Surgical Endocrinology

1. Surgical Endocrinology University of Virginia Clinical Clerkship in Surgery Peter I. Ellman M.D.

2. Plan for Talk • Review the objectives as outlined by the Lawrence text. • Discuss the anatomy, physiology, pathophysiology, diagnosis and treatment of thyroid, parathyroid and adrenal gland disorders. • Discuss the MEN syndromes.

3. Objectives for the Thyroid Gland • Discuss the evaluation and differential dx of a patient with a thyroid nodule. • List the different types of thyroid cancer, their cell types of origin, and the appropriate theraputic strategy for each. • Major risk factors for carcinoma of the thyroid gland and prognostic variables that dictate therapy. • SX of Hyperthyroidism, DDX and TX

4. Objectives for the Parathyroid Glands • Understand the role of the parathyroid glands in the physiology of calcium hemostasis. • List the causes, symptoms, and signs of hypercalcemia. • Know the difference between 1°, 2°, 4° hyperparathyroidism. • Discuss the evaluation and ddx of a paitent with hypercalcemia. • Understand the management of acute and severe hypercalcemia. • Surgical indications for hyperparathyroidism • Complications of parathyroid surgery.

5. Objectives for the Adrenal Glands • Describe the clinical features of Cushing’s syndrome and discuss how lesions in the pituitary, adrenal cortex and extraadrenal sites are distinguished diagnostically. • Med and surg mgmt of patients with adrenal adenoma, pituitary adenoma causing adrenal hyperplasia, and with ACTH producing neoplasm. • Path, clinical features, lab findings, W/U, mgmt. of pt with 1° aldosteronism. • Discuss pheochromocytoma, signs and symptoms, W/U, mgmt. • Discuss adrenal cortical carcinoma, assoicated signs and symptoms, W/U managment. • Mgmt. and evaluation of incidentally discovered adrenal mass. • Causes of adrenal insufficiency in surgical setting, as well as clinical and laboratory findings (RECENT JAMA ARTICLE)

6. Thyroid Anatomy • Two lobes in neck, connected by isthmus at second tracheal ring. • Embryologic origin at site of foramen cecum on tongue—migrates ventral to the hyoid bone– why people get thyroglossal duct cyst. • Arerial supply 2: Superior thyroid artery via the external carotid and Inferior thyroid artery via the Thyrocervical trunk (off the subclavian). • Venous drainage 3: through the superior, middle and inferior thryoid veins.

7. Thyroid Physiology • Two groups of hormone producing cells • 1: Follicular cells produce, store and release T4 and T3 • 2: Parafollicular cells secrete calcitonin.

8. Follicular cells • Capture iodide from the circulation and concentrate it and then oxidize it (organification, occuring in the apical membranes of the cells) • Tyrosine residues of thyrogolbulin are then iodinated by oxidized iodides, forming monoiodotyrosine and diiodotyrosine which then couple to form T4 and T3-which is then stored. • When thyroid stimulating hormone (TSH) stimulates the thyroid, the iodinated thyroglobulin then is taken into the cell and is hydrolized to T4 and T3-which is then released into the circulation.

9. TSH • Besides stimulating the release of T3 and T4, TSH can stimulate the cell to increase production of thyroid hormones. • TSH production is stimulated by Thyrotropin-releasing hormone (TRH) which is secreted by the hypothalamus. This intern is controlled by a feedback mechanism. Increased T3 and T4 have a negative feedback mechanism on TRH as well as TSH

10. The parafollicular (aka C cells) • Secrete calcitonin which is stimulated by high serum calcium levels, which inhibits osteoclast activity, which in turn decreased calcium levels. • Total absence of these cells produces no demonstrable negative physiologic effect!

11. Objective T1:W/U of Thyroid Nodule • Always a thorough H & P (remember for oral exam). • Hx of irradiation to the head or neck? • Family history of MEN syndrome (will get to this later) • Carefully palpate the thyroid and regional lymph nodes. • How long has nodule been present? Any associated pain, hoarseness, dysphagia, dyspnea, or hemoptysis?

12. Objective T1:W/U of Thyroid Nodule • On physical exam: • Nodule should be carefully examined to assess size, consitency, extension and fixation. Single or multiple? • Is there cervical lymphadenopathy? • Is there a rapid pulse, tremor, exopthalmos? • Direct laryngoscopy is important in preoperative evaluation to assess for vocal cord paralysis.

13. Benign Toxic thyroid adenoma Cyst Papillary adenoma Follicular adenoma (most common adenoma) Colloid (macrofollicular) Fetal (microfollicular) Embryonal Hürthle cell adenoma Malignant Papillary CA Follicular CA Hürthle Cell CA Medullary CA Anaplastic CA Thyroid Lymphoma Metastatic Carcinoma to the Throid Gland. DDX of thyroid nodule

14. FNA • Fine needle aspiration is the single most important study in evaluating a thyroid mass. • Only 3% of patients with a benign dx on FNA have thryoid cancer, and 85% of nodules identified as malignant on FNA are cancers at resection. • 68% to 98% sensitive and 56% to 100% specific. • Approx 75% are classified as “benign”, 25% as “suspicious” and 5% as “malignant. • Follow patients with benign dx closely • Follicular adenomas cannot be distinguished from follicular carcinoma by FNA and warrants a surgical exploration--most likely total thyroidectomy. • do not do frozen section! It has been shown to be notoriously inaccurate!)

15. Other imaging modalities • Not required for the routine evaluation of the vast majority of thyroid nodules. • It is important to try and avoid the use of iondinated contrast materials preperatively. • This can impair postoperative tx. • Hot vs. Cold nodules. • A technicium thyroid scan may show a “cold” or hypofunctioning nodule. While it is c/w cancer, it could also be benign solid or cystic nodule that could be diagnosed with or even treated with FNA.

16. Use of ultrasound • Good for determining the size, number and location of thyroid nodules accurately. • Questionable use as a “screening tool”. Can increase the rate of finding incidentalomas.

17. Objective T2: List 7 Thyroid Carcinomas, Cell Types, and Tx. • Papillary CA • Follicular CA • Hürthle Cell CA • Medullary CA • Anaplastic CA • Thyroid Lymphoma • Metastatic Carcinoma to the Throid Gland.

18. Papillary CA • Divided into the papillary, mixed papillary/follicular and follicular variant of papillary. • Most Common Thyroid Malignancies! • Arises from Follicular Cells • Histologically associated with fibrosis, calicifications, squamous metaplasia, psammoma bodies, lymphatic invasion.

19. Papillary CA TX • Tx is somewhat controversial. At the very least pt needs ipsilateral lobectomy and isthmusectomy. Some surgeons recommend total thyroidectomy. It is important to know that you don’t just take out the nodule! • LND for clinically significant nodal disease. • Surgery is followed by scanning with radioactive iodine to detect residual normal thyroid tissue as well as metastatic disease (lungs and bones).

20. Follicular CA- Overview • Increased in regions of the world where iodine is deficient. • Dx of malignancy requires that either vascular or capsular invasion by tumor be demonstrated. • Again, FNA and Frozen Section cannot be trusted. Dx is deferred pending histologic review.

21. Follicular CA—Cell origins • Come from follicular cells (not surprising) • On histologic exam there is a paucity of colloid associated with follicular cells. • Extra points for knowing that follicular carcinomas that demonstrate only minor capsular invasion have a relatively benign course. • Vascular invasion indicates more aggressive behavior.

22. Follicular CA- Tx • Total thyroidectomy is recommended by many for virtually all patients, particularly those with lesions larger than 4cm. Some surgeons may elect to do just lobectomy and isthmusectomy. • Adjuvant therapy with radioactive iodine, as with papillary CA

23. Hürthle Cell CA-Overview • Less common than follicular ca and is often considered a subset of follicular ca. • More aggressive • Higher incidence of metastasis • Lower survivial rate • Similar difficulties in preoperative dx like follicular cell CA, but there may be a linear relationship between lesion size and malignancy. • In a study of 57 patients, th chance of malignancy when lesions are >4cm was 65%, and it was 17% when <1cm • Cell type is still of follicular cell origin.

24. Hurthle Cell CA Tx • For lesions >4cm, total thyroidectomy • For lesions <1cm, thyroid lobectomy and isthmusectomy, with completion thyroidectomy if the permanent histology proves to be cancer. • Follow up radioactive iodine??

25. Medullary CA (MTC)- Overview • Slow growing, but aggressive neuroendocrine tumor. • Metastasizes early to lymph nodes, then to liver, lungs and bones. • Originates from the parafollicular C cells!! • 80% of pateints with medullary CA have sporadic MTC, while in 20% people have an autosomal mutation in the RET protooncogene. • RETprotooncogene abnormalities are assocated with the MEN-IIA, MEN-IIB and familial medullary thyroid cancer (FMTC)

26. Presentation and Dx of MTC • FNA can be diagnostic, especially when the slides are assayed for calcitonin and CEA activity. Both are elevated. • Up to 75% presenting with sporadic MTC have lymph node mets.

27. Tx of Sporadic MTC • Screen for pheochromocytoma and hyperparathyroidism (rule out MEN syndrome) • Total thyroidectomy with central lymph node dissection (remember that 75%) and ipsilateral modified radical neck dissection. • No role for radioactive iodine.

28. Tx of familial forms of MTC • Got RET? • Sam Wells, a famously mean surgeon from Duke, then Wash U. famously showed that there is a role for prophylactic thyroidectomy could be beneficial after DNA testing of patients at risk. • Children with MEN IIA should undergo thyroidectomy at 5-6 years of age. • Routine central neck dissection has been advocated, but no lateral LND. • Children with MEN IIB have the most aggressive form of MTC. Total thyroidectomy should be performed ASAP, preferably before the age of 2.

29. Post surgical care for MTC • Often have persistently high levels of calcitonin. • This often will necessitate repeated aggressive neck dissection to root out any residual tissue. However, only 38% of these patients will eventually be normalized. These patients often have occult distant mets. Laparoscopic evaluation of the liver has been recently adopted prior to neck dissection. • Note that this is a slow growing tumor and patients with incurable metastatic disease can often live for decades. • Radiation may have a role, chemo does not.

30. Anaplastic CA • Rare– BAD NEWS • Patients present with rapidly expanding neck mass, often with aggressive invasion of local structures, often with airway compromise. • Derive from de-differentiated follicular adenoma/carcinoma. • Surgery is often not possible, and thus Chemotherapy and Radiation is the current treatment.

31. Thyroid Lymphoma • Like anaplastic ca, presents as a rapidly enlarging neck mass. • FNA combined with flow cytometry shows a monoclonal population of lymphocytes. • Tx is radiotherapy and chemotherapy. • Studies involving surgical debulking have failed to show any benefit.

32. Metastatic Carcinoma to the Throid Gland • Not as uncommon as you might think. • Autopsy series demonstrate 1% to 24% of patients who die of extrathyroidal malignancies. 5-7% are clinically significant. • Most often from Renal Cell CA (50% of cases) • There is a role for resection of these mets in some patients.

33. Objective T3-Risk factors for Thyroid CA • Hx of irradiation to the head and neck in childhood (used to be for tonsils, enlarged adenoids or thymus, even acne!), nuclear accidents • Iodine deficiency (goiter) • Female predominance 3:1 • More virulent in elderly patients • Genetic (MEN syndromes, FMTC) • Hashimoto’s thyroiditis (lymphoma) • Previous ca (particularly RCC)

34. Objective T4 Sx and Tx of Hyperthyroidism • Causes • Exogenous hormone • Subacute thyroiditis • Postpartum thyroiditis • Iodine induced hyperthyroidism • Struma ovarri • Functional metastatic thyroid carcinoma • Three that are Surgically Treated ARE: • Grave’s disease • Toxic multinodular goiter • Autonomously functioning toxic adenoma

35. Grave’s disease • Autoimmune disease • Clinical symptoms (of hyperthyroidism) • Palpitations, sweating, intolerance to heat, irritability, insomnia, nervousness, weigh loss, fatigue • Signs • Bruit over the gland, tremors, arrhythmias • Exopthalmos, edema of eyelids, pretibial edema.

36. Toxic Multinodular Goiter • Enlargement of the thyroid glands over a long period of time. • Treatment is medically initially, but the preferred treatment is surgical. • In setting of bilateral multiple nodules, total or near total thyroidecomy is indicated. • If nodules are predominantly on one side, then ipsilateral lobectomy and ithmusectomy are probably adequate.

37. Solitary Toxic Adenoma • Patients presenting with thyrotoxicosis and a dominant thyroid nodule. • Elevated T3, T4 and a suppressed TSH level. • Tx is administration of 131I or surgery. • Surgery is recommended for younger patients with moderate size to large nodules. • Lobectomy is usually adequate

38. Grave’s disease Tx • Medical for initial treatment. • Antithyroid drugs (propylthiouricil, iodine) • Recurrence is high if drugs are stopped • Surgical treatment • Bilateral total or near-total thyroidectomy • Pts will now need thyroid replacement for the rest of their life.

39. Parathyroid Gland Anatomy • Paired organs, normally with 2 on the posterior surface of each thyroid lobe. • Embryologic development from 3rd (inferior parathyroid gland with thymus) and and 4th (superior parathyroid gland and C cell precursors) pharyngeal pouches. • Art supply from inferior thryoid arteries. • Superior gland is usually posterior and lateral to the recurrent laryngeal nerve. • Inferior is anterior and medial to the recurrent laryngeal nerve.

40. Ob P1- parathyroid glands and the physiology of calcium hemostasis. • Synthesize and secret parathyroid hormone, which along with vitamin D maintains calcium hemostasis. PTH Calcium Renal resorption Bone resorption, urine phosphorus

41. List the causes, symptoms, and signs of hypercalcemia. • Stones • Nephrolithiasis • Bones • Painful resorption of bone • Moans and Psychatric overtones • Fatigue, depression, confusion • Abdominal groans • Peptic ulcer and pancreatitis

42. Know the difference between 1°, 2°, 4° hyperparathyroidism. • Primary Hyperparathyroidism PTH calcium (normal renal function) • 83% parathyroid adenoma, 15% parathyroid hyperplasia, carcinoma is rare 1-2% • Secondary Hyperparathyroidism poor renal functioncalcium, PO4 PTH normal Ca • Tertiary Hyperparathyroidism Hyperplastic parathyroids from chronic stimulation continue post renal transplant

43. Hyperparathyroidism Malignancy Hematologic PTHrP producer Hyperthyroidsm Multiple myeloma Sarcoidosis Milk-alkili syndrome Vit D or A intoxication Paget’s disease Immobilization Thiazide diuretics Addisonian Crisis Familial hypocalcuric hypocalcemia Neonatal severe hyperparathyroidism. Discuss ddx of a paitent with hypercalcemia.

44. Evaluation of Hypercalcemia • Send off PTH levels to diagnose primary versus other causes. • 24 hour urine calcium measurement and chloride to phosphate ratio (>33) • X-rays are diagnostic for Paget’s disease • EKG– will classically show shortened QT and prolonged PR interval. Check rate for bradycardia.

45. Understand the management of acute and severe hypercalcemia. • Mainstay of management is: • admittnance to hospital (severe is considered asymptomatic with >3.2mmol/L, or symptomatic patient) • Expand Volume with NSS or LR (500 ml bolus STAT) • Diurese with loop diuretics • Other meds may be started (bisphosponates, calcitonin, mithramycin ect.)

46. Indications for surgery • Nephrolithiasis, bone disease, and neuromuscular symptoms respond well to surgery. • Primary hyperparathyroidism due to adenoma is cured surgically by excision of the adenoma. All four glands must be identified though! • Primary hyperparathyriodism due to parathyroid hyperplasia is treated with subtotal parathyroidectomy (3 1/2) or total parathyroidectomy with autotranspantation into the arm.

47. On initial evaluation Markedly elevated CA Hx of life threatening hypercalcemia (??) Reduced Cr CL. Nephrolithiasis Markedly elevated 24hr U Ca Substantially reduced bone mass Following asymptomatic pt Pt becomes symptomatic Ca 1-1.6 mg/100 ml above normal Nephrolithiasis Decline in bone mass Neuro or psych problems Pt desire to fix. Surgical indications for asymptomatic hyperparathyroidism

48. Complications of parathyroid surgery. • Hypocalcemia • Persistent hypercalcemia • Recurrent laryngeal nerve injury

49. Adrenal anatomy • Paired structures living superior to the kidneys. They are flat and triangular, about 5 grams • Arterial supply (3 each) • Superior adrenal off inf. phrenic A. • Middle adrenal off the aorta • Inferior adrenal arising off the enal A. • Venous supply (one major on each) • Right adrenal vein drains into vena cava. • Left adrenal vein drains into the left renal vein

50. Cortex and Medulla • Cortex- mesodermal in origin • Zona glomerulosa • Production site of aldosterone • Zona fasiculata • Production site of cortisol and sex steroids • Zona reticularis • Production site of cortisol, androgens and estrogens. • Medulla-ectodermal in origin • Production center of catecholemines epinephrine and norepinephrine.