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366
M. Sakr
13.5.4 Diagnosis
Hürthle cell neoplasms can accurately be differentiated from nonneoplastic disorders by FNA,
but the differentiation of a benign from a malignant process is much more difcult. Diagnosis of
HCC is based on the presence of capsular or vascular invasion, ETE, or distant disease—features
that are not reliably determined by cytology and
are more reliably determined by permanent sections rather than by frozen section. The measurement of nuclear DNA content and ploidy patterns
has also been disappointing in the differentiation
of Hürthle cell adenomas and carcinomas [224].
As a result of these difculties, surgical therapy is
most often required to secure a correct diagnosis.
13.5.5 Dierential Diagnosis
When confronted with thyroid FNAs containing
oncocytic cells, it is important to keep in mind
that oncocytic changes may be encountered also
in other thyroid lesions than Hurthle cell neoplasms. Oncocytic changes are commonly seen,
at least focally, in conventional PTC; they are
even more widespread in the oncocytic, Warthinlike, and tall-cell variants.
Medullary thyroid carcinoma (MTC) and
parathyroid lesions can also exhibit oncocytic
changes. Immuno-cytochemistry may be useful
for resolving at least some of these differential
diagnoses. For example, cells derived from MTC
are positive for calcitonin but negative for thyroglobulin (Tg), whereas cells from HCC are negative for calcitonin but positive for Tg [247].
13.5.6 Management
13.5.6.1 To Operate or Not toOperate?
Not all lesions with Hurthle cells (HCs) on FNA
require surgical intervention. The importance of
clinical context must be emphasized. Given the
high incidence of malignancy in their series,
Azadian etal. [248] concluded that the cytological detection of HCs in FNA was an indication
for surgery after excluding HT.On the contrary,
subsequent studies suggested that the “percentage,” rather than the mere detection, of HCs
should guide the operative decision with the
detection of >50% HCs being an adequate criterion for opting surgery [249, 250].
In general, it is conceivable that aspirates with
scattered HCs, macro-follicular architecture, or
abundant, watery colloid, and those seen in the
context of HT without dominant nodules, as well
as those that do not meet the criteria for HCN
(<75% HCs) can generally be observed with surveillance US and repeat FNA when indicated.
13.5.6.2 If toOperate, How Much
toResect?
Given the relatively small proportion of HCCs
among HCN nodules and the benign course identied in most minimally invasive HCCs (miHCC),
Kroeker etal. [251], in agreement with previous
reports of Parikh etal. in 2013 [252], Melck etal.
in 2006 [241], and McHenry etal. in 1999 [253]
have advocated thyroid “lobectomy” for initial
management of HCNs keeping in mind two possibilities. Firstly, proceeding to TT may be decided
immediately if ETE or lymphadenopathy was
detected intra-operatively. Secondly, completion
thyroidectomy may be planned shortly after initial
surgery if HCC was revealed on parafn sections.
Additionally, in their large series, Haigh et al.
(2005) found no signicant association between
extent of thyroidectomy and survival [254].
On the other hand, because of the difculty in
differentiating benign from malignant HCNs and
the potential malignant behavior of benign
lesions, total thyroidectomy (TT), as an initial
surgery, was supported by Mills et al. [231],
Paunovic etal. [255], and Khaf etal. [256], as
they noticed favorable outcomes associated with
assertive resection. Moreover, a lower threshold
for selecting initial radical surgery was advocated
by Chen et al. [242], Sippel et al. [257], and
Zhang etal. [258], in large size tumors since they
detected signicant correlation with malignancy.
In fact, the latter opinion is fueled by several facts
such as the aggressive course identied in some
reports [259, 260], the low avidity for radioactive
iodine (RAI) [261], the low incidence of complications in experienced hands [242, 255], which
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13 Malignant Thyroid Disease
367
substantially increase in re-operative surgery, the
availability of replacement therapy, the privilege
of using thyroglobulin (Tg) as a marker for recurrence, and the potential use of RAI for ablating a
possible remnant [262].
13.5.6.3 To Use or Not toUse
Radioactive Iodine (RAI)?
Although HCCs generally fail to concentrate
RAI [263], its controversial role in management
is fueled by the varying results published in the
literature. In 2003, Lopez etal. [264] reported a
survival benet when used for remnant ablation
but not in metastatic disease. On the other hand,
in their series, Sanders et al. [261] stated that
using RAI did not improve outcome. Moreover,
Mills et al. [231] reported in 2003 a worse
disease- free survival conferred by RAI ablation
and therapy. However, the National
Comprehensive Cancer Network (NCCN) 2013
Guidelines have considered RAI ablation for suspected or proven thyroid bed uptake and RAI
treatment for suspected or proven RAI responsive residual tumor in postoperative management
of histologically proven HCC [265].
13.5.7 Prognosis
In general, HCCs are more aggressive than follicular and papillary carcinomas, with a 10-year
survival of 65%. The extent of disease and hence
surgery greatly inuences outcome. An aneuploid DNA pattern has also been shown to independently correlate with decreased patient
survival [224, 227]. Unlike follicular carcinomas,
lesion size, patient age, and histological grade do
not seem to signicantly inuence prognosis.
13.6 Anaplastic Thyroid
Carcinoma (ATC)
13.6.1 Introduction
Anaplastic thyroid carcinomas (ATCs) are undifferentiated tumors of the thyroid follicular epithelium, accounting for approximately 1–2% of
all thyroid malignancies with an annual incidence
of about 1–2 cases/million [266, 267]. Although
ATC is rare, it is one of the most aggressive
human cancers, and it causes up to 40% of deaths
from thyroid cancer. The average survival time of
ATC is only 6–8months and the 5-year survival
rate is only 0–10% [266, 268].
Approximately, 25% of patients with ATCs
have a past history of a well-differentiated thyroid cancer (WDTC), and another 25% harbors a
concurrent WDTC in the resected specimen
[269], which lead to the belief that early management of WDTC is essential to decrease the overall incidence of ATC.Despite different treatment
approaches, ATC grows rapidly, invades adjacent
tissues, and most patients die due to uncontrolled
local tumor invasion, or distant metastases. The
treatment options for ATC include surgery, chemotherapy and radiotherapy.
13.6.2 Clinical Aspects
Patients with ATCs are older than those with
other types, with a mean age of 65years. There is
a higher incidence in women, probably due to
overall higher incidence of thyroid disease in
females.
Anaplastic carcinoma usually presents as a
rapidly enlarging bulky neck mass (Fig.13.24).
The history is generally of short duration,
extending between 3 and 4 months. In most
cases, the disease has already spread beyond the
thyroid capsule into adjacent neck structures
(Fig.13.25) or has metastasized to the lungs at
the time of presentation. Symptoms related to
compression and invasion, such as hoarseness of
voice, dysphagia, cervical pain, and dyspnea, are
common. Metastases to distant sites generally
involve the lungs (75%), adrenal glands (33%),
and brain (15%).
Physical examination usually reveals a rm/
hard mass in the thyroid region that appears to be
xed and cannot be separated from the trachea.
Vocal cord paralysis, due to direct extension to
the RLN, is a common nding and LN enlargement is also quite frequent (approximately 80%).
In the majority of cases, mortality occurs in about
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368
Fig. 13.24 A 62-year-old gentleman with a large, hard,
irregular, and xed thyroid swelling, involving mainly the
right lobe and causing compression manifestations. It
proved by histology to be anaplastic carcinoma
M. Sakr
Fig. 13.26 Computed tomography (CT) scan showing a
large thyroid gland involving the trachea and esophagus
(anaplastic carcinoma)
require, in select cases, appropriate immunohistochemistry (IHC).
Computed tomography (CT) scan is very
helpful in evaluating the extent of the disease in
the central compartment, LN metastasis, and the
position of the trachea (Fig.13.26). Chest X-ray
is routinely performed to rule out gross
metastasis.
Fig. 13.25 A 47-year-old gentleman with a huge recurrent thyroid carcinoma with acute inammation on top.
First operation was performed for PTC. Biopsy of the
recurrence proved to be anaplastic carcinoma
6–12months because of advanced local disease,
distant metastases, airway problems, or cachexia.
13.6.3 Diagnosis
The presence of giant and spindle cells on FNA
should trigger the diagnosis. Conrmation may
be obtained by core or open biopsy, although
open biopsy is best avoided to avoid tumor fungation. It is important to rule-out poorly differentiated thyroid cancer or lymphoma. This may
13.6.4 Gross Appearance
Grossly, ATC appears as a large, necrotic, and
hemorrhagic mass that is typically widely invasive, often replacing most of the thyroid gland
parenchyma with inltration of the surrounding
soft tissue and adjacent structures of the neck.
The cut surface of the tumor can be brownish or
whitish in color, and in both cases, discrete yellowish areas of necrosis are usually evident.
13.6.5 Microscopic Appearance
Microscopically, ATCs are composed of highly
anaplastic cells, with variable morphology,
including (1) large spindle cells with a sarcomatous appearance (Fig. 13.27), (2) pleomorphic
giant cells, including occasional osteoclast-like
multinucleated giant cells (Fig.13.28), (3) squamoid cells resembling squamous carcinoma,
occurring in solid (Fig.13.29) or nest (Fig.13.30)
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13 Malignant Thyroid Disease
Fig. 13.27 Sarcomatoid ATCs. Spindle cells are pleomorphic and show a storiform pattern of growth
369
Fig. 13.30 Epithelioid-squamoid category, neoplastic
cells showing a nested architecture
Fig. 13.28 Neoplastic giant cells, characterized by pleomorphism and bizarre multiple hyper-chromatic nuclei
Fig. 13.29 Epithelioid-squamoid category, neoplastic
cells showing a solid architecture
t.me/Dr_Mouayyad_AlbtousH
Fig. 13.31 Residual foci of PTC seen in the lower right
corner. The main bulk of the tumor is composed of strands
of squamoid atypical cells and spindle neoplastic
elements
architecture [270], and (4) mixed spindle and
giant cells. Foci of papillary or follicular differentiation may be present in some tumors, suggesting an origin from a WDTC (Fig. 13.31).
Metastatic anaplastic carcinoma may be also
present in cervical LNs (Fig. 13.32).
Immunohistochemistry reveals that the neoplastic cells express epithelial markers like cytokeratine but are usually negative for markers of
thyroid differentiation, like Tg. Carcino-
370
Fig. 13.32 LN metastasis of WDTC with anaplastic
areas. Residual foci of PTC are present in the right upper
corner, but the metastatic deposits are made mainly of
spindle cells and necrotic areas
embryonic antigen (CEA) may be localized in
certain areas of the tumor [271, 272]. Most of the
anaplastic thyroid cancers show a high index of
P53 mutation [273], which may play an important role in the progression of DTC to ATC [274].
The expression of ras mutation in WDTC reects
an early event of oncogene activation, while the
high expression of P53 in ATC suggests a late
event.
13.6.6 Treatment
M. Sakr
respectively; P<0.0001), which showed that the
important role of surgical treatment in ATC [281].
13.6.6.2 Treatment ofCervical Lymph
Nodes (LNs)
For patients with clinical or pathological cervical
LNs, levels II–VI neck dissection should be performed. For clinical negative cervical LNs, level
VI neck dissection is performed.
13.6.6.3 Patients withExtra-Thyroidal
Extension (ETE)
Patients may just undergo tracheotomy and tumor
biopsy when they suffer from a wide range of
tumor, severely invaded trachea (narrow diameter<0.5cm), or poor health status. Surgical margins are classied by the pathologist as R0, R1,
and others; R0 indicates that no cancerous cells
seen microscopically, while R1 means that cancerous cells can be seen microscopically.
Several studies reported that R0 (−ve surgical
margin), and R1 (gross resection, positive microscopic margin) might result in substantial
improvement inlocal control and survival; however, most of these studies are biased because
they are retrospective and not randomized to control for bias factors such as extent of disease or
adjuvant treatments [282, 283].
The main treatment strategies of ATC are surgery,
radiotherapy (RT), chemotherapy, and biotherapy
[275–279], and radical surgical treatment is still a
key therapeutic method affecting the prognosis.
13.6.6.1 Treatment oftheTumor
andThyroid
For patients with tumor limited in unilateral thyroid lobe, TT is performed, while thyroidectomy
with extensive resection of the surrounding tissues is performed for patients with tumor
involved the surrounding tissues.
Some authors reported that survival outcomes
were signicantly higher in patients with resectable tumors than in those with unresectable
tumors [267, 278, 280, 281]. Sugitani’s study
(2012) showed that the 1-year survival rate was
signicantly higher in resectable tumors than in
the unresectable tumors (39.0% and 10.0%,
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13.6.6.4 Postoperative
Radiotherapy(RT)
It has been recommended that postoperative RT
with a dose of >40Gy is recommended in stage
IV-A and IV-B patients, and palliative doses
should also be used to improve quality of life in
some patients with widespread disease. Some
scholars also suggested that postoperative RT
might be effective in the treatment of ATC [284].
A study by Glaser SM showed that high-dose RT
(>59.4Gy) resulted in improved survival in ATC,
and that RT is considered a prognostic factor
[285].
13.6.6.5 Chemotherapy
Chemotherapeutic drugs, including cisplatin,
doxorubicin, vincristine, were used to treat ATC
patients commonly; however, it is still controversial whether chemotherapy can prolong the sur-
13 Malignant Thyroid Disease
371
vival time and improve prognosis [286, 287].
Theoretically, chemotherapy can control the
small metastatic sites around the main primary
tumor, reduce tumor dissemination, or increase
tumor resection rate by shrinking the tumor, or
improve the effect of RT and improve the longterm curative effect. Nevertheless, strong evidence to prove the above opinions is lacked of
[288, 289]. Liu etal. [290] also showed that chemotherapy might be an independent factor affecting prognosis in multivariate analysis. Busnard
suggested that preoperative chemo–RT can
improve tumor resection rate and improve prognosis [291]; however, Mclve found that it did not
signicantly prolong survival time in patients
who accepted a comprehensive treatment based
on surgery and chemo-RT [140].
Kim and Leeper showed promising results in
the mid-1980s with the use of Adriamycin-based
chemotherapy and external beam radiation therapy
(EBRT). Unfortunately, in spite of the aggressive
treatment approach of chemotherapy, RT in various forms, and salvage surgery, the overall outcome has essentially remained unchanged [292].
Venkatesh etal., from MD Anderson, reported
a large study of 121 patients with ATC [293].
About 25% of their patients had areas of
WDTC.The mean survival for the entire group
was 7.2 months. Their experience showed that
younger patients lived longer and patients who
presented at an earlier stage responded better
than a patient with metastases at the time of
presentation.
13.6.6.6 Treatment Policy
Since the average life expectancy of patients with
ATC is 6–12months, the role of initial aggressive
surgery is always questioned. Some studies
showed that multimodal therapy combining surgery, chemotherapy, and RT might achieve better
results in avoiding death from local invasion and
improving survival in some patients; however,
ATC has an extremely low cure rate even with the
very best treatments, and treatment of ATC is
mostly palliative [275–277]. Surgical resection
with adjuvant RT and chemotherapy may prolong
survival or improve quality of life; however,
strong evidence is needed to support this conclu-
sion [278]. The optimal multimodal therapy policy is still debated and a standardized treatment
strategy remains to be established. Furthermore,
the rare incidence of ATC and its aggressive
nature make it difcult to compare the outcomes
of different treatments, especially in studies with
small cohorts [275, 276].
13.6.7 Prognosis
The 5-year relative survival rate of ATCs, all of
which are considered stage IV, is around 7%
(based on patients diagnosed between 1985 and
1991).
Independent factors affecting the prognosis of
patients who underwent treatment were (1) primary tumor size (diameter < 4 cm), (2) distant
metastases, (3) surgery, RT, chemotherapy, and
(4) tumor residue. Multivariate analysis showed
that distant metastases, surgery, radiotherapy, and
tumor residue could predict the prognosis [290].
Some studies showed that white blood cell
count and whether to accept surgery plus postoperative RT were the independent factors inuencing prognosis of ATC [294]. Lo in 1999 reported
that age may affect prognosis, and limited lesion
means a better prognosis, while co-existence of
WDTC may have nothing to do with prognosis; the
size of primary tumor was related to prognosis, and
the tumor resection rate was higher when the tumor
diameter was <5–6cm, which leads to a good prognosis [295]. Thus, age and tumor size may also be
prognostic factors of ATC patient [285, 296].
13.7 Medullary Thyroid
Carcinoma (MTC)
13.7.1 Introduction
Medullary thyroid carcinomas (MTCs) are neuroendocrine neoplasms derived from the parafollicular cells or C-cells of the thyroid and
account for approximately 5% of thyroid neoplasms [297]. Similar to normal C-cells, MTCs
secrete calcitonin, the measurement of which
plays an important role in the diagnosis and post-
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372
M. Sakr
operative follow-up. In some instances, the tumor
cells elaborate other polypeptide hormones, such
as serotonin, adrenocortico-trophic hormone
(ACTH), and vasoactive intestinal peptide (VIP),
which are responsible for the para-neoplastic
syndrome as a presentation of familial MTC
(FMTC) (e.g., Cushing syndrome due to ACTH
or diarrhea due to VIP).
Approximately, 70% of MTCs arise “sporadically.” The remainder occurs in the setting of
multiple endocrine neoplasia (MEN) syndrome
2A or 2B, or as familial tumors without an associated MEN syndrome (FMTC), inherited as
autosomal dominant (Table 13.15) [298]. This
necessitates an integrated management approach
to both the patients and their families. Activating
point mutation in the RET proto-oncogene plays
an important role in the development of both
familial and sporadic MTC.
When MTC arises as part of a familial syndrome, treatment of the other endocrine tumors is
required. Distant metastatic spread may occur to
the liver, lungs, and bone. Patients may survive
for many years even with a signicant tumor burden. However, MTC causes death by either local
complications, such as invasion of vital structures
in the neck and upper mediastinum, or by complications of distant metastases [299].
13.7.2 Clinical Presentation
Both forms of MTC (sporadic and familial) are
lesions of adulthood, with a peak incidence in
the 40s and 50s. Cases associated with MEN
types 2A or 2B occur in younger patients.
Patients with MTC present a neck lump, metastasis, dysphagia, and hoarseness. The tumor frequently spreads to regional lymphatics,
including paratracheal, jugular chain, and upper
mediastinal LNs. Systemic effects may occur
due to coincident secretion of calcitonin and
other peptides (frequent loose stools, vasomotor
ushing, and less commonly Cushing syndrome). In all cases, a comprehensive family
history must be taken to include rst- and second-degree relatives to search for features of
MTC or other endocrinopathies (MEN2).
13.7.3 Gross Features
Sporadic lesions are usually solitary, rm, pale
gray, and inltrative. Bilaterality and multicentricity are common in familial cases. Larger
lesions often contain areas of necrosis and hemorrhage and may extend through the capsule of
the thyroid.
Table 13.15 Features of medullary thyroid carcinoma (MTC)
Clinical
setting
Sporadic
MTC
MEN-2A Multifocal,
MEN-2B Multifocal,
FMTC Multifocal,
MTC medullary thyroid carcinoma, MEN multiple endocrine neoplasia, FMTC familial medullary thyroid carcinoma,
AD autosomal dominant, HPT hypoerparathyoidism
Features of
MTC
Unifocal None None Somatic RET mutations in
bilateral
bilateral
bilateral
Inheritance
pattern Associated abnormalities Genetic defect
>20% of tumors
AD Pheochromocytomas, HPT Germ-line missense mutations
in extra-cellular cysteine
condons of RET
AD Pheochromocytomas, mucosal
neuromas, megacolon, skeletal
abnormalities
AD None Germ-line missense mutations
t.me/Dr_Mouayyad_AlbtousH
Germ-line missense mutation in
tyrosine kinase domain of RET
in extra-cellular or intra-cellular
cysteine condons of RET
13 Malignant Thyroid Disease
373
13.7.4 Microscopic Picture
Microscopically, MTC is composed of polygonal
to spindle-shaped cells, which may form nests,
trabeculae, and even follicles [300]. Small, more
anaplastic cells are present in some tumors and
may be the predominant cell type. Acellular amyloid deposits derived from calcitonin polypeptides are present in the stroma in many cases
(Fig.13.33), although it is not necessary for the
diagnosis. About 25% of medullary carcinomas
do not contain amyloid [301] and calcications
are usually noted in areas of amyloid deposition.
Calcitonin is readily demonstrable within the
cytoplasm of the tumor cells.
Electron microscopy reveals variable numbers
of membrane-bound electron-dense granules
within the cytoplasm of neoplastic cells. One of
the features of FMTC is the presence of multicentric C-cell hyperplasia in the surrounding thyroid parenchyma, a feature that is usually absent
in sporadic lesions. Thus, the presence of multiple prominent clusters of C-cell hyperplasia
throughout the gland should raise the specter of
inherited predisposition, even if a family history
is not present.
– A baseline value of calcitonin [302].
– A 24-h urine sample assayed for catechol-
amines and metanephrines to rule out phaeochromocytoma and serum calcium (Ca) to
exclude hyperparathyroidism (HPT). These
tests should be performed in all MTC patients
prior to neck surgery even in the absence of a
positive family history or symptoms.
– RET mutation analysis to establish the possi-
ble genetic basis for the disease.
– A stimulation test with Ca/pentagastrin may
be indicated to conrm a diagnosis of MTC
preoperatively in relatives of patients with
FMTC, to exclude the rare causes of falsepositive basal calcitonin elevation, or when
calcitonin levels are only mildly elevated
[302].
– Routine preoperative staging of MTC with
US, CT/MRI (chest, thorax, and abdomen) is
not essential prior to rst-time intervention as
it does not alter the need for neck surgery.
These investigations, however, may provide
the surgeon with information to guide the
extent of surgery in the central neck compartment and superior mediastinum.
13.7.5 Investigations
Preoperative investigations should include the
following:
Fig. 13.33 MTC (at the center and to the right), which is
much more cellular than the adjacent normal thyroid follicles (at the left). Note the pink hyaline material with the
appearance of amyloid (arrow)
13.7.6 Staging ofMTC
Medullary thyroid cancer is classied differently
from WDTC as shown in Table13.16. The TNM
stage “grouping” of MTC is summarized in
Table13.17.
13.7.7 Treatment
13.7.7.1 Surgical Treatment
Surgical treatment of MTC is inuenced by several factors: (1) ineffectiveness of RAI because
MTC cells do not take up iodine, (2) multicentricity of MTC in 90% of patients with the hereditary forms of the disease and in 20% of patients
with the sporadic form, (3) Nodal spread in about
50% of MTC patients (with the exception of children whose MTC is discovered as part of a
genetic or biochemical screening program), and
(4) the availability of assessment of the adequacy
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374
M. Sakr
Table 13.16 TNM staging of MTC
Stage Description
I T1 tumor, <10mm, with no LNs (N0) or
metastases (M0)
II Larger tumors (T2), also without LNs (N0) or
metastases (M0)
III Classication involves LNs
IV Indicates the presence of distant metastases
Table 13.17 Stage grouping of MTC
Stage TNM stage grouping
I T1, N0, M0
II T2–3, N0, M0
III T1–3, N1a, M0
I VA T4a, N0-1a, M0 or T1-4a, N1b, M0
IVB T4b, any N, M0
IVC Any T, any N, M1
of surgical extirpation by measuring postoperative stimulated-calcitonin levels.
The aims of rst-time surgical treatment of
MTC are loco-regional control (neck and superior mediastinum), and in some patients, to obtain
a biochemical and clinical cure. Therefore, as an
appropriate treatment, it is widely accepted that
all patients with established MTC should undergo
“total thyroidectomy (TT) and central LN dissection “(level VI).
Patients with pT2–4 tumors, or palpable LNs in
the central or lateral compartment should in addition undergo “bilateral selective neck dissection”
of levels IIa–Vb. In the absence of direct invasion,
the sternocleidomastoid muscle (SCM), internal
jugular vein (IJV), and spinal accessory nerve
(SAN) should be conserved. Routine dissection of
levels I, IIb and Va is not required unless there are
palpable/suspicious nodes at these sites. When
there is strong suspicion or evidence of level VII,
the patient should be considered for further surgery, which will require a sternotomy [303].
Patients with distant metastases at presentation often have prolonged survival. Even in the
presence of disseminated disease, surgery (TT
and central compartment node dissection) should
be considered to prevent subsequent compromise
of the trachea, esophagus, and RLNs.
“Prophylactic surgery” should be offered to
“disease-free carriers” of germ line RET muta-
tions, identied by genetic screening programs
[304]. Ideally, these patients would be expected
to have C-cell hyperplasia (CCH) rather than
MTC but, in many cases, by the time of presentation the transition from CCH to MTC will have
occurred. It is important to distinguish the need
for therapeutic surgery from prophylactic surgery. This will depend upon genotype, age, and
basal calcitonin.
Children with MEN-2B should undergo “prophylactic thyroidectomy” within the rst year of
life. Children with MEN-2A should undergo prophylactic thyroidectomy before the age of 5years
[305, 306]. In children with MEN-2A under
10years, it may be unnecessary to perform LN
dissection. In older children and those with
MEN-2B, central lymphadenectomy should
probably be performed at the time of thyroidectomy. Gene carriers from kindred with FMTC
should undergo prophylactic thyroid surgery
after the age of 10 years; LN dissection is not
indicated before the age of 20years.
Investigation of persistent or increasing
hyper-calcitoninemia: postoperative samples
should be measured no earlier than 10days after
thyroidectomy [302]. Plasma calcitonin levels
are most informative 6 months after surgery
[302]. There is good evidence that meticulous
initial surgery reduces the risk of postoperative
hyper-calcitoninemia, but high calcitonin levels
after surgery are a common nding. This will
depend upon the preoperative basal calcitonin,
stage of the tumor at presentation, and adequacy
of initial surgery.
True local recurrence is unusual after adequate
initial surgery. When initial surgery was incomplete, re-operation on the neck (lymphadenectomy of the central and/or lateral compartments)
with curative intent should be considered.
Mediastinal lymphadenectomy may be necessary
when there is a strong suspicion of, or proven
nodal disease at this site.
It is important to distinguish loco-regional,
persistent/recurrent disease from distant microor macro-metastases as the cause of hypercalcitoninemia. Noninvasive imaging (chest and
abdominal CT or MRI and cervical and/or
abdominal US, bone scan) should be performed
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13 Malignant Thyroid Disease
375
but may not be helpful because of the morphological pattern of metastatic MTC in the lung and
liver (miliary disease). Laparoscopy or selective
arteriography may identify occult hepatic metastases. Other less invasive options to detect metastatic MTC in patients with rising calcitonin and
negative whole-body CT or MRI include pentavalent
131
99m
I-MIBG,
Tc-dimercaptosuccinic acid (DMSA),
111
In-octreotide, and 18FDG-PET
scans.
Re-operative surgery in the neck and mediastinum should be considered in persistent or recurrent MTC, even when there are known distant
metastases, to prevent the complications of large
volume disease affecting the airway, esophagus, or
laryngeal nerves. Reoperation, at present, appears
to offer the most consistent improvement in calcitonin levels, compared to other treatments [307].
13.7.7.2 Radiotherapy
andChemotherapy
Routine adjuvant external beam radiotherapy
(EBRT) has not been shown to improve survival
but may improve the relapse-free rate if there is
gross residual disease or extensive nodal disease
[308]. Chemotherapy is generally ineffective but
may be tried for progressive and symptomatic
disseminated disease. Radiolabeled-somatostatin
analogue and/or
131
I-MIBG treatment may be
useful in some cases but have not been evaluated
in clinical trials. Alpha-interferon may also have
a role; however, the evidence base is scanty at
present.
13.7.9 Molecular Genetics: Genetic
Investigation ofaPatient
withMTC
About 25% of MTCs are hereditary, as part of
MEN2/FMTC syndrome. Lack of family does
not exclude heritable disease. The disease may
not be apparent in relatives because of ‘skipped’
generations, or an isolated case may be the start
of a new family. Inherited MTC without other
endocrinopathies also occurs. It is inherited in
similar ways but tends to be more indolent than
other forms of MTC [309]. Because of the rarity
of MTC and the complexity of genetic investigation and management, cases should be managed
by a specialist clinical service in close liaison
with a regional genetics center.
13.7.9.1 Clinical History
A clinical history suggestive of MEN-2 syndrome would include (1) symptoms/history of
phaeochromocytoma and parathyroid disease,
(2) features of MEN-2B such as facies, constipation/diarrhea, mucosal neuromas, medullated
corneal nerve bres, marfanoid habitus, colonic
ganglioneuromatosis, Hirschsprung’s disease
(may be associated with MEN-2), and (3) family
history including all rst- and second-degree
relatives, with attention to features suggestive of
MEN-2 (thyroid, adrenal, and parathyroid
disease).
13.7.9.2 Genetic Testing
13.7.8 Follow-Up
Lifelong follow-up is recommended. Response to
primary surgery can be assessed clinically and by
the measurement of serum calcitonin and tumor
markers, usually 6 months after surgery [302].
Elevated but stable calcitonin postoperatively
may be treated conservatively, provided treatable
disease has been excluded radiologically.
Progressively rising levels should trigger imaging for further staging. In the absence of recurrent symptoms, appropriate follow-up intervals
are 6–12months.
t.me/Dr_Mouayyad_AlbtousH
Before Testing
The patient should be referred to the clinical
genetics service. Because of the possibility of
heritable disease, every case of MTC should be
offered genetic testing unless there are good reasons for not undertaking this. Testing should
always begin with the affected individual, if
available. If the affected individual is not available then decision and strategy for testing should
be discussed with the clinical genetics service.
Before blood is taken, a clear explanation must
be given of the nature of the test, the possible outcomes, and the implications of a positive or negative result for the individual and the family.
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