Principles of endocrine surgery

1. Principlesofendocrinesurgery Navid Ostad Martin LimiKvamme

2. Goiter • Diffuse Thyroid enlargement most commonly results fromprolonged stimulation by TSH • Such stimulation may be the result of hypothyroidism or of hyperthyroidism • Iodine deficiency is the most common cause of goiter in developing countries • A goiter may also develop from ingestion of goitrogens(factors blocking synthesis of thyroid hormone). Goitrogens are found in vegetables in BRASICCAE family( rutabagas, cabbage, turnips, cassava) • Medications that act goitrogenic include: thioamides, thiocyanates. • A congenital goiter associated with Hypothyroidism (sporadic cretism) may occur as a result of defect in one of the steps in synthesis of thyroid hormone.

3. Goiter - Pathogenesisand pathology • Goiter resulting from impaired thyroid hormone synthesis we see a progressive FALL in serum t4 and a progressive RISE in serum TSH. As TSH increases, iodine turnover is accelerated and the ratio of T3 secretion relative to T4 secretion is INCREASED • Goiter development is associated with LOW T4, LOW T3, elevated TSH and patient becomes clinically hypothyroid • IN EARLY stages of goites development there is a diffuse enlargement of the gland with cellular hyperplasia caused by TSH stimulation • Later there is enlarged follicles and accumulation of thyroglobulin.

4. GoiterAssociatedwithHypothyroidism and Hyperthyroidism • Goiter associated with hypothyroidism • iodine deficiency that interferes with hormone biosynthesis • iodine excess blocking secretion of hormone • goitrogen in diet or water • thioamides, thiocyanates(nitroprusside) • aniline derrivatives: eg. sulfonamides, aminosalicylic acid • litium blocking secretion of hormone • Congenital disorders with various defects in biosynthesis(sporadic cretinism): • Defective iodine transport, absence of peroxidase, synthesis of abnormal thyroglobulin, • Peripheral and pituitary resistance to thyroid hormone • Goiter associated with Hyperthyroidism • Graves disease( TSH-R(stim) ab stimulation) • toxic multinodular goiter (autonomous hyperfunction) • Germ cell tu( hcg stim) • Pituitary adenoma causing TSH overproduction • Thyroiditis causing enlargement due to infiltraion and edema.

5. Thyroidneoplasm • Benign • Adenomas • Malignant • Papillary (more than 85% of cases) • Medullary (5% to 15% of cases) • Follicular (less than 5% of cases) • Anaplastic (5% of cases)

6. Adenomas • Adenomas of the thyroid are benign neoplasms derived from follicular epithelium. Follicular adenomas usually are solitary. The majority of adenomas are nonfunctional, a small proportion produce thyroid hormones (toxic adenomas), causing clinically apparent thyrotoxicosis. In general, follicular adenomas are not forerunners to carcinomas • Most adenomas of the thyroid manifest as painless nodules.Larger masses may produce difficulty in swallowing. • After injection of radioactive iodine, most adenomas take up iodine less eagerly than normal thyroid parenchyma. Therefore on scanning, adenomas appear as cold nodules compared to the neighboring normal thyroid gland. Preoperative techniques used in evaluation of suspected adenomas are ultrasonography and fine needle aspiration biopsy. Thyroid adenomas carry an excellent prognosis and do not recur or metastasize.

7. Malignancies • Medullarycarcinoma • Theseareneuroendocrineneoplasms derived from the parafollicular cells of the thyroid. • Theysecrete calcitonin, which plays an important role in the diagnosis and postoperative follow-up evaluationof patients • Theytend to arise sporadically in about 70% of cases • Manifests mostoften as a mass in the neck, sometimes with dysphagia or hoarseness • Papillary carcinoma • These tumors may occur at any age and are usually associated with previous exposure to ionizing radiation. • Nonfunctional tumors so they manifest most often as a painless mass in the neck • The longterm survival is dependent on several factors, including age, the presence of extrathyroidal extension, and presence of distant metastases (stage)

8. Malignancies • Follicular carcinoma • They are more common in women (3:1) • It’s is more frequent in areas with dietary iodine deficiency • These neoplasms tend to metastasize through the bloodstream to the lungs, bone, and liver • Anaplastic carcinoma • They are aggressive, with a mortality rate approaching 100% • Metastases to distant sites are common

9. THYROIDITIS • Hashimoto • Characterized by gradual thyroid failure secondary to autoimmune destruction of the thyroid gland. • Most prevalent between the ages of 45 and 65 years and is more common in women than in men (10:1 to 20:1) • Painless enlargement of the thyroid, usually associated with some degree of hypothyroidism • Hashimoto thyroiditis often have other autoimmune diseases and are at increased risk for the development of B cell non-Hodgkin lymphomas

10. THYROIDITIS • Quervain thyroiditis • Much less common than Hashimoto disease • Most common between the ages of 30 and 50 and occurs more frequently in women than in men • Is believed to be caused by a viral infection • A majority of patients have a history of an upper respiratory infection just before the onset of thyroiditis • The onset is acute, characterized by pain in the neck (particularly with swallowing), fever, malaise, and some enlargement of the thyroid

11. Surgical Management ofthyroiddisease • Preoperative Investigation • The tests usually consist of thyroid function tests, radioactive thyroid scans, thyroid ultrasound and most importantly, Fine Needle Aspiration Biopsy (FNAB) of the thyroid gland. Based on the results of these tests, along with a suitable history, a doctor may refer the patient to see a surgeon to determine whether surgical treatment is appropriate or helpful in a particular situation • Any patients who have had a change in voice or who have had a previous neck operation and/or who have suspected invasive thyroid disease should have their vocal cord function evaluated preoperatively. This is necessary to determine whether the recurrent laryngeal nerve that controls the vocal cord muscles is functioning normally and is becoming a norm of practice • If medullary thyroid cancer is suspected, patients should be evaluated for coexisting adrenal tumors and for hypercalcemia and hyperparathyroidism.

12. Surgical Management ofthyroiddisease • Indications for Surgery • Surgical treatment is particularly recommended for those patients with nodules that are considered cancerous • It is less likely for patients with Graves’ disease to require surgical treatment • Patients who have experienced radiation of the head and neck area, may develop a nodularity of the thyroid gland which may require surgical treatment • Patients on occasion may develop an enlargement of the thyroid gland to the extent of pressure on the trachea. In this situation surgery is effective and may be preferred • If cancer is present in the thyroid gland, the surgeon should make a search for a spread of cancer to lymph nodes of the neck. If the lymph nodes of the neck are involved, they may require removal by an operation called a modified neck dissection in which there is a minimal derangement of function and appearance • Following operation, the incision is stitched carefully and the patient usually can be discharged on the first or second day following surgery

13. Surgical Management ofthyroiddisease • Side effects • Immediately after surgery, the patient may experience a swelling of the neck in the area of the incision, a sore throat, some difficulty in swallowing, and some discomfort at the back of the neck from the position during surgery. All these problems are usually of moderate degree and disappear after days or after a few weeks • Ocassionally fluid will build up underneath the incision and the surgeon will have to drain this with a needle and syringe. . Infrequently there will be some change of the voice This is usually due to a form of laryngitis following irritation by the anaesthetic tube. This should disappear in a few weeks or even months time. While an injury of the recurrent nerve can cause hoarseness or weakness of the voice, this is an unusual event and should be completely avoidable. The occurrence of low calsium state is not uncommon and is easily treated by calsium supplement. • Postoperative Treatment • Following surgery, replacement treatment with thyroxine is mandatory for all patients whose entire thyroid gland was removed and for some patients with partial thyroidectomy. • If a patients’ condition is that of a cancer, he/she may require treatment with radioactive iodine. This depends on the final report of the tissue examined by a doctor called a pathologist. • All patients undergoing thyroidectomy have a follow-up of their thyroid function tests • Thyroglobulin tests should also be done to detect possible recurrence of cancer

14. POSTOPPERATIVE COMPLICATIONS OF THYROID • Postoperative bleeding • The incidence of bleeding after thyroid surgery is low (0.3-1%), but an unrecognized or rapidly expanding hematoma can cause airway compromise and asphyxiation. Patients present with neck swelling, neck pain, and/or signs and symptoms of airway obstruction • Physical examination; remove all bandaging and examine the neck for swelling • Imaging studies may be useful in cases of mild neck swelling without airway compromise • Fiberoptic laryngoscopy may be warranted in patients with airway issues without apparent wound hematoma, to assess vocal fold function • Injury to the recurrent laryngeal nerve • Recurrent laryngeal nerve (RLN) injury results in true vocal-fold paresis or paralysis. Deliberate intraoperative identification and preservation of the RLN minimizes the risk of injury.

15. POSTOPPERATIVE COMPLICATIONS OF THYROID • Hypoparathyroidism • Hypoparathyroidismcanresult from direct trauma to the parathyroidglands, devascularizationof the glands, or removalof the glandsduringsurgery. Postoperative hypoparathyroidism, and the resultinghypocalcemia, may be permanent or transient. Hypocalcemiaafterthyroidectomy is initiallyasymptomatic in mostcases • Evaluationofparathyroidfunction is performed in eitherof the followingways: • Followionized calcium (or total calcium and albumin) levelsperioperatively • Measure PTH postoperatively; a normal levelaccuratelypredictsnormocalcemia • Injury to the SuperiorLaryngealNerve • The externalbranchof the superiorlaryngealnerve (SLN) is probably the nervemostcommonlyinjured in thyroidsurgery. Trauma to the nerveresults in an inability to lengthen a vocalfold and, thus, inability to create a high-pitched sound

16. POSTOPPERATIVE COMPLICATIONS OF THYROID • Thyrotoxic storm is an unusualcomplicationthatmayresult from manipulation of the thyroidglandduringsurgery in patients withhyperthyroidism. It candeveloppreoperatively, intraoperatively, or postoperatively. Signs and symptoms ofthyrotoxic storm are as follows: • Anesthetized patients: Evidenceofincreasedsympathetic output (eg, tachycardiahyperthermia) • Awake patients: Nausea, tremor, and altered mental status • Cardiacarrhythmiasmayalsooccur • Progression to coma in untreatedpatients • Infection • Currently, postoperative infectionoccurs in less than 1-2% of all thyroidsurgerycases. Sterile surgicaltechnique is the key to prevention; routineuseofperioperative antibiotics has not proven to be beneficial. • Hypothyroidism • Hypothyroidism is an expectedsequelaof total thyroidectomy. Measurementof TSH levels is the mostusefullaboratory test for detecting or monitoringofhypothyroidism in thesepatients • The needfor reoperation • Scar • Tightness in neckwith motion and swallowingresolved by fysiotherapy

17. Hyperthyroidism • Thyrotoxicosis is a hypermetabolic state due to elevated circulating levels of free T3 and T4 • Symptoms: • Skin tends to be soft, warm, and flushed • Heat intolerance and excessive sweating are common • Increased sympathetic activity and hypermetabolism result in weight loss despite increased appetite • Hypermotility, malabsorption, and diarrhea • Palpitations and tachycardia are common • Patients frequently experience nervousness, tremor, and irritability • Proptosis, but only in Graves disease • The diagnosis of hyperthyroidism is based on clinical features and laboratory data. The measurement of serum TSH is the most useful single screening test for hyperthyroidism

18. Hyperthyroidism – Treatment • Radioactive iodine • It’s by far the simplest treatment, it has been used for over 40 years and there is no known evidence of any harmful effects • After treatment with radioactive iodine, it is hoped that enough of the thyroid gland remains to function normally. Occasionally (10-20% of patients), the gland becomes overactive again since the abnormal stimulating antibody is still being produced by the lymphocytes • AntithyroidDrugs • Patients must take tablets for many months or years • Once treatment is stopped, there is only about a 50% chance that the disease will not flare up again • Thyroidectomy (thyroid surgery) • Surgery is sometimes recommended for the 80% of patients under the age 20 who have a recurrence of hyperthyroidism after antithyroid drugs • It’s also recommended for patients of any age in whom the goitre is so big that it causes blockage of the trachea or food esophagus

19. Hypothyroidism • Hypothyroidism is caused by any structural or functional derangement that interferes with the production of adequate levelsofthyroidhormone • Causes: • Dietary deficiency of iodine (most common) • Autoimmune • The clinical manifestations of hypothyroidism include cretinism (hypothyroidismdeveloping in infancy or earlychildhood) and myxedema (hypothyroidism developing in older children and adults) • Treatment of hypothyroidism is usually simple, in the form of a tablet of thyroid hormones taken once a day. This hormone pill usually contains T4 hormones and is to be taken on an empty stomach preferably in the morning separately from other medications

20. Cretinism • Cretinism refers to hypothyroidism developing in infancy or early childhood. This disorder was common in areas of the world where dietary iodine deficiency is endemic • It is now much less frequent because of the widespread supplementation of foods with iodine • Clinical features of cretinism include: • Impaired development of the skeletal system and central nervous system, with severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia

21. ENDOCRINE TUmors OF PANCREAS • Incidence and Mortality • They account for 3% to 5% of pancreatic malignancies and overall have a better prognosis than the more common pancreatic exocrine tumors • Five-year survival is about 55% when the tumors are localized and resected but only about 15% when the tumors are not resectable • Tumors of the endocrine pancreas are a collection of tumor cell types collectively referred to as pancreatic neuroendocrine tumors (NETs) • These tumors originate in islet cells • Prognostic Factors • Most islet cell cancers are functional, but about 15% are nonfunctional, with presentations similar to the far more common exocrine adenocarcinomas of the pancreas. Because of the presence of several cell types in the pancreatic islets. The clinical manifestations in functional tumors may result from the distinctive metabolic effects of the polypeptide(s) secreted by the cancer cells rather than from tumor bulk or metastatic disease • Nonfunctional tumors tend to present at later clinical stages with symptoms attributable to mass effect or metastases. Although nonfunctional tumors do not produce specific clinical syndromes, they may secrete inactive amine and peptide products such as the following: • Neurotensin, Alpha-hcg, neuron specific enolase, pancreatic polypeptide, chromogranin A

22. ENDOCRINE TUmors OF PANCREAS • Gastrinoma • AssociatedwithZollinger-Ellison syndrome (ZES) is a syndromeofunrelentingpepticulcerdisease, Esophageal reflux, diarrhea, and gastrichyperacidity, associatedwith a gastrin-producingtumor. It accounts for less than 1% of all pepticulcerdisease. It’sassociatedwith the MEN-1 syndrome and up to 50% aremalignant • Glucagonoma • Alpha cell tumor. is the thirdmost common endocrine-secretingislet cell tumor. About 75% ofglucagonomasaremalignant.Characteristicsof it is: Necrolyticmigratoryerythema, hyperglycemia, and venousthrombosiscomprise a virtuallydiagnostic triad. Other major signs and symtomesare Diabetes, characteristicrash(esp in perimenopausalmiddleagedwomen), anorexia, weight loss, anemia, diarrhea

23. ENDOCRINE TUmors OF PANCREAS • Insulinoma • Insulinomas are the most common islet tumors cell but still rare • Diagnosis og hypoglycemia is based on whipples triad: 1) symptomes and signs of hypoglycemia 2) association of low plasma glucose level 3) reversibility of symptomes on admin. Of glucose. Are far more likely to be benign than malignant • Fasting hypoglycemia associated with an elevated insulin level is pathognomonic • Miscellanous Islet tumors • VIPoma (Verner-Morrison Syndrome) is characterized by watery diarrhea, hypokalemia, and achlorhydria • These tumors can generally be easily localized by CT scan • Somatostatinoma

24. ENDOCRINE TUmors OF PANCREAS • Somatostatinoma • These tumors are particularly rare. A classic triad of symtomes frequently occurs with secretion of somatostatin: 1) Diabetes mellitus because of its inhibition of insulin and glucagon secretion. 2) cholelithiasis because of its inhibition of gallbladder motility and 3) steatorrhea because of its inhibition of pancreatic exocrine function. Hypochlorhydria, diarrhea and anemia can also occur • CT scan, MRI, and endoscopic ultrasound can usually help localize and stage the tumor. Most of these tumors are malignant and have metastases at diagnosis • Majority is found in pancreas but some can be located in duedenum or jejenum. Diabetes associated somatostatin is mild and not ketosis prone • Are often solitary, large and frequently metastatized by time of diagnosis

25. Anatomy and physiologyof the adrenalglands • The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol • They are found above the kidneys and consist of a series of layers with different structure and functions. Each gland has an outer cortex which produces steroid hormones and an inner medulla. • Blood supply: • The superior suprarenal artery, a branch of the inferior phrenic artery • The middle suprarenal artery, a direct branch of the abdominal aorta • The inferior suprarenal artery, a branch of the renal artery • Venous blood is drained from the glands by the suprarenal veins, usually one for each gland: • The right suprarenal vein drains into the inferior vena cava • The left suprarenal vein drains into the left renal vein or the left inferior phrenic vein

26. Anatomy and physiologyof the adrenalglands • The adrenal cortex itself is divided into three zones: • Zona glomerulosa (mineralocorticoids, help in the regulation of blood pressure and electrolyte balance) • Zona fasciculate (glucocorticoids, their functions include the regulation of metabolism and immune system suppression) • Zona reticularis (androgens, that are converted to fully functional sex hormones in the gonads and other target organs) • The adrenal medulla is at the centre of each adrenal gland • The chromaffin cells of the medulla are the body's main source of the catecholamines adrenaline and noradrenaline, released by the medulla. Approximately 20% noradrenaline (norepinephrine) and 80% adrenaline (epinephrine) are secreted here

28. TumorsofAdrenalglands • Malignant Adrenal Gland Tumors • Adrenocortical Cancer, which originates in the cortex of the adrenal gland. It is a rare cancer, There are two main types of adrenocortical cancer: • Functioning is the most common type and accounts for about 70% of adrenal cancers. These tumors make hormones, such as cortisol, androgens or aldosterone. Occur any age. Two rare inherited causes are Li freumeni syndrome and Beckwith – Wiedemann syndrome. In Most cases they are large, invasive with stron tendency to invade adrenal vein, vena cava and lymphatics • Non-functioning tumors do not produce hormones

29. TumorsofAdrenalglands • Malignant and Benign pheochromocytomas begin in the medulla. They are extremely rare. Neoplasms composed of chromaffin cells which synthesize and release catecholamines and other peptide hormones. They are of special importance because they give rise to surgically correctable form of hypertension. • Rule of tens: • 10 % extrarenal: occuring in sites such as Zuckerkandl organ(bifurcation of aorta or origiin of IMA) and carotid body where they are called paragangliomas • 10% Bilateral • 10% are malignant although the associated hypertension represents a serious complication of even benign tumors • 10% familial • In Other cases pheochromocytomas secrete other hormones such as ACTH, and somatostatin • Clinical features: The predominant clinical manifestation is hypertensive episode associated with tachycardia, palpitations headache, sweating, tremor, sometimes assocaiated with pain in abdomen or chest nausea and vomiting

30. TumorsofAdrenalglands • Benign AdrenalGlandTumors • Adenomas, a typeof non-canceroustumor. Most do not cause hyperfunctioning and areusuallyencountered as incidentalfindings • Cushing’sSyndrome, in which the adrenalglandproduces an excess ofcortisol, a hormonethatplays a part in regulatingbloodpressure, heartfunction and the body’sreaction to stress. Cushing’ssyndrome is rare. Overproductionofcortisolmay be caused by: • A benign tumor on the adrenalglandcalled an adenoma • An abnormalityof the pituitarygland, usually a tumor (alsocalledCushing’sdisease) • Long-term useofcorticosteroidmedications (such as prednisone) • Benign or malignanttumors in other areas of the bodythatproduceadrenocorticotropichormone (ACTH) (ectopic ACTH syndrome)

31. CushingSyndrome Common signs and symptomsinvolve progressive obesity and skin changes, such as: Weightgain and fattytissuedeposits, particularlyaround the midsection and upper back, in the face (moon face), and between the shoulders (buffalohump) Pink or purple stretch marks (striae) on the skin of the abdomen, thighs, breasts and arms Thinning, fragile skin thatbruiseseasily Slow healing ofcuts, insect bites and infections Acne Women with Cushing syndrome may experience: Thicker or more visible body and facial hair (hirsutism) Irregular or absent menstrual periods • Men with Cushing syndrome may experience: • Decreased libido • Decreased fertility • Erectile dysfunction

33. TumorsofAdrenalglands • Hyperaldosteronism, which is caused by a small tumor in the adrenal gland that makes too much aldosterone or an enlargement (hyperplasia) of the adrenal glands. A high level of aldosterone plays a part in the body’s salt and potassium balance, and may cause high blood pressure. In fact, it is believed that 10% of people with high blood pressure have hyperaldosteronism

34. TumorsofAdrenalglands • Incidentaloma • Since most incidentalomas are nonfunctioning adenomas, the workup should be selective to avoid unnecessary expense and procedures. The workup should include a complete history and physical examination with specific reference to a history of previous malignancy and signs and symptoms of Cushing syndrome or pheochromocytoma. Hyperaldosteronism, pheochromocytoma, and virilizing or feminizing adrenocortical carcinoma should be investigated • All functioning tumors should be excised

35. Surgical management ofadrenalglandtumors • Before the era of laparoscopic procedures, open adrenalectomy was the only surgical approach to adrenal neoplasms. Since the introduction of laparoscopic adrenalectomy in 1992, the majority of benign adrenal lesions have been removed by various laparoscopic techniques

36. Openadrenalectomy • The choice of conventional open methods for adrenalectomy depends on the size, location, and etiology of the adrenal mass, and the patient's body habitus and associated medical conditions • The open approaches are: • The flank or posterior (the incision is made through the bed of the twelfth rib for the flank or posterior approach and since exposure with this approach is limited, it should only be used to remove tumors up to 5 cm in size) • The anterior or transabdominal (it is through a midline or upper abdominal transverse incision, the advantages of this approach include access to the entire peritoneal cavity and the ability to treat bilateral adrenal disease, extra-adrenal disease or other intra-abdominal pathology. This approach is recommended for large malignant tumors) • The transthoracic or thoracoabdominal (The thoracoabdominal approach is made through a midline incision that extends into the chest through the tenth or eleventh intercostal space. The transthoracic approach uses an incision through the tenth rib on the right or eleventh rib on the left. Both of these approaches provide wide direct exposure and are well suited for tumors larger than 12 cm)

37. Laparoscopicadrenalectomy • Laparoscopic approaches in current use are: • Lateral transperitoneal (flank) • Anterior • Posterior retroperitoneal

38. Lateral transperitoneal (flank) adrenalectomy • The patient is positioned in a lateral decubitus position with the side of the diseased adrenal gland up. Four trocars are inserted in the flank area, one under the subcostal area at the anterior axillary line and three under the twelfth rib along a line lateral to the first one • This method allows one to inspect much of the abdominal cavity and provides wider exposure for removing relatively larger glands than can be removed with the retroperitoneal approach.

39. Posterior retroperitoneal adrenalectomy • The patient is placed in a semi-jackknife prone position. A balloon trocar is inserted 2.5 cm lateral to the twelfth rib into the retroperitoneum to create a working space. Three more trocars are introduced into the created retroperitoneal space under direct vision • The kidney is retracted downward with an atraumatic retractor placed through the port under the twelfth rib • Besides decreasing pain and length of hospitalization, the retroperitoneal approach allows one to perform a bilateral adrenalectomy without repositioning the patient • Due to its limited working space, large tumors cannot be removed (up to 5 cm)

40. Open vs Laparoscopicadrenalectomy

41. Postoperative complications • Complication rates are significantly higher in open surgery compared to laparoscopic procedures. • In open surgery, lung problems are the most common complications occurring in approximately 6% of patients, these include pneumonia and atelectasis • The risk of requiring a blood transfusion is higher with open than laparoscopic surgery • Adrenal insufficiency is a life-threatening problem where the body is not making enough cortisol. This complication can happen in patients who have had bilateral adrenalectomy who are not on enough steroids post-operatively. • Symptoms of this condition include feeling generally unwell, nausea, vomiting and confusion. Patients in this situation may need steroid medication for up to one year following surgery and for those who have had both adrenals removed, will require lifelong steroids.

42. Specificcomplications • Phaeochromocytoma • Intraoperative increased blood pressure (hypertensive crisis), due to the massive release of catecholamines upon handling of the tumour • Postoperative decreased blood pressure (hypotension) and massive fluid requirements following the fluid shifts that follow catecholamine control • Adrenal Cortex Tumour • Addisonian crisis (decreased adrenal cortical function) can occur after the removal of a glucocorticoid-secreting tumour. This is due to the suppression of the non-affected adrenal gland by negative feedback from the prior excess steroid production

43. MULTIPLE ENDOCRINE NEOPLASM SYNDORMES • The MEN syndromes are conditions which cause overactivity and enlargement in certain endocrine glands.  MEN syndromes are usually inherited conditions and therefore they run in families • There are three main types of multiple endocrine neoplasia: MEN 1, MEN 2a and MEN 2b • Each type of MEN is associated with a specific cluster of illnesses

46. MULTIPLE ENDOCRINE NEOPLASM 1 Treatment • Hyperparathyroidism • Surgery is the definitive treatment. Subtotal or total parathyroidectomy with forearm autotransplantation is performed with an open bilateral neck exploration. The recommended timing of surgery in a patient is controversial. Recurrent hypercalcemia is common. Transcervical thymectomy may need to be performed at the same time, owing to the mortality associated with malignant carcinoid tumors of the thymus. • Gastrinoma • Inhibition ofacidhypersecretion is achievedwith proton pump inhibitors. Histamine receptor antagonists may be added. Nonmetastaticgastrinomaslocated in the pancreasare rare butcan be surgicallyexcised. Removaloftumorslargerthan 2 cm in diameter reduces the frequencyof liver metastasis, which is an important prognostic factor. Surgicalcureofmultipleduodenalgastrinomas is difficult and is not associatedwith a highdisease-freestate. More extensive gastrointestinalsurgery, such as Whipplepancreaticoduodenectomy, can be associatedwith a highercure rate at the expenseof a higher operative mortality risk. Othernovelapproaches, such as chemotherapeutic agents or hormonal therapywithsomatostatin analogs, can be considered to treatdisseminatedgastrinomas.

47. MULTIPLE ENDOCRINE NEOPLASM 1 Treatment • Insulinoma • No curative long-term medical treatment exists for insulinomas. Surgical removal of the tumor is the treatment of choice. Unresectable tumors can be treated with diazoxide or octreotide. Chemotherapeutic agents or hepatic artery embolization has been used to treat metastatic disease. Insulinomas are most often single, large tumors that can be enucleated. Resection may result in cure, although insulinomas in patients with multiple endocrine neoplasia type 1 may be multicentric and small. A problem in these familial cases is that the lesion detected radiologically may not be the one causing hypoglycemia. Insulin measurements in the portal or hepatic veins may be required to localize the source of excess insulin secretion. • Glucagonomas • Surgical removal of the tumor is the treatment of choice. Usually, this involves excision of the tail of the pancreas. However, often times, metastases have already occurred at the time of diagnosis. Somatostatin analogs, chemotherapeutic agents, and hepatic artery embolization have also been used.

48. MULTIPLE ENDOCRINE NEOPLASM 1 Treatment • Vasoactive intestinal polypeptide tumor (VIPoma) • Somatostatin analogs control symptoms in 80% of cases, although surgical cure should be attempted. • Pituitary tumors • Treatment is similar to non-MEN1–associated pituitary tumors. Prolactinomas are treated with bromocriptine or cabergoline. Octreotide or lanreotide is used for somatotrophinomas. Transsphenoidal tumor removal with radiotherapy can be used if necessary. • Carcinoid tumors • If resectable, surgery is the treatment of choice. For unresectable tumors, treatment with radiotherapy or chemotherapeutic agents can be used. Somatostatin analogs can help with symptoms and may shrink some tumors. • Cutaneous manifestations of MEN1 • Management is conservative for lipomas, facial angiofibromas, and collagenomas. Local excision can be performed if desired.

49. MULTIPLE ENDOCRINE NEOPLASM 2A Treatment • The treatment for adrenal medullary hyperplasia or phaeochromocytoma is bilateral adrenalectomy, since the incidence of bilateral disease is high, and the mortality from phaeochromocytoma in MEN2 about 15%, usually due to sudden death. • If an adrenal lesion is identified at the same time as MTC, the adrenalectomy should be performed first. • Total thyroidectomy has been recommended for patients as young as 3 years for MEN2A if they contain the genetic mutation. • Hyperparathyroidism: subtotal parathyroidectomy is advised, along with cervical thymectomy because of the increased risk of supernumerary parathyroid glands. Persistent or recurrent hyperparathyroidismis unusual and less likely to occur in MEN2A patients than in MEN1 patients.

50. MULTIPLE ENDOCRINE NEOPLASM 2b Treatment • Thyroidectomy with lymph node clearance should be performed at the earliest possible age in individuals with the phenotypic features, since MTC is biologically aggressive in these patients and has been reported as early as 15 months of age, with metastases by the age of 3 years. In patients with the genetic mutation for MEN2B, total thyroidectomy is recommended in infancy. • In those patients not identified by screening, thyroidectomy should still be performed, unless there are distant metastases, usually to lung or liver. It is probable that in all patients with palpable tumours, metastases to local lymph nodes will be present, so a central lymph node dissection should also be performed, probably with lateral node sampling to look for further spread. • The most useful markers in the follow-up of MTC are plasma calcitonin and carcinoembryonic antigen