Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_808_Библиотеки_им_академика_М_И_Перельмана.pdf
198
S. Sen and D. T. Abraham
(Rearranged during Transfection) on chromosome 10q11.2, and is seen in both in
the hereditary as well as in certain sporadic forms. But the hereditary thyroid cancer
in MEN 2A and 2B and FMTC have the germline mutations. Approximately 50%
of sporadic forms have the somatic mutations [1, 3].
RET germline mutations in hereditary MTC induce increase in C-cell population
popularly known as C-cell hyperplasia (Fig. 15.1) and regarded as the precursor of MTC.
15.2.1 Clinical Spectrum ofMTC
MTC is usually a cytological or histological surprise except in hereditary forms
when patients are diagnosed by genetic screening. MTC presents as nondescript
thyroid nodule and does not have any characteristic clinical or sonological features.
Patients with hereditary MTC (HMTC) presents at a much younger age, but vary
based on type of mutations. However, the sporadic MTC (SMTC), the presents
fourth to a sixth decade as a solitary nodule and up to 70% such patients have
regional lymph node metastases, and 10–15% of them have distant metastasis.
The C-cells synthesise and secrete hormones or biological amines such as calcitonin, CEA, ACTH, corticotrophin-releasing hormone, chromogranin, serotonin,
neurotensinase, histaminases and so on. Excess secretion of these chemicals brings
about paraneoplastic symptoms such as ushing, diarrhoea, ectopic Cushing’s syndrome, and cholestasis. Serum levels of calcitonin and Carcinoembryonic Antigen
(CEA) are generally used for diagnosis, prognostication and follow-up of MTC.The
serum concentrations of these markers are directly related to the C-cell mass [3].
Syndromic association of neoplasms of endocrine glands are rare disease combination. Medullary thyroid cancer is the most common neoplasm of multiple endocrine
neoplasia type 2A and 2B and shows autosomal dominant inheriting pattern. When a
genetic mutation of RET gene is identied, the chance of phenotype expression occurring is close to 100% and a prophylactic thyroidectomy shall prevent the cancer.
Fig. 15.1 C-cell
hyperplasia with atypical
C-cells
15 An Update onMedullary Thyroid Carcinoma
199
John H Sipple described the association of pheochromocytoma to thyroid cancer
in 1961, and this syndrome is named after him. MEN 2A is now known to include
parathyroid tumours, and is also the commonest MEN syndrome including 95% of
them. There are four clinical variants of MEN 2A:
• Classical MEN 2A
• MEN 2A with cutaneous lichen amyloidosis (CLA)
• MEN 2A with Hirschsprung’s disease (HD)
• Familial MTC (FMTC)
• Classical MEN 2A:
RET germline mutations occur in codons 609, 611, 618, 620 or 634in classic
MEN 2A, and MTC is the presenting symptom of 95% patients; however, fewer
patients present with pheochromocytoma and hyperparathyroidism. The inci-
dence of latter two components of MEN 2A varies and depends on the type of
RET-specic mutation. Majority of the pheochromocytomas are bilateral, benign
and multicentric, and conned adrenal gland [3, 5]. PHPT is generally asymp-
tomatic and due to hyperplasia of 1–4 parathyroids.
• MEN 2A with Cutaneous Lichen Amyloidosis (CLA):
Approximately 10% of MEN 2A indicative skin lesions characterised by subepi-
dermal deposition of keratin in the scapular region of the back, about T1–T6
dermatomal distribution. Patient used to have excessive pruritus which often
exacerbates with stress and relieved with exposure to sunlight. The area becomes
hyper pigmented and may present as ‘notalgiaparasthetica’ which is a sensory
neuropathy involving dorsal spinal nerves (Fig.15.2). The skin lesions may pres-
ent at an younger age and herald the onset of clinically evident MTC later
[3, 6, 7].
• MEN 2A with HD:
Hirschsprung’s disease occurs in about 7% of MEN 2A patients since RET muta-
tion are also one of the genetic causes of the colonic lesion. As in HD, it is due
to the failure of neural crest cells to form submucosal and myenteric cells [3, 8,
9]. The association of the colonic lesion with MTC is rare.
Fig. 15.2 Patient with
MEN 2A and cutaneous
lichen amyloidosis
involving the scapular
region
200
S. Sen and D. T. Abraham
• Familial MTC:
Familial medullary thyroid cancer (FMTC) is characterised by hereditary MTC
but with no associated other endocrine tumours such as pheochromocytoma and
PHPT.Presently, this is also recognised as a variant of MEN 2A [3, 9, 10].
15.3 MEN 2B
Unlike the MTC associated with the other hereditary syndromes, the biological
behaviour of thyroid cancer in MEN 2B is different, developing early in life and is
very aggressive. Mostly, MTC associated with MEN 2B presents with loco-regional
and develop distant metastases. The commonest genetic changes MEN 2B is the
RET mutation involving the 918 codons, while about 5% have RET mutation in the
883 codons. Pheochromocytoma is found in about 50% of patients but parathyroids
are always spared.
These patients have a characteristic appearance which involves a distinctive
faces with thick lips, fascial skeletal involvement with high arched palate, marfanoid body habitus (pectus excavatum, pes cavus, slipped femoral epiphyses) and
ophthalmic abnormalities (inability to make tears, eyelid eversion, ptosis). About
50% have mucosal ganglioneuromas involving the lip, buccal mucosa, gingival,
intestinal submucosal, and myenteric plexus [3, 7, 8] as depicted in Fig.15.3.
Fig. 15.3 Patient of MEN
2B with oral mucosal
ganglioneuromas and
eyelid eversion (arrow)
a
C
b
15 An Update onMedullary Thyroid Carcinoma
201
15.3.1 RET Proto-Oncogene
About one-fourth of MTC have germline mutation of RET proto-oncogene and this
percentage is steadily increasing after mutational study has become routine for
MTC patients. The genetic background decides the clinical behaviour of the tumour
and the introduction of mutation analysis markedly revolutionised the treatment of
MTC, especially in familial MTC.The surgical treatment and surveillance pattern
can be tailor-made based upon the type of RET mutation to obtain a better clinical
outcome. RET screening has opened to a new possibility of prophylactic surgery
and help to choose the ideal time to do it. MTC is the rst example of primary prevention of cancer in humans.
• Structure of RET proto-oncogene:
Genetic changes near the centromere of chromosome 10 which contains 21 exons
was rst describes by Takahashi in 1985. This transforming mutation controls the
tyrosine kinase enzyme which mediates through plasma-membrane bound receptor
and controls various functions of cells including proliferation. RET receptors seen in
cells originating from neural crest like C-cells. RET receptor protein 1114 amino acid
chain with extracellular, transmembrane and intracellular domain. The extracellular
domain has four cadherin-like domain (CLD) and cysteine rich regions (Fig.15.4).
The cadherin-like domain is connected to transmembrane region and thereby to intracellular domain. The genetic activation leads on to genesis of a dimeric complex
encompasses 2 RET proteins, 2 ligand molecules and 2 GFR α (GDNF co-receptors
α). This change signals cell proliferation, differentiation and survival pathways.
RET
Cadherin Domain
Exon
5
Exon
Cysteine Domain
ell Membrane
Ty rosine Kinase Domain
Ty rosine Kinase Domain
Exon
10
Exon
11
Exon
13
Exon
14
Exon
15
Exon
16
8
RET
a
GFL
GFRα
RET
b
GFL
GFRα
Fig. 15.4 (a) A diagram showing structure of RET receptor protein with exons involved, (b) A
picture of a cis and trans model of RET activation with ligand binding [10, 11].
202
S. Sen and D. T. Abraham
15.4 Evaluation andDiagnosis
The primary evaluation encompasses complete clinical examination, radiological
assessment, and cytological/histological studies—generally known as ‘triple
assessment’.
• There is no distinctly different clinical presentation for MTC patients and most
patients report with an incidentally detected thyroid nodule. However, a positive
family history of thyroid cancer is a signicant pointer. Patient who has function-
ing pheochromocytoma has episodes of panic with sweating and headache.
Patients with palpable thyroid MTC nodule frequently have metastatic lymph
nodes involvement [1, 3, 8]. Routine estimation of serum calcitonin and CEA is
not a part of thyroid nodule evaluation but are always done when MTC is sus-
pected. Implications of serum markers are discussed elsewhere.
• Radiological assessment:
The rst imaging is always ultrasound of the neck is a non-invasive and maps the
regional nodal involvement. Chances of distant metastases are high when the
serum calcitonin more than 500pg/ml and higher imaging are strongly indicated
[2, 3, 10]. The usual locations of distant metastases are lungs and liver and a
Computed Tomography (CT) scan and Magnetic Resonance Imaging (MRI) are
sensitive to pick up these metastases. Routine use of FDG-PET CT or F DOPA
PET CT is not advisable in the preoperative set up. An isotope bone scan may be
done skeletal metastases are suspected.
• Pathological evaluation:
Fine needle aspiration cytology (FNAC) typically shows moderate to marked
cellularity and multiple patterns like plasmacytoid or epithelioid types of cells.
These cells are characterised by eccentric nuclei and have the characteristic
neuroendocrine type of ‘salt and pepper’ chromatin with inconspicuous nucle-
oli (Fig.15.5). The presence of amyloid is conrmed by Congo-red staining.
Fig. 15.5 HE stains 400×,
showing polygonal cells
with round nuclei, salt, and
pepper (granular)
cytoplasm
15 An Update onMedullary Thyroid Carcinoma
Fig. 15.6 Calcitonin
immunohistochemistry
showing positivity
After harvesting a cell block immunohistochemistry studies for calcitonin
(Fig.15.6), CEA, and chromogranin can be done on the FNAC sample as well
[3, 11–13]
15.4.1 Tumour Markers
203
The two tumour markers of importance in diagnosis and prognostication in MTC
are serum calcitonin and serum CEA.Serum level of calcitonin is highly sensitive and specic marker in diagnosing MTC.Serum levels above 100pg/ml is
highly predictive of MTC.The serum levels of these markers are also important
in formulating the management protocol. A raised level of serum calcitonin may
help in the early detection of locoregional metastasis and/ or metastasis. However,
a raised CEA (though a more non-specic biomarker), as compared to serum
calcitonin, indicates more aggressive disease or poorly differentiated MTC [3,
14, 15].
15.4.2 Rearranged During Transfection (RET) Testing
Genetic studies are now routine recommendation for all MTC after proper counselling. When the index patient is found RET positive, all the rst-degree relatives are
also counselled for RET mutation analysis. The RET testing can be targeted based
on the phenotype presentation. If a patient is suspected to have MEN 2A, then codon
specic testing targeting exon 10 (for codons 609, 611, 618, 620) and exon 11 (for
codons 630, 634) followed by exons 8,13,14,15 and 16, if no mutation is detected in
exon 10 and 11. Likewise, when MEN 2B is suspected, then exon 16 (for codon
918) and exon 15 (for 883) are tested. However, there may be instances where no
discernible phenotype is evident, in which case the whole RET sequence analysis is
advisable [3, 16, 17].
204
S. Sen and D. T. Abraham
When the RET mutation is found positive screening for the other components of the
MEN syndrome like pheochromocytoma and primary hyperparathyroidism (PHPT) is
necessary. The screening begins based on the type of mutation since the phenotype
expression appears at different time span in life. In the highest risk category, screening
for both pheochromocytoma and PHPT may start as early as 11 years and in the high
and moderate risk categories, it may start at 16 years. The biochemical screening
includes 24-h urinary metanephrine and normetanephrine for pheochromocytoma and
serum PTH, calcium, albumin, and phosphorus for PHPT.If pheochromocytoma coexists with MTC at the time of initial diagnosis the surgery for pheochromocytoma precedes the surgery for MTC.PHPT is operated concurrently with MTC [3]
15.4.3 Risk Stratification ofMTC-ATA 2015 Guidelines
Risk stratication aims at the timing of prophylactic thyroidectomy for the carriers of
germline mutations. The prophylactic removal of organ shall be planned when it is
expendable or the secretions or function can be effectively supplemented or supported.
Based on genetic testing, American Thyroid Association (ATA) 2015 guidelines
stratied MTC into three groups (Table15.1). The risk stratication helps to prognosticate the disease and indicates the appropriate time for prophylactic thyroidectomy on mutation carriers.
• Highest risk (MEN 2B and codon 918 mutations)
• High risk (MEN 2A and codon 634, 883 mutations)
• Moderate risk (Hereditary MTC with codon mutations other than mutations in
918, 883, and 634) (Table15.1)
15.4.4 Surgical Management
The primary treatment for MTC is well planned surgery which should ensure a
complete removal of tumour tissue since there are no effective adjuvant in the management of MTC.An effective primary surgery is the only hope for the cure. Also
Table 15.1 American Thyroid Association MTC risk stratication [3]
ATA risk category
Codon specic
mutation
Aggressiveness Very Yes Moderate
Age at onset Within 1st
Timing of
prophylactic
surgery
Highest risk High risk
918 634, 883 321
<5 years Adult-onset
year of life
In 1st year
of life
5 years or earlier
depending on serum
calcitonin levels
Moderate risk
532, 533
609, 611, 618, 620, 630, 631,
635, 649, 666, 768, 790, 791,
804, 844, 891, 912
When serum calcitonin levels
start increasing or earlier
15 An Update onMedullary Thyroid Carcinoma
205
for the mutation carriers are recommended appropriately timed thyroidectomy to
avert chance cancer.
A central compartment lymph node dissection is always done in N0 patients
along with total thyroidectomy since a re-entry in this location is technically more
demanding and chances of complications are high. There are proponents of prophylactic ipsilateral lateral neck dissection in N0 patients with calcitonin >20pg/ml.
The probability of bilateral deep cervical lymph node metastases is high when the
serum calcitonin is >100pg/ml and so there are suggestions to modify the extent of
surgery based on calcitonin levels. Contralateral prophylactic lateral neck dissection
is also recommended when basal serum calcitonin is more than 200 pg/ml.
Lymphadenectomy from the superior mediastinum is recommended when metastases in mediastinal lymph nodes are suspected. Incidental detection of MTC of diagnostic hemithyroidectomy is occasionally encountered, however a completion
thyroidectomy is not always mandatory when a hereditary cancer is excluded and
serum calcitonin is normalised [1, 3, 8, 18, 19].
15.4.5 Postoperative Management
Following total thyroidectomy, patients are placed on replacement dose of levothyroxine. Hypocalcaemia is frequently seen following a central compartment dissection and given oral calcium and vitamin D supplementation. Majority of patients
recover by short-term course of supplementation.
The rst review is usually done after 3 months of surgery for estimation of
the serum calcitonin and due to long half-life of the tumour marker. During the
rst review, thyroid hormone levels, serum calcitonin, serum CEA, and serum
total/albumin corrected calcium are estimated after a complete clinical
examination.
• Replacement dose of levothyroxine
• Clinical examination
• Measurements of serum calcitonin and CEA.Serum calcitonin level within nor-
mal reference level suggests a favourable outcome. Serum calcitonin elevated
but below 150pg/ml is indicative of locoregional residual disease. Generally,
neck ultrasound is done to assess the regional lymph nodes and residual disease
in the thyroid bed.
A serum calcitonin level >150pg/ml is highly suggestive of distant metas-
tases and suitable imaging such as CECT of the neck, thorax, and abdomen
and symptom- directed high-resolution cross-sectional imaging are
indicated.
The patient has to be instructed to comply with the follow-up protocol of 6–12
months visit thereafter. The tumour markers are measured at every visit and suitable
imaging schedule is charted out based on these values. The formula to calculate the
calcitonin doubling time is now available and is a valuable prognostic indicator. A
doubling time of more than 25 months has a good prognosis while a doubling time
of less than 6 months has a worse prognosis [1, 3, 20, 21].
206
S. Sen and D. T. Abraham
15.4.6 Management ofLocoregional Recurrence andMetastasis
The common locoregional residual disease is the persistence or recurrence in
regional lymph nodes. There may be soft tissue residual disease usually following
gross extrathyroidal disease at the time of primary surgery.
Lymph nodal recurrence in a previously unexplored lymph node stations is managed with well-planned compartment-oriented lymph node dissection. Majority of
occasions, the metastatic lymph nodes in lateral neck are operable but for encasing
the carotid vessels. The vital structures such as the laryngeal nerves, parathyroid
glands trachea and oesophagus are carefully preserved intact to avoid severe morbidity. In high volume centres, a well-planned surgery ensures adequate clearance
and a normal calcitonin level is achieved.
A curative surgery with preservation of vital structures is not always possible due
to inltration. External Beam Radiation Therapy (EBRT) is the next option when
residual lesion is present. Generally, EBRT is indicated in patients with gross residue, high risk of local recurrence, risk of airway obstruction, and extensive extrathyroidal inltration and massive lymph node metastases [3, 22, 23].
The treatment protocol for patients with distant metastases are designed on caseto- case basis but in principle based on balance between benet of treatment and
treatment related morbidity. The cancer per se progresses slowly and treatment
related morbidity should be minimalised and should not compromise quality of life.
Hence, to summarise, the main aim is to provide maximum locoregional control
where feasible, palliate symptomatic metastasis, or treat life-threatening metastasis.
There is no role of systemic therapy in low-volume metastatic disease or stable
disease.
Cytotoxic chemotherapy has a very limited role in metastatic MTC and
5- urouracil, doxorubicin, and dacarbazine were tried with no signicant response.
Majority of MTC express somatostatin receptors and so radiolabelled molecules
such as Yttrium90 DOTA, Lutetium
treatment. This novel mode of delivering targeted radiation is evolving for
MTC.Peptide receptor radionuclide therapy (PRRT) using
90
Y-DOTATOC are used for treatment purpose with promising results in halting
disease progression. Octreotide, or Iodine
in the setting of metastatic disease [3, 24].
177
DOTA Indium
131
MIBG have shown partial response and
111
are used for diagnosis and
177
Lu-DOTATATE and
15.4.7 Targeted Therapy inMTC
Targeted therapy in cancer aims at the proteins that stimulate the excess cell proliferation and is useful when the genetic changes are well established. These are agents
that block the steps of the over expression pathways and controls the growth and
spread of cancer.
Tyrosine Kinase Inhibitors (TKIs) are now used to treat advanced MTC and molecules like Vandetanib (ZETA trial) and Cabozantinib (EXAM trial) are approved
by FDA.Selective RET inhibitors such as Selpercatinib- LOXO-292 (Libretto-001
15 An Update onMedullary Thyroid Carcinoma
207
trial) and Pralsetinib (ARROW trial) are also now approved for treatment of
advanced MTC.These drugs are reported to have improved safety and potency in
MTC treatment. More molecules TKI family such as Soranib, Lenvitanib,
Sunitanib and Pazopanib are in various stages of trials. Pembrolizumab, an immunomodulator, is also in under phase 2 trial and published data of the results are not
yet available. Nelnavir, a HIV protease inhibitor, was found to target heat shock
protein 90 chaperone (HSP90) which is required for folding and stability of RET
mutants [24–26].
15.5 Conclusion
MTC is a differentiated thyroid cancer of neuroendocrine origin arising from parafollicular C-cells. It is mainly of two types, familial and sporadic type, the familial
type being positive for RET mutation. As it is not radioiodine avid, surgery is the
mainstay of treatment. In the familial type, genetic counselling can be done and
screening of families where indicated can be done. Hence, depending on the type of
RET mutation and risk stratication, prophylactic surgery may be offered to
mutation- positive patients before onset of clinical disease.
References
1. Al-Rawi M, Wheeler MH.Medullary thyroid carcinoma—update and present management
controversies. Ann R Coll Surg Engl. 2006;88(5):433–8.
2. Stamatakos M, Paraskeva P, Stefanaki C, Katsaronis P, Lazarus A, Saoleas K, et al.
Medullary thyroid carcinoma: the third most common thyroid cancer reviewed. Oncol Lett.
2011;2(1):49–53.
3. Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, etal. Revised American Thyroid
Association Guidelines for the management of medullary thyroid carcinoma. Thyroid.
2015;25(6):567–610.
4. Mehrotra PK, Mishra A, Mishra SK, Agarwal G, Agarwal A, Verma AK.Medullary thyroid
cancer: clinico-pathological prole and outcome in a tertiary care center in North India. World
J Surg. 2011;35(6):1273–80.
5. Yip L.Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg. 2003;138(4):409.
6. Gagel RF, Levy ML, Donovan DT, Alford BR, Wheeler T, Tschen JA. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med.
1989;111(10):802–6.
7. Stratakis CA.Hereditary syndromes predisposing to endocrine tumors and their skin manifestations. Rev Endocr Metab Disord. 2016;17(3):381–8.
8. Raam M, Cherian AJ, Paul MJ, Abraham DT.An update on medullary carcinoma thyroid. J
Head Neck Physicians Surg. 2019;7(2):45.
9. Wells SA, Pacini F, Robinson BG, Santoro M.Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98(8):3149–64.
10. Machens A, Dralle H.Biomarker-based risk stratication for previously untreated medullary
thyroid cancer. J Clin Endocrinol Metab. 2010;95(6):2655–63.
11. Desai SS, Sarkar S, Borges AM.A study of histopathological features of medullary carcinoma
of the thyroid: cases from a single institute in India. Indian J Cancer. 2005;42(1):25.