DSA20 - Pathology of Adrenal and MEN

mesoderm; neural crest

The Adrenal Cortex is derived from the (mesoderm/neural crest), while the Adrenal Medulla is derived from the (mesoderm/neural crest)

- LIPID POOR & less cytoplasm (other than cortical cells)

- Secretes MINERALOCORTICOIDS (Aldosterone)

How does the Zona Glomerulosa (2) appear and what does it secrete?

- LARGEST LAYER

- Has FOAMY CYTOPLASM (cytoplasm w/ small lipid vacuoles)

- Secretes GLUCOCORTICOIDS

How does the Zona Fasciculata (3) appear and what does it secrete?

-Appetitie (MORE)

-BP (MORE via more Aldo or sensitivity to NE/Epi)

-Insulin resistance (MORE)

-Glucose (MORE via more Gluconeogenesis/Lipolysis/Proteolysis)

-Fibroblast (LESS ==> less healing from less collagen synthesis)

-Immune/Inflammatory Response (LESS)

-Bone Forming (LESS via less osteoblast & collagen --> osteoporosis)

What are the functions of Cortisol (a major Glucocorticoid)?

(think "A BIG FIB")

- DARKEST LAYER (GRANULAR and EOSINOPHILIC Cytoplasm)

- Secretes ANDROGENS

How does the Zona Reticularis (4) appear and what does it secrete?

cholesterol

All adrenal cortex hormones are derived from ()

Part of the SNS - releases "Stress Hormones"

What is the function of the Adrenal medulla?

CHROMAFFIN CELLS

- Large polygonal neuroendocrine cells in nests & clusters around vessels

-BASOPHILIC (BLUE) CYTOPLASM (stains yellow/brown w/ chrome stain)

How does the Adrenal Medulla appear?

ACTH-INDEPENDENT Cushing Syndrome (Hypercortisolism)

Define Condition:

-Hx & Path:

> Exogenous Use

>> MCC overall

>> Path: Bilateral Adrenal Cortical Atrophy d/t negative feedback inhibition of ACTH (More exogenous cortisol --> LESS ACTH ==> Atrophy)

> Primary Adrenal Neoplasm (Adenoma/Carcinoma)

>> Path: More Endogenous cortisol --> Less ATCH --> Atrophy of ONLY the uninvolved adrenal gland

-Sx/PE: MOON FACIES

> Metabolic Syndrome (HTN, Hyperglycemia, HLD)

> Obesity (TRUNCAL, ROUND MOON FACIES)

> Osteoporosis

> Neuropsych (Depression, Anxiety, Irritability)

> Facial plethora (excess blood flow ==> REDNESS)

> Androgen Excess (Acne, Hirsuitism)

> Cataracts

> Immunosuppression

> Ecchymoses (easy bruising)

> Skin changes (STRIAE: More MSH --> Hyperpigmentation)

-Dx: Labs

Adrenal Neoplasm

> ACTH = LOW

> High Dose Dexa Test = Not Needed

> CRH Stim Test = Not Needed

ACTH-DEPENDENT Cushing Syndrome (Hypercortisolism)

Define Condition:

-Hx & Path:

> Secreting Pituitary Tumor (DISEASE)

>> Path: More ACTH --> Bilateral Adrenal Cortical Hyperplasia ==> MORE CORTISOL

> Ectopic ACTH production (Paraneoplastic from SCLC)

>> Path: More ACTH --> Bilateral Adrenal Cortical Hyperplasia ==> MORE CORTISOL

-Sx/PE: MOON FACIES

> Metabolic Syndrome (HTN, Hyperglycemia, HLD)

> Obesity (TRUNCAL, ROUND MOON FACIES)

> Osteoporosis

> Neuropsych (Depression, Anxiety, Irritability)

> Facial plethora (excess blood flow ==> REDNESS)

> Androgen Excess (Acne, Hirsuitism)

> Cataracts

> Immunosuppression

> Ecchymoses (easy bruising)

> Skin changes (STRIAE: More MSH --> Hyperpigmentation)

-Dx: Labs

DISEASE (Pituitary Tumor)

> ACTH = HIGH

> High Dose Dexa Test = Suppression (Less ACTH/cortisol)

> CRH Stim Test = More ACTH/Cortisol

ECTOPIC

> ACTH = HIGH

> High Dose Dexa Test = No Change

> CRH Stim Test = No Change

Congenital Adrenal Hyperplasia (CAH)

Define Condition:

Autosomal RECESSIVE disorders that are caused by a deficiency of congenital adrenal enzymes (21-hydroxylase & 11Beta-hydroxylase) involved in adrenal steroid biosynthesis

-Path: Enzyme deficiency -> ↓ cortisol -> ↑ ACTH -> bilateral adrenal hyperplasia -> ↑ non-cortisol hormone synthesis (MORE ANDROGENS, mineralocorticoids)

> 21-Hydroxylase Deficiency (95%)

>> Shunted toward MORE ANDROGENS --> Ambiguous genitalia & virilization in females

>> LESS ALDOSTERONE =

>>> MORE Potassium, but LESS SODIUM

>>> MORE Renin

> 11B-Hydroxylase Deficiency (5%)

>> Some more Androgens --> Ambiguous genitalia & virilization in females

>> MORE 11-DEOXYCORTICOSTERONE (EFFECTIVE MINERALOCORTICOID)

>>> More Na retention ==> Higher BP

>>> Less K, Less Renin

-Sx/PE:

> Ambiguous Genitalia and Virilization in FEMALES

> 11B-Hydroxylase Deficiency

>> HIGHER BP

-Dx: Labs

> 21-Hydrox

>> Potassium = HIGH

>> Sodium = LOW

>> Renin = HIGH

> 11B-Hydrox

>> Potassium = LOW

>> Sodium = HIGH

>> Renin = LOW

Primary Adrenocortical Insufficiency

Define Condition:

Deficiency of Adrenal Hormones d/t issues w/ Adrenal Gland itself

-Hx: Damage to Adrenal Gland (ACUTE or CHRONIC)

> Autoimmune Adrenalitis

> Adrenal Infex

> Metastatic cancer to Adrenals

> Adrenal Hemorrhage

-Sx/PE:

> Weakness

> Fatigue

> SALT CRAVING (Can't reabsorb Na+)

> Hypotension

> Wt Loss

> N/V

> Hyperpigmentation (More POMC --> More ACTH & MSH) esp in sun exposed areas, palmar creases, nail beds, mucous membranes

-Dx: Depends on cause

Autoimmune Adrenalitis

Define Cause of Primary Adrenocortical Insufficiency:

-Hx:

> MCC of Primary Adrenocortical Insufficiency in HIGH INCOME COUNTRIES

-Path/Sx/PE: May be a/w Autoimmune Polyglandular Syndrome (APS) 1

> Adrenocortical Insufficiency

> Muco-cutaneous Candidiasis

> Hypoparathyroidism

-Dx:

> Gross: Adrenal glands are irregularly shrunken due to autoimmune destruction

> Micro: Lymphocytic infiltrate in cortex

Adrenal Infection

Define Cause of Primary Adrenocortical Insufficiency:

-Hx:

> MCC = TB (esp in low-income countries)

> Disseminated fungal infections (Histoplasma capsulatum, Coccidioides immitis)

> AIDS induced infections (CMV, Mycobacterium avium-intracellulare)

-Dx: if TB

> Caseating Granuloma in gland

Metastatic spread to Adrenals

Define Cause of Primary Adrenocortical Insufficiency:

Cancer spread to adrenals from LUNG or BREAST cancer

Adrenal Hemorrhage

Define Cause of Primary Adrenocortical Insufficiency:

-Hx:

> Waterhouse-Friderichsen Syndrome = bilateral adrenal hemorrhage in the setting of sepsis (usually d/t Neisseria meningitidis); usually d/t sepsis-induced endothelial injury or DIC

> Anticoagulant Therapy

> Trauma

Secondaty Adrenocortical Insufficiency

Define Condition:

Deficiency of Adrenal Hormones d/t issues w/ PITUITARY

-Path: Hypopituitarism = ↓ pituitary ACTH -> ↓cortisol, ↓androgens

-Sx/PE: No Hyperpigmentation (b/c no ACTH or MSH)

-Dx: Labs

> No Hyperkalemia

Mixed Adrenocortical Insufficiency

Define Condition:

Deficiency of Adrenal Hormones d/t issues w/ PITUITARY AND ADRENAL GLAND

-Hx: From Abrupt withdrawal of Long-Term Exogenous Glucocorticoids (TRANSPLANT PTS)

-Path: Glucocorticoids stopped --> Adrenal Gland atrophy

Adrenocortical Adenomas

Define Condition:

BENIGN; Most are NONFUNCTIONAL (90%)

-Hx: Found incidentally (incidentalomas)

-Dx:

> Gross:

>> Well-circumscribed yellow tumor with capsule

>> Small (1-2 cm)

> Micro: Cells similar to cells found in zona fasciculata

Adrenocortical Carcinomas (ACC)

Define Condition:

RARE & MALIGNANT Epithelial tumor (1/2 are functional)

-Prog: SIZE (larger => worrisome); Overall poor prognosis with 5 year mortality 50 - 90%

-Tx: Surgical Resection

Pheochromocytoma

Define Condition:

Proliferation of chromaffin cells

-Hx: MC Tumor of Adrenal Medulla in Adults

-Path: Most FUNCTIONAL (Secrete Catecholamines)

> A/w mutations

>> RET (MEN2A & MEN2B)

>> VHL

>> NF-1

**Rule of 10s**

> 10% = Malignant

> 10% = Bilateral

> 10% = OUTSIDE Adrenal Glands (paragangliomas = thorax, abdomen, pelvis)

> 10% = Children

-Sx/PE: EPISODIC SX (5Ps)

> Pressure (More BP)

> Pain (HA)

> Perspiration

> Palpitation/Tachycardia

> Pallor

-Dx:

> Labs:

>> 24 Hr Urine =

>>> MORE CATECHOLAMINES (Epi/ME)

>>> MORE METANEPHRINES (Metabolites) in Urine OR PLAMSA

> Gross:

>> Well circumscribed tumor

>> Size varies from small to large masses

> Micro:

>> Polygonal to spindle-shaped cells arranged in nests

>> Cells have abundant finely granular cytoplasm due to neurosecretory granules containing catecholamines

>> “Salt and pepper” chromatin - characteristic of neuroendocrine tumors

>> (+) chromogranin,

(+) synaptophysin (neuroendocrine markers) immunohistochemistry stains

-Prog: Depends on METASTASES

MEN1

Define Condition:

AUTOSOMAL DOMINANT Inherited Genetic Syndrome d/t mutation in the MEN1 Tumor Suppression gene on Chromosome 11

-Hx:

> Usually at YOUNGER AGE than sporadic tumors

> Often Multifocal

> More aggressive and recur more

-Path:

> Preceded by clonal endocrine hyperplasia

> Mutations of gene stops encoding of menin protein (regulates gene transcription) --> Increased risk of Endocrine Tumors:

>> Primary Hyperparathyroidism (Parathyroid Adenoma)

>> Pancreatic Endocrine Tumors

>>> Leading cause of death in Syndrome

>>> Aggressive/Functional

>>> Ex: Gastrinomas, Insulinomas, Glucagonomas, Somatostatinomas

>> Pituitary Tumors

>>> MC = Lactotroph adenoma/prolactinoma

>>> Somatotroph (GH) Adenoma

MEN Type 2A

Define Condition:

AUTOSOMAL DOMINANT Inherited Genetic Syndrome d/t mutation in the RET Tumor Proto-oncogene on Chromosome 10

-Path: GAIN OF FUNCTION MUTATION of RET Tumor Proto-Oncogene that encodes TK Receptor

> 2 Ps, 1 M

>> Parathyroid (10-20% --> Primary Hyperparathyroidism)

>> Pheochromocytoma (50%)

>> Medullary Thyroid Carcinoma (in almost ALL pts)

>>> Usually multifocal

>>> C-cell hyperplasia in adjacent "normal" thyroid

MEN Type 2B

Define Condition:

-Path: 95% of cases are from a single amino acid substitution mutation in RET proto-oncogene

1 P, 2 Ms

> Medullary thyroid carcinoma

>> Tumors usually multifocal

>> More aggressive than in MEN 2A

> Pheochromocytoma

> Extra endocrine manifestations

>> Mucosal neuromas (lips, tongue)

>> Intestinal ganglioneuromas (GI tract)

>> Marfanoid habitus (i.e. tall, lanky)

> No hyperparathyroidism