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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