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Surgery_Schwartz. urine collections for cortisol and 17-hydroxy steroids performed over the second day. Failure to suppress urinary cortisol by 50% confirms the diagnosis of an ectopic ACTH-producing tumor. Patients suspected of having ectopic tumors should also undergo testing for MTC and pheochro-mocytoma. Bilateral petrosal vein sampling also is helpful for determining whether the patient has Cushing’s disease or ecto-pic Cushing’s syndrome.Brunicardi_Ch38_p1625-p1704.indd 168901/03/19 11:22 AM 1690SPECIFIC CONSIDERATIONSPART IIThe CRH test also is helpful in determining the etiology of Cushing’s syndrome. Ovine CRH (1 μg/kg) is administered intravenously, followed by serial measurements of ACTH and cortisol at 15-minute intervals for 1 hour. Patients with a primary adrenal hypercortisolism exhibit a blunted response (ACTH peak <10 pg/mL), whereas those with ACTH-dependent Cushing’s syndrome demonstrate a higher elevation of ACTH (>30 pg/mL). CRH stimulation also can enhance the useful-ness of


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Surgery_Schwartz. a blunted response (ACTH peak <10 pg/mL), whereas those with ACTH-dependent Cushing’s syndrome demonstrate a higher elevation of ACTH (>30 pg/mL). CRH stimulation also can enhance the useful-ness of petrosal vein sampling. Patients with pituitary tumors also have a higher peak ACTH than those with ectopic ACTHproducing tumors.Radiologic Studies. CT and MRI scans of the abdomen can identify adrenal tumors with 95% sensitivity. They also are helpful in distinguishing adrenal adenomas from carcinomas, as discussed in the subsequent section “Adrenocortical Cancer.” MRI scans have the added advantage of allowing assessment of vascular anatomy. Adrenal adenomas appear darker than the liver on T2-weighted imaging. Radioscintigraphic imag-ing of the adrenals using NP-59 also can be used to distinguish adenoma from hyperplasia. Reports suggest that “cold” adrenal nodules are more likely to be cancerous, although this distinc-tion is not absolute. NP-59 scanning is most useful in identi-fying


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Surgery_Schwartz. adenoma from hyperplasia. Reports suggest that “cold” adrenal nodules are more likely to be cancerous, although this distinc-tion is not absolute. NP-59 scanning is most useful in identi-fying patients with an adrenal source of hypercortisolism and primary pigmented micronodular hyperplasia.Thin-section head CT scans are 22% sensitive, and contrast-enhanced brain MRI scans are 33% to 67% sensitive at identifying pituitary tumors. Inferior petrosal sinus sampling for ACTH before and after CRH injection has been helpful in this regard and has a sensitivity approaching 100%. In this study, catheters are placed in both internal jugular veins and a periph-eral vein. A ratio of petrosal to peripheral vein ACTH level of >2 in the basal state and >3 after CRH stimulation is diagnostic 1) Overnight DST2) 24-hour urinary free cortisol3) 11:00 pm salivary cortisol1) Plasma ACTH2) High-dose DST and urinary cortisolConfirm the diagnosisACTH gradient?Determine source of


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Surgery_Schwartz. is diagnostic 1) Overnight DST2) 24-hour urinary free cortisol3) 11:00 pm salivary cortisol1) Plasma ACTH2) High-dose DST and urinary cortisolConfirm the diagnosisACTH gradient?Determine source of hypercortisolismDecreased ACTHLack of suppressionCT scan adrenalsIncreased ACTHPositive Increased ACTHLack of suppressionEquivocalresultsFurther testingBilateral petrosalvein samplingAdrenalsourcePituitarysourceEctopic ACTHsourceSTEPS IN DIAGNOSISDIAGNOSTIC STUDIESYesNoFigure 38-44. Diagnosis of Cushing’s syndrome. ACTH = adrenocorticotropic hormone; CT = computed tomography; DST = dexamethasone suppression test.Brunicardi_Ch38_p1625-p1704.indd 169001/03/19 11:22 AM 1691THYROID, PARATHYROID, AND ADRENALCHAPTER 38of a pituitary tumor. In patients suspected of having ectopic ACTH production, CT or MRI scans of the chest and anterior mediastinum are performed first, followed by imaging of the neck, abdomen, and pelvis if the initial studies are negative.Treatment Laparoscopic


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Surgery_Schwartz. production, CT or MRI scans of the chest and anterior mediastinum are performed first, followed by imaging of the neck, abdomen, and pelvis if the initial studies are negative.Treatment Laparoscopic adrenalectomy is the treatment of choice for patients with adrenal adenomas. Open adrenalectomy is reserved for large tumors (≥6 cm) or those suspected to be adrenocortical cancers. Bilateral adrenalectomy is curative for primary adrenal hyperplasia.The treatment of choice in Cushing’s disease is transsphe-noidal excision of the pituitary adenoma, which is successful in 80% of patients. Pituitary irradiation has been used for patients with persistent or recurrent disease after surgery. However, it is associated with a high rate of panhypopituitarism, and some patients develop visual deficits. This has led to increased use of stereotactic radiosurgery, which uses CT guidance to deliver high doses of radiotherapy to the tumor (photon or gamma knife) and also bilateral laparoscopic


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Surgery_Schwartz. deficits. This has led to increased use of stereotactic radiosurgery, which uses CT guidance to deliver high doses of radiotherapy to the tumor (photon or gamma knife) and also bilateral laparoscopic adrenalectomy. Patients who fail to respond to either treatment are candidates for pharmacologic therapy with adrenal inhibitors (medical adrenalectomy) such as ketoconazole, metyrapone, or aminoglutethimide.Patients with ectopic ACTH production are best managed by treating the primary tumor, including recurrences, if possible. Medical or bilateral laparoscopic adrenalectomy has been used to palliate patients with unresectable disease and those whose ectopic ACTH-secreting tumor cannot be localized.Patients undergoing surgery for a primary adrenal ade-noma secreting glucocorticoids require preoperative and post-operative steroids due to suppression of the contralateral adrenal gland. These patients are also at increased predisposition for infectious and thromboembolic complications, the


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Surgery_Schwartz. and post-operative steroids due to suppression of the contralateral adrenal gland. These patients are also at increased predisposition for infectious and thromboembolic complications, the latter due to a hypercoagulable state resulting from an increase in clotting factors including factor VIII and von Willebrand’s factor com-plex, and by impaired fibrinolysis. Duration of steroid therapy is determined by the ACTH stimulation test. Exogenous ste-roids may be needed for up to 2 years but are needed indefi-nitely in patients who have undergone bilateral adrenalectomy. This latter group of patients also may require mineralocorticoid replacement therapy. Typical replacement doses include hydro-cortisone (10–20 mg every morning and 5–10 mg every eve-ning) and fludrocortisone (0.05–0.1 mg/d every morning).Adrenocortical Cancer. Adrenal carcinomas are rare neo-plasms with a worldwide incidence of two per 1 million. These tumors have a bimodal age distribution, with an increased inci-dence in


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Surgery_Schwartz. morning).Adrenocortical Cancer. Adrenal carcinomas are rare neo-plasms with a worldwide incidence of two per 1 million. These tumors have a bimodal age distribution, with an increased inci-dence in children and adults in the fourth and fifth decades of life. The majority are sporadic, but adrenocortical carcinomas also occur in association with germline mutations of p53 (Li-Fraumeni syndrome) and MENIN (multiple endocrine neoplasia type 1) genes. Loci on 11p (Beckwith-Wiedemann syndrome), 2p (Carney complex), and 9q also have been implicated. Somatic p53 mutations are present in up to 33% of tumors, and LOH at the p53 locus has been reported in >85% of adreno-cortical carcinomas. In addition, insulin-like growth factor II is overexpressed in 90% of tumors, and approximately 30% harbor somatic activating mutations in the b-catenin gene. Recently identified genes mutated in adrenal cancers include ZNRF3 (an E3 ubiquitin ligase) and others involved in chromatin modeling and several


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Surgery_Schwartz. somatic activating mutations in the b-catenin gene. Recently identified genes mutated in adrenal cancers include ZNRF3 (an E3 ubiquitin ligase) and others involved in chromatin modeling and several microRNAs. Patterns of mutations may also help better define prognosis in adrenocortical cancers.104Symptoms and Signs Approximately 50% of adrenocorti-cal cancers are nonfunctioning. The remaining secrete cortisol (30%), androgens (20%), estrogens (10%), aldosterone (2%), or multiple hormones (35%). Patients with functioning tumors often present with the rapid onset of Cushing’s syndrome accompanied by virilizing features. Nonfunctioning tumors more commonly present with an enlarging abdominal mass and abdominal or back pain. Rarely, weight loss, anorexia, and nau-sea may be present.Diagnostic Tests Diagnostic evaluation of these patients begins with measurement of serum electrolyte levels to rule out hypokalemia, urinary catecholamines to rule out pheochromo-cytomas, an overnight 1-mg


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Surgery_Schwartz. Tests Diagnostic evaluation of these patients begins with measurement of serum electrolyte levels to rule out hypokalemia, urinary catecholamines to rule out pheochromo-cytomas, an overnight 1-mg dexamethasone suppression test, and a 24-hour urine collection for cortisol, and 17-ketosteroids to rule out Cushing’s syndrome.CT and MRI scans are useful to image these tumors (Fig. 38-45). The size of the adrenal mass on imaging studies is the single most important criterion to help diagnose malig-nancy. In the series reported by Copeland, 92% of adrenal can-cers were >6 cm in diameter.105 The sensitivity, specificity, and likelihood ratio of tumor size in predicting malignancy (based on Surveillance, Epidemiology, and End Results program data) were reported as 96%, 51%, and 2 for tumors ≥4 cm, and 90%, 78%, and 4.1 for tumors ≥6 cm.106 Other CT imaging charac-teristics suggesting malignancy include tumor heterogeneity, irregular margins, and the presence of hemorrhage and adjacent


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Surgery_Schwartz. ≥4 cm, and 90%, 78%, and 4.1 for tumors ≥6 cm.106 Other CT imaging charac-teristics suggesting malignancy include tumor heterogeneity, irregular margins, and the presence of hemorrhage and adjacent lymphadenopathy or liver metastases. Moderately bright signal intensity on T2-weighted images (adrenal mass–to–liver ratio 1.2:2.8), significant lesion enhancement, and slow washout after injection of gadolinium contrast also indicate malignancy, as does evidence of local invasion into adjacent structures such as the liver, blood vessels (IVC), and distant metastases. FDG-PET or PET-CT scans may have some utility in distinguishing benign from malignant lesions, as discussed in the section on incidentalomas. Once adrenal cancer is diagnosed, CT scans of the chest and pelvis or FDG-PET or PET-CT scans are per-formed for staging. The tumor-node-metastasis (TNM) staging system for adrenocortical carcinoma is depicted in Table 38-19. Up to 70% of patients present with stage III or IV


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Surgery_Schwartz. or PET-CT scans are per-formed for staging. The tumor-node-metastasis (TNM) staging system for adrenocortical carcinoma is depicted in Table 38-19. Up to 70% of patients present with stage III or IV disease.Pathology Most adrenocortical cancers are large, weigh-ing between 100 and 1000 g. On gross examination, areas of Figure 38-45. Computed tomography scan of the abdomen show-ing a left adrenocortical cancer with synchronous liver metastasis.Brunicardi_Ch38_p1625-p1704.indd 169101/03/19 11:22 AM 1692SPECIFIC CONSIDERATIONSPART IIhemorrhage and necrosis often are evident. Microscopically, cells are hyperchromatic and typically have large nuclei and prominent nucleoli. It is very difficult to distinguish benign adrenal adenomas from carcinomas by histologic examination alone. Capsular or vascular invasion is the most reliable sign of cancer. Weiss and associates studied a combination of nine criteria for their usefulness in distinguishing malignant from benign adrenal tumors:


Surgery_Schwartz

Surgery_Schwartz. or vascular invasion is the most reliable sign of cancer. Weiss and associates studied a combination of nine criteria for their usefulness in distinguishing malignant from benign adrenal tumors: nuclear grade III or IV; mitotic rate greater than 5 per 50 high-power fields; atypical mitoses; clear cells comprising 25% or less of the tumor; a diffuse architecture; microscopic necrosis; and invasion of venous, sinusoidal, and capsular structure. Tumors with four or more of these criteria were likely to metastasize and/or recur.107 Rarely, the diagnosis of malignancy of a completely resected adrenal tumor is often only made in retrospect by the finding of metastatic disease many years later. Molecular markers such as Ki67 (indicating proliferative activity) can also be useful in this regard.Treatment The most important predictor of survival in patients with adrenal cancer is the adequacy of resection. Patients who undergo complete resection have 5-year actuarial survival rates ranging


Surgery_Schwartz

Surgery_Schwartz. most important predictor of survival in patients with adrenal cancer is the adequacy of resection. Patients who undergo complete resection have 5-year actuarial survival rates ranging from 32% to 48%, whereas median survival is <1 year in those undergoing incomplete excision. Therefore, adrenocor-tical carcinomas are treated by excision of the tumor en bloc with any contiguously involved lymph nodes or organs such as the diaphragm, kidney, pancreas, liver, or IVC. This is best accomplished by open adrenalectomy via a generous subcostal incision or a thoracoabdominal incision (on the right side). The incisions should permit wide exposure, minimize chances of capsule rupture and tumor spillage, and allow vascular control of the aorta, IVC, and renal vessels, as needed.Mitotane or o,p-DDD or 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane, which is a derivative of the insec-ticide DDT, has adrenolytic activity and has been used in the adjuvant setting and for the treatment of


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Surgery_Schwartz. 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane, which is a derivative of the insec-ticide DDT, has adrenolytic activity and has been used in the adjuvant setting and for the treatment of unresectable or metastatic disease. However, the therapeutic effectiveness is conflicting, and consistent improvement in survival rates is lacking. Moreover, the drug is associated with significant GI and neurologic side effects, particularly at the effective doses of 2 to 6 g/d. Terzolo and associates retrospectively evaluated the use of mitotane in the adjuvant setting and reported signifi-cantly increased recurrence-free survival in the treatment group, even in long-term follow-up.108,109 However, a study of several centers in the United States failed to show similar results.110 The routine use of this medication awaits evaluation in random-ized, controlled trials. Determination of blood mitotane levels is helpful to ascertain whether therapeutic and nontoxic levels are present.


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Surgery_Schwartz. use of this medication awaits evaluation in random-ized, controlled trials. Determination of blood mitotane levels is helpful to ascertain whether therapeutic and nontoxic levels are present. Adrenocortical tumors commonly metastasize to the liver, lung, and bone.Surgical debulking is recommended for isolated, recurrent disease and has been demonstrated to prolong survival. Sys-temic chemotherapeutic agents used in this tumor include etopo-side, cisplatin, doxorubicin, and, more recently, paclitaxel, but consistent responses are rare, possibly due to the expression of the multidrug resistance gene (MDR-1) in tumor cells. In vitro data indicate that mitotane may be able to reverse this resistance when combined with various chemotherapeutic agents. Results from the First International Randomized Trial in Advanced or Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) showed that patients receiving etoposide, doxorubicin, cispla-tin, and mitotane had better response rates and


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Surgery_Schwartz. Randomized Trial in Advanced or Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) showed that patients receiving etoposide, doxorubicin, cispla-tin, and mitotane had better response rates and progression-free survival rates than patients receiving streptozotocin and mitotane.111 There has been recent interest in the use of sura-min, a growth factor inhibitor, as therapy for adrenocortical carcinoma; however, this requires further study, particularly because this drug may be associated with significant neurotoxic-ity. Gossypol, a naturally occurring insecticide (from the cotton plant Gossypium species), also appears to inhibit the growth of adrenocortical cancer cell lines and tumors in vivo. However, poor response rates combined with high death rates in limited clinical studies have reduced enthusiasm for this agent. Adre-nocortical cancers also are relatively insensitive to conventional external-beam radiation therapy. However, this modality is used in the adjuvant setting in


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Surgery_Schwartz. reduced enthusiasm for this agent. Adre-nocortical cancers also are relatively insensitive to conventional external-beam radiation therapy. However, this modality is used in the adjuvant setting in patients with incomplete resections and palliation of bony metastases. Ketoconazole, metyrapone, or aminoglutethimide may also be useful in controlling steroid hypersecretion. Targeted molecular therapies such as VEGF/EGF-receptor inhibitors, tyrosine-kinase inhibitors, and IGF-2 inhibitors have had disappointing results in patients with ACC.Sex Steroid Excess. Adrenal adenomas or carcinomas that secrete adrenal androgens lead to virilizing syndromes. Although women with virilizing tumors develop hirsutism, amenorrhea, infertility, and other signs of masculinization, such as increased muscle mass, deepened voice, and temporal bald-ing, men with these tumors are more difficult to diagnose and, hence, usually present with disease in advanced stages. Chil-dren with virilizing tumors have


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Surgery_Schwartz. mass, deepened voice, and temporal bald-ing, men with these tumors are more difficult to diagnose and, hence, usually present with disease in advanced stages. Chil-dren with virilizing tumors have accelerated growth, premature development of facial and pubic hair, acne, genital enlargement, and deepening of their voice. Feminizing adrenal tumors are less common and occur in men in the third to fifth decades of life. These tumors lead to gynecomastia, impotence, and testicular atrophy. Women with these tumors develop irregular menses or dysfunctional uterine bleeding. Vaginal bleeding may occur in postmenopausal women. Girls with these tumors experience precocious puberty with breast enlargement and early menarche.Diagnostic Tests Virilizing tumors produce excessive amounts of the androgen precursor, DHEA, which can be measured Table 38-19TNM Staging for adrenocortical cancerTUMORNODEMETASTASISSTAGET1N0M0IT2N0M0IIT1N1M0IIIT2N1M0IIIT3Any NM0IIIT4Any NM0IIIAny TAny NM1IVPrimary tumor


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Surgery_Schwartz. precursor, DHEA, which can be measured Table 38-19TNM Staging for adrenocortical cancerTUMORNODEMETASTASISSTAGET1N0M0IT2N0M0IIT1N1M0IIIT2N1M0IIIT3Any NM0IIIT4Any NM0IIIAny TAny NM1IVPrimary tumor (T): T1, size ≤5 cm without local invasion; T2, size >5 cm without local invasion; T3, any size with local invasion but no involvement of adjacent organs; T4, any size with involvement of adjacent organs.Nodes (N): N0, no involvement of regional nodes; N1, positive regional lymph nodes.Metastasis (M): M0, no known distal metastases: M1, distant metastases present.Used with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017.Brunicardi_Ch38_p1625-p1704.indd 169201/03/19 11:22 AM 1693THYROID, PARATHYROID, AND ADRENALCHAPTER 38in plasma or urine as 17-ketosteroids. Patients with feminiz-ing tumors also have elevated urinary 17-ketosteroids in addi-tion to increased estrogen levels.


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Surgery_Schwartz. PARATHYROID, AND ADRENALCHAPTER 38in plasma or urine as 17-ketosteroids. Patients with feminiz-ing tumors also have elevated urinary 17-ketosteroids in addi-tion to increased estrogen levels. Androgen-producing tumors often are associated with production of other hormones such as glucocorticoids.Treatment Virilizing and feminizing tumors are treated by adrenalectomy. Malignancy is difficult to diagnose histologi-cally but is suggested by the presence of local invasion, recur-rence, or distal metastases. Adrenolytic drugs such as mitotane, aminoglutethimide, and ketoconazole may be useful in control-ling symptoms in patients with metastatic disease.Congenital Adrenal Hyperplasia. CAH refers to a group of disorders that result from deficiencies or complete absence of enzymes involved in adrenal steroidogenesis. 21-Hydroxylase (CYP21A2) deficiency is the most common enzymatic defect, accounting for >90% of cases of CAH. This deficiency pre-vents the production of 11-deoxycortisol and


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Surgery_Schwartz. adrenal steroidogenesis. 21-Hydroxylase (CYP21A2) deficiency is the most common enzymatic defect, accounting for >90% of cases of CAH. This deficiency pre-vents the production of 11-deoxycortisol and 11-DOC from progesterone precursors. Deficiency of glucocorticoids and aldosterone leads to elevated ACTH levels and overproduction of adrenal androgens and corticosteroid precursors such as 17hydroxyprogesterone and Δ4-androstenedione. These com-pounds are converted to testosterone in the peripheral tis-sues, thereby leading to virilization. Complete deficiency of 21-hydroxylase presents at birth with virilization, diarrhea, hypovolemia, hyponatremia, hyperkalemia, and hyperpig-mentation. Partial enzyme deficiency may present at birth or later with virilizing features. These patients are less prone to the salt wasting that characterizes complete enzyme deficiency. 11β-Hydroxylase deficiency is the second most common form of CAH and leads to hypertension (from 11-DOC accumula-tion),


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Surgery_Schwartz. less prone to the salt wasting that characterizes complete enzyme deficiency. 11β-Hydroxylase deficiency is the second most common form of CAH and leads to hypertension (from 11-DOC accumula-tion), virilization, and hyperpigmentation. Other enzyme defi-ciencies include 3β-hydroxydehydrogenase and 17-hydroxylase deficiency. Congenital adrenal lipoid hyperplasia is the most severe form of CAH, which is caused by cholesterol desmolase deficiency. It leads to the disruption of all steroid biosynthetic pathways, thus resulting in a fatal salt-wasting syndrome in phe-notypic female patients.Diagnostic Tests The particular enzyme deficiency can be diagnosed by karyotype analysis and measurement of plasma and urinary steroids. The most common enzyme defi-ciency, absence of 21-hydroxylase, leads to increased plasma 17-hydroxyprogesterone and progesterone levels because these compounds cannot be converted to 11-deoxycortisol and 11-DOC, respectively. 11β-Hydroxylase deficiency is the next most


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Surgery_Schwartz. increased plasma 17-hydroxyprogesterone and progesterone levels because these compounds cannot be converted to 11-deoxycortisol and 11-DOC, respectively. 11β-Hydroxylase deficiency is the next most common disorder and results in elevated plasma 11-DOC and 11-deoxycortisol. Urinary 17-hydroxyprogesterone, andro-gens, and 17-ketosteroids also are elevated. The dexamethasone suppression test (2–4 mg divided four times a day for 7 days) can be used to distinguish adrenal hyperplasia from neoplasia. CT, MRI, and iodocholesterol scans generally are used to local-ize the tumors.Treatment Patients with CAH traditionally have been man-aged medically, with cortisol and mineralocorticoid replacement to suppress the hypothalamic-pituitary-adrenal axis. However, the doses of steroids required often are supraphysiologic and lead to iatrogenic hypercortisolism. More recently, bilateral laparoscopic adrenalectomy has been proposed as an alternative treatment for this disease and has been successfully


Surgery_Schwartz

Surgery_Schwartz. supraphysiologic and lead to iatrogenic hypercortisolism. More recently, bilateral laparoscopic adrenalectomy has been proposed as an alternative treatment for this disease and has been successfully performed in a limited number of patients for various forms of CAH.Disorders of the Adrenal MedullaPheochromocytomas. Pheochromocytomas are rare tumors with prevalence rates ranging from 0.3% to 0.95% in autopsy series and approximately 1.9% in series using biochemical screening. They can occur at any age, with a peak incidence in the fourth and fifth decades of life, and have no gender predilec-tion. Extra-adrenal tumors, also called functional paraganglio-mas, may be found at sites of sympathetic ganglia in the organ of Zuckerkandl, neck, mediastinum, abdomen, and pelvis. Pheo-chromocytomas often are called the 10 percent tumor because 10% are bilateral, 10% are malignant, 10% occur in pediatric patients, 10% are extra-adrenal, and 10% are familial.Pheochromocytomas occur in families


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Surgery_Schwartz. often are called the 10 percent tumor because 10% are bilateral, 10% are malignant, 10% occur in pediatric patients, 10% are extra-adrenal, and 10% are familial.Pheochromocytomas occur in families with MEN2A and MEN2B in approximately 50% of patients. Both syndromes are inherited in an autosomal dominant fashion and are caused by germline mutations in the RET proto-oncogene. Another syndrome with an increased risk of pheochromocytomas is von Hippel-Lindau (VHL) disease, which also is inherited in an autosomal dominant manner. This syndrome also includes retinal angioma, hemangioblastomas of the central nervous system, renal cysts and carcinomas, pancreatic cysts, and epi-didymal cystadenomas. The incidence of pheochromocytomas in the syndrome is approximately 14%. The gene causing VHL has been mapped to chromosome 3p and is a tumor suppres-sor gene. Pheochromocytomas also are included within the tumor spectrum of neurofibromatosis type 1 (NF1 gene) and other neuroectodermal disorders


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Surgery_Schwartz. been mapped to chromosome 3p and is a tumor suppres-sor gene. Pheochromocytomas also are included within the tumor spectrum of neurofibromatosis type 1 (NF1 gene) and other neuroectodermal disorders (Sturge-Weber syndrome and tuberous sclerosis), Carney’s syndrome (gastric epithelioid leio-myosarcoma, pulmonary chondroma, and extra-adrenal para-ganglioma), MEN1 syndrome, and the familial paraganglioma and pheochromocytoma syndrome are caused by mutations in the succinyl dehydrogenase family of genes (SDHB, SDHC, and SDHD), which comprise portions of the mitochondrial complex II.112 More recently, mutations in SDHA and SDH5 have also been identified. Additional susceptibility loci include TMEM127 (involved in the mTORC1-signaling pathway) and MAX (myc-associated factor X).Symptoms and Signs Headache, palpitations, and diaphoresis constitute the “classic triad” of pheochromocytomas. Symp-toms such as anxiety, tremulousness, paresthesias, flushing, chest pain, shortness of breath,


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Surgery_Schwartz. Signs Headache, palpitations, and diaphoresis constitute the “classic triad” of pheochromocytomas. Symp-toms such as anxiety, tremulousness, paresthesias, flushing, chest pain, shortness of breath, abdominal pain, nausea, vomit-ing, and others are nonspecific and may be episodic in nature. Cardiovascular complications such as myocardial infarction and cerebrovascular accidents may ensue. These symptoms can be incited by a range of stimuli including exercise, micturition, and defecation. The most common clinical sign is hyperten-sion. Pheochromocytomas are one of the few curable causes of hypertension and are found in 0.1% to 0.2% of hypertensive patients. Hypertension related to this tumor may be paroxys-mal with intervening normotension, sustained with paroxysms or sustained hypertension alone. Sudden death may occur in patients with undiagnosed tumors who undergo other surgeries or biopsy.Diagnostic Tests Biochemical Studies. Pheochromocytomas are diagnosed by testing 24-hour urine


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Surgery_Schwartz. alone. Sudden death may occur in patients with undiagnosed tumors who undergo other surgeries or biopsy.Diagnostic Tests Biochemical Studies. Pheochromocytomas are diagnosed by testing 24-hour urine samples for catecholamines and their metab-olites as well as by determining plasma metanephrine levels. Urinary metanephrines are 98% sensitive and also about 98% specific for pheochromocytomas, whereas VMA measure-ments are slightly less sensitive and specific. False-positive VMA tests may result from ingestion of caffeine, raw fruits, Brunicardi_Ch38_p1625-p1704.indd 169301/03/19 11:22 AM 1694SPECIFIC CONSIDERATIONSPART IIBAFigure 38-46. A left-sided pheochromocytoma (arrows) imaged by a computed tomography scan of the abdomen (A) and a metaiodoben-zylguanidine scan viewed posteriorly (B).or medications (α-methyldopa). Fractionated urinary catechol-amines (norepinephrine, epinephrine, and dopamine) also are very sensitive but less specific for pheochromocytomas. Because extraadrenal


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Surgery_Schwartz. medications (α-methyldopa). Fractionated urinary catechol-amines (norepinephrine, epinephrine, and dopamine) also are very sensitive but less specific for pheochromocytomas. Because extraadrenal sites lack phenylethanolamine N-methyltransferase, these tumors secrete norepinephrine, whereas epinephrine is the main hormone secreted from adrenal pheochromocytomas. Many physiologic and pathologic states can alter the levels of plasma catecholamines. Hence, they often are thought to be less accurate than urinary tests. Both epinephrine and norepi-nephrine should be measured, as tumors often secrete one or the other hormone. Sensitivities of 85% and specificities of 95% have been reported using cutoff values of 2000 pg/mL for norepinephrine and 200 pg/mL for epinephrine. Clonidine is an agent that suppresses neurogenically mediated catecholamine excess but not secretion from pheochromocytomas. A normal clonidine suppression test is defined by a decrease of basal cate-cholamine levels to


Surgery_Schwartz

Surgery_Schwartz. that suppresses neurogenically mediated catecholamine excess but not secretion from pheochromocytomas. A normal clonidine suppression test is defined by a decrease of basal cate-cholamine levels to <500 pg/mL within 2 to 3 hours after an oral dose of 0.3 mg of clonidine. Chromogranin A is a monomeric, acidic protein, which is stored in the adrenal medulla and other neuroendocrine tumors and released along with catecholamine hormones. It has been reported to have a sensitivity of 83% and a specificity of 96% and is useful in conjunction with catechol-amine measurement for diagnosing pheochromocytomas. Some studies have shown that plasma metanephrines should be the first-line test to identify pheochromocytomas, as the predictive value of a negative test is very high and normal levels exclude pheochromocytoma in patients with preclinical disease or dopa-mine secreting tumors. Although sensitivities of 96% to 100% have been reported, specificity is lower at 85% to 89% and may be much


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Surgery_Schwartz. pheochromocytoma in patients with preclinical disease or dopa-mine secreting tumors. Although sensitivities of 96% to 100% have been reported, specificity is lower at 85% to 89% and may be much lower at 77% in elderly patients. Although attractive because of the simplicity of a blood test, measurement of plasma metanephrines is generally reserved for cases for which there is a high index of suspicion.Radiologic Studies. Radiologic studies are useful to localize tumors and to assess the extent of spread once the diagnosis has been made with biochemical tests. CT scans are 85% to 95% sensitive and 70% to 100% specific for pheochromocytomas (Fig. 38-46A). The scans should be performed without con-trast to minimize the risk of precipitating a hypertensive crisis, although some recent studies suggest that intravenous contrast may be used. Images should include the region from the dia-phragm to the aortic bifurcation so as to include the organ of Zuckerkandl. CT scans do not provide


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Surgery_Schwartz. suggest that intravenous contrast may be used. Images should include the region from the dia-phragm to the aortic bifurcation so as to include the organ of Zuckerkandl. CT scans do not provide functional information and cannot definitively diagnose pheochromocytomas. MRI scans are 95% sensitive and almost 100% specific for pheo-chromocytomas because these tumors have a characteristic appearance on T2-weighted images or after gadolinium. MRI is also the study of choice in pregnant women as there is no risk of radiation exposure. Metaiodobenzylguanidine (MIBG) is taken up and concentrated by vesicles in the adrenal medullar cells because its structure is similar to norepinephrine. Normal adrenal medullary tissue does not take up appreciable MIBG. 131I-radiolabeled MIBG is, therefore, useful for localizing pheo-chromocytomas (Fig. 38-46B), especially those in ectopic posi-tions. This test has a reported sensitivity of 77% to 89% and a specificity ranging from 88% to 100%.Treatment The


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Surgery_Schwartz. for localizing pheo-chromocytomas (Fig. 38-46B), especially those in ectopic posi-tions. This test has a reported sensitivity of 77% to 89% and a specificity ranging from 88% to 100%.Treatment The medical management of pheochromocytomas is aimed chiefly at blood pressure control and volume repletion. Irreversible, long-acting α-blockers such as phenoxybenzamine are started 1 to 3 weeks before surgery at doses of 10 mg twice daily, which may be increased to 300 to 400 mg/d with rehydra-tion. Patients should be warned about orthostatic hypotension. β-Blockers such as propranolol at doses of 10 to 40 mg every 6 to 8 hours often need to be added preoperatively in patients who have persistent tachycardia and arrhythmias. β-Blockers should only be instituted after adequate α-blockade and hydration to avoid the effects of unopposed α stimulation (i.e., hypertensive crisis and congestive heart failure) and are typically initiated 3 to 4 days preoperatively. Patients also should be volume


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Surgery_Schwartz. to avoid the effects of unopposed α stimulation (i.e., hypertensive crisis and congestive heart failure) and are typically initiated 3 to 4 days preoperatively. Patients also should be volume repleted preoperatively to avoid postoperative hypotension, which ensues with the loss of vasoconstriction after tumor removal. Other α-blockers such as prazosin, terazosin, and doxazosin, which are selective α1-adrenergic blockers, have a better side effect profile and are preferable to phenoxybenzamine when long-term Brunicardi_Ch38_p1625-p1704.indd 169401/03/19 11:22 AM 1695THYROID, PARATHYROID, AND ADRENALCHAPTER 38pharmacologic therapy is needed, as in patients with metastatic pheochromocytoma. Nicardipine is the most commonly used calcium channel blocker and inhibits norepinephrine-mediated calcium transport into vascular smooth muscle. When used as the primary mode of treatment, it appears to be just as effec-tive as αand β-blockade preoperatively and for intraoperative


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Surgery_Schwartz. calcium transport into vascular smooth muscle. When used as the primary mode of treatment, it appears to be just as effec-tive as αand β-blockade preoperatively and for intraoperative hemodynamics.113 In some patients, catecholamine-synthesis inhibitors such as α-methyl-p-l-tyrosine (metyrosine) may need to be added if standard αand β-blockade is poorly tolerated or is ineffective in reaching target blood pressure and when moder-ate intraoperative tumor manipulation is anticipated.Adrenalectomy is the treatment of choice for patients with pheochromocytoma. The chief goal of surgery is to resect the tumor completely with minimal tumor manipulation or rupture of the tumor capsule. Surgery should be performed with both noninvasive and invasive monitors, including an arterial line and central venous lines. In patients with congestive heart failure or underlying coronary artery disease, Swan-Ganz catheters may be necessary. Stress must be avoided during anesthesia induc-tion, and use of


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Surgery_Schwartz. venous lines. In patients with congestive heart failure or underlying coronary artery disease, Swan-Ganz catheters may be necessary. Stress must be avoided during anesthesia induc-tion, and use of inhaled agents like isoflurane and enflurane are preferred because they have minimal cardiac depressant effects. Fentanyl, ketamine, and morphine should be avoided as they can potentially stimulate catecholamine release from the tumor. The common medications used for intraoperative blood pres-sure control include nitroprusside, nitroglycerin, phentolamine, and nicardipine. Intraoperative arrhythmias are best managed by short-acting β-blockers such as esmolol. Adrenalectomy usu-ally was performed via an open anterior approach to facilitate detection of bilateral tumors, extra-adrenal lesions, or metastatic lesions. However, most pheochromocytomas <5 cm in diameter can be safely resected laparoscopically. Postoperatively, these patients are prone to hypotension due to loss of adrenergic


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Surgery_Schwartz. or metastatic lesions. However, most pheochromocytomas <5 cm in diameter can be safely resected laparoscopically. Postoperatively, these patients are prone to hypotension due to loss of adrenergic stim-ulation and consequent vasodilatation and therefore need large volume resuscitation.Hereditary Pheochromocytomas. Inherited pheochromo-cytomas tend to be multiple and bilateral. Generally, unilat-eral adrenalectomy is recommended in the absence of obvious lesions in the contralateral adrenal gland because of Addison’s disease, requiring lifelong steroid replacement in patients under-going bilateral adrenalectomy. For patients with tumors in both adrenal glands, cortical-sparing subtotal adrenalectomy may preserve adrenocortical function and avoid the morbidity of bilateral total adrenalectomy. Laparoscopic subtotal adrenal-ectomy has been shown to provide short-term clinical results comparable to total adrenalectomy, with reduced surgical morbidity and may be done as a unilateral or


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Surgery_Schwartz. Laparoscopic subtotal adrenal-ectomy has been shown to provide short-term clinical results comparable to total adrenalectomy, with reduced surgical morbidity and may be done as a unilateral or bilateral subtotal procedure.114 However, these patients remain at risk for recur-rent pheochromocytoma, which has been reported in 20% of patients with VHL disease a median of 40 months after partial adrenalectomy, and in 33% of MEN2 patients followed for 54 to 88 months after surgery. Autotransplantation of adrenocortical tissue after total adrenalectomy may be another option for these patients. However, the transplanted cortical tissue rarely pro-vides full function, and steroid replacement usually is required.Malignant Pheochromocytomas. Approximately 12% to 29% of pheochromocytomas are malignant, and these tumors are associated with decreased survival. There are no definitive histologic criteria defining malignant pheochromocytomas. In fact, pleomorphism, nuclear atypia, and abundant


Surgery_Schwartz

Surgery_Schwartz. and these tumors are associated with decreased survival. There are no definitive histologic criteria defining malignant pheochromocytomas. In fact, pleomorphism, nuclear atypia, and abundant mitotic fig-ures are seen in benign tumors. Capsular and vascular invasion may be seen in benign lesions as well. Malignancy usually is diagnosed when there is evidence of invasion into surrounding structures or distant metastases. The most common sites for met-astatic disease are bone, liver, regional lymph nodes, lung, and peritoneum, although the brain, pleura, skin, and muscles may also occasionally be involved. Some studies also suggest that older patient age and larger tumors are associated with a higher risk of malignancy. Although risk of malignancy increases with size for all pheochromocytomas, size does not seem to reliably predict malignancy in pheochromocytomas with local disease only.115 Given this difficulty of defining malignancy clinically (in the absence of metastatic disease), a


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Surgery_Schwartz. size does not seem to reliably predict malignancy in pheochromocytomas with local disease only.115 Given this difficulty of defining malignancy clinically (in the absence of metastatic disease), a number of other features such as DNA ploidy, tumor size, and necrosis, neuropeptide Y mRNA expression, and serum neuron-specific enolase expres-sion have been studied. Malignant pheochromocytomas are more likely to express p53 and bcl-2 and have activated telom-erase. Recent data suggest that flow cytometry and molecular markers such as expression of Ki-67, tissue inhibitor of metal-loproteinase, and COX-2 also have shown some use in deter-mining malignancy. When pheochromocytomas develop in the MEN syndromes, they rarely are malignant. In contrast, patients with germline SDHB mutations appear to have a higher propen-sity for extra-adrenal and malignant tumors. In general, soft tis-sue lesions are treated with resection if feasible. External-beam radiation can be used for unresectable


Surgery_Schwartz

Surgery_Schwartz. to have a higher propen-sity for extra-adrenal and malignant tumors. In general, soft tis-sue lesions are treated with resection if feasible. External-beam radiation can be used for unresectable lesions or symptomatic skeletal metastases. Therapeutic 131I-MIBG irradiation may be useful in patients with diffuse disease showing 123-I-MIBG uptake on a diagnostic scan. Chemotherapy regimens typically use cyclophosphamide, vincristine, and dacarbazine with vari-able response rates. However, molecular targeted therapies such as sunitinib have shown some promising results.The Adrenal IncidentalomaAdrenal lesions discovered during imaging performed for unre-lated reasons are referred to as incidentalomas. This definition excludes tumors discovered on imaging studies performed for evaluating symptoms of hormone hypersecretion or staging patients with known cancer. The incidence of these lesions iden-tified by CT scans ranges from 0.4% to 4.4%.Differential Diagnosis. The differential diagnosis


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Surgery_Schwartz. of hormone hypersecretion or staging patients with known cancer. The incidence of these lesions iden-tified by CT scans ranges from 0.4% to 4.4%.Differential Diagnosis. The differential diagnosis of adre-nal incidentalomas is shown in Table 38-20. Nonfunctional cortical adenomas account for the majority (36–94%) of adre-nal incidentalomas in patients without a history of cancer. In a series of patients from the Mayo Clinic, no nonfunctional Table 38-20Differential diagnosis of adrenal incidentalomaFUNCTIONING LESIONSNONFUNCTIONING LESIONSBenignBenign Aldosteronoma Cortisol-producing adenoma Sex steroid–producing adenoma Pheochromocytoma Cortical adenoma Myelolipoma Cyst Ganglioneuroma HemorrhageMalignant Adrenocortical cancer Metastasis Malignant pheochromocytoma Adrenocortical cancerBrunicardi_Ch38_p1625-p1704.indd 169501/03/19 11:22 AM 1696SPECIFIC CONSIDERATIONSPART IIlesion progressed to cause clinical or biochemical abnormali-ties. However, other studies indicate that 5%


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Surgery_Schwartz. 169501/03/19 11:22 AM 1696SPECIFIC CONSIDERATIONSPART IIlesion progressed to cause clinical or biochemical abnormali-ties. However, other studies indicate that 5% to 20% of patients with apparently nonfunctioning cortical adenomas have under-lying, subtle abnormalities of glucocorticoid secretion, and a rare benign-appearing incidentaloma is a cancer.By definition, patients with incidentalomas do not have clinically overt Cushing’s syndrome, but subclinical Cushing’s syndrome is estimated to occur in approximately 8% of patients. This disorder is characterized by subtle fea-tures of cortisol excess, such as weight gain, skin atrophy, facial fullness, diabetes, and hypertension, accompanied by loss of normal diurnal variation in cortisol secretion, autonomous cor-tisol secretion, and resistance to suppression by dexamethasone. Total cortisol produced and 24-hour urinary cortisol levels may be normal. Examination of the natural history of subclinical Cushing’s syndrome indicates


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Surgery_Schwartz. resistance to suppression by dexamethasone. Total cortisol produced and 24-hour urinary cortisol levels may be normal. Examination of the natural history of subclinical Cushing’s syndrome indicates that, although most patients remain asymptomatic, some do progress to clinically evident Cushing’s syndrome. Furthermore, cases of postoperative adre-nal crisis from unrecognized suppression of the contralateral adrenal have been reported, making preoperative identification of this condition imperative, particularly in the era of early dis-charge following laparoscopic adrenalectomy.The adrenal is a common site of metastases of lung and breast tumors, melanoma, renal cell cancer, and lymphoma. In patients with a history of nonadrenal cancer and a unilat-eral adrenal mass, the incidence of metastatic disease has been reported to range from 32% to 73%. Myelolipomas are benign, biochemically nonfunctioning lesions composed of ele-ments of hematopoietic and mature adipose tissue, which are rare


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Surgery_Schwartz. disease has been reported to range from 32% to 73%. Myelolipomas are benign, biochemically nonfunctioning lesions composed of ele-ments of hematopoietic and mature adipose tissue, which are rare causes of adrenal incidentaloma. Other less commonly encountered lesions include adrenal cysts, ganglioneuromas, and hemorrhage.Diagnostic Investigations. The diagnostic workup of an adrenal incidentaloma is aimed at identifying patients who would benefit from adrenalectomy (i.e., patients with function-ing tumors and tumors at increased risk of being malignant). It is not necessary for asymptomatic patients whose imaging studies are consistent with obvious cysts, hemorrhage, myelolipomas, or diffuse metastatic disease to undergo additional investigations. All other patients should be tested for underlying hormonally active tumors using (a) a low-dose (1 mg) overnight dexametha-sone suppression test to rule out subclinical Cushing’s syndrome and 17-ketosteroids (if sex steroid excess is


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Surgery_Schwartz. for underlying hormonally active tumors using (a) a low-dose (1 mg) overnight dexametha-sone suppression test to rule out subclinical Cushing’s syndrome and 17-ketosteroids (if sex steroid excess is suspected); (b) a 24-hour urine collection for catecholamines, metanephrines, VMA, or plasma metanephrine to rule out pheochromocytoma; and (c) in hypertensive patients, serum electrolytes, plasma aldosterone, and plasma renin to rule out an aldosteronoma. In patients with a high index of suspicion for subclinical Cushing’s (those with hypertension, obesity, or diabetes), three tests (i.e., dexamethasone suppression test, salivary cortisol, and 24-hour urine free cortisol) may be used. Confirmatory tests can be per-formed based on the results of the initial screening studies.Determination of the malignant potential of an inciden-taloma is more difficult. The risk of malignancy in an adrenal lesion is related to its size. Lesions >6 cm in diameter have an approximate risk of malignancy of


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Surgery_Schwartz. the malignant potential of an inciden-taloma is more difficult. The risk of malignancy in an adrenal lesion is related to its size. Lesions >6 cm in diameter have an approximate risk of malignancy of about 25%.82 However, this size cutoff is not absolute because adrenal carcinomas also have been reported in lesions <6 cm. Carcinomas account for 2% of lesions <4 cm and 6% of lesions 4.1 to 6 cm in size. This has led to increased use of the imaging characteristics of incidentalomas to predict malignancy. Benign adrenal adenomas tend to be homogeneous, well encapsulated, and have smooth and regular margins. They also tend to be hypoattenuating lesions (<10 Hounsfield units) on CT scanning. In contrast, adrenal cancers tend to be hyperattenuating (>18 Hounsfield units) and inhomo-geneous, have irregular borders, and may show evidence of local invasion or adjacent lymphadenopathy. On MRI T2-weighted imaging, adenomas demonstrate low signal inten-sity when compared to the liver (adrenal


Surgery_Schwartz

Surgery_Schwartz. have irregular borders, and may show evidence of local invasion or adjacent lymphadenopathy. On MRI T2-weighted imaging, adenomas demonstrate low signal inten-sity when compared to the liver (adrenal mass-to-liver ratio <1.4), whereas carcinomas and metastases have moderate inten-sity (mass-to-liver ratio 1.2:2.8). Pheochromocytomas are extremely bright, with mass-to-liver ratios >3. Unfortunately, the ranges overlap, and signal intensity is not 100% reliable for determining the nature of the lesion. Radionuclide imaging with NP-59 also has been used to distinguish between various adre-nal lesions, with some investigators suggesting that uptake of NP-59 was 100% predictive of a benign lesion (adenoma), whereas absence of imaging was 100% predictive of a nonade-nomatous lesion. However, the technique has not gained wide-spread acceptance because patients need to be given cold iodine 1 week before the study to prevent thyroid uptake, imaging needs to be delayed by 5 to 7 days after


Surgery_Schwartz

Surgery_Schwartz. the technique has not gained wide-spread acceptance because patients need to be given cold iodine 1 week before the study to prevent thyroid uptake, imaging needs to be delayed by 5 to 7 days after administration of the contrast, and false-positive and false-negative results occur. FDG-PET or PET-CT scans may have some utility in distin-guishing potentially malignant from benign lesions in cases of inconclusive CT densitometry. However, caution must be exer-cised for false-positive (some adenomas and pheochromocyto-mas) and false-negative results (small lesions or those with hemorrhage or necrosis).116 FNAB cannot be used to distinguish adrenal adenomas from carcinomas. This being said, FNAB is useful in the setting of a patient with a history of cancer and a solitary adrenal mass. The positive predictive value of FNAB in this situation has been shown to be almost 100%, although false-negative rates of up to 33% have been reported. Biopsies usually are performed under CT guidance, and


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Surgery_Schwartz. predictive value of FNAB in this situation has been shown to be almost 100%, although false-negative rates of up to 33% have been reported. Biopsies usually are performed under CT guidance, and appropriate testing to rule out pheochromocytomas should be undertaken before the procedure to avoid precipitating a hypertensive crisis.Management. An algorithm for the management of patients with incidentalomas is shown in Fig. 38-47. The AACE and American Association of Endocrine Surgeons (AAES) have published management guidelines for patients with adrenal incidentalomas.117 Patients with functional tumors or obviously malignant lesions should undergo adrenalectomy. The optimal management of patients with subclinical Cushing’s syndrome is controversial, especially due to the paucity of data from high-quality prospective trials. In general, operative intervention is advised in patients with subclinical Cushing’s syndrome with suppressed plasma ACTH levels and elevated urinary cortisol levels


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Surgery_Schwartz. high-quality prospective trials. In general, operative intervention is advised in patients with subclinical Cushing’s syndrome with suppressed plasma ACTH levels and elevated urinary cortisol levels because these patients are at high risk for progression to overt Cushing’s syndrome. The adrenal incidentaloma guide-lines also recommend adrenalectomy in patients with worsening hypertension, abnormal glucose tolerance, or osteoporosis.For nonfunctional lesions, the risk of malignancy needs to be balanced with operative morbidity and mortality. The AACE/AAES guidelines recommend that lesions with suspicious fea-tures on imaging studies such as heterogeneity, irregular cap-sule, or adjacent nodes should be treated by adrenalectomy. Nonoperative therapy, with close periodic follow-up, is advised for lesions <4 cm in diameter with benign imaging characteris-tics, whereas adrenalectomy is recommended for lesions ≥4 cm in size due to the increased risk of


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Surgery_Schwartz. close periodic follow-up, is advised for lesions <4 cm in diameter with benign imaging characteris-tics, whereas adrenalectomy is recommended for lesions ≥4 cm in size due to the increased risk of cancer.1011Brunicardi_Ch38_p1625-p1704.indd 169601/03/19 11:22 AM 1697THYROID, PARATHYROID, AND ADRENALCHAPTER 38Questions1) Low dose DST2) Plasma metanephrines or 24 h urine catecholamines, VMA, metanephrines3) Plasma aldosterone, renin activity, electrolytesAdrenalectomyYesNoPast historyof cancer?YesSolitarymetastasisyesNoConsideradrenalectomySystemic therapySee question 3<4 cm,Benign imaging featuresNoRepeat imaging in 3–6 months, biochemicalevaluation annually˜4 cm, Indeterminate orsuspicious imagingfeaturesAdrenalectomy1Is the tumorfunctioning?2Is the tumormetastatic?3Is it at highrisk of beingmalignant?Figure 38-47. Management algorithm for an adrenal incidentaloma. CT = computed tomography; DST = dexamethasone suppression test; VMA = vanillylmandelic acid.However, several


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Surgery_Schwartz. of beingmalignant?Figure 38-47. Management algorithm for an adrenal incidentaloma. CT = computed tomography; DST = dexamethasone suppression test; VMA = vanillylmandelic acid.However, several important points must be considered in the management of these patients. First, size criteria for malig-nancy are not definitive and are derived from a selected series of patients. Second, the actual size of adrenal tumors can be underestimated by at least 1 cm by modalities such as CT and MRI scans because tumors are larger in a cephalocaudal axis. Third, the natural history of incidentalomas is variable and depends on the underlying diagnosis, age of the study popula-tion, and the size of the mass. Older patients are more likely to have nonfunctioning adenomas. Existing data in terms of the long-term behavior of these nonfunctional lesions, although limited, indicate that malignant transformation is uncommon. Furthermore, tumors that increase in size by at least 1 cm over a 2-year follow-up


Surgery_Schwartz

Surgery_Schwartz. behavior of these nonfunctional lesions, although limited, indicate that malignant transformation is uncommon. Furthermore, tumors that increase in size by at least 1 cm over a 2-year follow-up period and those with subtle hormonal abnor-malities appear to be more likely to enlarge. Overt hormone overproduction is more likely in tumors >3 cm and those with increased NP-59 uptake. Surgeons are more likely to operate on a 40-year-old patient with a 4-cm lesion, while electing to follow an 80-year-old patient with a similar lesion but multiple concurrent comorbidities. Based on the above considerations, some surgeons use a size threshold for adrenalectomy with a nonfunctioning homogeneous tumor of 3 to 4 cm in young patients with no comorbidities and 5 cm in older patients with significant comorbidity.Lesions that grow during follow-up also are treated by adrenalectomy. Myelolipomas generally do not warrant adrenal-ectomy unless there is concern regarding malignancy, which is rare, or


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Surgery_Schwartz. comorbidity.Lesions that grow during follow-up also are treated by adrenalectomy. Myelolipomas generally do not warrant adrenal-ectomy unless there is concern regarding malignancy, which is rare, or bleeding into the lesion, which is more likely in myelo-lipomas >4 cm in size. These tumors, even when large, can be removed laparoscopically. Resection of solitary adrenal metas-tases in patients with a history of nonadrenal cancer has been demonstrated to lead to prolonged patient survival. Suspected adrenal metastases also may be resected for diagnosis.There is no consensus regarding the follow-up of patients with adrenal incidentaloma. The AACE/AAES guidelines recommend repeating hormonal screening with a 1-mg dexa-methasone suppression test and urinary catecholamines and metabolites yearly for 5 years as the risk of hypersecretion appears to plateau after this time period. It also recommends repeat imaging at 3 to 6 months and then annually for 1 to 2 years. Less frequent imaging is


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Surgery_Schwartz. for 5 years as the risk of hypersecretion appears to plateau after this time period. It also recommends repeat imaging at 3 to 6 months and then annually for 1 to 2 years. Less frequent imaging is reasonable or small (<2 cm), uniform, hypodense cortical nodules in patients without a his-tory of malignant disease. Adrenalectomy is recommended for lesions that grow ≥1 cm or if autonomous hormone secretion develops during follow-up.Adrenal InsufficiencyAdrenal insufficiency may be primary, resulting from adrenal dis-ease, or secondary, due to a deficiency of ACTH (Table 38-21). The most commonly encountered causes of primary adrenal insufficiency are autoimmune disease, infections, and meta-static deposits. Spontaneous adrenal hemorrhage can occur in patients with fulminant meningococcal septicemia (Water-house-Friderichsen syndrome). Bilateral adrenal hemorrhage also can occur secondary to trauma, severe stress, infection, and coagulopathies and, if unrecognized, is lethal. Exogenous


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Surgery_Schwartz. (Water-house-Friderichsen syndrome). Bilateral adrenal hemorrhage also can occur secondary to trauma, severe stress, infection, and coagulopathies and, if unrecognized, is lethal. Exogenous glucocorticoid therapy with suppression of the adrenal glands is the most common cause of secondary adrenal insufficiency.Symptoms and Signs. Acute adrenal insufficiency should be suspected in stressed patients with any of the relevant risk factors. It may mimic sepsis, myocardial infarction, or pulmo-nary embolus and presents with fever, weakness, confusion, nausea, vomiting, lethargy, abdominal pain, or severe hypoten-sion. Chronic adrenal insufficiency, such as that occurring in patients with metastatic tumors, may be more subtle. Symptoms include fatigue, salt craving, weight loss, nausea, vomiting, and Brunicardi_Ch38_p1625-p1704.indd 169701/03/19 11:22 AM 1698SPECIFIC CONSIDERATIONSPART IIabdominal pain. These patients may appear hyperpigmented from increased secretion of CRH and ACTH,


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Surgery_Schwartz. and Brunicardi_Ch38_p1625-p1704.indd 169701/03/19 11:22 AM 1698SPECIFIC CONSIDERATIONSPART IIabdominal pain. These patients may appear hyperpigmented from increased secretion of CRH and ACTH, with increased α-melanocyte-stimulating hormone side-products.Diagnostic Studies. Characteristic laboratory findings include hyponatremia, hyperkalemia, eosinophilia, mild azote-mia, and fasting or reactive hypoglycemia. The peripheral blood smear may demonstrate eosinophilia in approximately 20% of patients. Adrenal insufficiency is diagnosed by the ACTH stimulation test. ACTH (250 μg) is infused intravenously, and cortisol levels are measured at 0, 30, and 60 minutes. Peak cor-tisol levels <20 μg/dL suggest adrenal insufficiency. ACTH levels also allow primary insufficiency to be distinguished from secondary causes. High ACTH levels with low plasma cortisol levels are diagnostic of primary adrenal insufficiency.Treatment. Treatment must be initiated based on clinical sus-picion alone, even


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Surgery_Schwartz. from secondary causes. High ACTH levels with low plasma cortisol levels are diagnostic of primary adrenal insufficiency.Treatment. Treatment must be initiated based on clinical sus-picion alone, even before test results are obtained, or the patient is unlikely to survive. Management includes volume resuscita-tion with at least 2 to 3 L of a 0.9% saline solution or 5% dex-trose in saline solution. Blood should be obtained for electrolyte (decreased Na+ and increased K+), glucose (low), and cortisol (low) levels; ACTH (increased in primary and decreased in sec-ondary); and quantitative eosinophilic count. Dexamethasone (4 mg) should be administered intravenously. Hydrocortisone (100 mg intravenously every 8 hours) also may be used, but it interferes with testing of cortisol levels. Once the patient has been stabilized, underlying conditions such as infection should be sought, identified, and treated. The ACTH stimulation test should be performed to confirm the diagnosis. Glucocorticoids


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Surgery_Schwartz. patient has been stabilized, underlying conditions such as infection should be sought, identified, and treated. The ACTH stimulation test should be performed to confirm the diagnosis. Glucocorticoids can then be tapered to maintenance doses (oral hydrocortisone 15–20 mg in the morning and 10 mg in the evening). Mineralo-corticoids (fludrocortisone 0.05–0.1 mg daily) may be required once the saline infusions are discontinued.Adrenal SurgeryChoice of Procedure. Adrenalectomy may be performed via a laparoscopic or open approach. In either approach, the gland may be approached anteriorly, laterally, or posteriorly via the retroperitoneum. The choice of approach depends on the size and nature of the lesion and expertise of the surgeon. Laparo-scopic adrenalectomy has rapidly become the standard proce-dure of choice for the excision of most benign-appearing adrenal lesions <6 cm in diameter. The role of laparoscopic adrenalec-tomy in the management of adrenocortical cancers is


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Surgery_Schwartz. the standard proce-dure of choice for the excision of most benign-appearing adrenal lesions <6 cm in diameter. The role of laparoscopic adrenalec-tomy in the management of adrenocortical cancers is controver-sial. The data with respect to local tumor recurrence and intra-abdominal carcinomatosis from laparoscopic adrenalec-tomy for malignant adrenal tumors that were not appreciated as such, preoperatively or intraoperatively, are conflicting. Although laparoscopic adrenalectomy appears to be feasible and safe for solitary adrenal metastasis118 (provided there is no local invasion and the tumor can be resected intact), open adrenalec-tomy or laparoscopic-assisted open adrenalectomy is the safest option for suspected or known adrenocortical cancers and malig-nant pheochromocytomas. Technical considerations and surgeon experience, rather than absolute tumor size, usually determine the size threshold for laparoscopic resection. Hand-assisted lapa-roscopic adrenalectomy may provide a


Surgery_Schwartz

Surgery_Schwartz. considerations and surgeon experience, rather than absolute tumor size, usually determine the size threshold for laparoscopic resection. Hand-assisted lapa-roscopic adrenalectomy may provide a bridge between laparo-scopic adrenalectomy and conversion to an open procedure. There have been no randomized trials directly comparing open vs. laparoscopic adrenalectomy. However, studies have shown that laparoscopic adrenalectomy is associated with decreased blood loss, postoperative pain, and narcotic use; reduced length of hospital stay; and faster return to work.Laparoscopic Adrenalectomy. The procedure is performed under general anesthesia. Arterial lines are used routinely, and central lines are necessary for patients in whom massive fluid shifts are anticipated (e.g., those with large, active pheochro-mocytomas). A nasogastric tube and Foley catheter are rec-ommended. Routine preoperative antibiotics are not needed, except in patients with Cushing’s syndrome. The adrenals can be removed


Surgery_Schwartz

Surgery_Schwartz. pheochro-mocytomas). A nasogastric tube and Foley catheter are rec-ommended. Routine preoperative antibiotics are not needed, except in patients with Cushing’s syndrome. The adrenals can be removed laparoscopically via a transabdominal (anterior or lateral) or retroperitoneal (lateral or posterior) approach. The lateral approach is preferred by most laparoscopic surgeons and uses gravity to aid retraction of surrounding organs. Patients, however, need to be repositioned for a bilateral procedure. The anterior transabdominal approach offers the advantage of a con-ventional view of the abdominal cavity and allows a bilateral adrenalectomy to be performed without the necessity of repo-sitioning the patient. The posterior retroperitoneal approach has also been gaining popularity in recent years, particularly in patients with previous anterior abdominal surgery and peri-toneal adhesions. In addition, several centers have successfully utilized robotic approaches for both lateral


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Surgery_Schwartz. recent years, particularly in patients with previous anterior abdominal surgery and peri-toneal adhesions. In addition, several centers have successfully utilized robotic approaches for both lateral transabdominal and retroperitoneal laparoscopic adrenal surgery. Single incision laparoscopic adrenalectomy is another option. While these latter approaches are feasible,119 their widespread use awaits analysis of long-term outcomes data and cost analyses. The lateral trans-abdominal approach is widely used and described in detail in the following section.12Table 38-21Etiology of adrenal insufficiencyPRIMARYSECONDARYAutoimmune (autoimmune polyglandular disease types I and II)Exogenous glucocorticoid therapyInfectious—TB, fungi, CMV, HIVBilateral adrenalectomyHemorrhage—spontaneous (Waterhouse-Friderichsen syndrome) and secondary to stress, trauma, infections, coagulopathy, or anticoagulantsPituitary or hypothalamic tumorsMetastasesPituitary hemorrhage (postpartum Sheehan’s


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Surgery_Schwartz. (Waterhouse-Friderichsen syndrome) and secondary to stress, trauma, infections, coagulopathy, or anticoagulantsPituitary or hypothalamic tumorsMetastasesPituitary hemorrhage (postpartum Sheehan’s syndrome)Infiltrative disorders—amyloidosis, hemochromatosisTrans-sphenoidal resection of pituitary tumorAdrenoleukodystrophy Congenital adrenal hyperplasia Drugs—ketoconazole, metyrapone, aminoglutethimide, mitotane CMV = cytomegalovirus; HIV = human immunodeficiency virus; TB = tuberculosis.Brunicardi_Ch38_p1625-p1704.indd 169801/03/19 11:22 AM 1699THYROID, PARATHYROID, AND ADRENALCHAPTER 38Umbilicus1234Figure 38-48. Positioning of the patient and placement of trocars for a laparoscopic adrenalectomy. Four trocars are placed from the mid-clavicular to the anterior axillary line.Triangular ligamentInferiorvena cavaPancreasSpleenABLiverRight adrenalLeft adrenalFigure 38-49. Technique of laparoscopic adrenalectomy. Expo-sure of the right adrenal is facilitated by division of the


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Surgery_Schwartz. ligamentInferiorvena cavaPancreasSpleenABLiverRight adrenalLeft adrenalFigure 38-49. Technique of laparoscopic adrenalectomy. Expo-sure of the right adrenal is facilitated by division of the triangular ligament (A) and dissection and reflection of the spleen and tail of the pancreas aids in identifying the left adrenal (B).Lateral Transabdominal Approach The patient is placed in the lateral decubitus position, and the operating table is flexed at the waist to open the space between the lower rib cage and the iliac crest (Fig. 38-48). The surgeon and assistant both stand on the same side, facing the front of the patient. Pneumoperi-toneum is created using a Veress needle or insufflation via a Hasson port. In general, four 10-mm trocars are placed between the midclavicular line medially and anterior axillary line later-ally, one to two fingerbreadths below the costal margin (see Fig. 38-48), although additional ports may be placed, if needed. A 30° laparoscope is inserted through the


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Surgery_Schwartz. anterior axillary line later-ally, one to two fingerbreadths below the costal margin (see Fig. 38-48), although additional ports may be placed, if needed. A 30° laparoscope is inserted through the second or midcla-vicular port. Most of the dissection is carried out via the two most lateral ports. However, the instruments and ports may be changed to provide optimum exposure, as needed.For a right adrenalectomy, a fan retractor is inserted through the most medial port to retract the liver. An atrau-matic grasper and an L-hook cautery are inserted via the two lateral ports for the dissection. The right triangular ligament is divided, and the liver is rotated medially (Fig. 38-49A). Rarely, the hepatic flexure of the colon may need mobilization during a right adrenalectomy. The right kidney is identified visually and by palpation with an atraumatic grasper. The adrenal gland is identified on the superomedial aspect of the kidney. Gerota’s fascia is incised with the hook cautery.


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Surgery_Schwartz. kidney is identified visually and by palpation with an atraumatic grasper. The adrenal gland is identified on the superomedial aspect of the kidney. Gerota’s fascia is incised with the hook cautery. Dissection of the adrenal is started superomedially and then proceeds inferiorly, dissect-ing around the adrenal in a clockwise manner. The periadrenal tissues are grasped or moved with a blunt grasper to facilitate circumferential dissection. The right adrenal vein is identified at its junction with the IVC, ligated with clips, and divided using endoscopic scissors. Alternatively, a vascular stapler may be used to divide the vein endoscopically. There may be a second adrenal vein on the right. Generally, two clips are left on the vena cava side. Although early identification of the adrenal vein is helpful to facilitate mobilization and prevent injury, it can be dissected whenever it is safe to do so. Early ligation of the adrenal vein makes it easier to mobilize the gland but may make


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Surgery_Schwartz. vein is helpful to facilitate mobilization and prevent injury, it can be dissected whenever it is safe to do so. Early ligation of the adrenal vein makes it easier to mobilize the gland but may make subsequent dissection more difficult due to venous congestion. The arterial branches to the adrenal gland can be electrocoagu-lated if small or clipped and divided.For a left adrenalectomy, the fan retractor is used to retract the spleen. The splenic flexure is mobilized early, and the lat-eral attachments to the spleen and the tail of the pancreas are divided using the electrocautery (Fig. 38-49B). Gravity allows the spleen and the pancreatic tail to fall medially. The remain-der of the dissection proceeds similarly to that described for the right adrenal. In addition to the adrenal vein, the inferior phrenic vein, which joins the left adrenal vein medially, also needs to be Brunicardi_Ch38_p1625-p1704.indd 169901/03/19 11:22 AM 1700SPECIFIC CONSIDERATIONSPART IIABAnterior


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Surgery_Schwartz. vein, the inferior phrenic vein, which joins the left adrenal vein medially, also needs to be Brunicardi_Ch38_p1625-p1704.indd 169901/03/19 11:22 AM 1700SPECIFIC CONSIDERATIONSPART IIABAnterior approachCThoracoabdominal approachPosterior approachFigure 38-50. Incisions for open adrenalectomy. Anterior approach (A), posterior approach (B), and thoracoabdominal approach (C).Anterior Approach The adrenals may be removed via a mid-line incision or bilateral subcostal incision (Fig. 38-50). The for-mer allows adequate infraumbilical exposure for examination of extra-adrenal tumors, whereas the latter provides better superior and lateral exposure. For the right side, the hepatic flexure of the colon is mobilized inferiorly, and the triangular ligament is incised to retract the liver medially and superiorly. A generous Kocher maneuver is used to mobilize the duodenum anteriorly and expose the retroperitoneal fat and the IVC (Fig. 38-51A). Gerota’s fascia is incised, and the gland is


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Surgery_Schwartz. and superiorly. A generous Kocher maneuver is used to mobilize the duodenum anteriorly and expose the retroperitoneal fat and the IVC (Fig. 38-51A). Gerota’s fascia is incised, and the gland is freed of surround-ing fibro-fatty tissue and the kidney inferiorly. The lateral and superior surfaces usually are mobilized first. Then, the short, right adrenal vein is dissected, ligated, and divided, taking care not to injure the hepatic veins and IVC. On the left side, the adrenal is located cephalad to the pancreatic tail and just lateral to the aorta. For large tumors, the adrenal is best approached by medial visceral rotation to mobilize the spleen, colon, and pan-creas toward the midline (Fig. 38-51B). An alternative approach is to enter the lesser sac by division of the gastrocolic ligament. The pancreas is mobilized superiorly by incision of its inferior dissected, doubly clipped, and divided. As with the right adrenal vein, the left-sided veins also can be divided with a vascular


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Surgery_Schwartz. The pancreas is mobilized superiorly by incision of its inferior dissected, doubly clipped, and divided. As with the right adrenal vein, the left-sided veins also can be divided with a vascular stapler. Once the dissection is complete, the area of the adrenal bed can be irrigated and suctioned. A drain is rarely necessary. The gland is placed in a nylon specimen bag, which is brought out via one of the ports after morcellation, if necessary.Posterior Retroperitoneal Approach The retroperitoneal approach provides a more direct access to the adrenal gland and avoids abdominal adhesions in patients who have had previous abdominal surgery. Furthermore, bilateral adrenalectomy can be performed without repositioning the patient. Intraoperative ultrasound is helpful for identifying the adrenal, but the dis-section and exposure are more difficult because the working space is limited. This makes vascular control difficult and also renders it unsuitable for large (>5 cm) lesions. This


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Surgery_Schwartz. adrenal, but the dis-section and exposure are more difficult because the working space is limited. This makes vascular control difficult and also renders it unsuitable for large (>5 cm) lesions. This tech-nique is being increasingly used for small adenomas causing hyperaldosteronism.The patient is placed in the prone-jackknife position, and the operating table is flexed at the waist to open the space between the posterior costal margin and the pelvis. Palpation is used to identify the position of the twelfth rib. Percutane-ous ultrasound is performed to determine the outline of the underlying kidney and adrenal. When done laparoscopically, the surgeon stands on the side of the adrenal to be removed, and the assistant stands on the opposite side. A 1.5-cm incision is placed 2 cm inferior and parallel to the twelfth rib, laterally at the level of the inferior pole of the kidney. Gerota’s space is entered under direct vision using a 12-mm direct viewing trocar with a 0° laparoscope


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Surgery_Schwartz. and parallel to the twelfth rib, laterally at the level of the inferior pole of the kidney. Gerota’s space is entered under direct vision using a 12-mm direct viewing trocar with a 0° laparoscope through the muscle layers of the posterior abdominal wall. Alternatively, blunt dissection with the surgeon’s finger also can identify the space behind Gerota’s fascia. The trocar is then replaced by a dissecting balloon, which is manually inflated using a hand pump under direct vision through the laparoscope. A 12-mm trocar is then reinserted into this space, and CO2 is insufflated to 12 to 15 mmHg pressure. The 0° laparoscope is replaced by a 45° laparoscope. Two addi-tional 5or 10-mm trocars are placed, one each on either side of the first port. Laparoscopic ultrasound then is used to help locate the adrenal gland and vessels. The adrenal dissection is begun at the superior pole and then proceeds to the lateral and inferior aspect. The medial dissection usually is performed last, and the


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Surgery_Schwartz. the adrenal gland and vessels. The adrenal dissection is begun at the superior pole and then proceeds to the lateral and inferior aspect. The medial dissection usually is performed last, and the vessels are identified and divided as described in the earlier “Lateral Transabdominal Approach” section.Open Adrenalectomy. Open adrenalectomy may be per-formed via four approaches, each with specific advantages and disadvantages. The anterior approach allows examination of the abdominal cavity and resection of bilateral tumors via a single incision. The posterior approach avoids the morbidity of a lapa-rotomy incision, especially in patients with cardiopulmonary disease and those prone to wound complications (Cushing’s syndrome) and avoids abdominal adhesions in patients who have undergone previous abdominal surgery. Recovery time is also quicker and hospitalization shorter. However, the retroperi-toneal exposure is difficult, particularly in obese patients, and the small working space makes


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Surgery_Schwartz. abdominal surgery. Recovery time is also quicker and hospitalization shorter. However, the retroperi-toneal exposure is difficult, particularly in obese patients, and the small working space makes it unsuitable for tumors >6 cm in diameter. The lateral approach is best for obese patients and for large tumors because it provides a bigger working space. The thoracoabdominal approach is most useful for en bloc resection of large (>10 cm), malignant lesions. However, it is associated with significant morbidity and should be used selectively.Brunicardi_Ch38_p1625-p1704.indd 170001/03/19 11:22 AM 1701THYROID, PARATHYROID, AND ADRENALCHAPTER 38ABRightadrenalSpleenPancreasPancreasColonLeftadrenal v.LeftkidneyFigure 38-51. Technique of open adrenalectomy. Exposure of the right adrenal is facilitated by a Kocher maneuver to mobilize the duodenum and upward retraction of the liver (A). The left adrenal can be exposed by medial visceral rotation of the spleen and pan-creas (B). v. =


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Surgery_Schwartz. is facilitated by a Kocher maneuver to mobilize the duodenum and upward retraction of the liver (A). The left adrenal can be exposed by medial visceral rotation of the spleen and pan-creas (B). v. = vein.peritoneal attachments, thus exposing the left kidney and adre-nal. The gland is then mobilized as on the right side.Posterior Approach The patient is placed prone on the operat-ing table, similar to the laparoscopic approach. A hockey stick or curvilinear incision may be used, and extended through the latissimus dorsi and sacrospinous fascia. The twelfth rib gener-ally is excised at its base, and the eleventh rib is retracted supe-riorly to reveal the pleura and the lateral arcuate ligament of the liver on the right side. The pleura also is mobilized cephalad, and the adrenal and kidney are identified. The superior aspect of the gland is dissected first, and the superior vessels are identi-fied and ligated. This prevents superior retraction of the adrenal gland. The remainder of the


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Surgery_Schwartz. are identified. The superior aspect of the gland is dissected first, and the superior vessels are identi-fied and ligated. This prevents superior retraction of the adrenal gland. The remainder of the gland is then dissected and the adre-nal gland and tumor removed. The resulting space generally is filled with perinephric fat and closed in layers. A chest X-ray is obtained postoperatively to rule out a pneumothorax.Lateral Approach The patient is placed in a lateral position with the table flexed, and an incision is made between the elev-enth and twelfth ribs or subcostally. The dissection then is per-formed as indicated previously in “Anterior Approach.”Complications of Adrenal Surgery. Patients with Cushing’s syndrome are more prone to infectious (incisional and intra-abdominal abscess) and thrombotic complications. Creation of pneumoperitoneum may result in injury to various organs from Veress needle and trocar insertion, subcutaneous emphysema, pneumothorax, and hemodynamic


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Surgery_Schwartz. and thrombotic complications. Creation of pneumoperitoneum may result in injury to various organs from Veress needle and trocar insertion, subcutaneous emphysema, pneumothorax, and hemodynamic compromise. Excessive retraction and dissection may lead to bleeding from injury to the IVC and renal vessels, or from injury to surrounding organs such as the liver, pancreas, spleen, and stomach. Postopera-tive hemodynamic instability may be evident in patients with pheochromocytomas, and patients are at risk of adrenal insuffi-ciency after bilateral adrenalectomy and sometimes after unilat-eral adrenalectomy (unrecognized Cushing’s syndrome or, very rarely, Conn’s syndrome). Long-term morbidity results mainly from injury to nerve roots during trocar insertion, which can lead to chronic pain syndromes or muscle weakness, although this is more of an issue in case of open procedures.Approximately 30% of patients who undergo bilateral adrenalectomy for Cushing’s disease are at risk of developing


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Surgery_Schwartz. or muscle weakness, although this is more of an issue in case of open procedures.Approximately 30% of patients who undergo bilateral adrenalectomy for Cushing’s disease are at risk of developing Nelson’s syndrome from progressive growth of the preexisting pituitary tumor. This leads to increased ACTH levels, hyper-pigmentation, visual field defects, headaches, and extraocular muscle palsies. Transsphenoidal pituitary resection is the ini-tial mode of therapy, and external-beam radiotherapy is used in patients with residual tumor or extrasellar invasion.REFERENCESEntries highlighted in bright blue are key references. 1. Rayess HM, Monk I, Svider PF, Gupta A, Raza SN, Lin HS. Thyroglossal duct cyst carcinoma: a systematic review of clinical features and outcomes. Otolaryngol Head Neck Surg. 2017;156:794-802. 2. Cernea CR, Ferraz AR, Nishio S, Dutra A, Jr, Hojaij FC, dos Santos LR. Surgical anatomy of the external branch of the superior laryngeal nerve. Head Neck.


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Surgery_Schwartz. Head Neck Surg. 2017;156:794-802. 2. Cernea CR, Ferraz AR, Nishio S, Dutra A, Jr, Hojaij FC, dos Santos LR. Surgical anatomy of the external branch of the superior laryngeal nerve. Head Neck. 1992;14:380-383. 3. Pujol-Borrell R, Gimenez-Barcons M, Marin-Sanchez A, Colobran R. Genetics of Graves’ disease: special focus on the role of TSHR gene. Horm Metab Res. 2015;47:753-766. 4. Hagen F, Ouellette RP, Chapman EM. Comparison of high and low dosage levels of I-131 in the treatment of thyrotoxicosis. N Engl J Med. 1967;277(11):559-562. 5. Singer RB. Long-term comparative cancer mortality after use of radio-iodine in the treatment of hyperthyroidism, a fully reported multicenter study. J Insur Med. 2001;33:138-142. 6. Cundiff JG, Portugal L, Sarne DH. Parathyroid adenoma after radioactive iodine therapy for multinodular goiter. Am J Otolaryngol. 2001;22:374-375. 7. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thy-roid Association guidelines for diagnosis and management of


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Surgery_Schwartz. iodine therapy for multinodular goiter. Am J Otolaryngol. 2001;22:374-375. 7. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thy-roid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343-1421. 8. Krohn K, Paschke R. Somatic mutations in thyroid nodular disease. Mol Genet Metab. 2002;75:202-208.Brunicardi_Ch38_p1625-p1704.indd 170101/03/19 11:22 AM 1702SPECIFIC CONSIDERATIONSPART II 9. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thy-roid Association task force on thyroid hormone replacement. Thyroid. 2014;24:1670-1751. 10. Brook I. Microbiology and management of acute suppura-tive thyroiditis in children. Int J Pediatr Otorhinolaryngol. 2003;67:447-451. 11. Sheng Q, Lv Z, Xiao X, et al. Diagnosis and management of pyriform sinus fistula: experience in 48 cases. J Ped Surg. 2014;49:455-459. 12. Moshynska O, Saxena A. Clonal


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Surgery_Schwartz. 2003;67:447-451. 11. Sheng Q, Lv Z, Xiao X, et al. Diagnosis and management of pyriform sinus fistula: experience in 48 cases. J Ped Surg. 2014;49:455-459. 12. Moshynska O, Saxena A. Clonal relationship between Hashi-moto’s thyroiditis and thyroid lymphoma. J Clin Pathol. 2008;61(4):438-444. 13. Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypo-thyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304:1365-1374. 14. Pusztaszeri M, Triponez F, Pache JC, Bongiovanni M. Rie-del’s thyroiditis with increased IgG4 plasma cells: evidence for an underlying IgG4-related sclerosing disease? Thyroid. 2012;22:964-968. 15. Soh SB, Pham A, O’Hehir RE, Cherk M, Topliss DJ. Novel use of rituximab in a case of Riedel’s thyroiditis refractory to glucocorticoids and tamoxifen. J Clin Endocrinol Metab. 2013;98:3543-3549. 16. Knudsen N, Laurberg P, Perrild H, Bulow I, Ovesen L, Jorgensen T. Risk factors for goiter and thyroid nodules. Thy-roid. 2002;12:879-888. 17. Ron E.


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Surgery_Schwartz. J Clin Endocrinol Metab. 2013;98:3543-3549. 16. Knudsen N, Laurberg P, Perrild H, Bulow I, Ovesen L, Jorgensen T. Risk factors for goiter and thyroid nodules. Thy-roid. 2002;12:879-888. 17. Ron E. Thyroid cancer incidence among people living in areas contaminated by radiation from the Chernobyl accident. Health Phys. 2007;93:502-511. 18. Peiling Yang S, Ngeow J. Familial non-medullary thyroid cancer: unraveling the genetic maze. Endocr Relat Cancer. 2016;23:R577-R595. 19. Cibas ES, Ali SZ; Conference NCITFSotS. The Bethesda System for reporting thyroid cytopathology. Am J Clin Pathol. 2009;132(5):658-665. 20. Nobrega LH, Paiva FJ, Nobrega ML, et al. Predicting malig-nant involvement in a thyroid nodule: role of ultrasonography. Endocr Pract. 2007;13:219-224. 21. Chen M, Zhang KQ, Xu YF, Zhang SM, Cao Y, Sun WQ. Shear wave elastography and contrast-enhanced ultrasonog-raphy in the diagnosis of thyroid malignant nodules. Mol Clin Oncol. 2016;5:724-730. 22. Penna GC, Vaisman F, Vaisman


Surgery_Schwartz

Surgery_Schwartz. Zhang SM, Cao Y, Sun WQ. Shear wave elastography and contrast-enhanced ultrasonog-raphy in the diagnosis of thyroid malignant nodules. Mol Clin Oncol. 2016;5:724-730. 22. Penna GC, Vaisman F, Vaisman M, Sobrinho-Simoes M, Soares P. Molecular markers involved in tumorigenesis of thyroid carcinoma: focus on aggressive histotypes. Cytogenet Genome Res. 2016;150:194-207. 23. Caronia LM, Phay JE, Shah MH. Role of BRAF in thyroid oncogenesis. Clin Cancer Res. 2011;17:7511-7517. 24. Zane M, Scavo E, Catalano V, et al. Normal vs cancer thy-roid stem cells: the road to transformation. Oncogene. 2016;35:805-815. 25. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thy-roid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016;2(8):1023-1029. 26. Hay ID, Grant CS, Taylor WF, McConahey WM. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective


Surgery_Schwartz

Surgery_Schwartz. indolent tumors. JAMA Oncol. 2016;2(8):1023-1029. 26. Hay ID, Grant CS, Taylor WF, McConahey WM. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery. 1987;102:1088-1095. 27. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery. 1988;104:947-953. 28. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab. 1990;71:414-424. 29. AJCC Cancer Staging Manual. 8th ed. New York: Springer-Verlag; 2017. 30. Miyauchi A, Kudo T, Miya A, et al. Prognostic impact of serum thyroglobulin doubling-time under thyrotropin suppres-sion in patients with papillary thyroid carcinoma who under-went total thyroidectomy. Thyroid. 2011;21:707-716. 31. Bhaijee F, Nikiforov YE. Molecular analysis of thyroid tumors. Endocr Pathol.


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Surgery_Schwartz. in patients with papillary thyroid carcinoma who under-went total thyroidectomy. Thyroid. 2011;21:707-716. 31. Bhaijee F, Nikiforov YE. Molecular analysis of thyroid tumors. Endocr Pathol. 2011;22:126-133. 32. Cady B, Sedgwick CE, Meissner WA, Wool MS, Salzman FA, Werber J. Risk factor analysis in differentiated thyroid cancer. Cancer. 1979;43:810-820. 33. Lee JH, Lee ES, Kim YS. Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid: a meta-analysis. Cancer. 2007;110:38-46. 34. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med. 1994;97(5):418-428. 35. Hay ID, Grant CS, Bergstralh EJ, Thompson GB, van Heerden JA, Goellner JR. Unilateral total lobectomy: is it sufficient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma? Surgery. 1998;124:958-964; discussion 64-66. 36. Mazzaferri EL, Massoll N. Management of papillary and follicular


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Surgery_Schwartz. surgical treatment for patients with AMES low-risk papillary thyroid carcinoma? Surgery. 1998;124:958-964; discussion 64-66. 36. Mazzaferri EL, Massoll N. Management of papillary and follicular (differentiated) thyroid cancer: new paradigms using recombinant human thyrotropin. Endocr Relat Cancer. 2002;9:227-247. 37. Bilimoria KY, Bentrem DJ, Ko CY, et al. Extent of sur-gery affects survival for papillary thyroid cancer. Ann Surg. 2007;246:375-381; discussion 81-84. 38. Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2006;16:109-142. 39. Adam MA, Pura J, Gu L, et al. Extent of surgery for papil-lary thyroid cancer is not associated with survival: an analysis of 61,775 patients. Ann Surg. 2014;260:601-605; discussion 605-607. 40. Haugen BR, Alexander EK, Bible KC, et al. 2015 Ameri-can Thyroid Association Management guidelines for adult patients with thyroid nodules and differentiated thyroid


Surgery_Schwartz

Surgery_Schwartz. discussion 605-607. 40. Haugen BR, Alexander EK, Bible KC, et al. 2015 Ameri-can Thyroid Association Management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1-133. 41. Ito Y, Miyauchi A, Oda H. Low-risk papillary microcarci-noma of the thyroid: a review of active surveillance trials. Eur J Surg Oncol. 2018;44(3):307-315. 42. Agrawal N, Evasovich MR, Kandil E, et al. Indications and extent of central neck dissection for papillary thyroid cancer: an American Head and Neck Society consensus statement. Head Neck. 2017;39:1269-1279. 43. Nikiforov YE, Ohori NP, Hodak SP, et al. Impact of muta-tional testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospec-tive analysis of 1056 FNA samples. J Clin Endocrinol Metab. 2011;96:3390-3397. 44. Alexander EK, Kennedy GC, Baloch


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Surgery_Schwartz. management of patients with cytologically indeterminate thyroid nodules: a prospec-tive analysis of 1056 FNA samples. J Clin Endocrinol Metab. 2011;96:3390-3397. 44. Alexander EK, Kennedy GC, Baloch ZW, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytol-ogy. N Engl J Med. 2012;367:705-715. 45. Nikiforov YE, Carty SE, Chiosea SI, et al. Highly accu-rate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer. 2014;120:3627-3634. 46. Weber F, Teresi RE, Broelsch CE, Frilling A, Eng C. A limited set of human MicroRNA is deregulated in follicular thyroid carcinoma. J Clin Endocrinol Metab. 2006;91:3584-3591. 47. Wylie D, Beaudenon-Huibregtse S, Haynes BC, Giordano TJ, Labourier E. Molecular classification of thyroid lesions by combined testing for miRNA gene expression and somatic gene alterations. J Pathol Clin Res.


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Surgery_Schwartz. Beaudenon-Huibregtse S, Haynes BC, Giordano TJ, Labourier E. Molecular classification of thyroid lesions by combined testing for miRNA gene expression and somatic gene alterations. J Pathol Clin Res. 2016;2:93-103.Brunicardi_Ch38_p1625-p1704.indd 170201/03/19 11:22 AM 1703THYROID, PARATHYROID, AND ADRENALCHAPTER 38 48. Benjamin H, Schnitzer-Perlman T, Shtabsky A, et al. Ana-lytical validity of a microRNA-based assay for diagnosing indeterminate thyroid FNA smears from routinely prepared cytology slides. Cancer Cytopathol. 2016;124:711-721. 49. Leboeuf R, Perron P, Carpentier AC, Verreault J, Langlois MF. L-T3 preparation for whole-body scintigraphy: a randomized-controlled trial. Clin Endocrinol (Oxf). 2007;67:839-844. 50. Lee J, Yun MJ, Nam KH, Chung WY, Soh EY, Park CS. Quality of life and effectiveness comparisons of thyroxine withdrawal, triiodothyronine withdrawal, and recombinant thyroid-stimulating hormone administration for low-dose radioiodine remnant ablation of


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Surgery_Schwartz. of life and effectiveness comparisons of thyroxine withdrawal, triiodothyronine withdrawal, and recombinant thyroid-stimulating hormone administration for low-dose radioiodine remnant ablation of differentiated thyroid carci-noma. Thyroid. 2010;20:173-179. 51. Iyer NG, Morris LG, Tuttle RM, Shaha AR, Ganly I. Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy. Cancer. 2011;117:4439-4446. 52. Snozek CL, Chambers EP, Reading CC, et al. Serum thyro-globulin, high-resolution ultrasound, and lymph node thyro-globulin in diagnosis of differentiated thyroid carcinoma nodal metastases. J Clin Endocrinol Metab. 2007;92:4278-4281. 53. Wertenbroek MW, Links TP, Prins TR, Plukker JT, van der Jagt EJ, de Jong KP. Radiofrequency ablation of hepatic metastases from thyroid carcinoma. Thyroid. 2008;18:1105-1110. 54. Cazzato RL, Bonichon F, Buy X, et al. Over ten years of sin-gle-institution experience in percutaneous image-guided


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Surgery_Schwartz. of hepatic metastases from thyroid carcinoma. Thyroid. 2008;18:1105-1110. 54. Cazzato RL, Bonichon F, Buy X, et al. Over ten years of sin-gle-institution experience in percutaneous image-guided treat-ment of bone metastases from differentiated thyroid cancer. Eur J Surg Oncol. 2015;41:1247-1255. 55. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioac-tive iodine-refractory, locally advanced or metastatic differ-entiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384:319-328. 56. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib ver-sus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621-630. 57. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13:897-905. 58. Falchook GS, Millward M, Hong D, et al. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid.


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Surgery_Schwartz. double-blind, phase 2 trial. Lancet Oncol. 2012;13:897-905. 58. Falchook GS, Millward M, Hong D, et al. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid. 2015;25:71-77. 59. Wells SA, Jr, Asa SL, Dralle H, et al. Revised American Thy-roid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567-610. 60. Thornton K, Kim G, Maher VE, et al. Vandetanib for the treat-ment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: U.S. Food and Drug Administration drug approval summary. Clin Cancer Res. 2012;18:3722-3730. 61. Elisei R, Schlumberger MJ, Muller SP, et al. Cabozan-tinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646. 62. Smallridge RC, Ain KB, Asa SL, et al. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012;22(11):1104-1139. 63. Zaidi N, Bucak E,


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Surgery_Schwartz. RC, Ain KB, Asa SL, et al. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012;22(11):1104-1139. 63. Zaidi N, Bucak E, Yazici P, et al. The feasibility of indocyanine green fluorescence imaging for identifying and assessing the perfusion of parathyroid glands during total thyroidectomy. J Surg Oncol. 2016;113:775-778. 64. McWade MA, Paras C, White LM, et al. Label-free intraop-erative parathyroid localization with near-infrared autofluores-cence imaging. J Clin Endocrinol Metab. 2014;99:4574-4580. 65. Barczynski M, Konturek A, Cichon S. Randomized clini-cal trial of visualization versus neuromonitoring of recur-rent laryngeal nerves during thyroidectomy. Br J Surg. 2009;96:240-246. 66. Clark JH, Kim HY, Richmon JD. Transoral robotic thyroid surgery. Gland Surg. 2015;4:429-434. 67. Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery. 1984;95:14-21. 68. Gilmour J. The gross anatomy of


Surgery_Schwartz

Surgery_Schwartz. thyroid surgery. Gland Surg. 2015;4:429-434. 67. Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery. 1984;95:14-21. 68. Gilmour J. The gross anatomy of the parathyroid glands. J Pathol. 1938;46:133. 69. Ward BK, Magno AL, Walsh JP, Ratajczak T. The role of the calcium-sensing receptor in human disease. Clin Biochem. 2012;45:943-953. 70. Balogh K, Racz K, Patocs A, Hunyady L. Menin and its inter-acting proteins: elucidation of menin function. Trends Endo-crinol Metab. 2006;17:357-364. 71. Duan K, Gomez Hernandez K, Mete O. Clinicopatho-logical correlates of hyperparathyroidism. J Clin Pathol. 2015;68:771-787. 72. Pardi E, Mariotti S, Pellegata NS, et al. Functional character-ization of a CDKN1B mutation in a Sardinian kindred with multiple endocrine neoplasia type 4 (MEN4). Endocr Con-nect. 2015;4:1-8. 73. Segiet OA, Deska M, Michalski M, Gawrychowski J, Wojnicz R. Molecular profiling in primary hyperparathyroidism. Head Neck.