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Pathology of Thyroid Diseases
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Pathology of Thyroid Diseases
Anatomy
Thyroid Gland
Anterior surface
Right, Left Lobe
Connected by narrow Isthmus
Thyroid Follicle
Cuboidal epithelium
Filled with Colloid
Parafollicular “C” cells
Hypothalamus-Pituitary-Thyroid Axis
Clinical Features of Thyroid Pathology
Hyperthyroidism
Hypothyroidism
Mass lesions of Thyroid
Hyperthyroidism Hypothyroidism
Clinical syndrome which results from
exposure of body tissues to excess
circulating levels of free thyroid
hormones
1°
• Developmental
(Thyroid Dysgenesis)
• Thyroid Hormone Resistance
Syndrome
• Post-ablative (Surgery, Radioiodine,
External Radiation)
• Autoimmune
(Hashimoto Thyroiditis)
• Iodine Deficiency
• Drugs (Lithium, Iodides,
p-adminosalicylic acid)
• Congenital Biosynthetic Defect
(Dyshormonogenetic Goiter)
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)
2°
• Hypothalamic Disorder
• Pituitary Failure
Infant/ Early Childhood (Cretinism) Impaired development of skeletal
system, CNS, intellectual growth
• Mental Retardation
• Short Stature
• Coarse Facial Features
• Protruding Tongue
• Umbilical Hernia
Older Child/ Adult (Myoedema)
Slowing of Physical, Mental Activity
Serum TSH ↑ Sensitive Screening Test
Thyroiditis
Inflammation of Thyroid Gland Infectious, Non-Infectious
Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis)
Subacute Granulomatous Thyroiditis (DeQuervain Thyroiditis)
Subacute Lymphocytic Thyroiditis
Autoimmune Thyroid Diseases
Hashimoto Thyroiditis Graves Disease
Hypothyroidism Hyperthyroidism
Congenital Anomalies of Thyroid Gland
Normal Development
Evagination of developing pharyngeal epithelium
that descends as part of Thyroglossal duct
from Foramen Cecum (at base of tongue) → Anterior Neck
Ectopic Thyroid Tissue
Lingual Thyroid (base of tongue)
Sites Abnormally High in Neck
Substernal Thyroid Gland due to Excessive Descend
Thyroglossal duct or cyst
Congenital anomalies
Persistent sinus remain as a vestigial remnant of
tubular development of thyroid gland
Part of tube may be obliterated leaving small segments to form cysts
(filled with mucinous secretion)
Site
• Midline of Neck
• Anterior to Trachea
• Base of Tongue → Normal Position of Thyroid Gland
Sites of Thyroglossal Duct/ Cyst
Thyroglossal Cyst
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Hashimoto Thyroiditis
(Chronic Lymphocytic Thyroi ditis)
Subacute Granulomatous Thyroi ditis
(DeQuervain Thyroiditis)
Graves Disease
(Toxic Goiter)
Most common cause of Hypothyroidism
45 – 60 y/o
Female ↑
Caused by
Viral Infection
Post-Viral Inflammatory Process
Common cause of Endogenous Hyperthyroidism
Diffuse Hypertrophy, Hyperplasia of
Thyroid Follicular Epithelial Cells
Autoimmune Destruction of Thyroid Gland
CD8 Cytotoxic T-cell mediated Cell Death
Cytokine mediated Cell Death
Binding of Antithyroid Antibodies followed by ADCC
Viral Initiated Antigenic Stimulation
to CD8 T cells
Result Follicular Destruction
Female ↑
20 – 40 y/o
Genetic Factors
• HLA-B8
• HLA-DR3
Enlargement
• Unilateral
• Bilateral
HLA-DR5
HLA-DR3 Autoimmune Thyroid Disease
IgG Antibodies against TSH-Receptor on
Thyroid Follicular Cells
• Thyroid Stimulating Ig
• Thyroid Growth-Stimulating Ig
• TSH-Binding Inhibitor Ig
Pathogenesis
Gross
Yellow-White
Rubbery
Histology
Aggregation of
• Lymphocyte
• Histiocyte
• Plasma Cells
Resulting Granuloma
Clinical Manifestation
Diffuse Enlargement of Thyroid Gland
Hyperthyroidism
Infiltrative Ophthalmopathy with resultant Exopthalmos
Localized, Infiltrative Dermopathy
Subacute Granulomatous Thyroi ditis Foreign body Giant Cells (GC)
Destruction of Thyroid Follicles
Pathogenesis
Gross
Diffusely Enlarged Thyroid Gland
Pale, Gray-Tan, Firm, Nodular (somewhat)
Atrophic Gland after Fibrosis
Histology Extensive Infiltration of Parenchyma by Mononuclear
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
Hashimoto’s Thyroiditis
Symmetrically Atrophic Thyroid Gland
Gross
Diffusely Enlarge Gland with Soft, Meaty Appearance
resembling normal muscle
Histology Crowding of Follicular Epithelium
Small Papillae projecting into Lumen, Encroach on Colloid
Papillae Colloid
Lack of
Fibrovascular cores
Pale
Scalloped Margin
Hashimoto’s Thyroiditis
Lymphoid Follicle (LF)
Atrophic Thyroid Follicle (TF)
Graves Disease
Diffuse Hyperplasia
Uniform, Diffuse Enlargement
Red Meaty appearance
Graves Disease
Follicles are lined by
Crowded, Tall, Columnar
Epithelium
Cells activity resorb the
Colloid (C) in ce nters of
follicles
Resulting Scalloped
appearance of the edges
of Colloid
Graves Disease
Tall columnar thyroid
epithelium lines the
hyperplastic infoldings into
colloid
Vacuoles are cleared in the
colloid next to epithelium
Scalloping out of Colloid
Hashimoto’s Thyroiditis
Thyroid Parenchyma is
replaced by dense
lymphocytic infiltrate
Lymphoid Follicles with
Germinal Centers
Hashimoto’s Thyroiditis
Lymphoid Follicle (LF)
Thyroid Follicles (TF)
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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 (Diffuse Hyperplasia)
Multinodular Goitre (MNG) (Nodular Hyperplasia)
Diffusely Enlarged gland without nodularity Recurrent episodes of Hyperplasia, Involution combined to produce
Irregular Enlargement of Thyroid Goiters
Colloid Endemic Sporadic Rupture of Follicle, Hemorrhages – Fibrosis
Enlarged Follicles filled
with Colloid
Geographical areas
where Soil, H2O, Food
supply with ↓ Iodine
↓ Frequent
Female ↑
Puberty, Young Female
Most Extreme Thyroid Enlargement
Long standing simple goiters can lead to MNG
Mistaken for Neoplasm
Goitrogens play role
Cassava
Cabbage
Cauliflower
Brussels Sprouts
Mass Effect
• Cosmetic effects
• Airway obstruction
• Dysphagia
• Compression of Large Vessels in Neck, Upper Thorax
2 Phases Gross
Multilobulated, Asymmetrically Enlarged glands
Brown, Gelatinous colloid containing
• Irregular Nodules
• Haemorrhage
• Fibrosis
• Calcification
• Cystic changes
Hyperplastic Colloid Invol ution
Diffuse, Symmetrically Enlarge Brown, Glassy, Translucent
Follicles lined by crowded columnar
cells which may
Pile Up, form Projections
Follicular Epithelium is
Flattened, Cuboidal
Colloid is Abundant
Diffuse Goiter
Mass Effect of Enlarged Thyroid Gland
Histology
Colloid-rich Follicles lined by Flattened, Inactive Epithelium
Areas of Follicular Hypertrophy, Hyperplasia with Degenerative Changes
• Haemorrhages
• Fibrosis
• Calcification
• Cystic changes
Multinodular Goitre
Nodular Enlargement of Thyroid gland
Irregular Nodularity on surface
Multinodular Goitre
Multiple Nodules
Areas of Cystic Degeneration,
Haemorrhage, Fibrosis, Calcification
Multinodular Goitre
Asymmetrical Enlargement
Irregular, Nodular Surface
Areas of Haemorrhages
Cystic Degeneration
Fibrosis
Multinodular Goitre (Colloid Goitre)
Varying sizes of Colloid filled distended
follicles
Separated by Fibrous Septae (FS)
Epithelial Linings are flat
Nodular Hyperplasia
with Benign Papillary formations
protruding into cystically dilated follicle
Nodular Hyperplasia
Sanderson’s Polster
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Neoplasms of Thyroid Gland
Follicular Adenoma
Gross Histology
Solitary, Spherical, Encapsulated,
Well-demarcated from surrounding parenchyma
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) Average size – 3cm in diameter
Bulging, Compress Adjacent Thyroid, Gray-White → Brown 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,
adjacent thyroid tissue (arrow)
Follicular Adenoma
Intact Fibrous Capsule
Follicular Adenoma
Solitary, Well-Circumscribed Nodule
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
Most Inherited
Associated with
MEN-2, RET protooncogene mutation
Genetic Factors
Mutations in RAS oncogenes
(most common – NRAS)
Genetic Factors
Mutation RET, NTRK1, BRAF oncogene
RAS Mutation
Genetic Factors
Inactivating Point Mutation in
p53 Tumour Suppression Gene
Environmental Factors
Exposure to Ionizing Radiation (particularly during 1st 2 decades of life) (especially Head, Neck region)
Long-standing Multinodular Goiter, Pre-existing Hashimoto Thyroiditis
Most common Thyroid Cancer
20 – 40 y/o
Associated with (Majority of Ca)
Previous Ionizing Radiation
Single Nodule
Well circumscribed or Infiltrative
Neuroendocrine Tumour Undifferentiated Tumour of
Thyroid Follicular epithelium Derived from Parafollicular C Cells
Difficult to distinguish from
Follicular Adenoma by gross examination
Secrete Calcitonin
(role in Diagnosis, Post-operative Follow up)
Aggressive Tumour, Rapidly Growing
Most Cases
Spread beyond Thyroid Capsule into
adjacent neck structure or
metastasize distantly
Gross
Solitary or Multifocal
Granular, discernible Papillary Foci
Foci of Calcification
Larger lesions – penetrate Capsule May elaborate other polypeptide hormone
• Somatostatin
• Serotonin
• VIP
Uniform cells forming small follicles containing
Colloid, sometimes lined by Hurthle cells
Capsular and/or Vascular Invasion Older Patients (65 y/o) ↑
Asymmetrically enlarged
Cystic Tumour
Contain Papillary Structures
Lymphatic Invasion (uncommon) 80% - Sporadic
20% - Association with MEN 2A, 2B
Morphology
Highly Anaplastic cells
• Large, Polymorphic Giant Cells
• Spindle cells with
Sarcomatous appearance
• Mixed Spindle cells, Giant cells
• Small cells
Invasive
Follicular Carcinoma
Capsular Invasion
Invasive
Follicular Carcinoma
Vascular Invasion
Gross
Solitary or Multiple Lesions
Involving Both Lobes
Firm, Pale, Gray→Tan, Infiltrative
Larger Lesion
• Foci of Haemorrhage
• Necrosis
• Extend through Capsule
Anaplastic Carcinoma
Giant Cell Type
Tan-White
Solid, Infiltrative Tumour
Ill-Defined margins in Right Lobe
Histology
Polygonal → Spindle shapped cells
Arranged in Nests, Trabeculae, Follicles
Acellular Amyloid Deposits
(derived from altered calcitonin molecules)
Calcitonin, Amyloid (demonstrated by IHC)
EM – Membrane bound electron dense
granules within cytoplasm of cells
Follicular Carcinoma
Capsular Invasion
Histology (Hallmarks)
Branching papillae
(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
Intranuclear Grooves
Psammoma Bodies
(Concentrically lamellated calcified structures
within cores of papillae)
Foci Lymphatic Invasion
Medullary Carcinoma
Tumour with Amyloid Anaplastic Carcinoma
Spindle Cell Type
Follicular Carcinoma
Metastatic Invasion into Bone
Medullary Carcinoma
Solid Pattern of Growth
Deposition of Amyloid
Papillary Carcinoma of Thyroid
Papillary Carcinoma of Thyroid
Fibrovascular cores (FVC)
lined by epithelium having clear nuclei
Small psammoma body (arrow)
Medullary Carcinoma (Congo Red Stain)
Amyloid Stroma
Medullary Carcinoma (Polarised microsp.)
Amyloid Papillary Carcinoma of Thyroid
Nuclear Grooving (arrows)
Medullary Carcinoma
+ve Immunohistochemical Stain
Calcitonin
Papillary Carcinoma of Thyroid
Nuclear Inclusion (arrow)
Papillary Carcinoma of Thyroid
Psammoma Bodies
(Fine Needle Aspiration Smear)
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