efficacy of adjuvant RAI in these patients.
and lateral cervical nodal compartments should be performed
There also continues to be a need for consensus regarding the
every 6–12 months in patients with HCC initially following
criteria needed to establish a diagnosis of minimally invasive
surgery, and then periodically depending on each patient’s
HCC in order to avoid potential overtreatment.
JAS is a member of the Data Monitoring Committee of the
Medullary Thyroid Cancer Consortium Registry, sponsored by
NovoNordisk, GlaxoSmithKline, Astra Zeneca, and Eli Lilly.
The authors report no other conflicts of interest in this work.
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access journal focusing on the pathological basis of all cancers, potential
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of management programs and new therapeutic agents and protocols on
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