PATHOLOGY 6020

SYLLABUS

ENDOCRINE ORGAN SYSTEM

SCHEDULE 2006

February 13th Monday

8:00am HSEB 1730 Path Pituitary Dr. Knight 1

9:00am HSEB 1730 Path Thyroid Dr. Knight 11

February 15th Wednesday

10:00am HSEB 1730 Path Adrenal Dr. Clayton 24

11:00am HSEB 1730 Path Parathyroid Dr. Clayton 35

February 16th Thursday

1:00-3:00pm HSEB 4300 Path LAB 1 Dr. Clayton / Staff Gross

February 21st Tuesday

1:00-2:00pm 3C310 Path LAB II Dr. Clayton/Staff 45Present CasePath Cases

February 28th Tuesday

8:00-11:00am HSEB 1700 FINAL EXAMINATION

Be sure to check the web for changes that may have occurred after printing

1

PATHOLOGY 6020 – YEAR 2005-2006PATHOLOGY OF THE PITUITARYDavid Knight, M.D.February 13th, Monday 8:00-9:00am

SUGGESTED READING: PATHOLOGIC BASIS OF DISEASE, 7th edition, pp 1156-1183; 6th edition, pp 1122-1129

OBJECTIVES: At the end of the lecture, reading assignment, and laboratory, the student should be able to:

1. Describe the laboratory tests useful for diagnosis of diseases of the pituitarya. GH d. Prolactinb. TSH e. LH/FSHc. ACTH f. ADH

2. List the pathologic appearance and clinical findings associated with pituitary adenomas

3. Describe the pathologic appearance and the clinical features of craniopharyngioma

4. Enumerate the etiologies for and the clinical consequences of hypopituitarism

5. List the clinical and the laboratory findings in a patient with diabetes insipidus

6. Describe the pathologic features of multiple endocrine neoplasia syndromes

Anatomy and Function1. The pituitary gland is located in the sella turcica and attached to the

region of the hypothalamus by the pituitary stalk.

2. Anterior pituitary (adenohypophysis) arises from an evagination of the roof of the mouth (Rathke’s pouch)

a. has a venous portal blood system originating in the hypothalamus

b. Releasing factors in general have a stimulatory influence on the anterior pituitary Exceptions: Somatostatin inhibits GH and TSH. Dopamine inhibits prolactin.

c. composed of cells that with routine staining are identified as acidophils, basophils, and chromophobes

Somatotrophs GHMammosomatotrophs GH and PRLLactotrophs PRLThyrotrophs TSHCorticotrophs ACTHGonadotrophs FSH and LH

2

3. Posterior pituitary (neurohypophysis) is of neuroectodermal origin - is an extension of hypothalamus

Receives the axons of nerve tracts running from the supraoptic and paraventricular hypothalamic nuclei where ADH and oxytocin are produced. These are stored and released from the neurohypophysis.

Normal pituitary (anterior & posterior)

Normal pituitary (anterior)

Pituitary Neoplasms1. Clinical manifestations:

a. pressure effect from expansion of the mass in the sella turcica and can be manifested as:

headaches (from expansion of the mass in the sella)

visual field defects (bitemporal hemianopsia)

hypopituitarism (by destruction of normal adenohypophyseal cells)

diabetes insipidus (from destruction of the posterior pituitary)

3

b. hormone production (manifestations depend upon the hormone produced)

2. Adenomas

a. Prolactinomas30% of all pituitary adenomas and the most common hyperfunctioning adenoma

Visual field defects are common, especially in men and postmenopausal women

Hypogonadism with infertility and oligomenorrhea or amenorrhea, with or without galactorrhea in women.

Hypogonadism with decreased libido, impotence, infertility in men. Galactorrhea rare in men

Most are chromophobesTreated with dopamine agonistsRemember that prolactin may be increased with any lesion that inhibits PIF (dopamine) such as adenomas, suprasellar tumors, cysts, head trauma etc.Prolactin may also be elevated by stress, drugs (dopamine antagonists and others), estrogen therapy, and renal failure.

Remember that prolactin may be increased with any lesion that inhibits hypothalamic regulatory hormones (adenomas, suprasellar tumors, cysts, etc.)

Prolactinoma: Laboratory Diagnosis

TRH stimulation testNormals: PRL increases to 2x base levels.Adenomas: 80% of patients have no rise, or a blunted rise in PRL

Chromophobe adenoma.

4

b. Growth hormone secreting adenomasAcromegaly appears if the adenoma occurs after puberty - subperiosteal apposition

Gigantism results when an adenoma occurs before puberty - linear bone growth

Can be chromophobic or acidophilic with routine H&E stain

Are slow growing and may be large, as symptoms develop insidiously

Most common childhood pituitary adenoma

Laboratory Diagnosis of Growth Hormone Secreting adenomas: Single best screening test is serum IGF-I

If elevated, GTT with GH measurements. In adenomas, GH does not decrease with a glucose load.

MRI of the Pituitary

Treat with surgery, radiation therapy or with somatostatin analogs like octreotide, often in combination

c. Null-cell adenomasNo morphologic or biochemical markers

Produce mass effects (visual field defects and headaches)

Hypopituitarism

Hyperprolactinemia (the so-called “stalk section effect” resulting from absence of PIF)

d. ACTH adenomasAre often microadenomas; most appear basophilic with H&E stain

Cause of Cushing’s disease

5

Nelson’s syndrome: appearance of an ACTH-producing adenoma following bilateral adrenalectomy for Cushing’s disease

Diagnosis made with elevated ACTH and ACTH elevation with metyrapone

e. Gonadotroph-cell adenomas and Thyrotroph cell adenomas

Small, slow growing and usually non-functioning clinically

Symptomatic gonadotroph tumors are unusual

Symptomatic thyrotroph cell tumors are rare

If symptomatic, may cause ovarian hyperstimulation with elevated estradiol causing amenorrhea in premenopausal and breast development and vaginal bleeding in prepubertal females.

3. Craniopharyngiomaa. Probably derived from remnants of Rathke’s pouch

b. Most common in children and young adults; usually present with headaches and visual disturbances

c. Can be located in the sella turcica, but most are in a “suprasellar” location

d. Calcifications are present radiographically in 75% of cases; are usually grossly cystic; microscopically the epithelium present may resemble a developing tooth or be squamous

e. Produces no hormones but can erode the sella and be locally invasive and difficult to eradicate

Craniopharyngioma. This epithelial tumor has cystic structures, spaces between the tumor cells. The tumor cells line up adjacent to the cysts, resembling the epithelium that produces developing teeth.

6

Hypopituitarism (anterior pituitary insufficiency)1. Caused by any destructive lesion, but because the physiologic reserve

capacity is great, 80-90% destruction is required

Major causes include:a. Nonsecretory pituitary adenomas are the most common cause

b. Pituitary necrosis - most commonly Sheehan’s syndrome (post-partum pituitary necrosis)

Other causes of vascular compromise include: hypotension, DIC, trauma, sickle cell anemia, vasculitis

c. Craniopharyngioma or other suprasellar lesions that interfere with the hypothalamic-pituitary axis

d. Empty sella syndrome - a poorly understood condition where radiographic techniques reveal an apparent absence of the pituitary

Microscopically, there is atrophy of the gland

Hypothetical cause involves herniation of the arachnoid through the sella with increased CSF pressure causing atrophy

e. Lymphocytic hypophysitis - a rare autoimmune condition of obscure etiology

2. Physiologic consequencesa. Adults - hypogonadism with loss of secondary sex characteristics

and sterility; children - growth retardation

b. TSH deficiency leading to hypothyroidism; ACTH deficiency resulting in secondary adrenal insufficiency

c. First to decrease is GH, then FSH/LH, then TSH, and finally ACTH

3. Laboratory diagnosisa. Low levels of testosterone or estrogen without a corresponding

increase in FSH/LH

b. Low T4 without an elevated TSH

c. Growth hormone does not increase with stimulation (L-dopa or insulin)

7

4. Differential diagnosis - multiple endocrine hypofunction secondary to autoimmune destruction. Here, pituitary hormones are elevated.

Posterior Pituitary InsufficiencyRare, but the usual cause is either idiopathic or a hypothalamic tumor

1. Deficiency of ADH causes diabetes insipidus with polyuria and secondary polydipsia

Here, serum osmolality is normal or increased and the urine specific gravity is low (less than 1.005) even with water deprivation.

The problem corrects with administration of ADH

2. Differential diagnosis is psychogenic polydipsia where patients can concentrate urine with water deprivation

3. Inappropriate ADH causes hyponatremia and hemodilution

Most commonly results from a paraneoplastic syndrome with ADH from an oat cell carcinoma of lung; other causes include pulmonary infections or CNS infection or hemorrhage

Multiple Endocrine Neoplasia1. These are a group of autosomal dominantly inherited disorders

characterized by the appearance of tumors in several endocrine organs. There are three syndromes.

2. MEN I (Wermer’s syndrome)a. Pituitary adenoma, Parathyroid hyperplasia or adenoma,

Pancreatic islet cell hyperplasia, adenoma, or carcinoma

b. often detected by hypercalcemia; deaths are due to the islet cell lesions

c. most of the pancreatic islet cell tumors secrete gastrin which causes multiple peptic and duodenal ulcers

3. MEN II (IIa or Sipple’s syndrome)a. Medullary carcinoma of thyroid, Pheochromocytoma of adrenal

medulla, and Parathyroid hyperplasia

b. The thyroid carcinomas tend to be multicentric; the pheochromocytomas tend to be bilateral or extra-adrenal

4. MEN III (IIb)

8

a. Medullary carcinoma of thyroid, Pheochromocytoma of adrenal medulla, mucocutaneous ganglioneuromas

b. Parathyroids are not involved

9

Case Study 1A 15 year-old male has increasingly severe headaches over a period of several months. His family physician can find nothing on physical examination. Eventually, a head CT scan is done which shows a suprasellar mass with calcifications. Which of the following findings is most likely to be present?

A. Chromophobe adenoma of the pituitaryB. Meningitis with H. influenzaeC. Nelson’s syndromeD. CraniopharyngiomaE. Head trauma

Case Study 2Following a precipitous delivery with substantial blood loss from a placenta previa, a 24 year-old primagravida is in stable condition. However, she is unable to breastfeed the baby. Then, over the next few months she notes a failure to return to normal menstrual cycles along with increasing fatigue, cold intolerance, and weight loss. What is the most likely underlying problem in this patient?

A. Chromophobe adenoma of the pituitary secreting prolactinB. Astrocytoma of the thalamus and hypothalamusC. Oat cell carcinoma of lungD. Empty sella syndromeE. Sheehan’s syndrome

Case Study 3A 27 year-old female develops amenorrhea, and then notes breast lactation occurs, even though she has not been pregnant. She does not have any other symptoms and is doing well in graduate school. These findings are most likely to be accompanied by:

A. A suprasellar mass on CT scan of the headB. Response to treatment with bromocriptine (a dopamine agonist)C. A non-secretory pituitary adenomaD. Increased soft tissue growth over timeE. Hyponatremia

Case Study 4A 63 year-old male has a chronic cough, but recently has noted blood-tinged sputum. A chest x-ray reveals an ill-defined hilar mass in the right lung. He is found to have a serum sodium of 120 mEq/L (normal 134 - 142 mEq/L). Which of the following findings is most likely to be present?

A. Low urine specific gravity (less than 1.005)B. Non-secretory chromophobe adenoma of pituitaryC. Bitemporal hemianopsiaD. Syndrome of inappropriate ADH secretionE. Decreased ACTH

Case Study 5A 22 year-old woman complains of vague abdominal pain along with some pain in her extremities. She has felt terrible and depressed for several months. Physical

10

examination reveals no major findings. A chest x-ray is normal. A serum chemistry panel reveals a calcium of 13.8 mg/dl with a serum albumin of 3.9 g/dl and PO4 of 2.2 mg/dl. At surgery, a 1cm mass in the left side of the neck adjacent to the thyroid gland is removed and sent to the surgical pathology lab for frozen section.

5. The pathologist’s diagnosis is most likely to be:A. Parathyroid carcinomaB. Medullary thyroid carcinomaC. Parathyroid adenomaD. Non-Hodgkin’s lymphomaE. Parathyroid hyperplasia

Further history: She is found to have an increased serum cortisol along with an increased plasma ACTH.

6. Which of the following radiologic findings is most likely to be present?A. A left adrenal massB. A sella turcica that is enlargedC. A lung noduleD. A suprasellar mass with calcificationsE. A mass compressing the trachea

Further history: A year later she develops mid-abdominal pains which are relieved by eating. She develops an iron deficiency anemia. Following an episode of vomiting a small amount of blood, an upper endoscopy is performed and multiple 0.5 to 1 cm benign gastric and duodenal ulcerations are found.

7. She was taken to surgery once more. What was the most likely finding?A. Adrenal medullary pheochromocytomaB. Aldosterone secreting adenoma of adrenal cortexC. Multiple gastrinomas of pancreasD. Medullary carcinoma of thyroidE. Oat cell carcinoma of lung

Further history: Prior to surgery, serum gastrin levels were found to be markedly elevated. At surgery, there was one larger 3 cm circumscribed mass at the head of the pancreas that completely obstructed the pancreatic duct and several smaller masses from 0.5 to 1 cm adjacent to the splenic artery. The pancreas was replaced by fibrofatty tissue and the pancreatic duct was not found distal to the large tumor. Microscopically, the masses were all consistent with islet cell tumors, and there was no normal remaining pancreatic parenchyma (either acini or islets).

8. The majority of the above findings can be explained by a syndrome that carries an increased risk for:A. Development of an extra-adrenal pheochromocytomaB. Diabetes mellitusC. Appearance of ganglioneuromasD. Medullary carcinoma of thyroidE. Similar findings in siblings

11

Answers:1. D; the age and the location and the presence of calcifications are all suggestive

of a craniopharyngioma2. E; post-partum pituitary necrosis led to the loss of pituitary hormones and

hypogonadism, hypothyroidism, and finally secondary adrenal insufficiency3. B; she is most likely to have a prolactinoma with the symptoms given4. D; he probably has an oat cell carcinoma of lung that is producing this

syndrome5. C; parathyroid adenomas are typically solitary masses, and they account for

most cases of hyperparathyroidism6. B; she has Cushing’s disease with a pituitary adenoma secreting ACTH. A lung

cancer as the source of ectopic ACTH would be rare at her age.7. C; islet cell tumors may secrete gastrin8. E; she has MEN I

12

PATHOLOGY 6020 - YEAR 2005-2006THYROID GLAND PATHOLOGYDavid Knight, MDFebruary 13th Monday 9:00-10:00am

SUGGESTED READING: PATHOLOGIC BASIS OF DISEASE, 7th edition, pp 1164-1183; 6th edition, pp 1130-1147

OBJECTIVES: At the end of the lecture, reading assignment, and laboratory, the student should be able to:

1. Describe the laboratory tests helpful in the diagnosis of thyroid diseases

a. Free Thyroxine (T4), Free Triiodothyronine (T3)b. TSHc. Antithyroid antibodiesd. Calcitonin

2. List the major clinical features of hyperthyroidism and hypothyroidism

3. Describe the gross and pathologic appearances of thyroid with:

a. Grave’s diseaseb. Toxic nodular goiterc. Nodular goiterd. Hashimoto’s thyroiditise. Subacute granulomatous thyroiditis

4. Describe the clinical characteristics with gross and microscopic pathologic appearance of:

a. Adenomasb. Papillary carcinomac. Follicular carcinomad. Medullary carcinomae. Anaplastic carcinoma

Thyroid anatomy and function

1. Two lobes (right and left, with upper and lower poles) connected by an isthmus at the anterior neck in the midline. Normal weight ranges from 10 to 30 gm. Upper pole (A) and lower pole (B) parathyroids are located behind the thyroid. Recurrent laryngeal nerve (C) and lymph nodes (D) are nearby. Thyroid sits anterior to thyroid cartilage (E) of trachea.

13

2. Embryologic derivation from endodermal thickening in the floor of the pharynx with downward migration from the foramen cecum at the base of the tongue.

May be incomplete, leaving aberrant thyroid tissue or a “thyroglossal duct cyst” in the midline of the neck.

3. Histologically, colloid-filled follicles are lined by cuboidal epithelium that responds to TSH

The interstitium contains neuroectodermally derived “C cells” that arise from the fourth pharyngeal pouch; secrete calcitonin.

4. Pituitary secretion of TSH in response to decreased level of thyroid hormone with feedback inhibition. Hypothalamic TRH stimulates the release of TSH.

5. Thyroid diseases in general have a female predominance.

Normal thyroid

Laboratory testing of thyroid function

1. Thyroid stimulating hormone (TSH): Elevated with primary thyroid failure (rarely with a pituitary adenoma). Decreased with pituitary failure, hyperthyroidism, or exogenous thyroid hormone administration

2. Free thyroxine (free T4) or Free T3: This measures T4 or T3 independent of the amount of TBG, to adjust for the amount of TBG and for variations in binding of T4 or T3 to TBG

3. Thyroid antibodies: The presence of antithyroglobulin and antimicrosomal autoantibodies suggests autoimmune disease (Hashimoto’s thyroiditis or Grave’s disease).

However, these antibodies can be found in other autoimmune diseases, and are not always present with thyroid autoimmune diseases.

14

4. Calcitonin: An increased amount is indicative of a medullary carcinoma or C-cell hyperplasia.

Hyperthyroidism

1. Definition: a hypermetabolic state secondary to increased free thyroid hormone.

2. Clinical findings are secondary to protein catabolism and enhanced sympathetic nervous system activity:

a. nervousness to emotional labilityb. heat intolerance and sweatingc. weight loss despite increased appetite (catabolism)d. muscular weakness and fine tremore. palpitations and tachycardia that exacerbates underlying heart

diseases leading to congestive failure and atrial fibrillation or angina

f. one feared complication is “thyroid storm” with fever, CHF, and coma

3. Etiologies:

a. Grave’s disease (90% of cases)b. Toxic multinodular goiter (Plummer’s disease - 5-10% of cases)c. rare: thyroiditis, thyroid carcinoma, TSH adenoma, struma ovarii

4. Laboratory diagnosis: elevated free T4 or T3; low TSH

5. Grave’s disease

a. Probable autoimmune etiology from defect in suppressor T-cell function; there are increased thyroid stimulating immunoglobulins (TSIs) that act upon TSH receptors to stimulate thyroid function as well as thyroid growth immunoglobulins (TGIs) that promote increase in size of the gland. In Grave’s disease, the action of the TSI is more striking than the TGI. There is a predilection in persons with HLA-DR3

b. Grossly results in a diffuse enlargement of the thyroid gland 2 to 3 times normal size; physical examination may reveal the presence of ophthalmopathy (exophthalmos) in about 1/3 of cases and dermopathy (pretibial myxedema) even less frequently

c. histologically there are prominent papillary infolding in the follicles, with tall columnar epithelium, scalloped colloid, and lymphocytic infiltrates between the follicles

15

Grave’s disease with thyroid hyperplasia. Note the scalloped colloid and tall columnar cells lining the follicles.

Hypothyroidism

1. Definition: hypometabolic state secondary to decreased thyroid hormone

2. Clinical appearance in children: cretinism with failure of mental and physical development

3. Clinical appearance in adults: myxedema with weakness, decreased mentation, sluggishness, cold intolerance, dry coarse skin and hair, alopecia, modest weight gain.

4. Etiologies:

a. chronic thyroiditis (Hashimoto’s disease)

b. dietary iodine deficiency (rare in USA because of iodized salt)

c. congenital: agenesis or hypoplasia of the gland, or biochemical enzymatic defect (all rare)

d. hypopituitarism

e. thyroidectomy (discovered by history and physical exam)

f. radiation (therapeutic with I-131, or accidental)

5. Laboratory diagnosis with decreased free T4, and elevated TSH. There is an increased TSH when the cause is “primary” hypothyroidism; the TSH is normal or low with “secondary” hypothyroidism due to lack of

16

pituitary function as detected by decrease in other pituitary hormones or a TRH stimulation test

Thyroid atrophy (history of Hashimoto’s)

Hashimoto’s thyroiditis

1. Autoimmune etiology with increased TGI and TSI antibodies (the action of the TGI predominates over the TSI) that stimulate enlargement of the gland. Additional blocking antibodies may mitigate the effect of TSIs. Predilection in persons with HLA-DR5.

2. Seen mostly in middle-aged women. Laboratory diagnosis is aided by increased titers of antithyroglobulin and antimicrosomal autoantibodies.

3. Clinical appearance may initially be that of transient hyperthyroidism, followed by a euthyroid state and then hypothyroidism as the thyroid atrophies over time (years).

4. Grossly, the thyroid is initially enlarged, rubbery, and typically not painful; eventually the inflammation leads to destruction and scarring with atrophy.

5. Microscopically, there is initially an abundant mononuclear cell infiltrate and lymphoid follicles with large pink “Hürthle cells.” Later, collagenous fibrosis, follicular atrophy, and some residual lymphoid infiltrates are seen.

6. Patients are at increased risk of developing lymphoma of the thyroid.

17

Hashimoto’s thyroiditis. Note the lymphocyte infiltrates with lymphoid follicles, and the thyroid epithelial cells with abundant pink cytoplasm (Hürthle cells) near the lymphoid infiltrate.

Subacute granulomatous thyroiditis (De Quervain’s disease)

1. Probably of viral origin and usually follows viral infection (such as respiratory influenza infection).

2. Presents as a painful, enlarged thyroid gland. Histologically, there is destruction of follicles with granulomatous inflammation and large foreign body giant cells.

3. Laboratory findings depend upon the course of the disease: initially the patient may be hyperthyroid, then hypothyroid, then normal.

4. This is usually a self-limited disease with a course over weeks to months.

Subacute thyroiditis, with granulomatous

inflammation, giant cells, and fibrosis.

18

Goiter

1. The most common disease of the thyroid; usually presents as thyroid enlargement; most patients are euthyroid; very rarely associated with hypothyroidism

2. Can be diffuse or multinodular; many multinodular thyroid goiters begin with diffuse enlargement

3. Clinical importance: can be confused with a thyroid carcinoma, and if large it can be cosmetically unpleasing to the patient

Nodular goiter. The thyroid is enlarged

and irregularly nodular, but without a dominant mass.

Thyroid neoplasms

1. Diagnosis made by workup starting with physical exam, thyroid function testing, and ultrasound

Most thyroid nodules are benign, so fine needle aspiration (FNA) is a useful technique for pathologic diagnosis but can be non-diagnostic at least 1/3 of the time

2. Adenomas

a. most are small solitary nodules (may be mimicked both clinically and pathologically by a nodular goiter)

b. most are “cold” on a scintigraphic scan

c. all have a follicular pattern; there is no such thing as a papillary adenoma. Sometimes the term “follicular neoplasm” is used when it is not apparent whether the lesion is benign or malignant.

19

In fact, 1 in 10 follicular neoplasms initially felt to be benign may prove to be malignant.

Follicular adenoma. Note the encapsulated tumor with smooth edges. Histologically, there are monotonous small follicles with little or no colloid, and a fibrous capsule which the adenoma does not invade through.

3. Papillary carcinoma (all papillary thyroid neoplasms are considered malignant); about 2/3 of all primary thyroid malignancies

a. grossly may present as a single or multiple masses and may often have been present for years before detection

b. histologically, they may be papillary, solid, or follicular.

Cytologically they typically have cells with clear (“ground glass”) nuclei. Psammoma bodies (laminated circular calcified concretions) may be present

c. tend to metastasize to regional lymph nodes; some papillary carcinomas may even initially present as an enlarged node from metastasis

20

d. long-term survival is common: >95% ten-year survival; the disease is more aggressive in the elderly

e. may occur following radiation exposure

Papillary Carcinoma. There is a hard, white mass in the thyroid. Histologically, there are papillary structures, laminated round blue calcified bodies called Psammoma bodies, and distinctive large, nearly clear (ground glass or Orphan Annie eye) nuclei.

4. Follicular carcinoma; about 1/4 of thyroid malignancies

a. grossly often difficult to distinguish from an adenoma (must look for capsular or vascular invasion)

b. histologically, diagnosed by the capsular or vascular invasion with absence of the features of papillary carcinoma

c. tend to metastasize hematogenously (lung and bone)

d. 90% five-year survival for minimally invasive tumors; prognosis is far worse for tumors with extensive invasion

21

Follicular Carcinoma. Note the capsular invasion in what would otherwise be a follicular adenoma.

5. Medullary carcinoma; about 10% of thyroid malignancies

a. derived from “C cells” and therefore has neuroendocrine features--may secrete calcitonin, ACTH, serotonin, somatostatin, etc.

b. grossly presents as single mass when the neoplasm occurs “sporadically” (70% of all cases) or multicentric masses when it is “familial”

c. histologically has polygonal cells arranged in nests; may have an amyloid stroma

d. can be associated with multiple endocrine neoplasia (MEN) syndromes

e. survival rate for familial forms (85% over 10 years) is double that of sporadic forms

Medullary Carcinoma. The tumor cells are in small nests in an amyloid stroma.

22

6. Anaplastic carcinoma; a rare thyroid malignancy

a. rare, aggressive neoplasm that is grossly hard and very invasive of surrounding tissues; occurs in older age range; very poor prognosis

b. histologically is undifferentiated with either small, spindled, or giant cells

Anaplasic carcinoma, with small, undifferentiated-appearing tumor cells.

7. Other: metastases are rare; lymphomas are uncommon

Case Study 1

You walk into the examining room and find a 23 year-old female pacing back and forth. She seems to be staring at you, and her hands are warm and tremulous. She says that she has been feeling very anxious and nervous for several months. Physical examination reveals a diffusely enlarged thyroid gland.

1. The best diagnosis is:

A. Toxic multinodular goiterB. Hashimoto’s thyroiditisC. Grave’s diseaseD. Papillary carcinomaE. Struma ovarii

2. Which of the following conditions most often produces non-painful enlargement of the thyroid gland in association with hypothyroidism?

A. Hashimoto’s thyroiditisB. Nodular goiter

23

C. De Quervain’s diseaseD. Grave’s diseaseE. Hypopituitarism

Case Study 2

An otherwise healthy 49 year-old female is found to have a firm. palpable nodule in the right side of the neck.

3. A “cold” thyroid nodule should make you most strongly suspect:

A. Papillary carcinomaB. Follicular adenomaC. Medullary carcinomaD. Grave’s diseaseE. De Quervain’s disease

4. If a metastatic tumor nodule were found in a cervical lymph node, the most likely primary neoplasm would be:

A. Follicular carcinomaB. Medullary carcinomaC. Papillary carcinomaD. Anaplastic carcinomaE. Lymphoma

Case Study 3

An otherwise healthy 45 year-old female has a feeling of fullness in the anterior neck. Physical examination reveals a diffusely enlarged, non-tender thyroid gland. The serum T3, T4, and TSH are all normal.

5. The most probable diagnosis is:

A. Subacute granulomatous thyroiditisB. Papillary carcinomaC. GoiterD. Grave’s diseaseE. Metastatic carcinoma to thyroid

6. If she had been hypothyroid, the most likely etiology would be:

A. Radiation therapyB. Congenital biochemical enzymatic defectC. Hypopituitarism

24

D. Chronic thyroiditisE. Iodine deficiency

Matching Questions

A. Metastases to bone and lungB. Psammoma bodiesC. Clonal lymphoid proliferationD. CalcitoninE. Spindle cells

7. Papillary carcinoma

8. Medullary carcinoma

Answers:

1. C; Grave’s disease is by far the most common cause for hyperthyroidism2. A; eventually, the thyroid may become atrophic3. B; most thyroid nodules are benign4. C; papillary carcinoma likes to metastasize to local nodes, and the metastasis

may be found first5. C; goiters are the most common thyroid disease and patients with them are

almost always euthyroid6. E; radiation, hypopituitarism, and chronic thyroiditis would lead to a small

thyroid; it is unlikely that she would be a healthy 45 year-old with a biochemical defect leading to hypothyroidism; iodine deficiency, however, is rare in the modern world

7. B; the diagnostic histologic feature of papillary carcinoma is the presence of clear (“orphan Annie eye”) nuclei, but about half of these cancers have psammoma bodies

8. D; these tumors have neuroendocrine features and can secrete substances other than calcitonin as well--ACTH, serotonin, etc.

25

PATHOLOGY 6020 - YEAR 2005-2006ADRENAL GLAND PATHOLOGYFrederic Clayton, MDFebruary 15th Wednesday 10:00-11:00am

SUGGESTED READING: PATHOLOGIC BASIS OF DISEASE, 7th edition, pp 1207-1223; 6th edition pp 1152-1166

OBJECTIVES: At the end of the lecture, reading assignment, and laboratory, the student should be able to:

1. Describe the laboratory tests helpful in diagnosis of adrenal diseases

a. Cortisol, with diurnal variationb. ACTH, ACTH stimulation testc. Dexamethasone suppression testc. Catecholamines, VMA, metanephrine, HVAd. Renin and aldosteronee. Routine electrolytes (Na, K) and glucose

2. Discuss the major clinical and pathologic features of:

a. Congenital adrenal hyperplasia with 21-hydroxylase deficiencyb. Addison diseasec. Cushing syndromed. Ectopic ACTH syndromese. Aldosterone excess, including Conn syndromef. Catecholamine excess

4. Describe the clinical, gross and microscopic findings in adrenal:

a. cortical atrophyb. cortical hyperplasiac. cortical adenomad. cortical carcinomae. pheochromocytomaf. neuroblastoma

Adrenal anatomy and function1. Adrenal gland – 4-6 grams

Adrenal cortexa. glomerulosa - secretes mineralocorticoids, principally

aldosterone, under the control of the renin-angiotensin mechanism along with serum potassium

b. fasciculata – secretes glucocorticoids, principally cortisol, under the control of ACTH from the pituitary

c. reticularis – secretes sex steroids

26

2. Adrenal medulla – chromaffin cells secrete catecholamines (norepinephrine and epinephrine).

Normal adrenal

From top: Adrenal cortex, with 3 layers

glomerulosa (mineralocorticoids), fasciculata (glucocorticoids), and reticularis (sex steroids). The adrenal medulla, at bottom, produces catecholamines.

Adrenal Insufficiency1. Primary can be acute or chronic

2. Secondary

3. Clinical features

a. weakness, nausea, vomiting and weight loss are seen in both primary and secondary adrenal cortical failure.

b. hyponatremia, hypovolemia, hypotension, skin pigmentation, and hyperkalemia are seen in primary failure

c. hypoglycemia is seen in secondary failure

27

Primary Acute Adrenocortical Insufficiency1. Crisis: seen in patients with chronic insufficiency or on exogenous

steroids with sudden requirement for increased steroid output

2. Lab test is plasma cortisol and ACTH

3. Massive adrenal hemorrhagea. seen in newborns, DIC, bacteremia

b. Waterhouse – Friderichsen Syndrome

- results from acute bacterial infection with sepsis and DIC: Neisseria meningitidis (meningococcus) is most often implicated, but can also occur with Haemophilus, Staphylococcus aureus, and pneumococcus

- adrenal is hemorrhagic and necrotic; patient’s skin shows extensive petechiae and/or purpura

Adrenal Waterhouse – Friderichsen.

The adrenal has extensive hemorrhage.

Primary Chronic Adrenocortical Insufficiency – Addison Disease1. Infiltration of gland by lymphoma, cancer, amyloid, sarcoid,

hemochromatosis and infections (TB)

2. Autoimmune adrenalitis

- More common in white women- 60-70% of cases- Sporadic or familial (HLA-B8 and DR-3)- multiple endocrine glands may be involved in 50%

3. Adrenals are small and scarred (1-3 gm)

4. ACTH is increased resulting in high melanotropic hormone and skin hyperpigmentation

28

Atrophic adrenal,

thin and pale (adjacent to a functional adenoma).

Secondary Adrenocortical Insufficiency1. Any disorder of the hypothalamus or pituitary that decreases ACTH

2. Exogenous steroids suppress ACTH and adrenal function

3. There is no hyperpigmentation

4. Aldosterone is usually normal (normal K+ and Na+ )

5. An ACTH challenge test results in increased cortisol levels, (cosyntropin)

Adrenal cortical hyperfunction Hypercortisolism1. Cushing Disease

A. Pituitary adenoma secreting ACTH - Cushing Disease is the leading cause of spontaneous hypercortisolism

B. W>M 5:1

C. 20 – 30 yo

29

D. Adrenal hyperplasia, bilateral

Adrenal cortical hyperplasia/Cushing

disease. The adrenal cortex is very thickened.

2. Cushing SyndromeA. Adrenal cortical neoplasms (adenoma, carcinoma) 15-30%

1. ACTH is low, cortisol is high2. Act autonomously, opposite gland is atrophic

B. Paraneoplastic syndrome with ectopic ACTH production (tumors such as oat cell carcinoma, medullary carcinoma of thyroid, or pheochromocytoma).

1. Bilateral cortical hyperplasia

C. Iatrogenic from chronic corticosteroid use (most common cause) - here the adrenals are atrophic

3. Clinical presentation:A. Caused by elevated glucocorticoids

a. hypertensionb. truncal obesity and “moon facies”, buffalo humpc. proximal muscular weakness and atrophy of Type II fibersd. thin skin, capillary fragility, loss of collagene. osteoporosis, often with compressed vertebral fracturesf. hyperpigmentation (if Cushing disease)g. acne, hirsutism, amenorrheah. glucose intolerance (diabetes)i. immune suppressionj. mental status changes, depression

3. Laboratory testsA. Screen with either 24 hour urinary free cortisol OR the overnight

(low dose ) dexamethasone suppression test. The plasma

30

cortisol is not suppressed in Cushing syndrome. High dose dexamethasone usually does suppress in Cushing disease.

B. Differential diagnostic tests include:

- Plasma ACTH, is decreased with adrenal neoplasms.- ACTH is increased with Cushing disease and ectopic ACTH production- CT or MRI to find mass in the adrenal

Adrenal cortical hyperfunction, Hyperaldosteronism1. Primary hyperaldosteronism

- Secrete aldosterone- Na+ retention and K+ excretion- Hypertension and hypokalemia- Suppression of renin-angiotensin system- Caused by adenoma or hyperplasia- Conn Syndrome

is caused by an adenoma is more common in women

2. “Secondary” hyperaldosteronism results from renal disease, cirrhosis, or congestive heart failure and is distinguished by increased renin.

Adrenal cortical nodular hyperplasia. The

cortex is thickened, but, unlike the prior photo, the cortex is quite nodular and irregular.

Adrenal Tumors1. Adenomas – many are nonfunctional

a. <2.5cm

b. encapsulated

31

Adrenal cortical adenoma. It is

homogeneous yellow, 1.8 cm in diameter, and encapsulated.

2. Adrenocortical Carcinomaa. Many are hormonally active and may combine Cushing syndrome

and virilization in the female and (rarely) feminization in the male

b. Not suppressed by dexamethasone. ACTH is decreased and does not respond to metyrapone.

c. Grossly are yellow with areas of necrosis; invasion and metastases prove that they are malignant; microscopically composed of clear cells that resemble adrenal cortex to highly anaplastic cells.

Adrenal cortical carcinoma (gross photo of very large tumor with renal invasion, and microscopic showing nuclear pleomorphism)

3. Pheochromocytoma - a tumor of chromaffin cells of the adrenal medulla

32

a. remember 10%: this describes the number of pheos that are malignant, extra-adrenal, part of multiple endocrine neoplasia syndromes, bilateral, and pediatric

b. clinical findings: the catecholamine secretion can lead to episodic or sustained hypertension, headache, flushing, perspiration, anxiety. May lead to cardiac failure, sudden death (arrhythmias, myocardial infarction, cerebrovascular accidents)

c. laboratory findings: increased catecholamines (plasma or urine), urine vanillylmandelic acid (VMA), and urine metanephrine

d. grossly, they are grey to red and can be large; microscopically, they are formed of nests of polygonal cells that resemble normal adrenal medulla. Electron microscopy shows neuroendocrine (dense) granules.

exhibit a chromaffin reaction when fixed in a dichromate solution (Zenker’s fixative)

Pheochromocytomas are red to grey on cut surface, and often quite vascular. The tumor cells are polygonal and have abundant amphophylic cytoplasm. By electron microscopy (lower picture), there are abundant small dense core granules containing catacholamines.

4. Neuroblastoma (a tumor of sympathetic ganglion cells)(This tumor will be covered in pediatrics)a. mostly seen in children <5 years of age; is the most common

solid extracranial malignant childhood neoplasm and accounts for 15% of childhood deaths from cancer

b. they can secrete catecholamines, VMA, and homovanillic acid (HVA), usually in small amounts, so hypertension and other symptoms of catecholamine excess are uncommon

c. often presents as abdominal enlargement with a mass and is metastatic at the time of diagnosis in 90% of patients

33

d. better prognosis in patients less than 11 months of age at the time of diagnosis, low stage, high VMA/HVA ratios, and absent n-myc gene

e. microscopically, this is one of the small round blue cell tumors. Immunoperoxidase or electron microscopy on the tumor tissue is often necessary in extra-adrenal sites

Congenital adrenal hyperplasia (Adrenogenital syndrome)1. A group of autosomal recessive enzymatic defects in the production of

cortisol resulting in decreased cortisol, increased ACTH, and adrenal hyperplasia.

2. 21-hydroxylase deficiency is the most common type. The enzyme is needed for cortisol and aldosterone production, but not androgen synthesis.

3. Produces virilization secondary to increased androgens.

4. Often presents soon after birth with salt wasting (loss of Na) due to lack of mineralocorticoids and glucocorticoids.

5. Adrenal cortex undergoes hyperplasia as ACTH increases with decreased cortisol.

CAH in female infant -- massive adrenomegaly and clitoromegaly

Case Study 1

A 68 year-old woman was found to have a blood pressure of 155/95 mm/Hg measured during a health fair sponsored by UUHSC. She still was hypertensive a week later when she saw her family physician. A routine serum chemistry panel showed: sodium 145 mEq/L (normal 135 - 145), potassium 2.9 mEq/L (normal 3.7 - 5.1), chloride 107

34

mEq/L (normal 98 - 108), and CO2 24 (normal 22 - 30). Her serum glucose was 105 mg/dl (normal 70 - 110). She felt fine. A physical examination revealed no abnormal findings. She was subsequently found to have a decreased plasma renin. An abdominal CT scan revealed a 2 cm mass in the left adrenal gland. Which of the following conditions is probably present?

A. Cushing’s syndromeB. Nelson’s syndromeC. Conn’s syndromeD. Congenital adrenal hyperplasiaE. Pheochromocytoma

Case Study 2A 19 year-old female was well until she complained of a sore throat that worsened throughout the day. She developed a high fever, then a severe headache and stiff neck. She was admitted to the hospital, and over the next few hours developed widespread petechiae and purpura, then severe hypotension. She died six hours after admission and only one day after the beginning of her symptoms. What was the major finding at autopsy?

A. Markedly hemorrhagic adrenalsB. Markedly atrophic and fibrotic adrenalsC. Caseating granulomas in the adrenalsD. Anterior pituitary necrosisE. Metastatic carcinoma involving adrenals

Case Study 3While bathing her 1 year-old baby boy, a mother notices that the baby’s abdomen seems larger than normal. The baby has not been feeding well lately, and is below the expected weight for his age. She takes the infant to the family physician who palpates a mass lesion in the abdominal region. An abdominal CT scan reveals a 5 cm mass in the left retroperitoneum displacing the left kidney. The most probable diagnosis is:

A. Congenital adrenal hyperplasiaB. Adrenal adenomaC. PheochromocytomaD. Adrenal cortical carcinomaE. Neuroblastoma

Case Study 4A 74 year-old female suffers severe back pain while picking up a basket of clothes. An x-ray reveals a fracture of T12 along with multiple compressed fractures of the vertebrae. Her skin is thin with areas of purpura. She has a serum glucose of 145 mg/dl. Her serum cortisol is normal. If her serum ACTH is decreased, the most likely pathologic finding is:

A. Pituitary adenomaB. Adrenal cortical carcinomaC. Adrenal adenomaD. Marked adrenal atrophyE. Bilateral adrenal hyperplasia

35

Answers:

1. C; this is the most common cause for hyperaldosteronism2. A; she had meningococcemia with Waterhouse-Friderichsen syndrome and the

fever, headache, and stiff neck are all typical for meningitis; Addison’s disease from an autoimmune basis would be a chronic process, and someone with tuberculosis would probably not be “well.” Persons at this age are unlikely to have metastatic carcinoma. If she had been pregnant, then pituitary necrosis with Sheehan’s syndrome would be a possibility, except that the adrenal failure would develop later.

3. E; this is one of the “small round blue cell” tumors4. D; she had rheumatoid arthritis and had received corticosteroid therapy for

many years; she had severe osteoporosis

36

PATHOLOGY 6020 - YEAR 2005-2006PARATHYROID PATHOLOGYFrederic Clayton, MDFebruary 15th Wednesday 11:00-12:00pm

SUGGESTED READING: PATHOLOGIC BASIS OF DISEASE, 7th edition, pp 1183-1189

OBJECTIVES: At the end of the lecture, reading assignment, and laboratory, the Student will be able to:

1. Describe the laboratory tests helpful in diagnosis of hyperparathyroidism.

a. Serum calciumb. Parathormone assays

2. List the clinical features of primary hyperparathyroidism.

3. Discuss the differential diagnosis of hypercalcemia

4. Describe the etiologies for and clinical features of secondary hyperparathyroidism.

5. Describe the bone lesions that accompany hyperparathyroidism.

6. Discuss etiologies for hypoparathyroidism and the clinical features of hypocalcemia.

Parathyroid Anatomy and Histology1. Derived embryologically from the 3rd and 4th pharyngeal pouches and 90%

of people have 4 glands.

2. Usually found close to 4 poles of the thyroid but may be anywhere along the path of the descent of the pharyngeal pouches into the anterior mediastinum.

3. Parathyroid glands each weigh 35 to 40 mg and are composed of:a. Chief cells

- Predominant cell type- Secretes PTH- Granular pink to clear

b. Oxyphil cells - Contain no secretory granules

c. Fat cells- Increase with age, up to 30% of gland.

37

Parathyroid, locations generally found

Parathyroid, Chief cells. Note normal

presence of fat admixed with the parathyroid. Parathyroid, Oxyphil cells (eosinophilic

cytoplasm).

38

Parathyroid PhysiologyPTH is regulated by free (ionized) calcium concentration in the blood (not trophic hormones).

Low calcium increases PTH.High calcium decreases PTH.PTH acts by binding a transmembrane receptor and activating a transduction pathway in bone, GI and renal cells.

Serum calcium is increased byActivating osteoclasts and bone resorptionIncreasing renal tubular reabsorptionActivating vitamin D in the kidneyIncreasing GI absorptionIncreasing renal P04 excretion

Hypercalcemia1. Most often detected on a routine serum chemistry panel

2. Differential diagnosis

a. Primary hyperparathyroidism - most common cause in outpatients(PTH nl: 15-75 pico gm /ml)(Calcium nl: 8.4-10.2 mg/dL)

b. Carcinoma

1. Secretion of a PTH-related protein (paraneoplastic syndrome, most often with squamous cell carcinoma of lung and renal cell carcinoma).

2. Carcinoma of breast, lymphoma, and multiple myeloma cause osteolytic metastases with release of TNFą and IL-1 that stimulate osteoclasts.

c. Rare causes of hypercalcemia include:

- Vitamin D toxicity- Granulomatous diseases (tuberculosis, sarcoidosis)- Drugs (thiazide diuretics)- Prolonged immobilization

Primary Hyperparathyroidism1. One of most common endocrine disorders (25 per 100,000)

Adenoma 75-80%

Hyperplasia 10-15%

39

Carcinoma <5%

Parathyroid hyperplasia. Normal parathyroids

are about 2 x 4 x 6mm. At least three of these glands are clearly enlarged.

2. Clinical symptoms: “Bones, stones, groans and moans”

a. Often there are no symptoms, just an elevated serum calcium or nonspecific weakness, anorexia, nausea, constipation.

b. Bones:Bone pain from osteoporosis, osteitis fibrosa cystica, “brown tumor” of bone and fractures.

- Prominence of osteoclasts and osteoblasts with thin cortex- Bone marrow cysts

c. Stones:Nephrolithiasis - 20% of cases have renal stones and obstruction leading to CRI.

d. Groans:Peptic ulcer disease (from increased secretion of gastrin), pancreatitis and gallstones

e. Moans:Depression, confusion, coma and seizures

f. Metastatic calcification (lung, kidney, stomach, heart)

g. Arrhythmias - shortened QT and prolonged PR intervals by EKG, which may proceed to first degree heart block and then to asystole

3. Laboratory findings

40

a. Elevated ionized serum calcium

b. Elevated or high normal PTHPTH and PTHrP can be distinguished Differentiates primary hyperparathyroidism from paraneoplastic syndrome.

c. Hypophosphatemia

4. Parathyroid adenomaa. 95% of cases are sporadic , the rest are associated with MEN-I.

b. Cells are monoclonal 1. PRAD-1 10-20% of adenomas2. MEN-1 20% of sporadic adenomas

c. Neoplastic cells grow and compress the adjacent normal gland. The neoplastic tissue is not admixed with fat.

d. Parathyroid surgery is an adventure:

- Adenomas are not that large (usually no more than 1 to 2 cm) and can be in a variable location.

- Differentiation of adenoma from hyperplasia for the pathologist can be difficult to impossible. Therefore, it is essential to confirm that the remaining glands are normal in size.

Adenomas may demonstrate cellular pleomorphism, but mitoses are rare.

Parathyroid adenoma. Note the near absence of fat in the adenoma, and the rim of normal tissue at the bottom.

41

Parathyroid adenoma. Monotonous cells,

many capillaries, and lack of fat.

5. Parathyroid hyperplasiaa. Usually involves the chief cells forming a multinodular pattern with decreased fat.

b. Usually all the glands are increased in size, but the enlargement may be asymmetrical sparing one or two glands.

c. 20% of cases are associated with multiple endocrine neoplasia (types I and II) and are monoclonal.

d. Treated with removal of 3 and 1/2 glands.

Parathyroid hyperplasia (all glands are

enlarged)

6. Parathyroid carcinomaa. Rare (about 1% of cases of primary hyperparathyroidism) form a grey-white mass composed of fairly normal cells forming nodules.

42

b. A third are large enough to be palpable at diagnosis (may be >10gm).

c. Criteria to diagnose malignancy requires mitotic activity and invasion (vascular and soft tissue) microscopically or metastases.

d. Serum calcium may be very high and typically exceeds 14 mg/dL at the time of diagnosis

e. Treated with en bloc excision of tumor, thyroid lobe, parathyroid, lymph nodes, and soft tissue, but 2/3 of cases recur.

Parathyroid carcinoma. A very large grey tumor. Histologically, there is nuclear pleomorphism, fibrosis, and invasion of adjacent tissues.

Secondary Hyperparathyroidism1. Caused by a disease which chronically depresses the serum calcium, which turns on PTH secretion, leading to a compensatory hyperplasia

2. Parathyroid glands are enlarged, but not symmetrically, there is chief cell nodular hyperplasia and decreased fat cells.

3. The most common cause is chronic renal failure (serum phosphate increased, calcium low normal or decreased, with increased PTH)

43

Rare causes include:Intestinal malabsorption of vitamin D and calcium and steatorrhea.

4. Clinical manifestations dominated by skeletal pain from bone lesions (osteitis fibrosa cystica) similar to those seen with primary hyperparathyroidism, and metastatic calcification5. Treatment - subtotal parathyroidectomy, with about 50 mg of parathyroid tissue left behind

Hypoparathyroidism1. Is much less common than hyperparathyroidism.

2. Causes:a. Most often results from accidental removal at surgery (thyroid surgery)

b. Congenital absence of all glands – seen in Di George Syndrome with thymic aplasia and abnormal immunity.

c. Primary (idiopathic) atrophy of glands is probably autoimmune. Patients have auto antibodies to calcium sensing receptors.

d. Familial hypoparathyroidism associated with primary adrenal insufficiency presents in childhood.

3. Findings include:a. Hypocalcemia, hyperphosphatemia, with decreased PTH

b. Tetany, muscle spasms and seizures, “Chvostek sign”

c. Mental status changes and Parkinson-like movements.

d. Prolonged QT on EKG.

e. Cataracts

f. Dental changes in children.

Case Study 1A 22 year-old female complains of vague abdominal pain along with some pain in her extremities. She has felt terrible and depressed for several months. Physical examination reveals no major findings. A chest x-ray is normal. A serum chemistry panel reveals a calcium of 13.8 mg/dl with a serum albumin of 3.9 g/dl and PO4 of 2.2 mg/dl.

1. What is the most likely cause of her problem?A. Metastatic carcinomaB. Parathyroid adenomaC. Chronic renal failureD. Pituitary adenoma

44

E. Thyroid carcinoma

Case Study 2A 54 year-old woman was found wandering aimlessly in a city park. She was dressed in an expensive business suit, but was disheveled, disoriented, and didn’t know her name. An uncashed paycheck in her purse was issued by a prestigious law firm. She was extremely weak and had an irregular heart rate. In the hospital, she was found to have a serum calcium of 15.8 mg/dl (normal 8.6 to 10.3) with an ionized calcium of 10.8 mg/dl (normal 4.6 to 5.3), total protein 5.8 g/dl, albumin 3.5 g/dl, urea nitrogen 23 mg/dL, and creatinine 1.1 mg/dL. A chest x-ray revealed clear lungs but osteolytic lesions of ribs and vertebrae.

2. What is the most likely cause for her hypercalcemia?A. Chronic renal failureB. Metastatic breast carcinomaC. Parathyroid adenomaD. TuberculosisE. Parathyroid carcinoma

Further history: A large, firm, irregular mass was palpable in the left breast that appeared fixed to the chest wall. Enlarged lymph nodes were palpable in the axilla. Biopsy revealed infiltrating ductal carcinoma. Efforts to reduce the calcium were not successful and she died.

3. What was the probable mechanism of death?A. Pulmonary edemaB. Marked anemia from bone marrow failureC. Cardiac arrestD. Acute renal failureE. Gastrointestinal hemorrhage

Case Study 3A 17 year-old girl presented with hemoptysis which led to a workup that revealed that she had Goodpasture’s syndrome. She progressed to end-stage renal disease and chronic renal failure within 18 months. She was placed on chronic hemodialysis. She developed severe hypertension. However, she had difficulty accepting the reality of her disease, and she missed dialysis appointments and did not take her medication for hypertension. She died suddenly and was found at autopsy to have congestive heart failure from hypertensive heart disease. At the time of her death she had a serum ionized calcium of 3.9 mg/dl.

4. Which of the following findings is most likely with this history?A. Intestinal malabsorptionB. DiGeorge syndromeC. Autoimmune hypoparathyroidismD. Secondary hyperparathyroidismE. Normal parathyroids with normal PTH level

5. A section of bone showed:A. Osteitis fibrosa cysticaB. Fibrous dysplasia

45

C. OsteosarcomaD. Giant cell tumorE. Osteopetrosis

Answers:

1. B; the increased serum calcium at this age is far more likely to be due to a parathyroid lesion than a malignancy elsewhere

2. B; the osteolytic lesions suggest metastases to bone, which are most likely from a carcinoma; parathyroid carcinomas are much less common and usually do not have widespread bone metastases

3. C; the high calcium leads to asystole4. D; she has secondary hyperparathyroidism with chronic renal failure; all 4

parathyroids were enlarged5. A; her bone changes are collectively called “renal osteodystrophy” because of

the underlying renal failure

46

Laboratory I - Thursday 2/16/06 1:00-3:00pm HSEB 4300Laboratory II - Tuesday 2/21/06 1:00-2:00pm HSEB 4300

About the cases:These cases were developed for the Endocrine Organ System Course by Dr. Juliana Szakacs in the Department of Pathology at the University of Utah. The use of Olympus and RadWeb at the University Hospital is restricted to physicians and caregivers with passwords. Please respect the privacy and confidentiality of patients at all times following HIPPA guidelines. The cases published on this website contain no personal identifiers.

How to use the cases for study:These cases will be presented in the same manner as the previous lab. Please present it as if you were a 3rd year student presenting your case to your attending. Don't forget to include references, and they should include references to books or articles, not just to the syllabus or what was said in lecture. Please turn in a copy of your answers to your instructor when you finish your presentation.

Goals and Objectives:Following the participation in lab sessions one and two, the student will be able to:

1. Use Olympus, E-chart and RadWeb to gather data on patients

2. Use the library electronic reference system or other literature to research data on diseases, therapies and drugs.

Students will understand the clinical findings, diagnostic criteria, treatments and pathophysiology of the following disorders:

1. Pheochromocytoma

2. Grave's Disease

3. Parathyroid adenoma and MENI

47

Case Notes

Case 1Part 11. What is your differential diagnosis?

2. What tests would you order?

Part 21. What is your differential diagnosis now?

Part 32. What do you expect to find at autopsy?

Part 41. What is the cell of origin of pheochromocytoma?

Part 5

1. What are the clinical findings suggestive of pheochromocytoma?

2. What laboratory tests are used to diagnose pheochromocytoma?

3. Describe the light microscopic findings and characteristic staining patterns of this tumor.

4. What characteristic features are seen on electron microscopy of this tumor?

5. What is the treatment of this tumor?

6. What familial syndromes are associated with pheochromocytoma?

Case 2Part 11. What is your differential diagnosis?

48

2. What testing would you like to do?

Part 21. What is your diagnosis?

Part 31. What is the diagnosis?

2. What testing do you want to do immediately during surgery?

Part 41. Was the surgery successful?

2. What follow-up will this patient need?

Part 51. What is the genetic abnormality in MEN1?

2. What organs are involved in MEN1 and what types of pathology may they exhibit?

3. What are the three syndromes included in MEN2?

4. What organs are involved in MEN2a?

5. What organs are involved in MEN2b (MEN3)?

6. How is parathyroid adenoma treated?

Case 3Part 1

1. What is your differential diagnosis?

2. What areas of the exam should you focus on?

49

3. What laboratory tests will you order?

Part 2

1. What is your diagnosis?

2. What treatment can be offered to this patient?

Part 3

1. Was the therapy effective?

1. What could be causing this?

2. In light of these findings, what treatment should be offered to the patient next?

Part 4

1. What is the pathologic diagnosis?

2. What tests should be run immediately after surgery?

Part 5

1. What is the etiology of Grave's Disease?

2. Who is usually affected by this disorder?

3. What is Grave's ophthalmopathy?

4. What is Grave's dermopathy?

50

5. What treatment will this patient need following surgery?

51