Pathology Of C-Cells And Parathyroid Glands

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CALCITONIN:

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32 amino acid peptide produced by thyroid
Reduces blood calcium in many species
Inhibits calcium absorption by intestines
Inhibits osteoclastic activity in bone
Inhibits renal tubular calcium reabsorption by kidney
UNCLEAR physiologic role in humans

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NORMAL C-CELLS IN THYROID PRODUCING CALCITONIN

C-cells comprise much less than 0.1% of the volume of the thyroid (Immunoperoxidase stain for calcitonin).

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C-CELL DISTRIBUTION
NOT UNIFORMLY DISTRIBUTED
MIDDLE THIRD OF LATERAL LOBES
DIFFERENT ORIGIN (NCC) THAN FOLLICULAR CELLS

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MEDULLARY THYROID CARCINOMA:

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8-10% of all thyroid malignancies

Sporadic (75-80%)
Familial (20-25%, AD inheritance)

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MEDULLARY (fleshy in appearance) CARCINOMA
"solid" appearance, fleshy, well-circumscribed

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MEDULLARY CARCINOMA
**amyloid stroma confined within tumor (amyloid derived from calcitonin molecule, we think); a HALLMARK of this tumor; would also be found in mets.**

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MEDULLARY CARCINOMA (CONGO RED* IN POLARIZED LIGHT)
*stain for amyloid, yellow-green

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MEDULLARY CARCINOMA STAINED FOR CALCITONIN
-most cells stain positive for calcitonin

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ULTRASTRUCTURE OF MEDULLARY CARCINOMA
**EM shows tumor cells filled with dense secretory granules; sites of calcitonin storage.**

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MEN2 SYNDROMES AND THEIR MANIFESTATIONS: 3

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1) MEN2A (MTC, PHEO, PT)

2) MEN2B (MTC, PHEO, mucosal neuromas, marfanoid habitus)

3) FMTC (MTC)

*All Autosomal dominant

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THYROID IN PT WITH MEN2A
Arrows = tumors (MTC)
*Familial forms are almost always bilateral and multi-centric.

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MEN2B
tall, long limbs, thick lips

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MEN2B
thick lips, bumps on tongue (mucosal neuromas)

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MEN2 SYNDROMES: where are the genetic defects?

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Caused by GERMLINE mutations in RET PROTO-ONCOGENE (10q11.2)

MEN2A --> codon 634 & others

MEN2B --> codon 938

FMTC --> codon 634 & others

**DON'T HAVE TO KNOW THE EXACT MUTATIONS, JUST THAT THERE ARE MUTATIONS**
**Diagnose familial syndromes based on genetic info gained from WBCs**

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DISTRIBUTION OF PARATHYROID GLANDS
-posterior aspect of thyroid
-upper derived from pouch 4
-lower derived from pouch 3

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L: shows PT closely associated with thyroid
R: PT is nearly enmeshed within thyroid
*Important to have experienced surgeons operating on the thyroid area for this reason.*

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NORMAL PARATHYROIDS
overall weight ~120 mg combined

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NORMAL PARATHYROID IN CHILD (LEFT)
*highly cellular; no fat

NORMAL ADULT (RIGHT)--gland gets fatty as we age

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PARATHYROID HORMONE (PTH):

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PTH synthesis is controlled by levels of ionized calcium in blood

Low levels of calcium stimulate synthesis of PTH

High levels of calcium suppress synthesis of PTH

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FUNCTIONS OF PTH:

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Activation of OCs with mobilization of calcium from bone

Increases renal tubular resorption of calcium

Increases conversion of vit D to its active dihydroxy form in kidneys

Increases urinary phosphate excretion

Augments calcium absorption from GI tract

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HYPERCALCEMIA: 2 important causes--

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*MALIGNANCY is the most common cause of clinically apparent hypercalcemia.

*1˚ HYPERPARATHYROIDISM is the most common cause of ASYMPTOMATIC hypercalcemia.

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MALIGNANCY ASSOCIATED HYPERCALCEMIA: 2 causes--

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1) Osteolytic metastases:
Cytokines; vitamin D related metabolites; RANKL (ligand for receptor activators of nuclear factor kB)

2) PTHrp (parathyroid hormone related protein).
Certain cancers (eg squamous cell carcinoma) synthesize PTHrp which has many of the actions of PTH

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PRIMARY HYPERPARATHYROIDISM:
define-
f:m
age effects

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*Autonomous overproduction of PTH by one (adenoma) or more (hyperplasia) parathyroid glands

*F:M = 3:1

*Increasing prevalence with age

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AGE SPECIFIC INCIDENCE RATES OF HYPERPARATHYROIDISM:

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Red bar: we developed automated ways to measure serum Ca levels. We got better at identifying it.

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PRIMARY HYPERPARATHYROIDISM:

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Excessive and dysregulated secretion of PTH from one or more enlarged PT glands

Mobilization of Ca from bone, renal conservation of Ca and increased GI resorption of Ca

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More people are being diagnosed now while asymptomatic.

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PATHOLOGY OF PRIMARY HYPERPARATHYROIDISM: prevalence of causes--

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Category: %
Adenoma 75-80
Hyperplasia 10-15
Carcinoma Less than 5%

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PATIENT WITH SEVERE PRIMARY HYPERPARATHYROIDISM--Capt Martell; 6-7 in height loss, kidney stones, pigeon chest, weakness
-had a mediastinal PT tumor.

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HEAD OF FEMUR IN PATIENT WITH HYPERPARATHYROIDISM

There is loss of bone within the medulla with the formation of multiple “brown” cysts (Brown tumors), which contain giant cells and iron-containing histiocytes.

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Image of brown tumor in 1˚ HYPERPARATHYROIDISM
Connective Tissue, OC like giant cells
Fe pigment (not visible here)

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DISSECTING OSTEITIS in 1˚ HYPERPARATHYROIDISM
Bone trabeculae are invaded by fibrous tissue with subsequent loss of bone matrix

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1˚ HYPERPARATHYROIDISM:
PARATHYROID ADENOMA WITH 3 NORMAL GLANDS
Autopsy specimen
This 3:1 is very typical

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Tumor highly cellular
1˚ HYPERPARATHYROIDISM

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1˚ HYPERPARATHYROIDISM
high power
not much pleomorphism or atypical features
BVs visible

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EVOLUTION OF PARATHYROID SURGERY:

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Conventional open parathyroidectomy

Open minimal access parathyroidectomy (focused based on scans)

Endoscopic parathyroidectomy

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1˚ HYPERPARATHYROIDISM
abnormality likely within the thymus

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Sestamibi Iodine Substraction Scan demonstrating a right lower parathyroid adenoma. Since Sestamibi is taken up both by the thyroid and parathyroid, a simultaneous iodine uptake scan is performed, allowing the thyroid image to be subtracted out, thereby revealing abnormal parathyroid glands.

A: Patient injected with Sestamibi – Technetium99 and Iodine123 with collimator on camera set to detect both isotopes.

B: Collimator set to detect only I123 in the thyroid.

C: Final image is generated by subtracting image B from Image A, revealing a right lower parathyroid adenoma (arrow).

S, salivary glands; T/P, thyroid and parathyroids; L, liver; H, heart.

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Assays are performed during surgery to verify drop in PTH. Helps confirm the removed gland was the source. High likelihood of surgical cure.

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Intraoperative assays aren't as good for double adenomas. Still helps.

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*fibrous tissue distinguishes from adenoma*

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*pleomorphism helps distinguish from adenomas

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BV invasion (BV outside of the tumor)

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PRIMARY HYPERPLASIA of the PT glands:

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All 4 glands may be involved but there is usually variation in the extent of involvement of individual glands.

May occur in association with multiple endocrine neoplasia syndromes or as a sporadic disorder

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multiple glands enlarged
treatment: total PTX and arm autograft in forearm

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-gland is enlarged
-smaller than normal amount of fat; hyperplasticity and cellularity

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enlarged gland with encapsulated lesion
"nodular hyperplasia"

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MULTIPLE ENDOCRINE NEOPLASIA (MEN) TYPE 1:

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Also known as Wermer Syndrome

Characterized by abnormalities of parathyroids, pituitary and pancreas (3P’s)

Hyperparathyroidism occurs in more than 95% (due to hyperplasia)

Multiple pancreatic endocrine tumors and frequent duodenal “gastrinomas” associated with Zollinger Ellinson syndrome

Pituitary tumors include prolactinomas and growth hormone producing tumors

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MULTIPLE ENDOCRINE NEOPLASIA(MEN) TYPE 1--genetics:

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Caused by germline mutations in MEN1 gene on chromosome 11q13

MEN1 gene is a tumor suppressor gene

MEN1 gene encodes menin, a 610 amino acid nuclear protein which plays a role in regulating the cell cycle and transcription

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FAMILIAL HYPOCALCIURIC HYPERCALCEMIA (FHH):

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*Autosomal dominant

*Hypercalcemia, hypocalciuria, normal or slightly elevated PTH levels

*Inactivating mutation of calcium sensing receptor gene

*Decreased sensitivity of receptors for calcium

*Normal or slightly hyperplastic parathyroid glands

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2˚ HYPERPARATHYROIDISM:

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*Any condition associated with a chronic depression in serum calcium leads to a compensatory INCREASED SYNTHESIS of parathyroid hormone:
-chronic renal failure, vitamin D deficiency, steatorrhea

*Hyperplasia of ALL parathyroid glands occurs

*Bone changes similar to those seen in primary hyperparathyroidism occur

*Metastatic calcification is common (Ca deposits in soft tissues)

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SECONDARY PARATHYROID HYPERPLASIA
Can't distinguish from 1˚ hyperplasia.

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SECONDARY HYPERPLASIA

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HYPOPARATHYROIDSM:

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*Surgically induced

*Congenital disorders (22q11.2 syndrome)

*Familial (chronic mucocutaneous candidiasis, primary adrenal insufficiency, hypoparathyroidism due to mutations in the autoimmune regulator gene (AIRE)).

*Idiopathic (autoantibodies against the calcium sensing receptor)

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PSEUDOHYPOPARATHYROIDISM:

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*Refers to end organ resistance to effects of parathyroid hormone

*Type 1A: Multihormone resistance and Albright hereditary osteodystrophy. Mutation is inherited on the maternal allele.

*Pseudopseudohypoparathyroidism. Albright hereditary osteodystrophy without multi- hormone resistance. Mutation is inherited on the paternal allele

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