ADRENAL MEDULLA

OBJECTIVES
1. Anatomy and Function of the Adrenal Medulla
2. Pheochromocytoma
3. Multiple Endocrine Adenomatosis Syndromes
4. Neuroblastoma

ANATOMY AND FUNCTION

PHEOCHROMOCYTOMA

Etiology
Most common in adults
F>M

Rule of 10s:
10% Malignant
10% Bilateral
10% Extra-medullar
10% Calcify
10% Kids
10% Familial ( Germline mutation in
RET gene)

Clinical Presentation
Hypertension, sustained or episodic, is the key symptom.
5 Ps:
Pressure (Increase BP)
Pain (Headache and Abdominal: Ileus)
Symptoms occur in spells
Perspiration
(relapse and remit)
Palpitations (Tachycardia)
Pallor
Associated with: Neurofibromatosis type 1, Von Hippel-Lindau disease, MEN 2A
and 2B.

Pathology

Diagnosis
Increased plasma metanephrines
Increased plasma normetanephrine
Increased 24-hour urine level of
metanephrine (100% sensitivity)
Increased 24-hour urine for vanillylmandelic
acid (VMA)
CT scan

Treatment
Adrenalectomy
Preoperative stabilization
Phenoxybenzamine (non selective -blocker)
Metyrosine (catecholamine synthesis inhibitor)
Liberal fluid and salt intake
Preoperative or intraoperative hypertensive crisis
Phentolamine or nitroprusside in concert with a - blocker

Paragangliomas
Pheochromocytoma arising from extra adrenal sites.
Carotid body tumors
Autosomal dominant transmission (Father inheritance)
SDHD gene (11q23), which encodes a subunit of
cytochrome B that has been proposed to participate in
oxygen sensing.
10% Malignant

MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES (MEN)

MEN
Inherited disorders
Genetic mutations
Development of benign or malignant tumors
Can appear in infants or very old people
3 main types:
MEN 1
MEN 2A
MEN 2B

MEN Type 1
Werner Syndrome
Parathyroid tumors, pancreatic tumors, pituitary tumors
Hyperparathyroidism (95%)
Pancreatic tumors (30-50%)
Excess gastrin
Vasoactive intestinal polypeptide
No hormone production

 Pituitary tumors
Prolactin
Growth Hormone
Corticotropin
No hormones

Men Type 2A
Sipple Syndrome
Medullary thyroid cancers (MTC), pheochromocytoma, parathyroid tumors
Pheochromocytoma (40-50%)
Parathyroid tumors
25%: kidney stones

MEN Type 2B
Medullary thyroid cancers (MTC), pheochromocytoma, neuromas
No family history
MTC
Infants
Neuromas
Mucous membranes
Megacolon
Spinal abnormalities, long limbs, loose joints

Treatment
No cure
Tumor removal
MTC fatal

NEUROBLASTOMA

Etiology
Neuroendocrine embryonal malignancy
tumor arising from any neural crest
element of the sympathetic nervous
system.
Composed of Neuroplastic neuroblasts.
Most common solid extracranial
neoplasms of childhood, accounting
for up to 10% of all childhood cancers
and 15% of cancer deaths in children.

Genetics
Autosomal dominant pattern of inheritance
Short arm of chromosome 16 affected locus
Deletions on chromosome 1 are frequent with unbalanced translocation with 17q.
Amplification of the N-MYC oncogene seen in roughly 20%
Hereditary neuroblastoma predisposition gene chromosome 16p12-13

Pathology
Homer-Wright pseudorosettes consist of eosinophilic neutrophils
surrounded by neuroblasts
Defined by a rim of dark tumor cells in a circumferential
arrangement around a central pale fibrillar core.
Schwann cell
Limited or no schwannian proliferation is seen and
mitosis are frequent.
By electron microscopy malignant neuroblasts show peripheral
dendritic processes with longitudinally oriented microtubules
and neurosecretory granules and filament.
NB infiltrate and metastasize to regional lymph nodes and
surrounding organs. Tumor can differentiate into ganglioneuroma.

Factors useful in predicting outcome of NB

Age
Site
Stage
Tumor histology
DNA ploidy
Genomic alterations

Clinical features
Abdominal pain
Palpable mass
bone joint pain
Periorbital ecchymosis
Cough
Dyspnea
Neurologic deficits
Urinary retention
Constipation
Paraneoplastic syndromes

Diagnosis
Laboratory evaluation

Urinary excretion of
catecholamines and their
metabolites are elevated in NB
patients.
Vanillylmandelic acid VMA 23
hour urinary serum
Homovanillic acid HVA
Dopamine

Questions
A 34-year-old man complains of sudden attacks of dizziness, blurred vision, and excruciating headaches of 4
months in duration. During one of these attacks, his blood pressure was 180/120 mm Hg. The patients father
had been treated for thyroid cancer about 15 years ago. Laboratory studies show normal serum levels of
aldosterone, renin, and angiotensin. A 24-hour urinalysis reveals increased metanephrines. Episodic
hypertension in this patient is most likely caused by a tumor in which of the following endocrine organs?
(A) Adrenal
(B) Kidney
(C) Parathyroid
(D) Pituitary
(E) Thyroid

Questions
An infant is born at term to a 25-year-old woman. On newborn physical examination, the infant is found to
have an enlarged abdomen, but there are no other abnormal findings except for slightly elevated blood
pressure. An abdominal ultrasound scan shows a right retroperitoneal mass in the adrenal gland. Which of the
following laboratory findings is most likely to be reported in this neonate?
(A) Increased urinary homovanillic acid (HVA) level
(B) Decreased serum calcium level
(C) Increased urinary free catecholamine level
(D) Increased serum corticotropin level
(E) Increased serum growth hormone level
(F) Increased serum prolactin level
(G) Increased serum cortisol level

Questions
A 37-year-old woman states that, although most of the time she feels fine, she has experienced episodes of
palpitations, tachycardia, tremor, diaphoresis, and headache over the past 3 months. When her symptoms are
worse, her blood pressure is in the range of 155/90 mm Hg. She collapses suddenly one day and is brought to
the hospital, where her ventricular fibrillation is converted successfully to sinus rhythm. On physical
examination, there are no remarkable findings. Which of the following laboratory findings is most likely to be
reported in this patient?
(A) Increased urinary homovanillic acid (HVA) level
(B) Decreased serum potassium level
(C) Increased serum free T4 level
(D) Increased urinary free catecholamines
(E) Decreased serum glucose level

Questions
A 27-year-old man sees his physician for evaluation of headaches that have occurred frequently for the past 3
months. On physical examination, he is afebrile, and his blood pressure is 140/85 mm Hg. There are no
neurologic abnormalities and no visual defects; however, he has a right thyroid mass. Laboratory studies show
that his serum calcitonin level is elevated. A total thyroidectomy is performed, and on sectioning, the thyroid has
multiple tumor nodules in both lobes. Microscopically, the thyroid nodules are composed of nests of neoplastic
cells separated by amyloid-rich stroma. The endocrinologist says that the patient's family members could be at
risk for development of similar tumors and advises that they undergo genetic screening. Which of the following
morphologic findings in the adrenal glands is most likely to be present in this patient?
(A) Bilateral 4-cm medullary masses
(B) Bilateral cortical atrophy
(C) Bilateral cortical nodular hyperplasia
(D) Solitary caseating granuloma
(E) Solitary 1-cm cortical mass with contralateral cortical atrophy
(F) Solitary 12-cm hemorrhagic cortical mass

Questions
These findings suggest multiple endocrine neoplasia (MEN) type IIA (Sipple syndrome) or possibly
MEN type IIB (Williams syndrome). These patients have medullary carcinomas of the thyroid,
pheochromocytomas, and parathyroid adenomas. This patient's headaches could be caused by
hypertension from a pheochromocytoma arising in the adrenal medulla. More than 70% of cases of
pheochromocytomas are bilateral when familial. This patient's thyroid mass is a medullary
carcinoma, which also tends to be multifocal in this syndrome. This syndrome is associated with
germline mutations in the RET proto-oncogene. Family members who inherit the same mutation are
at increased risk of developing similar cancers. Genetic screening followed by increased surveillance
of affected family members is advised.

Questions
A 4-year-old girl is brought to the pediatric clinic by her mother who reports that her daughter has decreased
appetite, lethargy, and an enlarging belly. Physical examination reveals a large, firm, irregular, nontender mass
in the childs abdomen. A CT-guided biopsy reveals neoplastic small blue cells. The childs malignant
neoplasm is removed and the surgical specimen is shown in the image. Which of the following laboratory
tests would be useful in monitoring this patient for recurrence of disease?
(A) Serum acetylcholine
(B) Serum a1-antitrypsin
(C) Serum potassium
(D) Urinary angiotensin
(E) Urinary vanillylmandelic acid

Questions
Genetic analysis of tumor cells taken from the patient described in the previous question may reveal which of
the following mutations?
(A) C-ras amplification
(B) Deletion of c-myc
(C) N-myc amplifi cation
(D) 8;21 chromosomal translocation
(E) 9;22 chromosomal translocation

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