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Pathology of Thyroid Diseases
Anatomy
Thyroid Gland
Anterior surface
Right, Left Lobe
Connected by narrow Isthmus
Hypothalamus-Pituitary-Thyroid Axis
Clinical Features of Thyroid Pathology
Hyperthyroidism
Hypothyroidism
Mass lesions of Thyroid
Hyperthyroidism
Clinical syndrome which results from
exposure of b ody tissues to excess
circulating levels of free thyroid
hormones
Hypermetabolic state
Due to over activity of
Sympathetic Nervous System
Causes
• Graves’ Disease (95%)
• Multinodular Goiter with Toxic
Nodule (Toxi c nodular goiter)
• Functioning Follicular Adenoma/
Carcinoma
• TSH secreting Pituitary Adenoma
(2°)
• Germ Cell Tumour
(Strauma ovarii, Choriocarcinoma)
• Thyroiditis (Hashimoto Thyroiditis)
• Hypothalamic Disorder (↑ TRH)
Thyroiditis
Inflammation of Thyroid Gland
Infectious, Non -In fectious
Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis)
Subacute Granulomatous Thyroiditis (DeQuervain Thyroiditis)
Subacute Lymphocytic Thyroiditis
Autoimmune Thyroid Diseases
Hashimoto Thyroiditis Graves Disease
Hypothyroidism Hyperthyroidism
Thyroid Follicle
Cuboidal epithelium
Filled with Colloid
Parafollicular “C” cells
Hypothyroidism
1°
• Developmental
(Thyroid Dysgenesis)
• Thyroid Hormone Resistance
Syndrome
• Post-ablative (Surgery, Radioiodine,
External Radiation) Congenital Anomalies of Thyroid Gland
• Autoimmune Normal Development
(Hashimoto Thyroiditis) Evagination of developing pharyngeal epithelium
• Iodine Deficiency that descends as part of Thyroglossal duct
• Drugs (Lithium, Iodides, from Foramen Cecu m (at base of tongue) → Anterior Neck
p-adminosalicylic acid ) Ectopic Thyroid Tiss ue
• Congenital Biosynthetic Defect Lingual Thyroid (base of tongue)
(Dyshormonogenetic Goiter) Sites Abnormally High in Neck
2° Substernal Thyroid Gland due to Excessive Descend
• Hypothalamic Disorder Thyroglossal duct or cyst
Congenital anomalies
• Pituitary Failure
Persistent sinus remain as a vestigial remnant of
Infant/ Early Childhood (Cretinism)
Impaired development of skeletal tubular development of thyroid gland
system, CNS, intellectual growth Part of tube may be obliterated leaving small segments to form cysts
(filled with mucinous secretion )
• Mental Retardation
Site
• Short Stature
• Midline of Neck
• Coarse Facial Features
• Anterior to Trachea
• Protruding Tongue
• Base of Tongue → Normal Position of Thyroid Gland
• Umbilical Hernia
Older Child/ Adult (Myoedema)
Slowing of Physical, Mental Activity
Serum TSH
↑ Sensitive Screening Test
Sites of Thyroglossal Duct/ Cyst Thyroglossal Cyst
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Hashimoto Thyroiditis Subacute Granulomatous Thyroi ditis Graves Disease

(Chronic Lymphocytic Thyroi ditis) (DeQuervain Thyroiditis) (Toxic Goiter)
Most common cause of Hypothyroidism Caused by Common cause of En dogenous Hyperthyroidism
45 – 60 y/o Viral Infection Diffuse Hypertrophy, Hyperplasia of
Female ↑ Post-Viral Inflammatory Process Thyroid Follicular Epithelial Cells
Autoimmune Destruction of Thyroid Gland Viral Initiated Antigenic Stimulation Female ↑
CD8 Cytotoxic T-cell mediated Cell Death to CD8 T cells 20 – 40 y/o
Cytokine mediated Cell Death Result Follicular Destruction Genetic Factors
Binding of Antithyroid Antibodies followed by ADCC Enlargement • HLA-B8
HLA-DR5 • Unilateral • HLA-DR3
HLA-DR3 • Bilateral Autoimmune Thyroid Disease
Pathogenesis Gross IgG Antibodies against TSH-Receptor on
Yellow-White Thyroid Follicular Cells
Rubbery • Thyroid Stimulating Ig
Histology • Thyroid Growth-Stimulating Ig
Aggregation of • TSH-Binding Inhibitor Ig
• Lymphocyte Clinical Manifestation
• Histiocyte Diffuse Enlargement of Thyroid Gland
• Plasma Cells Hyperthyroidism
Resulting Granuloma Infiltrative Ophthalmopathy with resultant Exopthalmos
Localized, Infiltrative Dermopathy
Pathogenesis

Gross
Diffusely Enlarged Thyroid Gland
Pale, Gray-Tan, Firm, Nodular (somewhat)
Atrophic Gland after Fibrosis
Subacute Granulomatous Thyroi ditis
Histology Foreign body Giant Cells (GC)
Extensive Infiltration of Parenchyma by Mononuclear
Destruction of Thyroid Follicles
Inflammatory Infiltrate, Fibrosis
• Lymphocytes
• Plasma Cells
• Well Developed Germinal Centers
Thyroid Follicles
• Atrophic
• Lined by Hurthle cells (Eosinophilic granular cytoplasm)
Interstitial Connective Tissue ↑, Abundant

Subacute Granulomatous Thyroi ditis

Gross
Diffusely Enlarge Gland with Soft, Meaty Appearance
resembling normal muscle
Histology
Crowding of Follicular Epithelium
Hashimoto’s Thyroiditis Small Papillae projecting into Lumen, Encroach on Colloid
Symmetrically Atrophic Thyroid Gland Papillae Colloid
Lack of Pale
Fibrovascular cores Scalloped Margin

Graves Disease
Diffuse Hyperplasia
Uniform, Diffuse Enlargement
Hashimoto’s Thyroiditis Red Meaty appearance
Lymphoid Follicle (LF)
Atrophic Thyroid Follicle (TF)

Graves Disease Graves Disease

Hashimoto’s Thyroiditis
Thyroid Parenchyma is
replaced by dense
lymphocytic infiltrate
Lymphoid Follicles with
Germinal Centers
Follicles are lined by
Crowded, Tall, Columnar
Hashimoto’s Thyroiditis Epithelium
Lymphoid Follicle (LF) Cells activity resorb the
Thyroid Follicles (TF) Colloid (C) in ce nters of
follicles
Resulting Scalloped
appearance of the edges
of Colloid
Tall columnar thyroid
epithelium lines the
hyperplastic infoldings into
colloid
Vacuoles are cleared in the
colloid next to epithelium
Scalloping out of Colloid
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Diffuse, Multinodular Goiters
Due to Impaired Synthesis of Thyroid Hormone
mainly caused by Dietary Iodine Deficiency
Compensatory ↑ of TSH
Hypertrophy, Hyperplasia of Follicular cells to overcome Hormonal Deficiency
Euthyroid Metabolic State

Diffuse Nontoxic (Simple) Goiter Multinodular Goitre (MNG)

(Diffuse Hyperplasia) (Nodular Hyperplasia)
Diffusely Enlarged gland without nodularity Recurrent episodes of Hyperplasia, Involution combined to prod uce
Goiters Irregular Enlargement of Thyroid
Colloid Endemic Sporadic Rupture of Follicle, Hemorrhages – Fibrosis
Enlarged Follicles filled Geographical areas ↓ Frequent Most Extreme Thyroid Enlargement
with Colloid where Soil, H2O, Food Female ↑ Long standing simple goiters can lead to MNG
supply with ↓ Iodine Puberty, Young Female Mistaken for Neoplasm
Goitrogens play role Mass Effect
Cassava • Cosmetic effects
Cabbage • Airway obstruction
Cauliflower • Dysphagia
Brussels Sprouts • Compression of Large Vessels in Neck, Upper Thorax
2 Phases Gross
Hyperplastic Colloid Invol ution Multilobulated, Asymmetrically Enlarged glands
Diffuse, Symmetrically Enlarge Brown, Glassy, Translucent Brown, Gelatinous colloid containing
Follicles lined by crowded columnar Follicular Epithelium is • Irregular Nodules
cells which may Flattened, Cuboidal • Haemorrhage
Pile Up, form Projections Colloid is Abundant • Fibrosis
• Calcification
• Cystic changes
Histology
Colloid-rich Follicles lined by Flattened, Inactive Epithelium
Areas of Follicular Hypertrophy, Hyperplasia with Degenerative Changes
• Haemorrhages
• Fibrosis
• Calcification
• Cystic changes

Diffuse Goiter
Mass Effect of Enlarged Thyroid Gland

Multinodular Goitre
Nodular Enlargement of Thyroid gland
Irregular Nodularity on surface
Multinodular Goitre
Multiple Nodules
Areas of Cystic Degeneration,
Haemorrhage, Fibrosis, Calcification

Multinodular Goitre (Colloid Goitre)

Multinodular Goitre Varying sizes of Colloid filled distended
Asymmetrical Enlargement follicles
Irregular, Nodular Surface Separated by Fibrous Septae (FS)
Areas of Haemorrhages Epithelial Linings are flat
Cystic Degeneration
Fibrosis

Nodular Hyperplasia Nodular Hyperplasia

with Benign Papillary formations Sanderson’s Polster
protruding into cystically dilated follicle
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Neoplasms of Thyroid Gland

Follicular Adenoma
Gross
Solitary, Spherical, Encapsulated,
Well-demarcated from surroun ding parenchyma
Average size – 3cm in diameter
Bulging, Compress Adjacent Thyroid, Gray-White → Brown
Histology
Constituent cells form unifor m-appearing Follicles containing Colloid
Epithelial cells vary in Cell, Nuclear Morphology
(Hurthle cell adenoma, Clear cell carcinoma, Signet ring cell adenoma)
Hallmark
Intact, Well formed capsule encircling tumor (distinguish from follicular carcinoma )

Follicular Adenoma
Focal Haemorrhagic area

Adenoma of Thyroid
Well circumscribed tumour
Sharp line of demarcation between tumour, Follicular Adenoma
adjacent thyroid tissue (arrow) Intact Fibrous Capsule

Follicular Adenoma
Solitary, Well-Circumscribed Nod ule
Surrounded by a
Thin White Capsule

Follicular Adenoma (FA)

Well-differentiated neoplasm
(closely resemble normal tissue)
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Carcinoma of Thyroid Gland
Papillary Carcinoma (75 – 85%) Follicular Carcinoma (10 – 20%) Medullary Carcinoma (5%) Anaplastic Carcinoma (< 5%)
Genetic Factors Genetic Factors Genetic Factors Genetic Factors
Most Inherited Mutations in RAS oncogenes Mutation RET, NTRK1, BRAF oncogene Inactivating Point Mutation in
Associated with (most common – NRAS) RAS Mutation p53 Tumour Suppression Gene
MEN-2, RET protooncogene mutation
Environmental Factors
st
Exposure to Ionizing Radiation (particularly during 1 2 decades of life) (especially Head, Neck region)
Long-standing Multinodular Goiter, Pre-existing Hashimoto Thyroiditis
Most common Thyroid Cancer Single Nodule Neuroendocrine Tumour Undifferentiated Tumour of
20 – 40 y/o Well circumscribed or Infiltrative Derived from Parafollicular C Cells Thyroid Follicular epithelium
Associated with (Majority of Ca) Difficult to distinguish from Secrete Calcitonin Aggressive Tumour, Rapidly Growing
Previous Ionizing Radiation Follicular Adenoma by gross examination (role in Diagnosis, Post-operative Follow up) Most Cases
Gross Larg er lesions – penetrate Capsule May elaborate other polypeptide hormone Spread beyond Thyroid Capsule into
Solitary or Multifocal Uniform cells forming small follicles containing • Somatostatin adjacent neck structure or
Granular, discernible Papillary Foci Colloid, sometimes lined by Hurthle cells • Serotonin metastasize distantly
Foci of Calcification Capsular and/or Vascular Invasion • VIP Older Patients (65 y/o) ↑
Lymphatic Invasion (uncommon) 80% - Sporadic Morphology
20% - Association with MEN 2A, 2B Highly Anaplastic cells
Gross • Larg e, Polymorphic Giant Cells
Solitary or Multiple Lesions • Spindle cells with
Involving Both Lobes Sarcomatous appearance
Firm, Pale, Gray→Tan, Infiltrative • Mixed Spindle cells, Giant cells
Larg er Lesion • Small cells
Asymmetrically enlarged • Foci of Haemorrhag e
Cystic Tumour • Necrosis
Contain Papillary Structures • Extend through Capsule
Histology
Polygonal → Spindle shapped cells
Invasive Invasive Arrang ed in Nests, Trabeculae, Follicles
Follicular Carcinoma Follicular Carcinoma Acellular Amyloid Deposits
Capsular Invasion Vascular Invasion (derived from altered calcitonin molecules)
Tan-White
Calcitonin, Amyloid (demonstrated by IHC)
Solid, Infiltrative Tumour
Ill-Defined margins in Right Lobe EM – Membrane bound electron dense
granules within cytoplasm of cells Anaplastic Carcinoma
Histology (Hallmarks)
Branching papillae Giant Cell Type
(Fibrovascular stalk covered by
single → multiple layers of
cuboidal epithelial cells)
Diagnostic Nuclear Features
• Clear or Empty
(Ground Glass, Orphan Annie Eye Nuclei)
• Intranuclear Inclusion Follicular Carcinoma
Intranuclear Grooves Capsular Invasion
Psammoma Bodies
(Concentrically lamellated calcified structures Medullary Carcinoma
within cores of papillae)
Tumour with Amyloid
Foci Lymphatic Invasion
Anaplastic Carcinoma
Spindle Cell Type

Follicular Carcinoma
Metastatic Invasion into Bone
Papillary Carcinoma of Thyroid
Medullary Carcinoma
Solid Pattern of Growth
Deposition of Amyloid

Papillary Carcinoma of Thyroid Medullary Carcinoma (Congo Red Stain)

Fibrovascular cores (FVC) Amyloid Stroma
lined by epithelium having clear nuclei
Small psammoma body (arrow)

Medullary Carcinoma (Polarised microsp.)

Amyloid
Papillary Carcinoma of Thyroid
Nuclear Grooving (arrows)

Medullary Carcinoma
Papillary Carcinoma of Thyroid +ve Immunohistochemical Stain
Papillary Carcinoma of Thyroid Psammoma Bodies Calcitonin
Nuclear Inclusion (arrow) (Fine Needle Aspiration Smear)