SEMINAR ON

CANCER OF THYROID GLAND

Presented by Dr. Yousuf F. Choudhury

PGT, ENT DepartmentModerated by

Prof. Dr. Shams UddinProf. & HOD, ENT Department

BRIEF EMBRYOLOGY OF

THYROID GLAND

• The thyroid gland is the first of the body's endocrine glands to develop, on approximately the 24th day of gestation.

• The thyroid originates from two main structures: the primitive pharynx and the neural crest. The rudimentary lateral thyroid develops from neural crest cells, while the median thyroid, which forms the bulk of the gland, arises from the primitive pharynx.

• The thyroid develops from the first and second pharyngeal pouch.

SURGICAL ANATOMYOF

THYROID GLAND

• Thyroid is made up of two lateral lobes, which extend from the sides of the thyroid cartilage down to the sixth tracheal ring

• The lobes are joined by isthmus in the midline which overlies the second to fourth tracheal ring.

• In addition, there is often a pyramidal lobe which projects up from isthmus usually on left-hand side.

• The trachea is enclosed in the pre-tracheal fascia

• The thyroid is bordered by the trachea and esophagus posteriorly and the carotid sheath laterally.

• The sternocleidomastoid muscle and the three strap muscles (sternohyoid, sternothyroid, and the superior belly of the omohyoid) border the thyroid gland anteriorly and laterally.

• The posteromedial aspect of the gland is attached to the side of the cricoid cartilage, first and second tracheal ring, by the posterior suspensory ligament (ie, Berry ligament). This firm attachment of the gland to the laryngoskeleton is responsible for movement of the thyroid gland and related structures during swallowing.

• Superficial to the sternohyoid muscle, lies the anterior jugular veins crossing over central neck.

• The cutaneous nerve C2, C3 run superficial to the deep investing layer of cervical fascia.

EXTERNAL BRANCH OF SUPERIOR LARYNGEAL NERVE AND JOLL’S TRIANGLE

• Joll's triangle is used to identify the location of external branch of superior laryngeal nerve during thyroid surgeries. Damage to this nerve during the surgical procedure may reduce the voice range in these patients. This triangle is also known as sternothyrolaryngeal triangle.

• Boundaries: Lateral - Upper pole of thyroid gland and superior thyroid vessels Superior - Attachment of the strap muscles and deep investing

layer of fascia to the hyoid Medial - Midline Floor - Cricothyroid muscle

• External branch of superior laryngeal nerve lies within this triangle.

ANATOMICAL VARIATION OF EBSLN

• Type I (Cernea’s type 1)- crosses superior thyroid pedicle more than 1 cm above superior thyroid pole into cricothyroid muscle

• Type II ( Cernea’s type 2 )- less than 1 cmType IIa – cranial to superior thyroid pole ( most

common variation) Type IIb – caudal to superior thyroid pole ( High

risk nerve during surgery )

RELATIONSHIP BETWEEN RECURRENT LARYNGEAL NERVE AND INFERIOR THYROID ARTERY

• The recurrent laryngeal nerve has significant but varying relationship with the inferior thyroid artery.

• On the left side, the recurrent laryngeal nerve passes behind the inferior thyroid artery in 50% of the cases and anterior to the artery in 20% of cases and may lie in between the branches of the inferior thyroid artery in 30% of cases.

• On the right side since the recurrent laryngeal nerve approaches the tracheoesophageal groove more laterally, these relations are different on the right side. In half of the cases the recurrent laryngeal nerve passes between the distal branches of the inferior thyroid artery, in 30% of patients it may lie anterior to the artery, and in 20% of cases it may lie deep to the inferior thyroid artery

BLOOD SUPPLY OF THRYOID

• The arterial blood supply to the thyroid gland is primarily from the right and left superior and inferior thyroid arteries, derived from the external carotid arteries and thyrocervical trunk, respectively.

• Superior thyroid artery is the first branch off the external carotid artery. It extends inferiorly to the superior pole of the thyroid lobe.

• In addition to supplying the thyroid, the superior thyroid artery is the primary blood supply to approximately 15 percent of superior parathyroid glands.

• The superior thyroid artery is a landmark for identification of the superior laryngeal nerve, which courses with the artery until approximately 1 cm from the superior thyroid pole

ARTERIAL BLOOD SUPPLY OF THYROID GLAND

• Inferior thyroid artery is a branch of the thyrocervical trunk which arises from the subclavian artery.

• The inferior thyroid artery courses posterior to the carotid artery to enter the lateral thyroid. The point of entry can extend from superior to inferior thyroid poles.

• The inferior thyroid artery also supplies the inferior parathyroid glands and approximately 85 percent of superior parathyroid glands.

• The RLN may course anterior or posterior to the inferior thyroid artery. In some cases, the RLN may branch into both an anterior and posterior position

• Thyroidea ima artery is found in approximately 3 percent of individuals and arises from the aortic arch or innominate artery and courses to the inferior portion of the isthmus or inferior thyroid poles

The venous drainage consists of the superior, middle, and inferior thyroid veins that drain into the internal jugular vein and innominate vein

Superior thyroid vein: It arises from the upper part of the lobe. It ends into the internal jugular vein. Middle thyroid vein: It arises from the middle of the lobe. It ends into the internal jugular vein. Inferior thyroid veins: Arise from the isthmus and lower parts of the lobes. Descend in front of the trachea. End into the left brachiocephalic vein

VEINOUS DRAINAGE OF THYROID

LYMPHATIC DRAINAGE OF THE THYROID GLAND

• Upper poles of the gland, isthmus and pyramidal lobe drains superiorly to level II & III

• Lateral aspect of each lobe drains to level III & IV

• Lower pole of the gland drains to peri- and para-tracheal nodes in level VI and then onto level IV and VII nodes

MAJOR MINOR

Middle jugular nodes – level III Pre-tracheal and para-tracheal nodes – level VI

Lower jugular nodes – level IV Superior mediastinal nodes – level VII

Posterior triangle nodes – level Vb

BRIEF HISTOLOGY OF THYROID

• Divided into lobules of 20-40 round to oval follicles, each 50-500 microns, with a single layer of cuboidal to low columnar epithelium

• Lumen contains colloid, which is scalloped and pale in follicles with active secretory activity, densely eosinophilic in inactive follicles and more flocculent (“like a clump or tuft of wool”) and basophilic in elderly

• Stroma contains C cells, formerly called para-follicular cells (actually are intra-follicular), derived from neural crest

• C cells represent 0.1% of gland, produce calcitonin, are present in middle and upper third of lateral lobes along central axes, are not present in extreme upper and lower poles or in isthmus

• C cells have pale / clear cytoplasm, oval nuclei, difficult to identify with H&E, use calcitonin stain

• Oncocytes (Hürthle cells, oxyphilic cells, Ashkenazy cells): large cells with abundant deeply eosinophilic granular cytoplasm and numerous mitochondria

Normal Thyroid follicular tissue Normal C cells stained with calcitonin antibody

BRIEF PHYSIOLOGY OF THYROID GLAND

THYROID HORMONE SYTHESIS

Plasmaiodide

Trapping of iodideinside thyroid cell

Active iodideintermediate

Iodination of tyrosine residueson thyroglobulin

(monoiodotyrosine anddiiodotyrosine

Coupling of iodotyrosylresidues to form

thyroxine (T4) andtriiodothyronine (T3)

Proteolysis ofthyroglobulin to

release T4 and T3into circulation

THE HYPOTHALAMIC PITUITARY THYROID AXIS

INTRODUCTION

CANCER OF THYROID GLAND

THYROID CANCER CLASSIFICATION

CANCER THYROID

DIFFERENTIATED THYROID

CANCER

PAPILLARY

THYROID CANCER

FOLLICULAR

THYROID CANCER

UNDIFFERENTIATED/

ANAPLASTIC THYROID CANCER

MEDULLARY THYROID

CARCINOMAOTHERS

EPIDEMIOLOGYThyroid is uncommon, making up around 1% of all

cancers.Worldwide, around 298,000 people were estimated to

have been diagnosed with thyroid cancer in 2012, with incidence rates varying across the world

Worldwide, around 37,800 people were estimated to have died from thyroid cancer in 2012, with mortality rates varying across the world

Male-female incidence Sex ratio is 1:3.1 in 480 men and 1 in 180 women will be diagnosed

with thyroid cancer during their lifetime

FREQUENCY OF THYROID CANCERCANCER PERCENTAGE

Papillary carcinoma 75 %

Follicular carcinoma 16 %

Medullary carcinoma 5 %

Anaplastic 3 %

Others ( Lymphoma, fibrosarcoma, SCC, hemangioendothelioma and metastatic carcinomas

1 %

DIFFERENTIATED THYROID CARCINOMA

DIFFERENTIATED THYROID CARCINOMA

RISK FACTORS :• Incidence of DTC is higher in women, older

patients and those with a family history.• Childhood exposure to radiation is one of the

main causes of Papillary Carcinoma• Long standing goitre may lead to Follicular

carcinoma.

PATHOLOGY AND CLASSIFICATION OF DTC• Papillary thyroid carcinoma(PTC)cells have special features like Orphan

nuclei and Psammoma bodies.• PTC tends to metastasize through lymphatics.• Most PTCs are multifocal i.e 80% and 50% of foci are found in bilateral

lobe.

CLASSIFICATION OF PTCPTC ( PAPILLARY/FOLLICULAR/MIXED)

FOLLICULAR VARIANT PTCTALL CELL VARIANT PTC

CRIBRIFORM PTCCOLUMNAR CELL VARIANT PTCPAPILLARY MICROCARCINOMA

SOLID VARIANT PTCDIFFUSE SCLEROSING VARIANT PTC

PAPILLARY THYROID CARCINOMA

• Follicular thyroid carcinoma ( FTC) are slow growing and metastasize through blood stream.

• FTC are not multifocal and do not invade lymphatic channels. LN

metastases are rare.

CLASSIFICATION OF FTC

MINIMALLY INVASIVE FTC (MIFC)• Capsular and/or vascular invasion

WIDELY INVASIVE FTC (WIFC ) [ Poor prognosis ]• Tumor infiltrates gland

FOLLICULAR THYROID CARCINOMA

MOLECULAR GENETICS OF DTC

• RET and TRK oncogenes undergoes oncogenic activation by rearrangement of chromosomes in PTC.

• RAS mutation leads to mitosis and reduced differentitation. Frequently found in follicular variant PTC, anaplastic carcinoma.

• BRAF mutation found in 40-70% of PTC except follicular variant. Seen in Anaplastic CA too. Have poor outcome.

• PAX8-PPARɣ translocation are commonly found in follicular carcinomas. PAX8-PPARɣ positive FTC are widely invasive

CLINICAL ASSESSMENT

HISTORY :• Solitary thyroid nodule ( Most common )• Cervical lymphadenopathy• Local compressive symptoms• Distant metastasis• Thyroid dysfunction• Family H/O thyroid disease• Radiation exposure in childhood

Examination• Nodule examination for size, numbers, shape, consistency,

fixation, A nodule is more likely to be malignant if :o H/O neck irradiation in childhoodo Endemic goitreo Hashimoto’s thyroiditis ( risk of lymphoma )o Prolonged stimulation by elevated TSHo Solitary thyroid noduleo Family or personal H/O thyroid adenomao H/O previous thyroid cancero Genetic factors- Familial thyroid cancer, Cowden’s syndrome, FAPo Age less than 14 years or more than 65 years• Neck examination for lymph nodes• Pharynx and larynx examination

INVESTIGATIONSCYTOLOGY FNACMost of the histological diagnosis can be made by FNAC except for follicular neoplasm. TRUCUT OPEN BIOPSYLABORATORY INVESTIGATIONS TSH, T4, T3 Serum Tg Serum Calcium Serum CalcitoninRADIOLOGY USG Scintigraphy using 123I or 99mTc.Hot or toxic nodules are highly unlikely to be malignant. CT neck and thorax MRI MR angiography

Thy1 Inadequate for diagnosis

Thy2 Benign disease

Thy3 Suspicious for neoplasia

Thy4 Suspicious for malignancy

Thy5 Positive for malignant disease

CLASSIFICATION OF THYROID NODULE CYTOLOGY

INVESTIGATION OF A SOLITARY OR DOMINANT THYROID NODULE

StagingStaging systems used for DTC in world are-• MACIS staging system ( Mayo clinic )

-Metastasis -Age at presentation -Completeness of surgical resection-Invasion (extrathyroidal)-Size It is probably the most reliable staging method available. Also known as the MAICS system.

• AMES staging system ( Lahey clinic )• GAMES classification ( Memorial Sloan Kettering hospital )• DAMES classification ( Karolinska Institute )• TNM classification ( AJCC ) [ Most accepted ]

STAGING

THYROID CANCER RISK STRATIFICATION

<45 years

Female

<2 cm

Intraglandular

Low

Absent

>45 years

Male

>4 cm

Extraglandular

High

Present

Low Risk High RiskIntermediate Risk

Mixture ofFeatures

Shaha AR, et al. Acta Otolaryngol. 2002;122:343-347.Shaha AR. Cancer Control. 2000;7:240-245.

Age

Gender

Size

Extent

Grade

DistantMetastases

Treated, %

Death Rate, %

39

<1

39

13

22

53

Surgery

TotalThyroidectomy ± Neck dissection

Hemi-thyroidectomy/Sub-total

thyroidectomy

Intermediate and High Risk

Low Risk

Diagnosis of Differentiated Thyroid Cancer

INITIAL TREATMENT STRATEGY

PHYSICAL EXAM & USG RAI ABLATION

TREATMENT OF THYROID CANCER WITH RADIOACTIVE IODINE

• Destroys remnants of normal thyroid tissue• Destroys thyroid cancer cells• Identifies distant metastases• Maximizes sensitivity and specificity of serum thyroglobulin• Dose 75-150mCi, max dose 1500mCi• Not indicated in

– Micropapillary carcinoma, <15mm lesion in young females– Lobectomy as treatment

• Complications: Xerostomia, menopause, azoospermia, flare phenomenon, BM suppression, AML

.

THYROXINE SUPPRESSIVE THERAPY• TSH suppression

– 0.1micro IU/ml in high risk disease• Thyroxine (T4) in doses 150-200mcg per day• Risks of osteoporosis, AF, cardiac risk in elderly needs management

EXTERNAL BEAM RADIOTHERAPY• Indications

– Unresectable disease– Non-iodine avid disease– Extrathyroid extension– Mediastinal bulky nodes– Gross local invasion with macro-or microscopic residual– Reccurrent neck disease not amenable to surgery– Palliation of inoperable metastatic disease

• Radioiodine therapy if to be given should be given before EBRT because EBRT reduces RAI uptake of tissues.

• Toxicities are mucositis, odynophagia, xerostomia, skin erythema, laryngitis

CHEMOTHERAPY• It’s use is restricted to symptomatic progressive disease when surgery, radiotherapy and RAI have

failed.• Doxorubicin in combination with cisplatin has demonstrated higher response rate .

POST TREATMENT

SURVEILLANCE FOR DTC AFTER TREATMENT

SERIAL Tg LEVELS ( OFF THYROXINE SUPPRESSION OR USE OF Rh TSH )

USG ± FNAC ± Tg estimation needle washout

DIAGNOSTIC I131 SCAN

F18-FDG-PET CT scan

_

_

_

+

+

+

TREATMENT

TREATMENT

FOLLOW UP

FOLLOW UP

• Four-six monthly check up in early years and then annually for at least ten years.

PROGNOSIS OF DTC

• 85% of patients with DTC :disease-free after initial treatment

• 10–15% : recurrent disease • 5%: distant metastases • Distant metastases :lungs (50%), bones (25%),

lungs and bones (20%) ,10-year-survival rates ranging from 25% to 42%

• Overall 20years survival-95%

HURTHLE CELL THYROID CARCINOMA

• Hürthle cell carcinoma of the thyroid gland is an unusual and relatively rare type of differentiated thyroid cancer.

• Hürthle cell cancer accounts for only about 3-10% of all differentiated thyroid cancers

• According to the World Health Organization (WHO), these neoplasms are considered a variant of follicular carcinoma of thyroid and are referred to as follicular carcinoma, oxyphilic type.

• Hürthle cell cancer has the highest incidence of metastasis among the differentiated thyroid cancers.

• Management is Total thyroidectomy followed by RAI scan and if required I131 treatment. EBRT can also be given as Hurthle cells are radiosensitive.

MEDULLARY THYROID CARCINOMA

MEDULLARY THROID CARCINOMA• Medullary thyroid cancer is a rare tumour that appears in two

distinct forms. The rarer familial form is genetically determined. The sporadic form is more common, but its aetiology has not been defined clearly so far.

• Some proposed risk factors for sporadic form are goitre, thyroid nodule, late menarche

• Three main clinical variants of genetically determined type MTC are– MEN type 2A ( Sipple syndrome )– MEN type 2B– Familial medullary thyroid carcinoma

PATHOLOGY & GENETICS• MTC arises from C cells ( parafollicular cells )that are found in the middle and

upper thyroid gland.• C cells are of neural crest origin migrated from ultimobranchial body and

secretes calcitonin.• Macroscopically , sporadic MTC tumors are usually solitary and unilateral

while familial MTC tumors are bilateral and multifocal.• MTC may be encapsulated or non-encapsulated with extension of tumor into

parenchyma. Nuclei are eccentric, pleomorphic and have low mitotic rate• Subtypes are papillary, follicular, squamous and oncocytic.• Immunochemistry- MTC cells stains positive for calcitonin, CEA,

chromogranin A. Thyroglobulin staining negative• RET mutation most common genetic cause both in sporadic and familial

types

Medullary thyroid carcinoma

CLINICAL ASSESSMENT• Age of presentation

• Clinical features of sporadic MTC Non-tender thyroid nodule Cervical lymphadenopathy Local mass effect Diarrhoea Flushing Bone pain

Sporadic 4th-5th decade

MEN 2A 2nd-3rd decade

MEN 2B 1st-2nd decade

FMTC 4th-5th decade

• Clinical Features of MEN type 2SYNDROME %

MEN 2A Medullary thyroid carcinoma 100

Phaechromocytoma 50

Hyperparathyroidism 10-20

Cutaneous Lichen Rare

Amyloidosis Rare

Hirschprung disease Very rare

MEN 2B Medullary thyroid carcinoma 100

Phaechromocytoma 50

Marfanoid habitus >95

Mucoasal neuromas >95

Intestinal ganglioneuromatosis >95

FMTC Medullary thyroid carcinoma 100

DIAGNOSIS & INVESTIGATIONS• Four or more MTC affected members of a kindred without

other endocrine tumors are required for clear diagnosis of Familial Medullary Thyroid Carcinoma

• INVESTIGATIONS –– FNAC alone or in combination with immunohistochemistry ( Gold

standard )– Serum Calcitonin ( basal and stimulated ), Serum CEA– USG Neck and abdomen– CT neck– MRI– Panel of tests for detection of phaechromocytoma like 24 hours

urine collection for fractionated catecholamines, metnephrines, normetanephrines

STAGING

• TNM staging

STAGE T N M

I T1 N0 M0

II T2,T3 N0 M0

III T1-T3 N1a M0

IVA T4a N0 M0

T4a N1a M0

T1 N1b M0

T2 N1b M0

T3 N1b M0

T4a N1b M0

T4a N0, N1b M0

T1-T4a N1b M0

IVB T4b Any N M0

IVC Any T Any N M1

TREATMENT

• Total thyroidectomy with central neck lymph node dissection ±lateral neck, mediastinal LN neck dissection.

• For persistent/recurrent MTC, localize the MTC again with the help of neck USG, CECT chest, Liver MRI, bone scintigraphy and axial skeleton MRI. If resectable, operate and if unresectable, systemic therapy.

• Systemic therapy include 131I-MIBG, octreotide and combination regimes of chemotherapeutic agents that include doxorubicin, streptozocin, 5FU & dacarbazin may partially prove useful in incurable diseases.

PROGNOSIS

• MTC responsible for 10-15% of deaths due to thyroid cancer.

• Overall survival at 10years is 56-96%• Children with MTC have survival rate at 5years

of 95%

ANAPLASTIC THYROID CARCINOMA

ANAPLASTIC THYROID CARCINOMA

• RISK FACTORS-– Goitre– Papillary Thyroid cancer– Follicular thyroid cancer– Iodine deficient areas– Male : Female ratio is 1:3

PATHOLOGY & GENETICS

• Anaplastic carcinoma of the thyroid (ATC) is believed to occur from a terminal dedifferentiation of previously undetected long-standing thyroid carcinoma (eg, papillary, follicular).

• ATC has a genetic association with oncogenes C-myc, H-ras,and Nm23. Mutations in BRAF, RAS, catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN, and APC genes have been found in ATC, and chromosomal abnormalities are common.

Anaplastic Thyroid Carcinoma Histology

CLINICAL ASSESSMENT

• Age of presentation : Peak incidence during 6th-7th decade but can be presented in the range 15-90 years old.

• Clinical Symptoms :– Rapidly growing neck mass ( most common )– Compressive symptoms like dysphagia, cough,

neck pain, dyspnoea– Bone pain due to bony metastasis– Neurological deficits due to brain metastasis.

• PHYSICAL EXAMINATION :– Dominant hard neck mass– Cervical lymphadenopathy ( 40% cases)– Pleural effusions due to lung metastasis– Bony pain and neurological deficit may be present

• Pharynx and larynx examination

INVESTIGATIONSCYTOLOGY FNAC TRUCUT OPEN BIOPSYLABORATORY INVESTIGATIONS TSH, T4, T3 Serum CalcitoninRADIOLOGY USG Scintigraphy using 123I or 99mTc.Hot or toxic nodules are highly unlikely to be malignant. CT neck and thorax MRI Brain Bone scanning

STAGING , TREATMENT & PROGNOSIS

• As per TNM staging, all anaplastic thyroid carcinoma patients are considered stage IV.

• TREATMENT IS MAINLY PALLIATIVE.• Radical EBRT and chemotherapy with

doxorubicin & cisplatin if the patient condition is good may increase the survival for few months or years.

• Five year survival is 7%

PRIMARY THYROID LYMPHOMA

PRIMARY THYROID LYMPHOMA• Thyroid lymphoma constitute only 3% of all Non Hodgkin’s

lymphoma.• Most common age of presentation 50-80 years.• Most of have history of Hashimoto’s disease.• Majority of thyroid lymphomas are of B-cell origin of

which diffuse large B-cell lymphoma accounts for 70%. MALT lymphoma are 6-27%.

• B symptoms of lymphoma are uncommon.• Treatment is 6 cycles of R-CHOP chemotherapy followed

by EBRT.• Prognosis is good.

THANK YOU VERY MUCH