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376
M. Sakr
Testing
Ideally, 10ml EDTA anti-coagulated blood should
be taken from the affected individual. The sample,
clinical details, and family history should be sent
to the appropriate genetics laboratory. Patients
with no special clinical features should be tested
rst for RET mutations in exons 10 and 11; if
these are negative, they should be tested for exons
13–16. Failure to screen exons 13–16 constitutes
an incomplete test. Patients with clinical features
of MEN-2B should be tested rst for mutations in
codon 918 and 922 (exon 16), 883 (exon 15) as
well as condons 804 and 806 (exon 14). Patients
with clinical features of Hirschsprung’s disease
should be tested rst for mutations in codons 609,
611, 618, and 620 (exon 10).
Mutation testing of Tumor: if no blood sample
is available from the affected individual, DNA
may be obtainable from either frozen or parafnembedded tumor. The RET mutations may be
either germ-line or somatic in origin. A somatic
MEN-2B-type (codon 918) mutation is commonly present in sporadic tumors but may also be
present in tumors from MEN-2A cases. This
nding cannot, therefore, be used to exclude heritable disease.
Action Based onResults
(a) If a mutation is found
Permission must be obtained from the
patient to disclose this result to anyone else,
including the general practitioner and family.
A plan should be made for the treatment of
the individual and for the further investigation of the family. Regarding the “individual,” mutation implies MEN-2 and thus
(depending on the site of the mutation) a
future risk of other MEN-2 components such
as further thyroid tumors, adrenal, and parathyroid disease. Regarding the “family,”
those at risk should be offered testing for the
specic RET mutation.
(b) If no mutation is found
It is essential to check with the genetics
laboratory that a complete mutation screen
has been carried out, to include exons 10, 11,
and 13–16 of the RET gene. If not, completion should be asked for. If there is strong
presumptive evidence from the individual or
family history of inherited disease then (1)
further research-based search for novel mutations is considered and discussed with the
clinical genetics department, and (2) biochemical screening of family members at
risk using stimulated (IV Ca/pentagastrin)
calcitonin testing from age 5years should be
considered.
If there is no clinical evidence to suggest
inherited disease, the need for stimulated calcitonin screening of family members at risk
is unclear. There are a few MEN-2 families
(mostly with FMTC only) in which RET
mutations have not so far been identied.
Thus, a failure to nd a RET mutation in an
isolated case of MTC cannot completely
exclude the possibility of heritable disease.
The extent of the remaining risk is very small
(around 1% or less), depending on the clinical features of the patient. Young age at onset
of the MTC (<35years) and the presence of
CCH in the thyroid are suggestive, but not
conclusive of inherited disease, nor does the
absence of these features exclude it. The correct action in this situation may differ from
family to family.
13.7.10 Prognosis
Although MTC can metastasize early, it often
progresses relatively slow. The long-term prognosis for MTC is not as favorable as for WDTC;
however, the prognosis is generally much better
than for anaplastic thyroid cancer.
13.7.10.1 Survival
For all types of MTC, the 5-year survival rate is
80–90%, and the 10-year survival rate is 60–75%.
The long-term survival rate (SR) often depends
on the stage of the cancer at the time of diagnosis
(Table13.18). If the disease is localized (has not
spread outside the thyroid) the prognosis is better, with a 10-year survival rate of approximately
90%. If the disease has spread only to regional/
local LNs or has invaded the regional soft tissue
or muscle of the neck, the 10-year survival rate is
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13 Malignant Thyroid Disease
377
Table 13.18 Survival of MTC according to stage
Stage 5-Year survival rate 10-Year survival rate
I Near 100% 95%
II Near 98% 85%
III 81% 75%
IV 40% 28%
about 75%. If the disease has spread to the liver,
lungs, or bone, the 10-year survival rate drops to
40%.
The rate of change of the serum calcitonin and
of CEA can be used to predict long-term survival.
Those individuals who have a doubling time (the
time it takes the serum calcitonin or CEA to double as assessed over a several years period) of
<2years are at greatest risk of dying from metastatic disease, whereas those with a doubling
time of >2 years have a much more favorable
course. Health monitoring should continue for
life.
Tumors with a codon 918 RET proto- oncogene
mutation may be more likely to be aggressive and
associated with a poorer outcome, according to
current thinking and the available peer reviewed
data.
13.7.10.2 Recurrence/Persistent
Disease
– Approximately one-third of MTC patients
will have a recurrence.
– Those with high levels of calcitonin at the
time of diagnosis are more likely to have per-
sistent disease or are more likely to experience
a recurrence.
– Almost one half of the patients with high cal-
citonin or CEA levels after surgery may expe-
rience persistent or recurrent disease.
– Even with persistent disease, MTC patients
can live a very long life.
– The amount of change of calcitonin or CEA
produced over the period of 1year can help
predict patient survival. The rate of increase
often correlates with the rate of tumor growth.
13.7.11 Multiple Endocrine
Neoplasia-2B (MEN-2B)
13.7.11.1 Recognition
– Any new patient with MTC, especially a child
or young adult, should be carefully assessed for
clinical features suggestive of MEN-2B [310].
– The clinical features of MEN-2B may be hard
to recognize and the syndrome is sometimes
diagnosed in error.
– More than 98% of MEN-2B patients reported
to date have mutations in either RET codon
918 (95%) or 883 (3%). Unless the clinical
evidence is strong, preferably with radiological and/or biopsy support, the absence of these
mutations excludes MEN-2B with high probability. Where there is doubt, the patient should
be referred for a specialist opinion [310].
13.7.11.2 The Child ofanMEN-2B
Patient
Because MEN-2B can present with clinically signicant MTC in the neonatal period and is often
metastatic by the time the patient is 5 or 6 years
old, treatment of the newborn child of a known
MEN-2B carrier should be planned in advance
with specialist advice. Because MTC occurs
early in MEN-2B and is particularly aggressive,
thyroid surgery in an affected child should be
done as early as possible, preferably before the
age of 12 months. Prenatal testing is possible.
Couples who ask about prenatal testing for
MEN-2 should be referred to a genetics clinic.
13.8 Poorly Dierentiated
Thyroid Carcinoma (PDTC)
13.8.1 Denition
Poorly differentiated thyroid carcinomas
(PDTCs) (Insular carcinomas) are a heterogeneous group of malignant thyroid tumors include
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378
M. Sakr
carcinomas that originate from follicular epithelium (often with evidence of coexistent papillary
or follicular carcinoma). However, Sakamoto
et al. proposed that the term PDTC should be
applied to the tumors that are solid or trabecular
and have loss of follicular and/or papillary architecture [311]. PDTC is considered a malignant
follicular cell neoplasm with limited evidence of
follicular cell differentiation, and with intermediate clinical behavior between WDTC and ATC.
13.8.2 Terminology
Insular carcinoma was described rst in 1984 by
Carcangiu et al. as a distinctive clinicopathological entity [312]. It is characterized histologically by “well-dened nests”
(insulae—hence called insular) comprised of
relatively small, uniform cells, and are associated
sometimes with small, thyroglobulin (Tg)-containing follicles. This neoplasm has been termed
the following:
– Insular/trabecular carcinoma.
– Primordial cell carcinoma.
– Poorly differentiated follicular carcinoma.
– Poorly differentiated papillary carcinoma.
– Solid type follicular carcinoma.
– High-risk thyroid carcinoma of follicular cell
origin.
13.8.3 Epidemiology
Insular carcinoma constitutes 0.3–6.7% of all
thyroid carcinomas. It is more common in Europe
and South America than USA, and usually affects
older patients (55–63 years) than WDTC
[312–314].
13.8.4 Etiology
Iodine deciency may be a risk factor for developing PDTC.There is no association with radiation exposure. Some tumors are “de novo,” some
arise from dedifferentiation of FTC or PTC.
13.8.5 Clinical Features/Biological
Behavior
The patient usually presents with a large, solitary,
thyroid mass, and may have a history of recent
growth in a long-standing uninodular or MNG.The
aggressive nature of this tumor is evident by the
presence of mitotic gures, foci of necrosis, and
frequent lympho-vascular invasion reaching
60–90% of cases. Nodal metastases to regional
LNs occur in 15–65% of cases, and hematogenous
metastases in 40–70%, mainly to the lungs and
bones, with a high mortality rate as compared with
conventional PTC and FTC.Extention to peri-thyroidal soft tissues has been reported in 60–70% of
cases. The biological behavior of PDTC is
described “intermediate” between WDTC and
ATC in terms of prognosis [312].
13.8.6 Imaging Studies
Insular carcinoma is characteristically “cold” on
scintigraphy (radioiodine scan) and positive on
FDG-PET scan (positron emission tomography).
US shows a nonhomogeneous hyoechoic mass in
the thyroid gland.
13.8.7 Pathology
13.8.7.1 Gross Description
Grossly, the tumor appears as a large (median
size: 5cm), grayish-white mass; some show soft
pale areas of necrosis. It has pushing margins,
may be partially encapsulated, and can have satellite nodules.
13.8.7.2 Microscopic (Histological)
Description
The diagnosis of PDTC cannot be made with certainty by FNA cytology and is primarily made by
histological examination. The common pathological features of PDTCs are solid/trabecular/
insular growth, large size, frequent ETE, extensive vascular invasion, presence of necrosis, and
increased mitotic activity (Fig.13.34). They may
be associated with well-differentiated compo-
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13 Malignant Thyroid Disease
Fig. 13.34 Insular carcinoma of the thyroid gland
(poorly differentiated thyroid carcinoma) with increased
mitotic activity
nents, of either follicular or papillary type, and
less frequently, with anaplastic carcinomas [315].
The “Turin Consensus Diagnostic Criteria”
(2010) include (1) solid/trabecular/insular growth
pattern, (2) no nuclear features of PTC, and (3)
presence of convoluted nuclei, or ≥ 3 mitotic
Figs/10 HPF, or tumor necrosis [316].
Rarely, PDTC can be seen as encapsulated
tumors; in this small subset, the survival is better
than expected for poorly differentiated thyroid
cancer. A distinct molecular pathway has been
reported in poorly differentiated carcinomas,
which almost exclusively involves RAS gene
alteration [269].
13.8.8 Molecular/Cytogenetics
Description
The main molecular features of PDTC are (1) alteration of the early event of thyroid carcinogenesis
(RAS family and BRAF mutation), and (2) alteration associated with dedifferentiation of WDTC
(mutation of p53, TERT, CTNNB1 and AKT1).
Recently, using molecular analysis by polymerase chain reaction (PCR)—single-strand conformation polymorphism analysis, Pilotti et al.
[313] demonstrated the presence of point mutations of the ras gene family in 5 of 8 insular car-
379
cinomas analyzed, with a high proportion of
CAA-3-AAA transversions at codon 61 of the
N-ras gene. This abnormality, however, was not
specic to insular carcinoma as it was also present with a similar frequency in the widely invasive variant of FTC.
It also has been found that the p53 gene is
mutated frequently (38% of patients) in patients
with insular carcinoma [317], and p53 overexpression frequently is present in areas of insular histotype with respect to surrounding areas of
WDTC.However, this nding was not conrmed
by others [318]. Moreover, mutations of the p53
gene are not specic and have been found commonly in ATC [319, 320]. In a patient who had
metastatic insular carcinoma with hyperfunction
due to an activating mutation of the TSH-R gene,
there was no alteration of the genes coding for
gsp, ras, PTC/ret, trk, or met [321]. The activat-
ing mutation was present both in the primary
tumor and in LN metastases.
13.8.9 Dierential Diagnosis
PDTC should be differentiated from the following malignancies:
– Anaplastic thyroid carcinoma (ATC): com-
pletely lacks follicular differentiation, promi-
nent nuclear pleomorphism and necrosis;
generally, Tg- TTF1.
– Hurthle cell neoplasm (HCN): the PDTC can
be predominantly composed of oncocytic
cells but can also have necrosis and≥3 mito-
ses/10 HPF.
– Metastatic carcinoma to the thyroid: pertinent
tumor history.
– Medullary thyroid carcinoma (MTC): also has
nesting pattern; but in addition, has prominent
vasculature, granular cytoplasm and nely
stippled chromatin, calcitonin + thyroglobu-
lin- with amyloid.
– Parathyroid carcinoma: PTH+.
– Solid variant of PTC: typical papillary nuclear
features throughout.
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M. Sakr
13.8.10 Treatment
Aggressive treatment (TT, neck dissection, RAI,
and suppressive thyroxine therapy) not typically
necessary for routine WDTC and not effective for
ATC may uniquely result in substantial benet in
PDTCs. Given the lack of morbidity and potential for benet,
131
I therapy should be considered
in all patients postoperatively [322–325].
However, some authors reported that in the presence of distant metastases, RAI therapy at the
standard dosage is clinically effective only in a
minority of patients; in most patients, the tumor
rapidly progresses despite repeated RAI administration. It is also recommended that EBRT should
be considered in all patients with PDTC with T3
tumors without distant metastasis, all patients
with T4 tumors, and all patients with regional LN
involvement.
13.8.11 Prognosis
Poor prognosis is associated with high stage and
older age (>45years). The overall 5-year survival
rate of these tumors is 60–70%. Older patients
with either papillary or follicular tumors had similar mortality rates as PDTCs.
Several reports have conrmed the high
aggressiveness of this tumor, with a recurrence/
metastasis rate ranging between 20% and 60%
[325–339]. However, in a recent study, no signicant difference in prognosis was observed
between patients with PDTC and patients with
widely invasive FTC [313]. It was also found that
the presence of an insular component (up to 90%)
in either FTC or PTC did not have an adverse
affect on prognosis [340]. Furthermore, a minor
insular component has been recognized as a feature of the macro-follicular variant of PTC; without affecting the excellent prognosis of these
patients [341]. These discrepant ndings may be
explained by the observation that PDTCs often
occur in patients with advanced age and large
tumor size, which are major factors for an adverse
prognosis and may explain the aggressiveness of
PDTC observed in some studies [323, 324, 342].
This issue is relevant to treatment; PDTCs usu-
ally maintain some of the functional characteristics of the follicular thyroid cells, such as iodine
uptake and Tg production. Therefore, when their
tumors become metastatic, patients with these
tumors can be treated with RAI, like patients
with WDTCs [343–346].
13.9 Thyroid Lymphoma
13.9.1 Introduction
Thyroid lymphomas comprise <5% of thyroid
malignancies and 2% of all lymphomas
[347–349]. The majority are non-Hodgkin’s lymphomas (NHL) of B-cell origin [348, 350, 351].
“Primary” lymphoma of the thyroid occurs, in
most cases, on a background of Hashimoto’s thyroiditis (HT), which is the only known risk factor
[352, 353] and can increase the risk of developing thyroid lymphoma by up to 60 times [354].
“Secondary” thyroid lymphoma can occur in
20% of patients dying from generalized lymphoma [355].
13.9.2 Clinical Presentation
The peak incidence of thyroid lymphoma is in the
sixth decade [356]. It occurs more than twice as
frequently in women [350, 351]. The most
common presentation is a rapidly growing thyroid mass that causes symptoms by compression
and/or inltration of surrounding neck organs
(Fig.13.35).
The most common symptoms are dyspnea,
dysphagia, choking, and pain [350]. The classic
symptoms of NHL (fever, night sweats, weight
loss) are present in only 10% of patients. Because
of the association with Hashimoto’s thyroiditis
(HT), a history of hypothyroidism is not uncommon (15%) [356]. Hyperthyroidism is rare.
Physical examination usually reveals a hard,
smooth, rubbery mass, which can be either bilateral or unilateral [351]. The thyroid gland may be
slightly tender and is often xed to adjacent
structures. Up to 50% will have palpable cervical
LNs [357]. It is important to distinguish between
t.me/Dr_Mouayyad_AlbtousH
13 Malignant Thyroid Disease
381
not be made on US alone; biopsy for conrmation is ultimately needed.
CT Scan andMRI
The local extent of the tumor (invasion of the trachea or esophagus, or retrosternal extension) can
be evaluated using either MRI or CT scan.
Lymphomas appear homogeneous on CT with
little to no calcications or necrosis, while ATC
tends to be more heterogeneous with prominent
calcications and necrosis [358]. Once the diagnosis of PTL has been established, imaging of the
entire body is necessary in order to stage the
patient accurately. CT scans of the head, neck,
chest, abdomen and pelvis are often used to see if
there is disease anywhere else in the body.
Fig. 13.35 A 52-year-old lady with a large thyroid gland,
rapidly growing over 2months and extending more on the
left side. Biopsy proved to be a lymphoma
ATC and thyroid lymphoma. Anaplastic thyroid
carcinoma is rapidly progressive with a poor
prognosis and a 2-year survival approaching 0%
compared to 80% for thyroid lymphoma [358].
13.9.3 Diagnosis
13.9.3.1 Laboratory Studies
Blood levels of LDH and β2-microglobulin may
be checked, as they can help predict a patient’s
prognosis for NHL.Thyroid function tests may
be somewhat useful, due to the high incidence of
hypothyroidism in patients with primary thyroid
lymphoma owing to the background of HT.
13.9.3.2 Imaging Studies
Ultrasonography (US)
A cervical US is a standard initial imaging study
in patients with thyroid disease and masses. US
for lymphoma usually shows an asymmetric
pseudocystic pattern that is frequently misinterpreted as benign simple cysts [356]. Certain US
features such as enhanced posterior echoes can
suggest the diagnosis, but a clear diagnosis can-
Positron Emission Tomography (PET)
Special tests, such as uorodeoxyglucose PET
(FDG-PET) scan appears to be a good imaging
modality for assessing the extent of
PTL.However, FDG-PET scan can be inaccurate
in patients with HT, where local inammation
can lead to false increased uptake in the thyroid
gland, and therefore false-positive results.
Nuclear Imaging
Nuclear imaging plays no role in the diagnosis of
thyroid lymphoma.
13.9.3.3 Cytology/Biopsy
Advances in FNA technology and immunocytochemical studies have now made FNA diagnosis of lymphoma possible in most patients
(Fig.13.36) [356]. Incision biopsy is not essential for the diagnosis of thyroid lymphoma [359].
13.9.4 Staging ofPrimary Thyroid
Lymphoma
Primary thyroid lymphoma is staged based on
the “Ann Arbor staging criteria” (Table13.19),
with up to 90% of patients presenting with early
stage disease. Lymphomas that affect organs
outside of the lymph system have “E” added to
their stage.
t.me/Dr_Mouayyad_AlbtousH
382
Fig. 13.36 Non-Hodgkin lymphoma (NHL) of the thyroid gland. Note the abundant large abnormal
lymphocytes
Table 13.19 Stging of primary thyroid lymphoma
Stage Description
I-E Lymphoma is contained within the thyroid
gland
II-E Lymphoma has spread outside the thyroid to
nearby LNs
III- ELymphoma has spread to LNs on both sides of
the diaphragm
IV- ELymphoma has spread throughout the body
M. Sakr
authors to result in a better response rate and
disease- free survival than either alone [347, 362,
363].
13.9.5.2 Surgical Role
Recently, FNA combined with modern immunephenotypic analysis has eliminated the need for
surgical intervention for diagnosis of lymphoma
[364]. Moreover, several studies have shown no
advantage to surgical resection in comparison to
RT or combined modality therapy [365, 366].
Therefore, it is generally accepted that thyroidectomy is not indicated for the treatment of thyroid
lymphoma [367] even when the complication
rate was no higher than that for benign disease
[368]. Some surgeons still, however, advocate
surgical decompression in the highly symptomatic patient [369, 370]. Surgical intervention may
also be needed on an urgent basis for decompression of the airway or tracheostomy, which may be
ultimately required in up to 25% of patients with
thyroid lymphoma during the course of their
treatment.
13.9.5 Treatment
13.9.5.1 Radiation Therapy (RT)/
Chemotherapy
Thyroid lymphomas are very sensitive to both
radiation and chemotherapy. For localized disease, radiotherapy (RT) of the neck and upper
mediastinum is the primary therapy. The local
response rate is dramatic and reaches up to 75%
[347, 360]. However, approximately 30% of
patients develop distant relapses [347], indicating
the need for adjuvant chemotherapy even in
patients who appear to have localized disease.
Chemotherapy can thus be used as an adjunct to
RT inlocalized disease or as the primary therapy
in advanced lymphomas. The standard chemotherapy consists of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) [351,
361]. Several different regimens have been used,
but no single combination has been proven to be
superior. Combining RT with chemotherapy
(combine modality) has been reported by several
13.9.6 Prognosis
Prognosis is generally excellent. The initial
remission rate reaches up to 85%; however, half
have been shown to suffer from a relapse within
10years [363]. Combined treatment with RT and
chemotherapy without extensive surgery have
been reported by several authors to have equal or
superior 5-year survival rates (SR) while avoiding the inherent risks of thyroid surgery [357].
Most deaths due to disease occur within the rst
3years of diagnosis [350].
Patients with stage IE disease tend to have a
better prognosis with a 5-year survival rate of
80%, as compared to 50% in those with stage IIE
disease [363]. Bulky tumors, extra-thyroidal
extension, and the presence of LN metastasis are
associated with a worse prognosis [362, 371].
Age is also a signicant prognostic factor, as in
other thyroid cancers. Patients less than 65years
have a substantially better prognosis with an
overall 5-year SR of 81% as compared to only
37% in those older than 65years [361].
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13 Malignant Thyroid Disease
383
Histological subtype can also help to dene
prognosis. The most common histologic subtype
is diffuse large B-cell lymphoma (50% of
patients) is associated with a high incidence of
disseminated disease and subsequent poor prognosis [353, 362]. The MALT lymphomas, which
are usually associated with Hashimoto’s thyroiditis, tend to be localized and have an excellent
prognosis [353] with a 5-year SR 90% [372].
The grade of the tumor affects the therapeutic
plan and hence prognosis. For low-grade lesions,
local therapy with surgery or RT may be adequate. For intermediate grade tumors, even if the
disease appears to be localized, the treatment
should consist of combined RT and chemotherapy. For high-grade tumors the mainstay of therapy is chemotherapy with or without radiation as
a local control adjuvant.
13.10 Metastatic Lesions
totheThyroid
13.10.1 Overview
Given the extensive blood supply to the gland,
the low incidence of metastases to the thyroid is
surprising [373]. Willis suggested that this is
inuenced by the glandular micro-environment;
the fast arterial blood ow and high concentration of oxygen and iodine could thus prevent the
anchorage and secondary growth of circulating
tumor cells [373].
While postmortem examination suggests that
as many as 24% of patients who die of nonthyroid malignancies have metastases to this
gland, these seem rare in clinical practice
[374–376]. Most patients (60–80%) who present
with thyroid metastasis are diagnosed in the setting of known previous malignancy and “occult”
primary tumor accounts for 20–40% of cases
[376, 377]. In addition, some patients are diagnosed during preoperative investigation, while
others will be diagnosed on histological examination of a thyroidectomy specimen.
Tumors metastasize to the thyroid via (1)
direct extension from tumors in adjacent structures, (2) retrograde lymphatic spread, or (3)
hematogenously. Hematogenous metastases to
the thyroid vary according to the tumor type.
Metastases can originate at almost any primary
site [378–385]. The most common primary
tumors are carcinomas of the kidney (renal cell
carcinoma-RCC), lung, colon, and melanoma
[386]. Because of the aggressive nature of lung
malignancies, patients are often treated with palliative intent from an early stage, and investigation for additional metastases is therefore
curtailed. In contrast, RCC is less aggressive, and
patients are more likely to be further investigated
and treated for metastatic disease.
13.10.2 Clinical Presentation
Metastasis to the thyroid gland accounts for
1–7% of all thyroid malignancies identied during the work-up of a thyroid nodule, occurring
most commonly during the sixth or seventh
decades of life [386].
An accurate clinical history is signicant. A
prior malignancy, as well as symptoms such as
hematuria or hemoptysis, may raise the possibility of an occult primary tumor in the kidneys or
lungs. However, many patients with thyroid
metastasis present with signs and symptoms
identical to those with primary thyroid disease.
One study indicates that 72% present with an
asymptomatic, palpable neck mass and 28% with
an incidental lesion identied on imaging [387].
Thyroid metastasis at an advanced stage within
the central neck may result in dysphagia and dysphonia, similar to aggressive thyroid malignancy.
Changes in thyroid function are late and relatively uncommon [377, 388].
13.10.3 Investigations/Diagnosis
13.10.3.1 Imaging
The accuracy of thyroid imaging has improved
with the introduction of high-resolution US,
cross-sectional [computed tomography/magnetic
resonance imaging (CT/MRI)] and functional
imaging [positron emission tomography (PET)].
Nevertheless, even sophisticated techniques can-
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M. Sakr
not reliably differentiate between primary thyroid lesions and metastases [389]. Metastases to
the thyroid most commonly have the following
US features; (1) hypoechoic lesion with poorly
circumscribed margins (80%), (2) no calcications, and (3) concurrent cervical lymphadenopathy (80%).
13.10.3.2 Fine Needle Aspiration
Cytology (FNAC)
FNAC can often be of assistance [390, 391]. In
the setting of metastatic lesions to the thyroid,
FNAC positive and negative predictive values of
89 and 93%, respectively, have been reported,
and application of molecular markers (e.g., the
BRAF growth promoter in PTC) and immunohistochemistry (IHC) may be of further help (e.g.,
CD-10in RCC) [392–394]. Poorly differentiated
tumors such as aggressive anaplastic thyroid cancers (ATC) are difcult to differentiate from-high
grade metastases by FNAC [389, 393, 395].
Despite its potential limitations, FNAC should be
the diagnostic procedure of choice for any patient
with a new thyroid nodule and a history of
malignancy.
13.10.3.3 Histology (Biopsy)
To increase the likelihood of a pre-operative
diagnosis, more invasive investigations such as
core or open biopsy have been considered [376,
396]. The multidisciplinary team must have a
high index of suspicion, particularly in patients
with a history of malignancy.
13.10.4 Treatment
13.10.4.1 Aims ofTreatment
Many patients who present with a thyroid metastasis will be treated with “palliative intent”. For
selected patients, however, lobectomy or TT may
be performed, either with the aim of “long-term
cure” or achieving “local control” [397]. Because
of the nature of reported surgical series, the percentage of patients who present with metastasis
to the thyroid who are considered candidates for
surgery is unclear. Local invasion of thyroid disease, irrespective of the source of malignancy,
results in dysphonia, dysphagia, hemoptysis, and
stridor. Unfortunately, few data exist on the frequency of presenting symptoms. In addition, the
patient’s tness and co-morbidities need to be
weighed against the likelihood of surgical
success.
If the metastasis is conned within the thyroid
gland without evidence of signicant extraglandular extension, thyroidectomy may be performed with minimal morbidity. In appropriately
selected cases, the aim would be to prevent
asphyxia and hemoptysis associated with uncontrolled disease in the central neck [398, 399]. In
the case of a relatively indolent primary malignancy present with an isolated thyroid metastasis
presenting many years after treatment for the index
tumor, surgery with curative intent is possible.
13.10.4.2 Surgical Strategy
A recent meta-analysis by Russel et al. (2016)
has suggested that those patients managed with
surgery experience better outcomes than those
managed expectantly [400]. This was most apparent for RCC, where median survival for those
managed expectantly was 6 months versus
27months for those who underwent surgery.
For those patients considered to be candidates
for surgery, when considering the extent of thyroidectomy, the aim should be to ensure removal
of all gross disease with an adequate margin. The
procedure will, therefore, depend on the extent of
disease. In “unilateral disease,” most authors recommend thyroid lobectomy rather than TT in
order to minimize risk to the contralateral RLN
and PTGs. However, some authors suggest that
lobectomy can be associated with positive margins and therefore favor TT [401]. Russell etal.
(2016) demonstrated a decrease in recurrence for
patients managed with TT versus thyroid lobectomy (13% versus. 5%, P < 0.005), although
studies included in this meta-analysis are likely
to have been subject to some selection bias [400].
In contrast to primary thyroid malignancy, metastases to the gland are not sensitive to RAI; therefore, TT is not mandatory as long as adequate
margins are achieved. However, patients with
“multifocal disease” may require primary TT
[375, 377].
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13 Malignant Thyroid Disease
385
Concomitant regional LN involvement is rare
in cases of metastasis to the thyroid; therefore,
prophylactic neck dissection is not recommended
[393, 401, 402]. However, the regional lymphatics should be fully assessed preoperatively, particularly in RCC [403]. RCC shows a tendency
toward vascular invasion, and involvement of the
internal jugular vein (IJV) has been described
both from nodal metastases to cervical LNs and
from metastases to the thyroid gland [399]. For
this reason, contrast-enhanced imaging of the
large vessels of the neck should be considered to
assess the relationship between disease and vasculature before surgery. In a “widely metastatic
disease,” surgical resection plays no role in the
management. In such cases, the treatment of
choice is systemic therapy for the primary tumor.
Currently, there is no evidence to support any
other adjuvant or alternative treatment to surgery.
This is partly because the most common primary
tumor is RCC, which is largely considered to be
resistant to radiotherapy (RT) [404].
13.10.5 Prognosis
13.10.5.1 Mean Survival
Although distant metastases are often an adverse
prognosticator, thyroid metastases may not have
as poor an outcome as elsewhere [387].
Nevertheless, 35–80% of patients with thyroid
involvement present with multiorgan metastases
[377, 387, 405].
Mean survival after surgery for thyroid metastasis is approximately 2years, with 42% 5-year
overall survival [376, 405]. However, in the
majority of those patients who are selected for
thyroid metastasectomy, long-term control of the
central neck can be achieved.
13.10.5.2 Prognostic Factors
(Prognosticators)
The rst factor is the “extent of metastases.”
When a thyroid metastasis is part of a widely
metastatic disease, the prognosis is poor with a
survival of <2years [379]. When the thyroid is
the only identied site of metastatic disease,
prognosis is better. In a series of 10 patients with
isolated disease, Chen et al., reported a 100%
local control at 5 years with a 60% 5-year survival [406]. If the primary tumor is amenable to
treatment with curative intent, the subgroup of
patients with isolated thyroid metastasis would
be candidates for curative treatment of the metastasis as well [407, 408].
The second factor affecting prognosis is the
“source (nature) of primary tumor.” Breast and
lung cancers tend to have the worst prognosis,
with a mean survival of only 3months [386]. The
best prognosis exists for RCC [406].
Renal cell carcinoma: Approximately, 20% of
patients with RCC are diagnosed with distant
metastases at the time of diagnosis. Another 30%
will go on to develop metastases during follow- up,
and some of these may present after a signicant
delay of up to 20years [409, 410]. Overall progno-
sis for these patients is poor, but thyroid metastasectomy for selected patients may offer good
survival rates (30%–50%), and long disease- free
intervals are reported [403]. Hence, the European
Association of Urology guidelines support treatment of thyroid metastases with surgery [411].
Lung cancer: Of the lung tumors known to
metastasize to the thyroid, non-small cell lung
cancer is the most common type [412].
Breast cacner: About 5–10% of patients with
breast present with distant metastases at the time
of diagnosis, and occasionally these are in the
thyroid. Evidence relating to the management of
thyroid metastases in cases of lung and breast
cancer is limited, though outcomes appear poor
[398, 401, 407].
Colorectal cancer (CRC): CRC has also been
reported to be associated with a low incidence of
thyroid metastases. One meta-analysis identied
31 cases of thyroid metastases reported between
1954 and 2006 [413]. These were usually accompanied with multiorgan distant metastases, and
hence, prognosis was poor, with only a 50% survival at 1year [413]. Treatment for these patients
was most commonly thyroidectomy with adjuvant chemotherapy and/or RT.The limited evidence available suggests that despite being
palliative, thyroidectomy in this setting was associated with reduced morbidity from thyroidassociated respiratory symptoms [413].
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