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By:

Dr. Khalid R. Murshid

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Embryology

Branchial pouches:

3rd :

inferior parathyroid and thymus.

4th :

superior parathyroid and ultimobranchial bodies which form the parafollicular ( c ) cells of the thyroid.

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Anatomy

Position Of The Parathyroids:

The superior parathyroid glands

The inferior parathyroid glands

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1- HYPERPARATHYROIDISM

1ry

2ry

3ry

2- HYPERCALCEMIA

3- PARATHYROID CARCINOMA

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Classification

Clinical Presentation

Lab Tests

Imaging Studies

Treatment

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• 1ry:

hyperfunction of the glands.

oversecretion of PTH due to :

Adenoma

Hyperplasia

or rarely, Carcinoma of the parathyroid glands.

2ry: reaction of the glands to hypocalcemia caused by chronic renal

failure.

3ry: Result from hyperplasia of the glands and loss of response to

serum calcium levels.

most often seen in patients with chronic renal failure 9

Epidemiology / Frequency - Incidence of 1ry HPT = 1 in 2,500. - between the 5th and 7th decades . -2-4 X more common in women , rare in children. - -Approximately 100,000 new cases of HPT are reported in the United States annually.

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Primary HPT

Asymptomatic or vague nonspecific symptoms

elevation of serum calcium levels

Hypercalcemia

- related signs and symptoms

- "stones, bones, abdominal groans and psychological overtones".

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Is the most common cause of hypercalcemia

Etiology:

1. one (90 %) or, two (2 %) benign parathyroid adenoma(s)

2. Multiglandular hyperplasia (8 %)

3. Parathyroid carcinoma (<1 %)

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PUD

Pancreatitis

HTN

MEN Syndrome

Familial HPT

Gout

Previous Radiation to neck

Band keratopathy 13

Renal (2ry) HPT - in patients with chronic renal disease and

intestinal malabsorption

- dramatic elevations of the PTH level

- normal or low serum calcium levels,

- marked bone demineralization related to renal osteodystrophy, soft tissue calcifications, and intense pruritus.

-

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Labs: High PTH, low Ph and almost normal calcium

Treatment: - Non Surgical…Oral calcium and vitamin D

- Surgery if;

1. Uncontrolled bone pain

2. Fractures

3. Pruritis

4. Ectopic calcifications

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3ry HPT - Presents similar to 2ry HPT.

- Patient had near-total parathyroidectomy or untreated 2ry HPT.

- - Progressive hyperphosphatemia of renal disease stimulates PTH, which causes hypercalcemia.

- High PTH, normal or high Ca.

- Corrected after renal transplant

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General / Clinical Features: <1% of cases of HPT

equally in males and females, and rarely before age 30yrs

Usually functional, producing symptoms of HPT and hypercalcemia but more severe, with:

- serum calcium levels greater than 14 mg/dL

- Markedly elevated serum PTH levels. If Untreated, leads to severe symptoms of HPT.

palpable mass semifixed

LN and distant mets usually not present at Dx

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PTH:

Increases serum Calcium through:-

1. Enhancing gastrointestinal absorption of calcium.

2. Stimulating the production of vitamin D3.

3. Inhibiting renal calcium excretion.

4. Increasing bone resorption .

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Effects of elevated serum calcium are:

- Central nervous system - Mental alterations, impaired memory, emotional instability, depression, sleepiness, and coma

- Neuromuscular - Proximal muscle weakness, joint and muscle pain due to calcium deposition, pruritus, and abnormal leg movements during sleep

- Gastrointestinal - Peptic ulcer, pancreatitis, nausea, vomiting, reflux, and loss of appetite

- Renal - Kidney stones, polyuria, nocturia, and renal failure with uremia

- Cardiovascular - Hypertension, left ventricular hypertrophy unrelated to hypertension

- Eye – Conjunctivitis, band keratopathy

- Skin – Pruritus

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Hypercalcemia

BONES;

arthralgia, path. #

STONES;

renal stones, renal failure, polyuria, polydipsia

ABDOMINAL GROANS;

PUD, pancreatitis, constipation

PSYCHIC MOANS; depression,

fatigue, weakness

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Parathyroid 1ry HPT Nonparathyroid Endocrine Thyrotoxicosis Pheochromocytoma Acute adrenal

insufficiency Malignancy Solid tumors Lytic bone metastases Lymphoma and leukemia Infections Sarcoidosis Tuberculosis

Medications Calcium

supplementation Thiazide diuretics Vitamin A or D

intoxication Lithium Dietary Milk Alkali Syndrome Other Paget’s Disease Immobilization

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Serum calcium or Ionised Ca2+: - In cases of 1ry or 3ry HPT heightened PTH leads to

increased serum calcium (hypercalcemia) due to:

- increased bone resorption

- reduced renal clearance of calcium

- increased intestinal calcium absorption

- Elevated ionized (Ca++) calcium may be a more reliable indicator of HPT.

- By contrast, in 2ry HPT effectiveness of PTH is reduced.

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Serum Phosphate:-

- In 1ry HPT, serum phosphate levels are

abnormally low as a result of decreased renal tubular phosphate reabsorption.

- This contrasts with 2ry HPT, in which serum phosphate levels are generally elevated because of renal disease.

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Laboratory Studies: Simultaneous calcium and PTH levels should be determined. Serum calcium and parathyroid hormone levels are usually elevated more markedly

than in benign 1ry HPT.

High Ca, Alk. Ph, PTH

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The gold standard of diagnosis is an elevated PTH level. Once that has been confirmed, one is to determine whether the HPT is 1y or 2ry in origin by obtaining a serum calcium level:

3ry HPT has a high PTH and a high serum calcium. It is differentiated from 1ry HPT by a history of chronic renal failure and 2ry HPT.

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PTH

serum calcium

Chronic renal failure

likely type of HPT

high

high

- ve 1ry HPT

high

low or normal

+ ve

2ry HPT

high

high

+ ve

3ry HPT

MEN I:

Parathyroid/Pancreas/Pituitary

MEN IIa:

Medullary/ Pheo/ Parathyroid

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Imaging Studies: Radiographs:

Hand films - May show subperiosteal bone resorption of the distal

phalanges.

Skull films - Have a characteristic "ground glass" or "salt and

pepper" appearance.

In severe cases, plain films reveal the classic bone finding, osteitis fibrosa cystica. It consists of bone cysts with or without pathologic fractures. These cysts are also known as Brown tumors.

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High-resolution ultrasonography:

- economic and informative.

- Shows enlarged glands and their relations and L.N.s.

-

- Can reveal multiple adenomas, hyperplasia of all 4 glands, and glands in ectopic cervical locations.

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- Can not identify mediastinal adenomas. 32

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CT scan:

- greater detail .

- Precise location of gland in relation to anatomy.

- Helpful in locating mediastinal adenomas

- helpful in staging and detecting metastatic disease.

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Technetium-99m labeled Sestamibi Scan: - specific affinity for abnormal parathyroid tissue.

- Also taken up by thyroid, but diminishes and is retained in the parathyroid.

- Is useful in identifying single and multiple parathyroid adenomas and hyperplasia.

- reveals ectopic glands.

- Lesions < 2cm in size are often difficult to pick up.

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A focus of radionuclide activity is seen in the lower pole of the right lobe of the thyroid . Surgery confirmed a parathyroid adenoma.

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THE INITIAL IMAGE (A)

shows the thyroid (th), submandibular glands (s), and a parathyroid adenoma (arrow).

A DELAYED 2-HOUR IMAGE (B) the radioactivity has faded in the thyroid and submandibular glands.

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Technetium 99m Sestamibi Scan

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MRI:

- Provides excellent contrast resolution.

- Images can be formatted in multiple planes (ie, axial, coronal, sagittal).

- Increased vascularity of the adenomas is ideal for identification with this modality.

- - May be useful in locating mediastinal adenomas.

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MRI

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Selective venography :-

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- Combination of ultrasonography and sestamibi scan provides maximum information and is cost effective.

- CT scan or MRI for mediastinum adenomas may be required when an adenoma is suspected in the thorax.

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- Endocrinologists should be consulted for HPT.

-

- Treatment for the three different types of HPT vary.

- Treatment is first directed at hypercalcemia.

- If HPT is caused by a tumor, it will almost always progress as the tumor grows, therefore Sx is a must.

- Testing for HPT should include:

PTH

Calcium level

Bone density

Vitamin D

Phosphorus

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-Medical Treatment:-

-Medical management of HPT is generally reserved for patients with poor medical conditions and who are poor surgical candidates.

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Indications for surgery Symptomatic patients fit for surgery Type of Sx:

Solitary parathyroidectomy for adenomas

3.5 parathyroidectomy for multiglandular hyperplasia OR

Total parathyroidectomy and reimplantation of 50 mg of gland in neck or forearm

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Consultations: Medical endocrinologist - Experienced surgeon - Interventional radiologist - Percutaneous ablation or embolization

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Medical Care:

No effective medical therapy is known.

Primarily geared toward management of the hypercalcemia

For rapid treatment of severe hypercalcemia: Volume loading and diuresis with a calcium-wasting

loop diuretic is the treatment of choice.

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Operative management:

Resection of the parathyroid cancer is the only effective Rx.

The goal is to remove the tumor en bloc

with any adherent tissue, and any enlarged lymph nodes.

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ACCORDING TO SITE CORTEX

ADENOMA FUNCTIONING NON-FUNCTIONING

CARCINOMA FUNCTIONING NON-FUNCTIONING

MEDULLA NEUROBLASTOMA PHEOCHROMOCYTOMA

BENIGN MALIGNANT

INCIDENTALOMAS FUNCTIONING

NON-FUNCTIONING

ADRENOCORTICAL CARCINOMAS 1RY

FUNCTIONING NON-FUNCTIONING

2RY

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BENIGN: Medulla

Benign Pheochromocytoma

Cortex Z. Glomerulosa Z. Fasiculata Z. Reticularis

MALIGNANT: 1ry

Medulla Neuroblastoma Malignant Pheochromocytoma

Cortex Adreno-cortical Carcinoma

2ry

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General:

- 1-10% of CT scans and MRIs detect adrenal incidentalomas (AIs) that are 5 mm or larger.

- Bilateral AMs should always raise the possibility of

hemorrhage. - 80% of AAs are nonfunctional and benign.

- 20%of AAs are either functional or malignant. - If Suspicion of Malignancy, FNA but R/O pheochromocytoma

first

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Approach Considerations The 2 main concerns with regard to an adrenal incidentaloma (AI) are: - (1) whether it is hormonally active (functional) - (2) whether it is malignant.

- Pheochromocytomas should be considered in all adrenal adenoma (AA) cases because:

- relatively common

- often overlooked

- failure to recognize may lead to death.

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SITE PHYSIOLOGY PATHOLOGY

MEDULLA

EPINEPHRINE NOREPINEPHRINE

NEUROBLASTOMA PHEOCHROMOCYTOMA

CORTEX Z. Glomerulosa

ALDOSTERONE

CONN’S DISEASE

Z. Fasiculata GLUCOCORTICOIDS

CUSHING’S SYNDROME

Z. Reticularis

SEX HORMONES

ADRENO-GENITAL SYNDROME

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- The medulla is located at the center of the gland.

- It is composed of neuroendocrine (chromaffin) cells which produce and release epinephrine (adrenaline) into the bloodstream in response to activation of the sympathetic nervous system.

- Neuroblastoma and pheochromocytoma are the two most important tumors which arise from the adrenal medulla.

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- aggressive cancer

- common pediatric cancer

- rapidly enlarging abdominal mass.

- highly curable when detected early

- Often produce elevated levels of catecholamine precursors, such as vanillylmandelic acid (VMA) and homovanillic acid, and may produce severe watery diarrhea through production of vasoactive intestinal peptide (VIP).

- Treatment of neuroblastoma includes surgery and radiation therapy for localized disease, and chemotherapy for metastatic disease.

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Pheochromocytoma

General:

•Peak incidence is 40-50 years •10% tumor •(10% bilateral, 10% malignant, 10% extra-adrenal, 10% multiple, 10% children and 10% familial) •May be found extra-adrenally in abdominal paravertebral sympathetic chain or ganglia in UB, pelvic nerves 58

Clinical Presentation: Tense, anxious, and cold sweating Extreme Tachycardia, flushing Tumors are not palpable bimanually Sustained or episodic hypertension Triad of intermittent attacks of

palpitations, sweating and headache Anxiety, vertigo Abdominal, loin pain

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Labs: Serum catecholamines 24-hour urine catecholamines, VMA Plasma free metanephrine…. sensitivity

99%

Imaging: USG, CT, MRI, MRA MIBG nuclear study

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U/S image of pheochromocytoma

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CT with contrast MRI

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MRA MIBG scan with normal uptake

in colon and liver… R pheo

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MIBG scan

Extra adrenal tumors Recurrent tumors Multiple tumors

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TREATMENT: - PRE-OP:

α-adrenergic blockade, +/- propranolol

- INTRA-OP:

IV fluid, alpha or beta blockers

Minimal tumor manipulation

- POST-OP: fluid, dopamine, angiotensin, norepinephrine and Follow-up q6m

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DIAGNOSIS :

Spread and Metastasis

TREATMENT :

Debulk

Medical Rx for hypertension

Chemo Rx

RRx for bony mets

PROGNOSIS :

5 yr survival – 50%

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Adrenocortical Adenomas:

- Benign

- >30 years old.

- About 15% are "functional", producing Hormones resulting in endocrine disorders such as Cushing’s Syndrome, Conn’s Disease (hyperaldosteronism), virilization of females, or feminization of males.

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SITE PHYSIOLOGY PATHOLOGY

MEDULLA

EPINEPHRINE NOREPINEPHRINE

PHEOCHROMOCYTOMA NEUROBLASTOMA

CORTEX Z. Glomerulosa

ALDOSTERONE

CONN’S DISEASE

Z. Fasiculata GLUCOCORTICOIDS

CUSHING’S SYNDROME

Z. Reticularis

SEX HORMONES

ADRENO-GENITAL SYNDROME

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Mineralocorticoid

Secreted By Zona Glomerulosa

Action On Distal Tubules:-

Absorption Of :

Na+ and H2O

Excretion Of :

K+ , H+ and Mg 2+

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CLINICAL PRESENTATION:- - Na+ reabsorption------

- HYPERTENSION – Headache

- K+ excretion------------

- HYPOKALEMIA- Weakness

- Polyuria

- polydipsia

- nocturia

- metabolic alkalosis

- tetany 70

PRIMARY:

From the Adrenal:

Adenoma (Conn’s Syndrome)

Hyperplasia

Carcinoma

SECONDARY:

Outside the Adrenal

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General: - Incidence:- 0.5% of Hypertensives - Sex:- 2F : 1M - Age:- 30-50 yrs - Etiology:- Adenoma 70% Hyperplasia 30%

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Labs:- - The test of choice is a plasma aldosterone–to–

renin ratio.

- A plasma aldosterone concentration–to–renin ratio greater than 30 and a plasma aldosterone concentration of greater than 0.5 nmol/L (18 ng/dL) are suggestive of primary aldosteronism.

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Localization :- - CT Scan

- Iodocholesterol Scan

- Venous Assay

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Treatment :- - Medical :-

diet, K+

Spironolactone, Amelioride, Nifedipine

- Surgical :-

pre-op:- restore K+ to normal

operative:- Open / Laparoscopic

post-op:- adequate salt in diet, Fluronef

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Operative Complications Of Hypokalemia:

Arrhythmia

Tetany ( due to metabolic alk)

Digoxin Toxicity

Renal Failure

Respiratory Paralysis

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Results of Surgery :-

Cure of Hypokalemia – 100%

Cure of Hypertension - 80%

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Cushing’s Cushing's Syndrome: -Pharmacologic glucocorticoid use for the treatment of inflammatory disorders.

Cushing's Disease: Glucocorticoid excess caused by an ACTH-hypersecreting pituitary microadenoma

Primary Adrenal Cushing's Syndrome: Is caused by autonomous adrenal cortisol production by adenoma, associated with an undetectable ACTH level

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Clinical features

Truncal Obesity – 90% Easy bruising -55% Striae – 70% Muscle weakness – 65% Osteoporosis – 55% Psychosis - 50% Plethora (a red facial appearance caused by thinning of the skin) Menstrual / sexual dysfunction – 75% Hirsutism /Acne – 70% Hypertension – 85% Hyperglycemia/ Glucosuria – 80% Edema / Hypo K+ - 40% Polyuria – 15% Delayed wound healing – 55% Pancreatitis 80

INVESTIGATIONS:

Labs: Serum and urinary cortisol levels

High or low ACTH levels

Imaging: MRI abdomen

MRI head…pituitary microadenoma

CT scan abdomen 81

TREATMENT Adrenelectomy …open or laparoscopy

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Cushing’s disease :- mitotane, enz. Inhibitors, RRx(1ry and bony mets). Sx, bil. Adrenalectomy. Trans-sphenoidal Hypophesectomy

Adrenal Tumor :- Sx, mitotane for CA.

Ectopic ACTH :- Sx, bil. Adrenalectomy, palliative meds.

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Rare but highly aggressive.

Any age.

May be:

Functional , producing steroid hormones and consequent endocrine dysfunction,

Non-Functional , presenting only after local or distant spread.

The most effective treatment is surgery, although not feasible for many patients. Chemotherapy, RRx, and hormonal therapy may also be employed.

The overall prognosis is poor 87

Classifying adrenal cancers:

I - Functional or nonfunctional

- More recent reports suggest that nonfunctional ACs may be more common than previously suggested.

- Virtually all feminizing adrenal tumors in men are malignant.

II - Primary and secondary metastatic adrenal tumors

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Most common potential

primaries include the

following:

Lung

Breast

Melanoma

Renal cell carcinoma

Extra-adrenal

lymphoma

Leukemias

Pancreatic carcinoma

Colonic carcinoma

Ovarian carcinoma

Adrenomedullary Ts

Malignant pheo

Ganglioneuroblastoma

Neuroblastoma

Primary adrenal lymphoma -

Unilateral or bilateral

Stromal malignancies

Neurofibrosarcoma

Angiosarcoma

Liposarcoma

Fibrosarcoma

Leiomyosarcoma

Myxosarcoma

Malignant teratoma

Familial polyposis coli

Gardner syndrome

Turcot syndrome

MEN-1 89

Clinical Presentation: Relatively rare Present with advanced disease Nonfunctional variants: Approximately 40% of patients with AC. Present with fever, weight loss, abdominal pain and tenderness, back pain, abdominal fullness, or symptoms related to metastases. In other cases, the mass is found incidentally. - The hormonally active variants constitute 60% of cases.

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Laboratory Studies for malignant tumors exclude excess hormone production.

CT scans and MRI The imaging studies of choice.

- Larger tumors ( > 4 cm) have a greater chance of being carcinomatous..

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The major imaging features for a possible AC on

adrenal imaging:

- Unilateral.

- Large size (larger than 4 cm in diameter)

- Irregular margin sometimes with local invasion, lymphadenopathy and

metastases.

- Demonstrate a soft-tissue inhomogeneous density on CT scans, which

enhances with contrast (>20 HU).

- They have an intermediate increased intensity on T2-wtd MRIs.

- Hemorrhage shows characteristic images of blood.

- Intralesional calcification

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Medical management Encompasses: (1) the treatment of endocrine excess syndromes; (2) the use of mitotane or several multi-agent chemotherapy regimens; (3) the treatment and prevention of potential complications; and (4) strategies for palliative and terminal care

issues, including symptom relief and management.

Radiation therapy

- Radiotherapy to the tumor bed may be considered in patients at high risk for local recurrence. - For palliative management of symptomatic metastases to bone or brain, or vena cava obstruction.

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Surgical Care:

-Surgical resection - When feasible, total resection.

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- Recurrent local and metastatic disease is

common In such settings, the only effective

treatment is attempted reoperation.

- Laparotomy vs laparoscopic resection.

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Follow-Up

Even after curative surgery, life-long follow-up

is mandatory because documented cases exist

of AC recurrence more than 10 years after

presumed curative surgery.

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Prognosis: Overall 5-year survival rate are approximately 20-35%.

Factors affecting Prognosis - Early detection of tumors .

- Total resection .

- Disease stage at diagnosis, Functional AC may have a better prognosis because they present earlier.

- Completeness of resection at surgery - Some suggest that children with AC have a better prognosis than adults.

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