Neoplasms of Thyroid and

Parathyroid

Dr. Bikash Gurung

First year resident
MS ENT-HNS
GMSM Academy of ENT-HN Studies
MMC,TUTH, IOM
 Road map
 Thyroid neoplasm  Parathyroid neoplasm

- Classification - Classification
- Pathogenesis - Specific pathology
* Molecular genetics - Clinical Presentation
- Specific thyroid tumours
pathology
- Clinical Presentation
WHO classification of tumours of the thyroid
gland (2017)
1.Follicular adenoma
2.Hyalinizing trabecular tumour
3.Other encapsulated follicular-patterned thyroid tumours
-Follicular tumour of uncertain malignant potential
-Well-differentiated tumour of uncertain malignant potential
-Non-invasive follicular thyroid neoplasm with papillary-like
nuclear features
4.Papillary thyroid carcinoma (PTC)
-Papillary carcinoma - Papillary microcarcinoma
-Follicular variant of PTC -Columnar cell variant of PTC
-Encapsulated variant of PTC -Oncocytic variant of PTC
WHO classification of tumours of the thyroid
gland (contd)
5.Follicular thyroid carcinoma (FTC), NOS
-FTC, minimally invasive
-FTC, encapsulated angioinvasive
-FTC, widely invasive
6.Hurthle (oncocytic) cell tumours
-Hurthle cell adenoma
-Hurthle cell carcinoma
7.Poorly differentiated thyroid carcinoma
8.Anaplastic thyroid carcinoma
9.Squamous cell carcinoma
WHO classification of tumours of the thyroid
gland (contd)
10.Medullary thyroid carcinoma
11.Mixed medullary and follicular thyroid carcinoma
12.Mucoepidermoid carcinoma
13.Sclerosing mucoepidermoid carcinoma with eosinophilia
14.Mucinous carcinoma
15.Ectopic thymoma
16.Spindle epithelial tumour with thymus-like differentiation
17.Intrathyroid thymic carcinoma
WHO classification of tumours of the thyroid
gland (contd)
18.Paraganglioma and mesenchymal / stromal tumours
 Paraganglioma
 Peripheral nerve sheath tumours (PNSTs)
Schwannoma
Malignant PNST
 Benign vascular tumours
Haemangioma
Cavernous haemangioma
Lymphangioma
 Angiosarcoma
 Smooth muscle tumours
Leiomyoma
Leiomyosarcoma
 Solitary fibrous tumour
WHO classification of tumours of the thyroid
gland (contd)
19.Hematolymphoid tumours
 Langerhans cell histiocytosis
 Rosai-Dorfman disease
 Follicular dendritic cell sarcoma
 Primary thyroid lymphoma
20.Germ cell tumours
 Benign teratoma (grade 0 or 1)
 Immature teratoma (grade 2)
 Malignant teratoma (grade 3)
21.Secondary tumours
Pathogenesis
Molecular Genetics of Thyroid Cancer

 Most have a monoclonal origin

May involve

activation of inactivation of tumor suppressor

oncogenes genes

RET , BRAF p53, PTEN

Genetic alterations in follicular cell–derived
malignancies of the thyroid gland
  proto-oncogene located on chr 1 0q 1
1.2 and encodes a transmembrane
tyrosine kinase receptor
 Its mutation primarily causes
Papillary thyroid carcinoma but also
caues medullary Ca
 RET/PTC-1 : 60% PTC
Mutation  RET/PTC-3 : 20-30% PTC
 Ret/PTC mutation (60% Ukrainian
Rearrangements
thyroid cancers after the Chernobyl
labelled as
accident)
RET/PTC 1-5
 ~ 95% of families with MEN 2A
 encode a signaling protein -stimulates mitosis and reduced
differentiation.
 RAS genes : Ki-RAS, N-RAS and Ha-RAS
 RAS mutations have been identified in around 50%
thyroid adenomas, follicular carcinomas and anaplastic
tumours,
but less common in papillary thyroid cancer
 specific marker for papillary carcinoma
 +ve in FNA sample indicates > 99% probability of thyroid cancer
 One third to one half of papillary thyroid carcinomas harbor a
gain-of-function mutation in the BRAF gene
 The presence of BRAF mutations in papillary carcinomas
correlates with adverse prognostic factors like metastatic disease
and extrathyroidal extension.
 RET/PTC rearrangements and BRAF point mutations are
not observed in follicular adenomas or carcinomas.
 PAX8/PPARγ rearrangement

 follicular carcinomas and oncocytic carcinomas.

 frequent vascular invasion, and tend to occur in younger
patients (castro et al 2007)
trk and met

 Trk is an oncogene in chromosome 1

 codes for a transmembrane tyrosine kinase receptor,
 mutated in 0-25 % PTC

 met is a transmembrane tyrosine kinase receptor for hepatocyte

growth factor (HGF)
 Specifically increased in papillary thyroid cancer
Tumour suppressor genes

 p53 inactivation
key event in progression from differentiated to anaplastic
carcinoma
Radiation
 generates reactive free radical - damage DNA
 risk is greater in the young
 usually well differentiated (papillary)
 multifocal in nearly two-thirds of cases
 Ret gene rearrangements in 55-85%
 Develop up to 40 years after Exposure (peak incidence is about 1 5-
25 Years)
 Family History
 Gardner's syndrome -100-fold increased risk of PTC

 Cowden's disease- PTC

 Medullary thyroid carcinoma - multiple endocrine neoplasm (MEN)

syndromes

Dietary iodine consumption

 Low iodine areas- follicular and anaplastic tumours

 High iodine areas - papillary cancer

Potential carcinogenic factors for thyroid
cancer
Specific neoplasms
Follicular adenoma
 classically occurs;
- as a solitary benign,
- encapsulated tumour
- shows follicular epithelial differentiation
- no evidence of either capsular or vascular invasion
 common in middle-aged women
 Not premalignant and rarely become toxic
 may become autonomous
 Follicular adenoma
 Grossly - smooth-contoured or gently
undulating, slender, fibrous delimiting capsule
Microscopic patterns ; mitoses are few
 architectural patterns;
normofollicular, microfollicular (foetal),
macrofollicular (colloid), solid, trabecular
and organoid
 Cytologic patterns;
solid, foetal, oxyphilic (oncocytic), clear cell,
signet ring cell and lipoadenoma,
 Follicular adenoma

Clear cell variant Signet ring variant

Atypical adenoma
 follicular tumour of uncertain malignant potential
 display some worrisome microscopical features though falling
short of unequivocal capsular or vascular infiltration
 Shows; irregularly thickened capsule,
partial thickness incursions into, but not
completely through, the capsule,
hypercellularity,
increased mitoses and/or abnormal forms and
nuclear atypia
 Atypical follicular adenoma

follicular tumour of uncertain

Whole mount preparation
malignant potential
 Hyalinizing trabecular tumours
 originally regarded as adenomas (hyalinizing trabecular
adenoma/HTA, paraganglioma-like adenoma of the thyroid/PLAT)
 rare benign thyroid tumors
 low to minimal malignant potential
 HTT is often misinterpreted as other thyroid tumors, including
papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma
(MTC), on fine-needle aspiration (FNA) cytology
 Has cytologic features, such as nuclear grooves and intranulcear
pseudoinclusions
Hyalinizing trabecular tumours

Minimally invasive HTT

 Hyalinizing trabecular tumours

 HTT; Immunopositive for cytokeratins, thyroglobulin and vimentin generally

negative for panneuroendocrine marker and calcitonin staining

helps to differentiate from paraganglioma proper and medullary thyroid

carcinoma.
Other encapsulated follicular-patterned
thyroid tumours
Follicular tumour of uncertain malignant potential

 lie morphologically and behaviourally between follicular adenoma and

follicular carcinoma
 1.atypical adenoma
2.adenoma with atypia,
3.well differentiated tumour of uncertain behavior
 RET/PTC expression seen in some cases
Malignant tumours of the thyroid gland

 Origin - from any of the cellular components of the

gland;
follicular cells, parafollicular cells, lymphoid cells
&stromal cells.
Follicular cell neoplasms – classified into
Differentiated - papillary, follicular
Undifferentiated - anaplastic

Parafollicular cell origin - medullary carcinoma

 Differentiated thyroid cancers
Papillary cell carcinoma
 80 percent of thyroid malignancy.
 Commonest pediatric thyroid malignancy
 In adults ; between the ages of 20 and 50 years (F>M)
 less pronounced gender bias in > 50 years old
 Excellent prognosis in younger patients.
 In areas of adequate dietary iodine, usually presents as a solitary
nodule in the thyroid
 In regions of iodine insufficiency multinodular goiter is common and
papillary can present as a more prominent or distinctive nodule
 Papillary cell carcinoma
 propensity for lymphatogenous spread
 High incidence (60 percent) of cervical lymph nodes involvement
in Levels III - VII
 The primary tumour may be impalpable
 20% have pulmonary metastases at presentation
 Ten-year survival
For minimal, occult or intra thyroid papillary carcinoma > 90
percent
For extrathyroidal - 60 percent
 Papillary cell carcinoma
 Macroscopically
 irregular outline and either a scirrhous or
granular, gritty texture often with
multiloculated cystic change and colloid contents
 firm and unencapsulated tumour (70%)
 multicentric in 80 %(frequently both lobes)

 Extent of papillary ca.

 Minimal (or microcarcinoma )
 IntrathyroidaI
 ExtrathyroidaI
 Papillary Thyroid Carcinoma

 Histologically :
 Pure papillary
 mixed papillary-follicular : most common
 Follicular variant of papillary carcinoma: rare
Papillary Thyroid Carcinoma

Psammoma bodies

Orphan Annie eye nucleus

PTC
 Papillary Thyroid Carcinoma

Tall cell variant of papillary thyroid Solid variant of papillary thyroid

carcinoma carcinoma.
Papillary Thyroid Carcinoma

Hobnail variant of PTC Warthin tumour-like variant

 Papillary Thyroid Carcinoma

Diffuse sclerosing variant cribriform-morular variant

 Follicular Carcinoma Thyroid
 eutopic thyroid gland and/or heterotopic thyroid tissue
 most common between 50 and 59 years (seldom under the age of 30
years.)
 ~5–15% of all thyroid cancers
 Mainly haematogenous spread
 bone or lung involvement(20-30%)
 Most commonly presents as a solitary thyroid nodule
 metastatic disease as a presenting feature in 11% of patients
 Arises de novo or less frequently as malignant change in a thyroid
swelling
 Lymph node involvement - less common ( ~ 10 %)
 Follicular Carcinoma Thyroid
Categories

Minimally invasive Encapsulated Widely invasive follicular

follicular carcinoma angioinvasive carcinoma

microscopical identified grossly by

Tumors with
transcapsular infiltrative,
limited vascular
invasion and/or destructive or
invasion
pericapsular vascular sometimes
(< 4) 
infiltration multinodular growth
Follicular Carcinoma Thyroid

 Encapsulated angioinvasive MIFC with limited (minimal) vascular

invasion, microscopic foci (up to 4 foci) show a low risk of
metastasis (approximately 5%).
 MIFC with more extensive lymphovascular infiltration (defined as
5 or more foci) is said to have higher likelihood of metastasis (up to
42%)
 WIFC is an aggressive neoplasm with a high risk of distant
secondaries (29–66%)
 Follicular carcinoma
 Gross: Minimally invasive: usually single
encapsulated nodule, with thickened and irregular
capsule
-Widely invasive: extensive permeation of
capsule or no capsule
 Histologically - composed of follicles with no papillary
structure
 Histological features of malignancy - capsular and
vascular invasion
histologic variants; -clear cell
-oxyphilic
 Hurthle Cell Tumor
 Eosinophilic cell, oncocyte or oxyphilic cell tumor
 limited ability to produce thyroglobulin, does not concentrate iodine
 Hurthle cells - also found in
nodular goitres,
chronic lymphocytic thyroiditis,
diffuse toxic goitre,
after radiation and chemotherapy,
as part of the ageing process,
 Hurthle Cell Tumor
 A higher proportion of oncocytic (oxyphil) tumours are malignant than
other follicular lesions
 Subclassified;
based upon morphology, immunohistochemical profiling and
molecular markers as
1)oncocytic (oxyphil) adenoma,
2)oncocytic (oxyphil) tumour of uncertain malignant potential,
3)minimally or widely invasive oncocytic (oxyphil)
carcinoma(Hurthle cell carcinoma)
 Hurthle Cell Tumor
 usually single nodule (solitary oxyphil follicular tumour, SOFT)
 May be multiple (multiple oxyphil follicular tumour, MOFT)
 sometimes associated with Hashimoto’s thyroiditis and/or conventional
papillary thyroid carcinoma
 Hurthe cell carcinoma; mostly sporadic
 3-10% of all differentiated thyroid cancers.
 The incidence of malignancy in oncocytic (oxyphil) cell neoplasms increases
with size (maximum dimensions)
-less than 1 cm  17%
-between 1 cm and 4 cm 23%
-larger than 4 cm 65%
 Hurthle Cell Tumor
 Contains hurthle cells(round cell with eosinophilic,
finely granular cytoplasm which is indicative of
abundant mitochondria)
 Malignant tumours - capsular and vascular invasion
 Lymph node metastases are common
 Poorly differentiated thyroid carcinoma
 spectrum of heterogeneous tumours showing limited evidence of follicular cell
differentiation
 Differentiated and undifferentiated carcinoma
 typically arise de novo, but they may occur through transformation of
differentiated carcinoma.
 They may progress to undifferentiated (anaplastic) carcinoma either ab initio or
after recurrence
Poorly differentiated thyroid carcinoma

Classical PDTC
 Medullary Ca Thyroid
 1st described by Jaquet (1906) as ‘‘malignant goiter with amyloid’’
 Origin- parafollicular or C cells (Williams.,1966)
 5-8 % of thyroid malignancy
 Regional lymph node metastasis 20 % and distant lymphatogenous
8% of cases at presentation
 Types:
• sporadic
• MEN 2A
• MEN 2B
• familial non-MEN
 Medullary Ca Thyroid
 Gross: may be demarcated or infiltrative,
sometimes encapsulated
 Microscopically; they comprise solid sheets, nests
and trabecula of cells separated by slender
fibrovascular septa
 immunophenotype is positive for CK,
calcitonin,TTF-1, CEA, (CD66e) and pan-
neuroendocrine markers
 S100 protein-positive more commonly seen in
hereditary cases
 MEN 2A (Sipple syndrome)
 MTC, pheochromocytoma, hyperparathyroidism
 most common clinical subtype of MEN 2 .
 age of onset third or fourth decade
 characterized by a triad of features: MTC, PHEO, and PHPT.
 Nearly 90% of gene carriers will develop MTC, 57% (unilateral or
bilateral PHEO ) & 15–30% PHPT
 caused by mutations affecting cysteine residues in codons 609, 611, 618,
and 620 within exon 10 and, most commonly, codon 634 in exon 11 of RET
 MEN 2B
 MTC, pheochromocytoma, ganglionomas, marfan habitus
 most rare and aggressive form of MEN
 Age – earlier in life
 more advanced stage at presentation
 PHEO at early age (~ 8 yrs)
 MTC – 10yr earlier than MEN2A
 absence of PHPT
 typical phenotypic features
 Tumours displaying joint follicular
and C-cell differentiation

 Classical medullary carcinoma areas may be intermingled with follicles or

papillae or even oxyphilic and solid areas
 follicular carcinoma plus MTC or papillary carcinoma plus MTC.
 The histogenesis of MMFC is controversial
 Anaplastic carcinoma
 2-10% of all thyroid cancers
 More common in the elderly and in women(60-
80years), rare before 50
 superimposed on a long-standing goitre
 Aggressively malignant, high metastatic potential
and rapidly invade surrounding structures, regional
lymph nodes and distant metastasis to any site Fig.cross-sectional slice through a thyroid
lobectomy specimen substantially
 de novo de-differentiation of a pre-existing neoplasm replaced by undifferentiated (anaplastic)
thyroid carcinoma. Shows solid, dense,
 Poor prognosis : median survival of 4 months and featureless and infiltrative nature
<10% 5-year survival rate
 Anaplastic Carcinoma
 Histologically,
- no characteristic architecture
- no resemblance to normal thyroid cells.
 Two categories
Fig a
- spindle cell pattern, fig.a
- pleomorphic giant cell pattern, fig.b
 Immunohistochemical staining:
cytokeratin and vimentin are at least focally positive
~90%
epithelial membrane antigen in ~50%
 
Fig b
 Primary thyroid Lymphoma

 < 5 percent of all cases of lymphoma

 Usually arises in a background of chronic autoimmune thyroiditis
 Presentation- rapidly increasing swelling of the neck in elderly
women
 Clinical presentation - similar to that of anaplastic thyroid
carcinoma
 Response to treatment and prognosis of lymphoma -excellent and
better than that of anaplastic cancer
 Primary thyroid Lymphoma

 Grossly- large grey fleshy masses, often

extending outside the capsule
 Histologically-majority are high-grade B cell
non-Hodgkin's lymphomas
 Primary Squamous cell thyroid cancer

 <1% of thyroid malignancies

 morphology of primary squamous carcinoma of
the thyroid is not distinctive,
 its appearance is identical to squamous carcinoma
arising elsewhere
 secondary SCC thyroid, which it could be due to a
direct extension of adjacent lesions or metastasis
from other primary foci are 10-times more
common
 Secondary tumors
 commonly affected by metastases either by direct extension from near
by structures, haematogenous or lymphatic spread
 metastatic malignant melanoma
 Metastatic renal cell carcinoma
 Other neoplasms and tumour-like lesions
 Rare, but distinct forms of primary thyroid carcinoma may morphologically
simulate tumours of salivary gland derivation,
 Notably
- muco-epidermoid carcinoma
- muco-epidermoid
- carcinoma with eosinophilia and
- secretory carcinoma/mammary secretory analogue carcinoma.
Other- rare tumors of thyroid

 Paraganglioma
 Germ cell tumours
 Leiomyoma
 Angiosarcoma
 Presenting symptoms of thyroid tumours
 solitary thyroid nodule - majority
 cervical lymphadenopathy – 40%
 rapidly enlarging goitre
 pain in the neck
 stridor due to tracheal compression
 dysphagia due to oesophageal compression
 hoarseness due to vocal cord palsy
 distant metastases
 history of radiation in childhood and/or a family history of thyroid
disease.
 A nodule is more likely to be malignant if;
 Positive family history
 Previous history of thyroid cancer
 Enlarging nodule (particularly on suppressive doses of thyroxine)
 Age < 14 or >65 years
 Male patient
 Past history of ionizing radiation
 Pain
 Compressive or invasive features such as stridor, dyspnea and
dysphagia
A nodule is more likely to be malignant if;

 Recurrent or rapidly filling cyst after aspiration

 Nodules that occur in Graves’ or Hashimoto thyroiditis
 TSH is elevated
 Thyroid antibodies positive
 Evaluation of the thyroid Nodule
(Physical Examination)
 Examination of the thyroid nodule:
 consistency - hard vs. soft
 size -
 Multinodular vs. solitary nodule
 multi nodular - 3% chance of malignancy
 solitary nodule - 5%-12% chance of
malignancy (Goldman., 1996)
 Mobility with swallowing
 Mobility with respect to surrounding tissues
 Well circumscribed vs. ill defined borders
Physical Examination
 palpation of the neck :
- lymphadenopathy
- carotid pulsation
- trachea displacement
- laryngeal crepitus
 Indirect or fiberoptic laryngoscopy
 vocal cord mobility
 evaluate airway
 preoperative documentation of any unrelated abnormalities
Investigations for thyroid nodule

 Thyroid function tests

 thyroxine (T4)
 triiodothyronin (T3)
 thyroid stimulating hormone (TSH)
Investigations for thyroid nodule
 Ultrasonography
Sonographically suspicious features of malignancy;

 Microcalcifications
 Hypoechoic, solid nodules
 Nodules with irregular or lobulated margins
 Intranodular vascularity
 Taller-than-wide shape
 Absent halo sign
 Signs of spread beyond the capsule of the nodule
Papillary Ca -microcalcifications
Follicular thyroid neoplasm
 Investigations for thyroid nodule
Fine needle aspiration cytology or biopsy (FAC/FNAB)
 aspiration may be reported as benign, malignant or indeterminate.
 Follicular or Hurthle cell tumours are reported as neoplasms because
FNAC cannot differentiate between benign and malignant lesions
 The diagnosis of high-grade non-Hodgkin lymphoma is generally
straight forward with adequate FNAC material
Papillary Ca
Follicular neoplasm
Medullary carcinoma
Anaplastic carcinoma
CT and MRI
 Provide adjunctive anatomic
information
 detection of lymph node
metastases
 Oesophageal, tracheal, and
jugular vein invasion
 mediastinal or retrotracheal
extension of thyroid masses
 iodinated contrast material
-alters radioactive iodine
uptake
 MR with contrast
(gadolinium) –does not
interfere with iodide uptake
Parathyroid gland neoplasms
Neoplasms of parathyroid gland
WHO (4th edition, 2017) classification
 Parathyroid adenoma
 Parathyroid carcinoma
 Secondary, mesenchymal and other tumour

Present as primary hyperparathyroidism

 Parathyroid adenomas
 Usually solitary, with the other glands showing evidence of suppressed
activity
 Double or multiple adenomas may occur
 More common in lower glands
 6th and 7th decades
 Sporadic or with syndromes
 Irradiation of neck : potential risk factor with a latency/interval period in
the order of 30–40 years
 Parathyroid adenomas
 Grossly : ovoid, soft, reddish-brown
 Microscopically - varying
compositions of chief, clear and oxyphil
cells
 Chief-cell adenoma by far the most
common
 Parathyroid adenomas
 Variants;
-cystic adenoma
-lipoadenoma
-papillary variant
-water clear adenoma
-Follicular variant
-Oxyphil adenoma (oncocytic adenoma)
-Microadenoma
-Atypical parathyroid gland adenoma (parathyroid neoplasm of uncertain
malignant potential
 Parathyroid carcinomas

 nearly always functioning tumours

usually with a very high serum calcium
and PTH.
 Age : 5th & 6th decade
 No gender predilection
 0.5–2% of all cases of primary
hyperparathyroidism
 Metastasis : 30% regional LN, Lung
(40%),liver(10%),bone
 Survival: 60-85% at 5yr
 Parathyroid carcinomas
 Macroscopic : firm, greyish-white
and adherent to adjacent structures
 Microscopically : capsular &
vascular invasion, marked fibrosis
with nodule formation, focal areas
of necrosis
 Immunohistochemistry :
Ki67, cytokeratin 14
 Clinical features
 Asymptomatic
 S/S of hyperparathyroidism, hypercalcemia
 General features : tiredness, malaise, dehydration and depression
 Renal features : Renal colic from stones, polyuria or nocturia,
haematuria and hypertension
 Bones : bone pain
 Abdominal : There may be abdominal pain
 Chondrocalcinosis and ectopic calcification : These are occasional
features
Investigation

 BIOCHEMICAL: plasma calcium, albumin, vitamin D and PTH

 LOCALIZATION STUDIES :
- high resolution ultrasound
- 99mTc-sestamibi scan
- selective angiography and venous sampling
- CT, MRI,PET scan
Thank you