Endocrine Organ Pathology: Functional Disorders and Histopathology

1.

Endocrine Organ Pathology
An architectural framework of functional status, etiological mechanisms, and detailed
histopathological morphology.
Made by Rahil Rafiq 09-A

2.

FRAMEWORK
Master Classification Schemes
Developmental & Congenital
Inflammatory & Autoimmune
Hyperplastic & Neoplastic
Diffuse / Multinodular Goiter: Compensatory
Agenesis / Aplasia: Complete developmental
Acute / Infectious: Rare direct microbial
hyperplasia to environmental or iodine
failure of the gland.
infections.
deficiency.
Autoimmune: T-cell and antibody mediated
Ectopic Tissue: Lingual thyroid or migration
(Hashimoto, Graves).
monoclonal Adenomas.
pathway rests.
Inborn Defects: Dyshormonogenesis and
Granulomatous: Post-viral subacute
synthesis pathway enzyme failures (e.g., TPO
destruction (de Quervain).
mutations).
Benign Neoplasms: Fully encapsulated
Malignant Carcinomas: Papillary, Follicular,
Anaplastic, and Medullary variations.

3.

HYPERFUNCTIONING STATES
True Hyperthyroidism (High RAIU)
Graves Disease (Diffuse Toxic Goiter)
Mechanism: TSH-receptor-stimulating autoantibodies (TSI/TRAb).
Gross Appearance: Symmetric, diffusely enlarged, hypervascular ("meat-like", red-brown).
Microscopic: Tall columnar cells, pseudopapillae without fibrovascular cores, pale scalloped colloid
with clear resorption vacuoles.
Toxic Multinodular Goiter (Plummer Disease)
Mechanism: Chronic iodine-deficiency goiter develops clonal, autonomous nodules carrying somatic
gain-of-function mutations (TSHR or GNAS).
Microscopic: Mix of hyperactive follicles (tall columnar epithelium with depleted colloid) adjacent to
inactive, dilated, colloid-distended follicles.

4.

LOW / SUPPRESSED RAIU
Destructive & Autonomous Thyrotoxicosis
Subacute Granulomatous (de Quervain)
Class: Post-viral granulomatous inflammation causing transient leakage.
Amiodarone-Induced (AIT)
Type 1: Iodine-induced hyperthyroidism (Jod-Basedow) driving underlying subclinical
Graves.
Microscopic: Patchy follicular destruction with neutrophilic microabscesses evolving into
Type 2: Direct chemical-induced destructive thyroiditis showing extensive follicular
foreign-body granulomas with multinucleated giant cells wrapped around colloid
disruption without true autoimmunity.
remnants.
Toxic Adenoma & Struma Ovarii
Subacute Lymphocytic Thyroiditis
Toxic Adenoma (Hot Nodule): Solitary neoplasm driven by monoclonal TSHR mutations;
Class: Autoimmune lymphocytic inflammation (milder, painless variant of Hashimoto,
extra-tumoral thyroid tissue is functionally suppressed and microscopically atrophic.
often postpartum).
Microscopic: Lymphocytic infiltration with focal collapse, lacking dense germinal centers
Struma Ovarii: Ectopic mature thyroid follicles inside an ovarian teratoma hypersecreting
and prominent Hürthle cell metaplasia.
T3/T4, leaving the neck gland completely quiescent on imaging.

5.

HYPOFUNCTIONING STATES
Primary Autoimmune Hypothyroidism
Hashimoto Thyroiditis
Mechanism: Progressive CD8+ T-cell and antibody-mediated destruction (anti-TPO, anti-Tg).
Gross Appearance: Rubbery, pale tan/white cut surface resembling a lymph node.
Microscopic: Dense lymphoplasmacytic infiltrate with germinal centers, follicular atrophy, and Hürthle
cell (oncocytic/Askanazy) metaplasia (plump cells with granular pink cytoplasm loaded with
degenerated mitochondria).
Atrophic Thyroiditis (Primary Myxedema)
Mechanism: High-titer TSH-receptor blocking antibodies (TBAb) starve follicles of trophic signals.
Pathology: Near-total loss of follicles replaced by extensive dense collagenous scar tissue. Shrunken,
fibrotic nubbin weighing < 5 g.

6.

HYPOFUNCTIONING STATES
Environmental, Congenital & Infiltrative
Endemic / Diffuse Non-Toxic Goiter
Mechanism: Dietary iodine deficiency causes decreased T3/T4, leading to compensatory high TSH and diffuse follicular cell hyperplasia. When
iodine intermittently returns, follicles fill with colloid (involution).
Microscopic: Huge, distended follicles lined by flattened, resting epithelium packed with dense, glassy colloid.
Congenital Hypothyroidism
Thyroid Dysgenesis (85%): Agenesis, hypoplasia, or ectopic tissue driven by developmental arrest (PAX8, FOXE1, NKX2-1 mutations).
Dyshormonogenesis (15%): Inborn enzyme deficiencies showing massive follicular hyperplasia devoid of colloid.
Infiltrative Hypothyroidism
Riedel Thyroiditis: IgG4-related destructive dense fibrous replacement invading past capsule into strap muscles.
Systemic Amyloidosis: Interstitial deposits in follicular basement membranes causing compression atrophy.

7.

MALIGNANT EPITHELIAL NEOPLASMS
Papillary & Follicular Carcinoma
Papillary Thyroid Carcinoma (PTC) – 80-85%
Genetics: BRAF V600E (most common), RET/PTC rearrangements.
Spread: Lymphatic invasion to regional cervical lymph nodes.
Diagnostic Triad: "Orphan Annie eyes" (optically clear nuclei with peripheral chromatin), Intranuclear
cytoplasmic pseudoinclusions/grooves, and Psammoma bodies (laminated calcospherites).
Follicular Thyroid Carcinoma (FTC) – 10-15%
Genetics: RAS mutations, PAX8-PPARG fusion gene.
Diagnostic Rule: Cytologically identical to a benign follicular adenoma. Malignancy strictly requires
histologic proof of transcapsular invasion or angioinvasion.
Spread: Hematogenous spread to bones and lungs.

8.

AGGRESSIVE & C-CELL TUMORS
Anaplastic & Medullary Carcinoma
Anaplastic Carcinoma (ATC)
Incidence: Extremely aggressive, <2% of cases. Dedifferentiates from pre-
Medullary Carcinoma (MTC)
Origin: Parafollicular C-cells (neuroendocrine origin; secretes calcitonin).
existing PTC or FTC.
Mutations: TP53, TERT promoter mutations.
Genetics: Activating point mutations in RET proto-oncogene. 25% familial
(MEN2A/MEN2B). Familial cases are bilateral with background C-cell
Gross Appearance: Rapidly expanding, bulky, necrotic, hard mass infiltrating
hyperplasia.
the trachea, esophagus, and carotid sheath.
Microscopic: Nests and cords of polygonal neuroendocrine cells surrounded
Microscopic: High-grade pleomorphic giant cells, spindle cells
(sarcomatoid), atypical mitoses, and geographic necrosis.
by dense acellular amyloid stroma (stains Congo Red positive).

9.

PARATHYROID PATHOLOGY
Primary Hyperparathyroidism
Solitary Parathyroid Adenoma (85-90%)
Class: Benign monoclonal chief cell neoplasm (PRAD1 or MEN1).
Microscopic: Sheets of uniform chief cells with complete absence of stromal fat. A compressed rim of
normal, fat-containing tissue is visible at the edge. The other 3 glands are atrophic.
Primary Parathyroid Hyperplasia (10-15%)
Pathology: Multiglandular chief cell/water-clear cell proliferation with stromal fat depletion across all
4 glands. Lacks a rim of normal compressed tissue.
Parathyroid Carcinoma (<1%)
Diagnostic Rule: Cellular pleomorphism alone is not diagnostic. Requires demonstration of capsular,
vascular, or perineural invasion / metastasis.

10.

REACTIVE & AUTONOMOUS PATHOLOGY
Secondary / Tertiary & End-Organ Damage
Secondary Hyperparathyroidism
Skeletal System (Osteitis Fibrosa Cystica)
Mechanism: CKD causes phosphate retention and lacks 1-alpha-hydroxylase activation of
Microscopic: Dissecting osteitis (osteoclasts boring through trabeculae) with
vitamin D, driving chronic hypocalcemia.
fibrovascular marrow replacement.
Pathology: Diffuse, symmetric compensatory reactive hyperplasia of all four glands.
Brown Tumors: Expansile lytic pseudotumors of osteoclast-like giant cells, fibroblasts,
and abundant hemosiderin.
Tertiary Hyperparathyroidism
Renal System
Mechanism: In long-standing ESRD, hyperplastic glands develop clonal autonomous
mutations, escaping feedback loops to drive massive PTH and high Calcium.
Nephrocalcinosis: Metastatic calcification within tubular basement membranes, leading to
tubular atrophy and interstitial fibrosis.

11.

LOW PTH OR RESISTANCE
Hypoparathyroidism & Receptor Resistance
Primary Hypoparathyroidism
Pseudohypoparathyroidism (Type 1A)
Iatrogenic (>70%): Inadvertent excision or devascularization during total
thyroidectomy or neck dissection.
Mechanism: Inactivating mutation in maternal GNAS1 allele (Gs-alpha).
Target organ receptor resistance to PTH.
Autoimmune (APS-1): AIRE gene mutation. Lymphocytic infiltration
followed by total fibrofatty replacement.
Biochemistry: High PTH, low Calcium, high Phosphate (parathyroids
function, but renal tubules cannot transduce via adenylate cyclase).
DiGeorge Syndrome: 22q11.2 microdeletion. Developmental failure of
3rd/4th pharyngeal pouches (absent parathyroid and thymus, conotruncal
cardiac defects).
Phenotype (Albright Hereditary Osteodystrophy): Short stature, round
facies, obesity, short 4th/5th metacarpals.

12.

SUMMARY
Master Diagnostic Matrix
Gland
Disease Entity
Pathological Category
Distinctive Microscopic Signature
Thyroid
Graves Disease
Autoimmune hyperplasia
Tall columnar cells, pseudopapillae, scalloped
colloid
Thyroid
Hashimoto
Autoimmune destructive
Germinal centers, follicular atrophy, Hürthle cells
Thyroid
de Quervain
Granulomatous
Multinucleated giant cell granulomas around
colloid
Thyroid
Papillary Carcinoma
Malignant neoplasm
Orphan Annie nuclei, grooves, psammoma bodies
Thyroid
Medullary Carcinoma
Neuroendocrine neoplasm
Sheets of C-cells in an acellular amyloid stroma
Parathyroid
Parathyroid Adenoma
Benign neoplasm
Uniform chief cells, zero stromal fat, rim of normal
tissue
Parathyroid
Secondary Hyperparathyroidism
Diffuse hyperplasia (reactive)
All 4 glands enlarged, chief cell proliferation, CKD
changes

13.

Questions & Discussion
Reviewing the pathological mechanisms of endocrine disorders.
Made by Rahil Rafiq 09-A

14.

Image Sources
https://webpath.med.utah.edu/jpeg4/ENDO023.jpg
Source: webpath.med.utah.edu
http://ilovepathology.com/wp-content/uploads/2016/05/hashimoto2.bmp
Source: ilovepathology.com
https://endoconsult.b-cdn.net/wp-content/uploads/PTC-with-psammoma-bodies.jpg
Source: myendoconsult.com
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d612/7395581/27b709bfd1d6/nihms-1613113-f0001.jpg
Source: pmc.ncbi.nlm.nih.gov