- Email: [email protected]
What’s new in general surgery: endocrine surgery1
What’s New in General Surgery: Endocrine Surgery Christopher R McHenry, MD, FACE, FACS
“What’s New in Surgery” evolves from the contributions of leaders in each field of surgery. In every instance the author has been designated by the appropriate Council from the American College of Surgeons’ Advisory Councils for the Surgical Specialties. This feature is now presented in issues of the Journal throughout the year.
going thyroidectomy. Regional anesthesia is associated with reduced length of stay and reduced nausea and vomiting postoperatively. Invasive cancer, large substernal goiters, patients requiring concomitant neck dissection, and obesity are considered absolute or relative contraindications to performing thyroidectomy under regional anesthesia. Minimally invasive video-assisted thyroidectomy (MIVAT) is a new approach that has been introduced as an alternative method for thyroidectomy. MIVAT is performed through a short incision that does not require neck extension or subcutaneous flap formation. Miccoli and colleagues3 performed a prospective, randomized comparison of MIVAT and conventional thyroidectomy for 49 patients with thyroid nodules less than 35 mm and thyroid volume less than 20 mL in the absence of thyroiditis. They demonstrated that the MIVAT could be performed safely with less pain and an improved cosmetic result compared with conventional thyroidectomy. But MIVAT was technically more challenging, took longer to perform, and was more costly. Where this will fit into the surgeons’ armamentarium for treatment of nodular thyroid disease is not yet clear. It will require further evaluation with larger number of patients before it is widely adopted. Reported rates for recurrent laryngeal nerve injury after thyroidectomy differ widely and may be a reflection of variations in surgical technique. Hermann and colleagues4 studied the incidence of recurrent laryngeal nerve injury in primary thyroidectomy for benign thyroid disease. Based on an analysis of more than 27,000 nerves at risk; they demonstrated that the incidence of recurrent laryngeal nerve injury was significantly reduced with routine exposure and dissection of the recurrent laryngeal nerve over its entire cervical course. They also showed that the incidence of recurrent laryngeal
In 2002, the American Association of Endocrine Surgeons began its 22nd year of existence. It continues to be a premier organization of endocrine surgeons. It was organized in 1980 to advance the science and art of endocrine surgery and to maintain high standards in the practice and art of endocrine surgery. One of its major challenges for the future is the education and training of endocrine surgeons. Its yearly meeting is the forum for presentation of the most up-to-date information and recent advances in the surgical treatment of diseases affecting the thyroid gland, the parathyroid glands, the adrenal glands, the endocrine pancreas, and the gastrointestinal tract. Much of this work will be reviewed and referenced in this article. THYROID Thyroid surgery is most often performed using a conventional open technique under general anesthesia. A desire to avoid general anesthesia and economic pressures have generated renewed interest in performing thyroidectomy under regional anesthesia.1,2 Regional anesthesia is achieved by performing a bilateral superficial cervical block using 0.5% bupivicaine with epinephrine, which is injected beneath the deep fascia of the neck at the midpoint posterior to the sternocleidomastoid muscles.2 Additional local anesthesia is also administered along the line of the incision. Specht and colleagues2 have demonstrated that regional anesthesia is a safe alternative to general anesthesia in selected patients underNo competing interests declared.
Received June 4, 2002; Accepted June 4, 2002. From the Department of Surgery, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH. Correspondence address: Christopher R McHenry, MD, Department of Surgery, # H 917, MetroHealth Medical Center, 2500 MetroHealth Dr, Cleveland, OH 44109-1998.
© 2002 by the American College of Surgeons Published by Elsevier Science Inc.
364
ISSN 1072-7515/02/$21.00 PII S1072-7515(02)01307-8
Vol. 195, No. 3, September 2002
nerve injury increased with the size of the resected thyroid tissue and extent of thyroid resection. Based on their results, surgical approaches that do not expose the recurrent laryngeal nerve cannot be recommended. The incidence of recurrent laryngeal nerve injury and hypoparathyroidism is a sensitive measure of the quality of thyroidectomies being performed and may reflect variations in surgeon experience. The relationship of volume of operations performed and outcomes has been examined for a number of surgical procedures and has recently become a focus for the business community.5 The Leapfrog Group, a large coalition of major corporations, is using information on quality of care to determine which institutions will be used to provide health care for their employees.6 The relationship of volume of operations performed and outcomes has also been examined for thyroid surgery but not to the extent of some other operations.7-9 Sosa and colleagues 7 demonstrated a significant inverse relationship between the volume of thyroidectomies performed and complication rates for individual surgeons in Maryland. The authors make a compelling case for referral of patients with known or suspected thyroid cancer or patients for whom total or near total thyroidectomy is necessary to high-volume surgeons. Other variables may also contribute to successful outcomes from thyroidectomy. Efforts to improve surgical training, establishment of fellowship programs for those interested in specializing in thyroid surgery, and provisions for consultation and supervision for new surgeons during their maturation process may also help to improve the quality of patient care.5 The challenge in the evaluation and management of patients with nodular thyroid disease is to distinguish patients at high risk for cancer who will benefit from thyroidectomy from patients with benign disease who can be observed. In most patients, a history, physical examination, fine-needle aspiration biopsy, and a screening serum TSH level are all that is necessary to decide on the most appropriate management of a thyroid nodule.10 Iodine-123 thyroid scintigraphy is of value only for patients with a fine-needle aspiration biopsy that is consistent with a follicular neoplasm or persistently nondiagnostic in patients with a low serum thyroid-stimulating hormone (TSH) level.10 Routine use of ultrasonography is unnecessary. Ultrasonography has value in helping to guide fine-needle aspiration biopsy in patients with nonpalpable nodules and for biopsying the solid component of a complex cystic-solid
McHenry
What’s New in General Surgery: Endocrine
365
nodule.11 When a nodule is palpable, the results of standard percutaneous and ultrasound-guided fine-needle aspiration biopsy are equivalent.11 As a result, standard fineneedle aspiration biopsy is preferable because of the higher cost of ultrasound-guided fine-needle aspiration biopsy. With increased use of positron emission tomography with 18F-fluorodeoxyglucose (FDG) for evaluation of patients with malignancy, incidental hot spots within the thyroid gland are being discovered, and a high rate of clinically relevant malignancy is being reported.12,13 The most likely explanation is that FDG-PET scans preferentially image malignant lesions because of their increased rate of glucose uptake and glycolysis.12 Cohen and coauthors13 reported a 2.3% incidence of thyroid FDG-PET incidentalomas and demonstrated that thyroid lesions with focal FDG uptake and higher standardized uptake values were more likely to be malignant and should be evaluated with ultrasound-guided fine-needle aspiration biopsy. Diffuse thyroidal FDG uptake is observed in patients with chronic lymphocytic thyroiditis and Graves’ disease. Thyroid cancer is the most common endocrine malignancy. It accounts for approximately 1.6% of all new malignant tumors diagnosed annually in the United States, 0.9% of cancers in men, and 2.6% of cancers in women.14 The incidence of thyroid cancer varies between 0.004% and 0.1% in the general population. As of 2002, the thyroid gland was the ninth most common cancer site for women.14 The American Cancer Society estimates 20,700 new cases of thyroid cancer (15,800 in women and 4,900 in men) and 1,300 deaths from thyroid cancer in the United States in 2002.14 Respiratory insufficiency from pulmonary metastases is the most common cause of death from thyroid cancer.15 The longterm prognosis for patients with differentiated thyroid cancer is generally very good, but tumor recurrence may occur in up to 20% of patients, underscoring the importance of longterm followup. Mazzaferri and Kloos16 demonstrated that after treatment of differentiated thyroid cancer, 10% of patients considered free of disease based on a serum thyroglobulin level less than 2 ng/mL while on thyroid hormone had persistent tumor when studied with recombinant human TSH. The diagnostic accuracy of serum thyroglobulin while on thyroid hormone therapy had a sensitivity of 36% and a false negative rate of 64%. Recombinant human TSH-stimulated serum thyroglobulin levels greater than 2 ng/mL had a sensitivity of 100%, a neg-
366
McHenry
What’s New in General Surgery: Endocrine
ative predictive value of 100%, and a 9% false positive rate. Diagnostic whole body scanning and measurement of radioactive iodine uptake added no additional information to that provided by recombinant human TSHstimulated serum thyroglobulin. The authors emphasize that tests to detect cancer should have a very high negative predictive value, which is not true for a low or undetectable serum thyroglobulin level while on thyroid hormone. Patients with no clinical evidence of residual or recurrent differentiated thyroid cancer and undetectable serum thyroglobulin levels while on thyroid hormone should periodically undergo measurement of serum thyroglobulin after TSH stimulation. A diagnostic whole body scan adds little and its omission will reduce cost. The treatment of well-differentiated thyroid cancer consists of thyroidectomy, iodine-131 administration, and thyrotropin suppression with thyroid hormone. Approximately 30% to 40% of well-differentiated thyroid cancers are resistant to radioactive iodine therapy. Zarnegar and associates17 have investigated the use of trichostatin A, a histone-deacetylating inhibitor, as a potential therapeutic agent for enhancing radioactive iodine uptake in patients with thyroid cancer. They demonstrated that the in vitro use of trichostatin A dramatically increased sodium iodine symporter gene expression and reduced the Pendren syndrome gene expression in cell lines from papillary, Hurthle cell, and follicular cell cancer. Although it has yet to be tested in humans, observed effects of trichostatin A might lead to enhanced radioactive iodine uptake in thyroid cancers with no or low radioactive iodine uptake. Medullary thyroid carcinoma, in contrast to most follicular cell-derived cancers, is notable for rapid lymphatic spread and systemic metastases. Hereditary forms account for 20% to 30% of all medullary thyroid carcinomas that occur as a result of germline mutations in various codons of the RET protooncogene. There is controversy over the appropriate age for prophylactic thyroidectomy in patients identified as carriers of mutations in the RET protooncogene. Patients with MEN 2B, caused by a mutation in codon 918 of the RET protooncogene, develop medullary thyroid cancer at a very early age and thyroidectomy is recommended in infancy.18 Patients with MEN 2A, caused by mutations in codons 609, 611, 618, 620, 630, and 634 develop medullary thyroid cancer later and preventative thyroidectomy has been recommended at 5 or 6 years of age.18
J Am Coll Surg
Ukkat and coworkers19 demonstrated that postponement of prophylactic thyroidectomy beyond 20 years of age in nonindex patients carrying germline mutations in the RET protooncogene exposes them to an unacceptably high risk of metastatic medullary thyroid cancer, which may preclude biochemical cure. The authors emphasize that prophylactic thyroidectomy should be performed before basal serum calcitonin levels turn positive. PARATHYROID A National Institutes of Health (NIH)-sponsored consensus conference was convened in April 2002 to reevaluate the 1990 guidelines for parathyroidectomy in primary hyperparathyroidism. A consensus statement is forthcoming. The 1990 consensus panel recommended parathyroidectomy in all symptomatic patients and in asymptomatic less than age 50 or with marked hypercalcemia (serum calcium greater than 11.5 mg/dL), hypercalciuria (24 hour urine calcium greater than 400 mg), renal insufficiency (a reduced creatinine clearance by more than 30% for age in the absence of another cause), or a reduction in bone mineral density greater than two standard deviations compared with age, gender, and race matched controls.20 Sywak and colleagues21 point out that the NIH Consensus Panel reserved the term asymptomatic for patients who presented with typical renal, bone, gastrointestinal, or neuromuscular manifestations of hyperparathyroidism. Nonspecific symptoms of hyperparathyroidism such as fatigue, irritability, mood swings, depression, and forgetfulness were not included in the NIH definition of symptomatic. Using a diseasespecific outcomes tool called the Parathyroidectomy Assessment of Symptoms Scores, Sywak and associates21 demonstrated that the so-called “asymptomatic” patients with hyperparathyroidism were indeed suffering from reversible, nonspecific manifestations and benefited from parathyroidectomy. In view of their observations that parathyroidectomy in primary hyperparathyroidism significantly improves vague nonspecific symptoms, they suggest that guidelines for parathyroidectomy should be broadened to include nonspecific manifestations of the disease. Since the 1990 NIH Consensus Development Conference on diagnosis and management of asymptomatic hyperparathyroidism, it has become evident that primary hyperparathyroidism is associated with increased mortality.22-24 Untreated hyperparathyroidism may re-
Vol. 195, No. 3, September 2002
duce a patient’s survival by approximately 10% when compared with expected values.24 The increased mortality has been attributed to cardiovascular disease and, less commonly, to malignancy or renal failure.22-24 Primary hyperparathyroidism has been reported to be associated with a number of cardiovascular sequelae.25 The cardiovascular sequelae and reduced survival observed in patients with primary hyperparathyroidism can be reversed by parathyroidectomy.25,26 Management of sporadic primary hyperparathyroidism has evolved to include minimally invasive parathyroidectomy.27 This is a technique designed for removal of a single adenoma localized by a preoperative technetium-99m-sestamibi scan. A focused exploration is performed under cervical block anesthesia using a small incision. An intraoperative parathyroid hormone assay is used for determining the adequacy of operation. Patients are discharged within 2 to 3 hours of operation. Udelsman27 has demonstrated that minimally invasive parathyroidectomy is associated with a significant reduction in operating room time and significant cost savings. Cure and complication rates are equivalent to those achieved by conventional parathyroidectomy. The postoperative course for patients with primary hyperparathyroidism who have undergone curative parathyroidectomy is characterized by persistent parathyroid hormone elevation in 27% of patients despite resolution of hypercalcemia.28 It is important to recognize that this is not a manifestation of persistent disease but is most likely a compensatory response to remineralization of cortical bone. This is usually a transient phenomenon resolving in most patients within 5 months of operation. From one of the largest databases of MEN-I-related hyperparathyroidism, Goudet and colleagues29 found that the most powerful factor for correction of hypercalcemia was performance of a subtotal parathyroidectomy, defined as removal of all parathyroid tissue except for the weight of one normal gland. Their results emphasize that MEN-I-related hyperparathyroidism is a multiglandular disease. In one of the largest series of reoperations for MEN-I hyperparathyroidism, Kivlin and coauthors 30 emphasized that the primary treatment of hyperparathyroidism in patients with MEN-I consists of either subtotal parathyroidectomy and transcervical thymectomy or a total parathyroidectomy, transcervical thymectomy, and parathyroid autotransplantation. Despite an “adequate operation” there remains a striking propensity for recurrence in this population of patients. Twenty-seven
McHenry
What’s New in General Surgery: Endocrine
367
percent of patients who underwent parathyroid autotransplantation developed autograft-mediated recurrence at a median of 15 months followup. This propensity for recurrence is attributed to the underlying mutation in the MEN-I gene, which is responsible for progressive neoplasia of any remaining parathyroid tissue. Decker and colleagues31 report that over the period from 1986 to 1998 a persistent fraction of patients with end-stage renal disease ultimately required parathyroidectomy for secondary or tertiary hyperparathyroidism despite the advances in dialysis and pharmacotherapy. In contrast to patients with primary hyperparathyroidism, patients with secondary or tertiary hyperparathyroidism are usually younger and more likely to have severe skeletal manifestations, profound symptomatic hypocalcemia after parathyroidectomy, and persistent or recurrent hyperparathyroidism.32 Patients with symptomatic secondary hyperparathyroidism have significant bone loss from the lumbar spine and the femoral neck. Chou and coworkers33 demonstrated that 6 months after successful parathyroidectomy, bone mass in the lumbar spine and the femoral neck increased significantly and osteopenia and osteoporosis improved significantly. Parathyroidectomy has recently been shown to produce a consistent and significant improvement in anemia, an increase in serum erythropoietin levels and platelet count, and improvement in nutritional status for patients with secondary hyperparathyroidism.34 ADRENAL The National Institutes of Health State of the Science Draft Statement on the management of clinically inapparent adrenal mass was completed on February 6, 2002, and can be accessed from the State of the Sciences Web site, http://consensus.NIH.gov/ta/021/021statement. htm. The panel of experts recommended that all patients with clinically inapparent adrenal masses undergo a 1-mg dexamethasone suppression test and measurement of either urine or plasma-free metanephrines. Patients who are hypertensive should also have serum potassium, serum aldosterone, and plasma renin activity measured. All pheochromocytomas, aldosterone-producing adenomas, and cortisol-producing adenomas in patients with signs and symptoms of hypercortisolism should be treated with adrenalectomy. They indicated that there are insufficient data to definitively recommend surgical therapy for patients with subclinical hypercortisolism. The panel also indicated that recommendations for sur-
368
McHenry
What’s New in General Surgery: Endocrine
gical treatment of nonfunctioning adenomas were derived from studies that were not standardized for inclusion criteria, length of followup, or methods for estimating risk of carcinoma. Recognizing these limitations, they recommended adrenalectomy for all tumors greater than 6 cm, observation for tumors less than 4 cm, and for tumors between 4 and 6 cm, other criteria should be considered before deciding whether to proceed with observation or surgery. In patients with tumors less than 4 cm that are unchanged in size on two imaging studies separated by 6 months with no evidence for hormonal hypersecretion for 4 years, further followup may not be warranted. Recent data suggest that the incidence of primary aldosteronism in patients with hypertension is higher than previously appreciated.35,36 Fardella and associates36 reported that the prevalence of primary aldosteronism was 9.5% among patients referred to their university outpatient clinic for evaluation and management of hypertension. It has previously been suggested that primary aldosteronism is rare, accounting for 1% or less of all patients with hypertension. The explanation for the higher prevalence of primary aldosteronism is related to the recognition that more than half of patients with primary aldosteronism have normal circulating potassium levels.35 In the past, the diagnosis was not pursued unless hypokalemia was present. Furthermore, primary aldosteronism may occur as a result of a biologically significant increase in serum aldosterone without the absolute level exceeding the upper limit of normal.35 This emphasizes the importance of determining the serum aldosterone/ plasma renin activity ratio to screen hypertensive patients. The aldosterone/plasma renin activity ratio is a more sensitive screening test than waiting for the serum aldosterone level to increase or the serum potassium level to decrease, both of which are late phenomena in patients with primary aldosteronism. Laparoscopic adrenalectomy is regarded as the treatment of choice for most patients with benign adrenal tumors. Open adrenalectomy is still considered the treatment of choice for adrenocortical carcinoma and malignant pheochromocytomas. Li and colleagues37 report the first descriptions of recurrent pheochromocytoma 34 to 48 months after laparoscopic adrenalectomy in three patients. The authors hypothesize that intraperitoneal seeding at the time of laparoscopic adrenalectomy was the cause for recurrence. Each of the patients had large tumors ranging in size from 5.5 to 6.5 cm. One
J Am Coll Surg
patient had a documented tumor disruption and spillage at the original operation. Tumor friability was noted in a second patient. A third patient had a 6.5-cm tumor that required extensive dissection and excessive tumor manipulation before the adrenal vein could be ligated. At reoperation, multiple small tumor nodules were found in the adrenal bed near the site of initial laparoscopic resection in all three patients. The authors suggest that pheochromocytomas greater than 5 cm may be more appropriately removed by an open approach. They conclude that regardless of whether an open or laparoscopic approach is performed, longterm followup is necessary for all patients after resection of a pheochromocytoma. The best test or tests for diagnosis of pheochromocytoma have yet to be definitively established. Lenders and coworkers38 performed a multicenter cohort study of patients treated for pheochromocytoma and compared results for 214 patients in whom the diagnosis of pheochromocytoma was confirmed with results from 644 patients who were determined not to have the tumor. Among all patients with pheochromocytoma, sensitivities were highest for measurements of plasma-free metanephrines at 99% followed by urinary fractionated metanephrines at 97%. Specificities were highest for urinary vanillylmandelic acid at 95% and urinary total metanephrines at 93%. The specificity for plasma-free metanephrines was 89%. But plasma concentrations of normetanephrine greater than 2.5 pg/mL or metanephrine greater than 1.4 pg/mL, which represent 4- and 2.5-fold increases above the upper limits of normal, indicated a pheochromocytoma with a 100% specificity.39 More than 80% of patients with pheochromocytoma have elevated plasma metanephrine levels that indicate a pheochromocytoma with 100% specificity.39 Lenders and colleagues38 concluded that measurement of plasma-free metanephrines is the best test for excluding or confirming pheochromocytoma and should be the first test chosen for diagnosis of the tumor. A negative test virtually excludes pheochromocytoma and no further biochemical testing is necessary. For patients with less than a 4-fold increase in plasma-free normetanephrine and less than a 2.5-fold increase in plasma-free metanephrine, it is important to differentiate a true positive from a false positive test. A careful history should be obtained to exclude potential sources for false positive test results, including: caffeic acid, a catechol present in coffee; acetaminophen; nicotine; tricyclic antidepressants; and phenoxybenzamine. Addi-
Vol. 195, No. 3, September 2002
tional biochemical testing should then be performed including repeat plasma free metanephrines and a 24-hour urine for catecholamines, metanephrines, and vanillylmandelic acid. Neumann and colleagues40 tested 271 unrelated patients who presented with apparent sporadic pheochromocytoma for mutations of the RET-protooncogene present in MEN 2A or 2B, the tumor suppressor gene of vonHippel Lindau disease, and the newly identified genes for succinate dehydrogenase subunit B and subunit D present in patients with pheochromocytoma and paragangliomas. Deleterious mutations were found in 24% of patients, two-thirds of whom had solitary disease and no signs or symptoms at presentation. They concluded that routine genetic analysis is indicated to identify pheochromocytoma-associated syndromes and to prompt genetic testing of all first-degree relatives of the carrier to determine the presence or absence of family-specific-mutations. It is also important to identify patients with familial pheochromocytoma because of the presence of associated endocrinopathies and the high incidence of bilateral disease. Brunt and colleagues41 treated 21 patients with familial pheochromocytoma; 12 (57%) had bilateral disease, with synchronous tumors in 2 patients and metachronous tumors in 10. At presentation, 48% of patients were asymptomatic, underscoring the importance of yearly biochemical screening in patients diagnosed with familial pheochromocytoma or a familial pheochromocytoma-associated syndrome. After initial adrenalectomy for familial pheochromocytoma, onethird of patients developed a contralateral pheochromocytoma within 5 years of followup. None of the patients experienced hypertensive crisis or other complications of undiagnosed pheochromocytoma during longterm followup. This, along with the minimally invasive nature of laparoscopic adrenalectomy, led the authors to recommend a unilateral approach for patients with a single imagable adrenal tumor and a normal contralateral adrenal gland. This approach is safe and allows for maintenance of functioning adrenal tissue for as long as possible. PANCREAS Insulinoma is the most common endocrine tumor of the pancreas. The biggest challenge in managing patients with an insulinoma is localization of the tumor. Precise localization of an insulinoma is imperative for surgical
McHenry
What’s New in General Surgery: Endocrine
369
cure. Controversy exists over what constitutes the best test for localization of an insulinoma. Most insulinomas are less than 2 cm in size, and conventional imaging studies such as CT or MRI frequently do not localize these tumors. Hiramoto and associates42 compared the results of invasive preoperative localization studies, either portal venous sampling or selective intraarterial calcium stimulation with hepatic venous sampling with intraoperative ultrasonography for 37 consecutive patients with a diagnosis of insulinoma without MEN. Intraoperative ultrasonography was found to be the single best localization study. Although intraoperative ultrasonography identified the majority of insulinomas, two tumors (5%) were missed in the tail of the pancreas, both of which were identified preoperatively by portal venous sampling in one patient and calcium arteriography in one patient. The authors recommend the use of both preoperative calcium arteriography and intraoperative ultrasonography for all patients diagnosed with an insulinoma. Richards and colleagues43 advocate a preoperative localization strategy for insulinoma that relies solely on endoscopic ultrasonography in 80% to 85% of patients. Arteriography with intraarterial calcium stimulation and hepatic venous sampling is obtained in the 10% to 15% of patients who have a negative endoscopic ultrasound and for patients with findings suggestive of malignancy. CT is obtained for patients with a large or locally invasive tumor to evaluate the liver for metastases. Most insulinomas are solitary and benign, and enucleation is the usual recommended surgical treatment. With successful preoperative localization, a laparoscopic approach is an option for resection for solitary, benign insulinomas. Iihara and associates44 have demonstrated that enucleation and resection of insulinomas may be accomplished laparoscopically with the aid of laparoscopic ultrasonography. A major concern in the operative treatment of hyperinsulinism is incomplete resection of hyperfunctioning tissue.43 This is an especially important concern in patients with multiple endocrine neoplasia type I, nesidioblastosis, and malignant insulin-producing tumors. Carneiro and coworkers45 reported their experience with a newly developed intraoperative, 8-minute immunochemiluminescent assay for insulin in eight patients with organic hypoglycemia secondary to a single, benign pancreatic insulinoma in six, multiple insulinomas in
370
McHenry
What’s New in General Surgery: Endocrine
one, and adult nesidioblastosis in one patient. Intraoperative criteria for successful treatment was return of insulin levels to the normal range and a fall in the insulin-glucose ratio below 0.4 15 minutes after tumor resection. Sensitivity of the assay was 83%, specificity 100%, and overall accuracy 89%. A rapid insulin assay may be helpful in avoiding incomplete resection of hyperfunctioning tissue. Proye and colleagues 46 and Amikura and coworkers47 were responsible for some of the initial work evaluating the use of insulin monitoring during resection of insulinoma but with an immunoradiometric assay requiring 30 to 60 minutes to obtain a result. Richards and associates 43 have indicated that failed surgical treatment of insulinoma occurs as a result of inability to discern malignancy intraoperatively, multiple foci of disease, islet cell hyperplasia, nesidioblastosis, or inexperience. They suggest that intraoperative insulin assays may lead to a reduction in operative failures by identifying persistent disease. GASTROINTESTINAL Zyromski and colleagues48 reviewed 27 patients with duodenal carcinoid tumors treated at the Mayo Clinic from 1976 to 1999. Most patients presented with abdominal pain and, less often, with vomiting, weight loss, gastrointestinal bleeding, or pancreatitis. Tumors were present in the first or second portion of the duodenum in all but two patients and the diagnosis was usually made by endoscopic biopsy. From a review of their treatment results, the authors suggest that tumors less than 1 cm can be endoscopically excised; for tumors between 1 and 2 cm an open transdudoneal excision should be performed to ensure complete resection. Size greater than 2 cm, invasion of the muscularis propria, and periampullary location appear to be associated with a more aggressive course and poorer prognosis. But it is unclear whether more extensive local-regional resection has an impact on outcomes. All patients with tumors 2 cm or larger who were resected for cure developed recurrent disease despite undergoing either segmental resection or pancreaticoduodenectomy. Like other carcinoid tumors, the duodenal carcinoids were associated with second malignancies in one-third of patients. REFERENCES 1. LoGerfo P. Local/regional anesthesia for thyroidectomy: Evaluation as an outpatient procedure. Surgery 1998;124:975–979.
J Am Coll Surg
2. Specht MC, Romero M, Barden CB, et al. Characteristics of patients having thyroid surgery under regional anesthesia. J Am Coll Surg 2001;193:367–372. 3. Miccoli P, Berti P, Raffaelli M, et al. Comparison between minimally invasive video-assisted thyroidectomy and conventional thyroidectomy: A prospective randomized study. Surgery 2001; 130:1039–1043. 4. Hermann M, Alk G, Roka R, et al. Laryngeal nerve injury in surgery for benign thyroid diseases: Effect of nerve dissection and impact of individual surgeon in more than 27,000 nerves at risk. Ann Surg 2002;235:261–268. 5. McHenry CR. Patient volumes and complications in thyroid surgery. Br J Surg (in press). 6. Birkmeyer JD, Finlayson EV, Birkmeyer CM. Volume standards for high-risk surgical procedures: Potential benefits of the Leapfrog initiative. Surgery 2001;130:415–422. 7. Sosa JA, Bowman HM, Tielsoti JM, et al. The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann Surg 1998;228:320–330. 8. LaMade W, Renz K, Willeke F, et al. Effect of training on the incidence of nerve damage in thyroid surgery. Br J Surg 1999; 86:388–391. 9. Mishra A, Agarwal G, Agarwal A, et al. Safety and efficacy of total thyroidectomy in hands of endocrine surgery trainees. Am J Surg 1999;178:377–380. 10. McHenry SR, Slusarczyk S, Ascari AT, et al. Refined use of scintigraphy in the evaluation of nodular thyroid disease. Surgery 1998;124:656–662. 11. Mittendorf EA, Tamarkin SW, McHenry CR. The results of ultrasound-guided fine-needle aspiration biopsy for evaluation of nodular thyroid disease. Surgery (in press). 12. Van den Bruel A, Maes A, DePotler T, et al. Clinical relevance of thyroid fluorodeoxyglucose-whole body positron emission tomography incidentaloma. J Clin Endocrinol Metab 2002;87: 1517–1520. 13. Cohen MS, Arslan N, Dehdashti F, et al. Risk of malignancy in thyroid incidentalomas identified by fluorodeoxyglucosepositron emission tomography. Surgery 2001;130:941–946. 14. Jemal A, Thomas A, Murray T, et al. Cancer statistics, 2002. CA Cancer J Clin 2002;52:23–47. 15. Kitamara Y, Shimizuk K, Nagahama M, et al. Immediate causes of death in thyroid carcinoma: Clinicopathological analysis of 161 fatal cases. J Clin Endocrinol Metab 1999;84:4043–4049. 16. Mazzaferri EL, Kloos R. Is diagnostic iodine-131 scanning with recombinant human TSH useful in the follow-up of differentiated thyroid cancer after thyroid ablation? J Clin Endocrinol Metab 2002;87:1490–1498. 17. Zarnegar R, Brunaud L, Kanauchi H, et al. Increasing the effectiveness of radioactive iodine therapy in the treatment of thyroid cancer using Trichostatin A (TSA), a histine deacetylase (HDAC) inhibitor. Surgery (in press). 18. Moley JF. Invited commentary: Are specific inherited mutations important in clinical management of hereditary cancer syndromes? Surgery 2002;131:382–383. 19. Ukkat J, Lorenz K, Hinze R, et al. Importance of early screening and prophylactic thyroidectomy in asymptomatic nonindex RET germline carriers. World J Surg 2001;25:713–717. 20. NIH Conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement. Ann Intern Med 1991;114:593–597. 21. Sywak MS, Knowlton ST, Pasieka JL, et al. Do the National Institutes of Health Consensus Guidelines for parathyroidec-
Vol. 195, No. 3, September 2002
22. 23. 24. 25.
26. 27. 28.
29.
30. 31. 32. 33. 34.
tomy predict symptom severity and surgical outcome in patients with primary hyperparathyroidism? Surgery (In Press). Sivula A, Pelkonen R. Long-term health risk of primary hyperparathyroidism: the effect of surgery. Ann Med 1996;28:95– 100. Hedback G, Tisell LE, Bengtsson BA, et al. Premature death in patients operated on for primary hyperparathyroidism. World J Surg 1990;14:839–836. Palmer M, Adami HO, Berstrom R, et al. Survival and renal function in untreated hypercalcemia. Population-based cohort study with 14 years of follow-up. Lancet 1987;1:59–62. Stefenilli T, Mayr H, Bergler-Klein J, et al. Primary hyperparathyroidism: incidence of cardiac abnormalities and partial reversibility after successful parathyroidectomy. Am J Med 1993; 95:197–202. Hedback G, Oden A, Tisell LE. The influence of surgery on the risk of death in patients with primary hyperparathyroidism. World J Surg 1991;15:399–407. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 2002;235:665–672. Mittendorf EA, McHenry CR. Persistent parathyroid hormone elevation following curative parathyroidectomy for primary hyperparathyroidism. Arch Otolaryngol Head Neck Surg 2002; 128:275–279. Goudet P, Cougard P, Verges B, et al. Hyperparathyroidism in multiple endocrine neoplasia Type I: Surgical trends and results of 256-patient series from Groupe d’Etude des Neoplasies Endocriniennes Multiples Study Group. World J Surg 2001;25: 886–890. Kivlin MH, Bartlett DL, Libutti SK, et al. Reoperations for hyperparathyroidism in multiple endocrine neoplasia type I. Surgery 2001;130:991–998. Decker PA, Cohen EP, Doffek KM, et al. Subtotal parathyroidectomy in renal failure: still needed after all these years. World J Surg 2001;25:708–712. McHenry CR, Wilhelm SM, Ricanati E. Refractory renal hyperparathyroidism: clinical features and outcome of surgical therapy. Am Surg 2001;67:310–317. Chou FF, Chen JB, Lee CH, et al. Parathyroidectomy can improve bone mineral density in patients with symptomatic secondary hyperparathyroidism. Arch Surg 2001;136:1064–1068. Yasunaga C, Matsuo K, Yanagida T, et al. Early effects of parathyroidectomy on erythropoietin production in secondary hyperparathyroidism. Am J Surg 2002;183:199–204.
McHenry
What’s New in General Surgery: Endocrine
371
35. Gordon RD, Stowasser M. Rutherford JC. Primary aldosteronism: Are we diagnosing and operating on too few patients? World J Surg 2001;25:941–947. 36. Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile and molecular biology. J Clin Endocrine Metab 2000; 85:1863–1867. 37. Li ML, Fitzgerald PA, Price DC, et al. Iatrogenic pheochromocytomatosis: A previously unreported result of laparoscopic adrenalectomy. Surgery 2001;130:1072–1077. 38. Lenders JWM, Pacak K, McClellan WM, et al. Biochemical diagnosis of pheochromocytoma: Which test is best? JAMA 2002;287:1427–1434. 39. Eisenhofer G. Biochemical diagnosis of pheochromocytoma. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 2001;134:317– 320. 40. Neumann HPH, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002;346:1459–1466. 41. Brunt LM, Lairmore TC, Doherty GM, et al. Adrenalectomy for familial pheochromocytoma in the laparoscopic era. Ann Surg 2002;235:713–721. 42. Hiramoto JS, Feldstein VA, LaBerge JM, et al. Intraoperative ultrasound and preoperative localization detects all occult insulinomas. Arch Surg 2001;136:1020–1026. 43. Richards ML, Gauger PG, Thompson NW, et al. Pitfalls in the surgical treatment of insulinoma. Surgery (in press). 44. Iihara M, Kanbe M, Okamoto T, et al. Laparoscopic ultrasonography for resection of insulinomas. Surgery 2001;130:1086– 1091. 45. Carneiro DM, Levi JU, Irvin GL. Rapid insulin assay for intraoperative confirmation of complete resection of insulinomas. Surgery (in press). 46. Proye CA, Pattou F, Carnaille B, et al. Intraoperative insulin measurement during surgical management of insulinomas. World J Surg 1998;22:1218–1224. 47. Amikura K, Nakamura R, Arai K, et al. Role of intraoperative insulin monitoring in surgical management of insulinoma. J Lap Adv Surg Tech 2001;11:193–199. 48. Zyromski NJ, Kendrick ML, Nagorney DM, et al. Duodenal carcinoid tumors: How aggressive should we be? J Gastrointest Surg 2002;5:588–593.
“What’s New in Surgery” evolves from the contributions of leaders in each field of surgery. In every instance the author has been designated by the appropriate Council from the American College of Surgeons’ Advisory Councils for the Surgical Specialties. This feature is now presented in issues of the Journal throughout the year.
going thyroidectomy. Regional anesthesia is associated with reduced length of stay and reduced nausea and vomiting postoperatively. Invasive cancer, large substernal goiters, patients requiring concomitant neck dissection, and obesity are considered absolute or relative contraindications to performing thyroidectomy under regional anesthesia. Minimally invasive video-assisted thyroidectomy (MIVAT) is a new approach that has been introduced as an alternative method for thyroidectomy. MIVAT is performed through a short incision that does not require neck extension or subcutaneous flap formation. Miccoli and colleagues3 performed a prospective, randomized comparison of MIVAT and conventional thyroidectomy for 49 patients with thyroid nodules less than 35 mm and thyroid volume less than 20 mL in the absence of thyroiditis. They demonstrated that the MIVAT could be performed safely with less pain and an improved cosmetic result compared with conventional thyroidectomy. But MIVAT was technically more challenging, took longer to perform, and was more costly. Where this will fit into the surgeons’ armamentarium for treatment of nodular thyroid disease is not yet clear. It will require further evaluation with larger number of patients before it is widely adopted. Reported rates for recurrent laryngeal nerve injury after thyroidectomy differ widely and may be a reflection of variations in surgical technique. Hermann and colleagues4 studied the incidence of recurrent laryngeal nerve injury in primary thyroidectomy for benign thyroid disease. Based on an analysis of more than 27,000 nerves at risk; they demonstrated that the incidence of recurrent laryngeal nerve injury was significantly reduced with routine exposure and dissection of the recurrent laryngeal nerve over its entire cervical course. They also showed that the incidence of recurrent laryngeal
In 2002, the American Association of Endocrine Surgeons began its 22nd year of existence. It continues to be a premier organization of endocrine surgeons. It was organized in 1980 to advance the science and art of endocrine surgery and to maintain high standards in the practice and art of endocrine surgery. One of its major challenges for the future is the education and training of endocrine surgeons. Its yearly meeting is the forum for presentation of the most up-to-date information and recent advances in the surgical treatment of diseases affecting the thyroid gland, the parathyroid glands, the adrenal glands, the endocrine pancreas, and the gastrointestinal tract. Much of this work will be reviewed and referenced in this article. THYROID Thyroid surgery is most often performed using a conventional open technique under general anesthesia. A desire to avoid general anesthesia and economic pressures have generated renewed interest in performing thyroidectomy under regional anesthesia.1,2 Regional anesthesia is achieved by performing a bilateral superficial cervical block using 0.5% bupivicaine with epinephrine, which is injected beneath the deep fascia of the neck at the midpoint posterior to the sternocleidomastoid muscles.2 Additional local anesthesia is also administered along the line of the incision. Specht and colleagues2 have demonstrated that regional anesthesia is a safe alternative to general anesthesia in selected patients underNo competing interests declared.
Received June 4, 2002; Accepted June 4, 2002. From the Department of Surgery, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH. Correspondence address: Christopher R McHenry, MD, Department of Surgery, # H 917, MetroHealth Medical Center, 2500 MetroHealth Dr, Cleveland, OH 44109-1998.
© 2002 by the American College of Surgeons Published by Elsevier Science Inc.
364
ISSN 1072-7515/02/$21.00 PII S1072-7515(02)01307-8
Vol. 195, No. 3, September 2002
nerve injury increased with the size of the resected thyroid tissue and extent of thyroid resection. Based on their results, surgical approaches that do not expose the recurrent laryngeal nerve cannot be recommended. The incidence of recurrent laryngeal nerve injury and hypoparathyroidism is a sensitive measure of the quality of thyroidectomies being performed and may reflect variations in surgeon experience. The relationship of volume of operations performed and outcomes has been examined for a number of surgical procedures and has recently become a focus for the business community.5 The Leapfrog Group, a large coalition of major corporations, is using information on quality of care to determine which institutions will be used to provide health care for their employees.6 The relationship of volume of operations performed and outcomes has also been examined for thyroid surgery but not to the extent of some other operations.7-9 Sosa and colleagues 7 demonstrated a significant inverse relationship between the volume of thyroidectomies performed and complication rates for individual surgeons in Maryland. The authors make a compelling case for referral of patients with known or suspected thyroid cancer or patients for whom total or near total thyroidectomy is necessary to high-volume surgeons. Other variables may also contribute to successful outcomes from thyroidectomy. Efforts to improve surgical training, establishment of fellowship programs for those interested in specializing in thyroid surgery, and provisions for consultation and supervision for new surgeons during their maturation process may also help to improve the quality of patient care.5 The challenge in the evaluation and management of patients with nodular thyroid disease is to distinguish patients at high risk for cancer who will benefit from thyroidectomy from patients with benign disease who can be observed. In most patients, a history, physical examination, fine-needle aspiration biopsy, and a screening serum TSH level are all that is necessary to decide on the most appropriate management of a thyroid nodule.10 Iodine-123 thyroid scintigraphy is of value only for patients with a fine-needle aspiration biopsy that is consistent with a follicular neoplasm or persistently nondiagnostic in patients with a low serum thyroid-stimulating hormone (TSH) level.10 Routine use of ultrasonography is unnecessary. Ultrasonography has value in helping to guide fine-needle aspiration biopsy in patients with nonpalpable nodules and for biopsying the solid component of a complex cystic-solid
McHenry
What’s New in General Surgery: Endocrine
365
nodule.11 When a nodule is palpable, the results of standard percutaneous and ultrasound-guided fine-needle aspiration biopsy are equivalent.11 As a result, standard fineneedle aspiration biopsy is preferable because of the higher cost of ultrasound-guided fine-needle aspiration biopsy. With increased use of positron emission tomography with 18F-fluorodeoxyglucose (FDG) for evaluation of patients with malignancy, incidental hot spots within the thyroid gland are being discovered, and a high rate of clinically relevant malignancy is being reported.12,13 The most likely explanation is that FDG-PET scans preferentially image malignant lesions because of their increased rate of glucose uptake and glycolysis.12 Cohen and coauthors13 reported a 2.3% incidence of thyroid FDG-PET incidentalomas and demonstrated that thyroid lesions with focal FDG uptake and higher standardized uptake values were more likely to be malignant and should be evaluated with ultrasound-guided fine-needle aspiration biopsy. Diffuse thyroidal FDG uptake is observed in patients with chronic lymphocytic thyroiditis and Graves’ disease. Thyroid cancer is the most common endocrine malignancy. It accounts for approximately 1.6% of all new malignant tumors diagnosed annually in the United States, 0.9% of cancers in men, and 2.6% of cancers in women.14 The incidence of thyroid cancer varies between 0.004% and 0.1% in the general population. As of 2002, the thyroid gland was the ninth most common cancer site for women.14 The American Cancer Society estimates 20,700 new cases of thyroid cancer (15,800 in women and 4,900 in men) and 1,300 deaths from thyroid cancer in the United States in 2002.14 Respiratory insufficiency from pulmonary metastases is the most common cause of death from thyroid cancer.15 The longterm prognosis for patients with differentiated thyroid cancer is generally very good, but tumor recurrence may occur in up to 20% of patients, underscoring the importance of longterm followup. Mazzaferri and Kloos16 demonstrated that after treatment of differentiated thyroid cancer, 10% of patients considered free of disease based on a serum thyroglobulin level less than 2 ng/mL while on thyroid hormone had persistent tumor when studied with recombinant human TSH. The diagnostic accuracy of serum thyroglobulin while on thyroid hormone therapy had a sensitivity of 36% and a false negative rate of 64%. Recombinant human TSH-stimulated serum thyroglobulin levels greater than 2 ng/mL had a sensitivity of 100%, a neg-
366
McHenry
What’s New in General Surgery: Endocrine
ative predictive value of 100%, and a 9% false positive rate. Diagnostic whole body scanning and measurement of radioactive iodine uptake added no additional information to that provided by recombinant human TSHstimulated serum thyroglobulin. The authors emphasize that tests to detect cancer should have a very high negative predictive value, which is not true for a low or undetectable serum thyroglobulin level while on thyroid hormone. Patients with no clinical evidence of residual or recurrent differentiated thyroid cancer and undetectable serum thyroglobulin levels while on thyroid hormone should periodically undergo measurement of serum thyroglobulin after TSH stimulation. A diagnostic whole body scan adds little and its omission will reduce cost. The treatment of well-differentiated thyroid cancer consists of thyroidectomy, iodine-131 administration, and thyrotropin suppression with thyroid hormone. Approximately 30% to 40% of well-differentiated thyroid cancers are resistant to radioactive iodine therapy. Zarnegar and associates17 have investigated the use of trichostatin A, a histone-deacetylating inhibitor, as a potential therapeutic agent for enhancing radioactive iodine uptake in patients with thyroid cancer. They demonstrated that the in vitro use of trichostatin A dramatically increased sodium iodine symporter gene expression and reduced the Pendren syndrome gene expression in cell lines from papillary, Hurthle cell, and follicular cell cancer. Although it has yet to be tested in humans, observed effects of trichostatin A might lead to enhanced radioactive iodine uptake in thyroid cancers with no or low radioactive iodine uptake. Medullary thyroid carcinoma, in contrast to most follicular cell-derived cancers, is notable for rapid lymphatic spread and systemic metastases. Hereditary forms account for 20% to 30% of all medullary thyroid carcinomas that occur as a result of germline mutations in various codons of the RET protooncogene. There is controversy over the appropriate age for prophylactic thyroidectomy in patients identified as carriers of mutations in the RET protooncogene. Patients with MEN 2B, caused by a mutation in codon 918 of the RET protooncogene, develop medullary thyroid cancer at a very early age and thyroidectomy is recommended in infancy.18 Patients with MEN 2A, caused by mutations in codons 609, 611, 618, 620, 630, and 634 develop medullary thyroid cancer later and preventative thyroidectomy has been recommended at 5 or 6 years of age.18
J Am Coll Surg
Ukkat and coworkers19 demonstrated that postponement of prophylactic thyroidectomy beyond 20 years of age in nonindex patients carrying germline mutations in the RET protooncogene exposes them to an unacceptably high risk of metastatic medullary thyroid cancer, which may preclude biochemical cure. The authors emphasize that prophylactic thyroidectomy should be performed before basal serum calcitonin levels turn positive. PARATHYROID A National Institutes of Health (NIH)-sponsored consensus conference was convened in April 2002 to reevaluate the 1990 guidelines for parathyroidectomy in primary hyperparathyroidism. A consensus statement is forthcoming. The 1990 consensus panel recommended parathyroidectomy in all symptomatic patients and in asymptomatic less than age 50 or with marked hypercalcemia (serum calcium greater than 11.5 mg/dL), hypercalciuria (24 hour urine calcium greater than 400 mg), renal insufficiency (a reduced creatinine clearance by more than 30% for age in the absence of another cause), or a reduction in bone mineral density greater than two standard deviations compared with age, gender, and race matched controls.20 Sywak and colleagues21 point out that the NIH Consensus Panel reserved the term asymptomatic for patients who presented with typical renal, bone, gastrointestinal, or neuromuscular manifestations of hyperparathyroidism. Nonspecific symptoms of hyperparathyroidism such as fatigue, irritability, mood swings, depression, and forgetfulness were not included in the NIH definition of symptomatic. Using a diseasespecific outcomes tool called the Parathyroidectomy Assessment of Symptoms Scores, Sywak and associates21 demonstrated that the so-called “asymptomatic” patients with hyperparathyroidism were indeed suffering from reversible, nonspecific manifestations and benefited from parathyroidectomy. In view of their observations that parathyroidectomy in primary hyperparathyroidism significantly improves vague nonspecific symptoms, they suggest that guidelines for parathyroidectomy should be broadened to include nonspecific manifestations of the disease. Since the 1990 NIH Consensus Development Conference on diagnosis and management of asymptomatic hyperparathyroidism, it has become evident that primary hyperparathyroidism is associated with increased mortality.22-24 Untreated hyperparathyroidism may re-
Vol. 195, No. 3, September 2002
duce a patient’s survival by approximately 10% when compared with expected values.24 The increased mortality has been attributed to cardiovascular disease and, less commonly, to malignancy or renal failure.22-24 Primary hyperparathyroidism has been reported to be associated with a number of cardiovascular sequelae.25 The cardiovascular sequelae and reduced survival observed in patients with primary hyperparathyroidism can be reversed by parathyroidectomy.25,26 Management of sporadic primary hyperparathyroidism has evolved to include minimally invasive parathyroidectomy.27 This is a technique designed for removal of a single adenoma localized by a preoperative technetium-99m-sestamibi scan. A focused exploration is performed under cervical block anesthesia using a small incision. An intraoperative parathyroid hormone assay is used for determining the adequacy of operation. Patients are discharged within 2 to 3 hours of operation. Udelsman27 has demonstrated that minimally invasive parathyroidectomy is associated with a significant reduction in operating room time and significant cost savings. Cure and complication rates are equivalent to those achieved by conventional parathyroidectomy. The postoperative course for patients with primary hyperparathyroidism who have undergone curative parathyroidectomy is characterized by persistent parathyroid hormone elevation in 27% of patients despite resolution of hypercalcemia.28 It is important to recognize that this is not a manifestation of persistent disease but is most likely a compensatory response to remineralization of cortical bone. This is usually a transient phenomenon resolving in most patients within 5 months of operation. From one of the largest databases of MEN-I-related hyperparathyroidism, Goudet and colleagues29 found that the most powerful factor for correction of hypercalcemia was performance of a subtotal parathyroidectomy, defined as removal of all parathyroid tissue except for the weight of one normal gland. Their results emphasize that MEN-I-related hyperparathyroidism is a multiglandular disease. In one of the largest series of reoperations for MEN-I hyperparathyroidism, Kivlin and coauthors 30 emphasized that the primary treatment of hyperparathyroidism in patients with MEN-I consists of either subtotal parathyroidectomy and transcervical thymectomy or a total parathyroidectomy, transcervical thymectomy, and parathyroid autotransplantation. Despite an “adequate operation” there remains a striking propensity for recurrence in this population of patients. Twenty-seven
McHenry
What’s New in General Surgery: Endocrine
367
percent of patients who underwent parathyroid autotransplantation developed autograft-mediated recurrence at a median of 15 months followup. This propensity for recurrence is attributed to the underlying mutation in the MEN-I gene, which is responsible for progressive neoplasia of any remaining parathyroid tissue. Decker and colleagues31 report that over the period from 1986 to 1998 a persistent fraction of patients with end-stage renal disease ultimately required parathyroidectomy for secondary or tertiary hyperparathyroidism despite the advances in dialysis and pharmacotherapy. In contrast to patients with primary hyperparathyroidism, patients with secondary or tertiary hyperparathyroidism are usually younger and more likely to have severe skeletal manifestations, profound symptomatic hypocalcemia after parathyroidectomy, and persistent or recurrent hyperparathyroidism.32 Patients with symptomatic secondary hyperparathyroidism have significant bone loss from the lumbar spine and the femoral neck. Chou and coworkers33 demonstrated that 6 months after successful parathyroidectomy, bone mass in the lumbar spine and the femoral neck increased significantly and osteopenia and osteoporosis improved significantly. Parathyroidectomy has recently been shown to produce a consistent and significant improvement in anemia, an increase in serum erythropoietin levels and platelet count, and improvement in nutritional status for patients with secondary hyperparathyroidism.34 ADRENAL The National Institutes of Health State of the Science Draft Statement on the management of clinically inapparent adrenal mass was completed on February 6, 2002, and can be accessed from the State of the Sciences Web site, http://consensus.NIH.gov/ta/021/021statement. htm. The panel of experts recommended that all patients with clinically inapparent adrenal masses undergo a 1-mg dexamethasone suppression test and measurement of either urine or plasma-free metanephrines. Patients who are hypertensive should also have serum potassium, serum aldosterone, and plasma renin activity measured. All pheochromocytomas, aldosterone-producing adenomas, and cortisol-producing adenomas in patients with signs and symptoms of hypercortisolism should be treated with adrenalectomy. They indicated that there are insufficient data to definitively recommend surgical therapy for patients with subclinical hypercortisolism. The panel also indicated that recommendations for sur-
368
McHenry
What’s New in General Surgery: Endocrine
gical treatment of nonfunctioning adenomas were derived from studies that were not standardized for inclusion criteria, length of followup, or methods for estimating risk of carcinoma. Recognizing these limitations, they recommended adrenalectomy for all tumors greater than 6 cm, observation for tumors less than 4 cm, and for tumors between 4 and 6 cm, other criteria should be considered before deciding whether to proceed with observation or surgery. In patients with tumors less than 4 cm that are unchanged in size on two imaging studies separated by 6 months with no evidence for hormonal hypersecretion for 4 years, further followup may not be warranted. Recent data suggest that the incidence of primary aldosteronism in patients with hypertension is higher than previously appreciated.35,36 Fardella and associates36 reported that the prevalence of primary aldosteronism was 9.5% among patients referred to their university outpatient clinic for evaluation and management of hypertension. It has previously been suggested that primary aldosteronism is rare, accounting for 1% or less of all patients with hypertension. The explanation for the higher prevalence of primary aldosteronism is related to the recognition that more than half of patients with primary aldosteronism have normal circulating potassium levels.35 In the past, the diagnosis was not pursued unless hypokalemia was present. Furthermore, primary aldosteronism may occur as a result of a biologically significant increase in serum aldosterone without the absolute level exceeding the upper limit of normal.35 This emphasizes the importance of determining the serum aldosterone/ plasma renin activity ratio to screen hypertensive patients. The aldosterone/plasma renin activity ratio is a more sensitive screening test than waiting for the serum aldosterone level to increase or the serum potassium level to decrease, both of which are late phenomena in patients with primary aldosteronism. Laparoscopic adrenalectomy is regarded as the treatment of choice for most patients with benign adrenal tumors. Open adrenalectomy is still considered the treatment of choice for adrenocortical carcinoma and malignant pheochromocytomas. Li and colleagues37 report the first descriptions of recurrent pheochromocytoma 34 to 48 months after laparoscopic adrenalectomy in three patients. The authors hypothesize that intraperitoneal seeding at the time of laparoscopic adrenalectomy was the cause for recurrence. Each of the patients had large tumors ranging in size from 5.5 to 6.5 cm. One
J Am Coll Surg
patient had a documented tumor disruption and spillage at the original operation. Tumor friability was noted in a second patient. A third patient had a 6.5-cm tumor that required extensive dissection and excessive tumor manipulation before the adrenal vein could be ligated. At reoperation, multiple small tumor nodules were found in the adrenal bed near the site of initial laparoscopic resection in all three patients. The authors suggest that pheochromocytomas greater than 5 cm may be more appropriately removed by an open approach. They conclude that regardless of whether an open or laparoscopic approach is performed, longterm followup is necessary for all patients after resection of a pheochromocytoma. The best test or tests for diagnosis of pheochromocytoma have yet to be definitively established. Lenders and coworkers38 performed a multicenter cohort study of patients treated for pheochromocytoma and compared results for 214 patients in whom the diagnosis of pheochromocytoma was confirmed with results from 644 patients who were determined not to have the tumor. Among all patients with pheochromocytoma, sensitivities were highest for measurements of plasma-free metanephrines at 99% followed by urinary fractionated metanephrines at 97%. Specificities were highest for urinary vanillylmandelic acid at 95% and urinary total metanephrines at 93%. The specificity for plasma-free metanephrines was 89%. But plasma concentrations of normetanephrine greater than 2.5 pg/mL or metanephrine greater than 1.4 pg/mL, which represent 4- and 2.5-fold increases above the upper limits of normal, indicated a pheochromocytoma with a 100% specificity.39 More than 80% of patients with pheochromocytoma have elevated plasma metanephrine levels that indicate a pheochromocytoma with 100% specificity.39 Lenders and colleagues38 concluded that measurement of plasma-free metanephrines is the best test for excluding or confirming pheochromocytoma and should be the first test chosen for diagnosis of the tumor. A negative test virtually excludes pheochromocytoma and no further biochemical testing is necessary. For patients with less than a 4-fold increase in plasma-free normetanephrine and less than a 2.5-fold increase in plasma-free metanephrine, it is important to differentiate a true positive from a false positive test. A careful history should be obtained to exclude potential sources for false positive test results, including: caffeic acid, a catechol present in coffee; acetaminophen; nicotine; tricyclic antidepressants; and phenoxybenzamine. Addi-
Vol. 195, No. 3, September 2002
tional biochemical testing should then be performed including repeat plasma free metanephrines and a 24-hour urine for catecholamines, metanephrines, and vanillylmandelic acid. Neumann and colleagues40 tested 271 unrelated patients who presented with apparent sporadic pheochromocytoma for mutations of the RET-protooncogene present in MEN 2A or 2B, the tumor suppressor gene of vonHippel Lindau disease, and the newly identified genes for succinate dehydrogenase subunit B and subunit D present in patients with pheochromocytoma and paragangliomas. Deleterious mutations were found in 24% of patients, two-thirds of whom had solitary disease and no signs or symptoms at presentation. They concluded that routine genetic analysis is indicated to identify pheochromocytoma-associated syndromes and to prompt genetic testing of all first-degree relatives of the carrier to determine the presence or absence of family-specific-mutations. It is also important to identify patients with familial pheochromocytoma because of the presence of associated endocrinopathies and the high incidence of bilateral disease. Brunt and colleagues41 treated 21 patients with familial pheochromocytoma; 12 (57%) had bilateral disease, with synchronous tumors in 2 patients and metachronous tumors in 10. At presentation, 48% of patients were asymptomatic, underscoring the importance of yearly biochemical screening in patients diagnosed with familial pheochromocytoma or a familial pheochromocytoma-associated syndrome. After initial adrenalectomy for familial pheochromocytoma, onethird of patients developed a contralateral pheochromocytoma within 5 years of followup. None of the patients experienced hypertensive crisis or other complications of undiagnosed pheochromocytoma during longterm followup. This, along with the minimally invasive nature of laparoscopic adrenalectomy, led the authors to recommend a unilateral approach for patients with a single imagable adrenal tumor and a normal contralateral adrenal gland. This approach is safe and allows for maintenance of functioning adrenal tissue for as long as possible. PANCREAS Insulinoma is the most common endocrine tumor of the pancreas. The biggest challenge in managing patients with an insulinoma is localization of the tumor. Precise localization of an insulinoma is imperative for surgical
McHenry
What’s New in General Surgery: Endocrine
369
cure. Controversy exists over what constitutes the best test for localization of an insulinoma. Most insulinomas are less than 2 cm in size, and conventional imaging studies such as CT or MRI frequently do not localize these tumors. Hiramoto and associates42 compared the results of invasive preoperative localization studies, either portal venous sampling or selective intraarterial calcium stimulation with hepatic venous sampling with intraoperative ultrasonography for 37 consecutive patients with a diagnosis of insulinoma without MEN. Intraoperative ultrasonography was found to be the single best localization study. Although intraoperative ultrasonography identified the majority of insulinomas, two tumors (5%) were missed in the tail of the pancreas, both of which were identified preoperatively by portal venous sampling in one patient and calcium arteriography in one patient. The authors recommend the use of both preoperative calcium arteriography and intraoperative ultrasonography for all patients diagnosed with an insulinoma. Richards and colleagues43 advocate a preoperative localization strategy for insulinoma that relies solely on endoscopic ultrasonography in 80% to 85% of patients. Arteriography with intraarterial calcium stimulation and hepatic venous sampling is obtained in the 10% to 15% of patients who have a negative endoscopic ultrasound and for patients with findings suggestive of malignancy. CT is obtained for patients with a large or locally invasive tumor to evaluate the liver for metastases. Most insulinomas are solitary and benign, and enucleation is the usual recommended surgical treatment. With successful preoperative localization, a laparoscopic approach is an option for resection for solitary, benign insulinomas. Iihara and associates44 have demonstrated that enucleation and resection of insulinomas may be accomplished laparoscopically with the aid of laparoscopic ultrasonography. A major concern in the operative treatment of hyperinsulinism is incomplete resection of hyperfunctioning tissue.43 This is an especially important concern in patients with multiple endocrine neoplasia type I, nesidioblastosis, and malignant insulin-producing tumors. Carneiro and coworkers45 reported their experience with a newly developed intraoperative, 8-minute immunochemiluminescent assay for insulin in eight patients with organic hypoglycemia secondary to a single, benign pancreatic insulinoma in six, multiple insulinomas in
370
McHenry
What’s New in General Surgery: Endocrine
one, and adult nesidioblastosis in one patient. Intraoperative criteria for successful treatment was return of insulin levels to the normal range and a fall in the insulin-glucose ratio below 0.4 15 minutes after tumor resection. Sensitivity of the assay was 83%, specificity 100%, and overall accuracy 89%. A rapid insulin assay may be helpful in avoiding incomplete resection of hyperfunctioning tissue. Proye and colleagues 46 and Amikura and coworkers47 were responsible for some of the initial work evaluating the use of insulin monitoring during resection of insulinoma but with an immunoradiometric assay requiring 30 to 60 minutes to obtain a result. Richards and associates 43 have indicated that failed surgical treatment of insulinoma occurs as a result of inability to discern malignancy intraoperatively, multiple foci of disease, islet cell hyperplasia, nesidioblastosis, or inexperience. They suggest that intraoperative insulin assays may lead to a reduction in operative failures by identifying persistent disease. GASTROINTESTINAL Zyromski and colleagues48 reviewed 27 patients with duodenal carcinoid tumors treated at the Mayo Clinic from 1976 to 1999. Most patients presented with abdominal pain and, less often, with vomiting, weight loss, gastrointestinal bleeding, or pancreatitis. Tumors were present in the first or second portion of the duodenum in all but two patients and the diagnosis was usually made by endoscopic biopsy. From a review of their treatment results, the authors suggest that tumors less than 1 cm can be endoscopically excised; for tumors between 1 and 2 cm an open transdudoneal excision should be performed to ensure complete resection. Size greater than 2 cm, invasion of the muscularis propria, and periampullary location appear to be associated with a more aggressive course and poorer prognosis. But it is unclear whether more extensive local-regional resection has an impact on outcomes. All patients with tumors 2 cm or larger who were resected for cure developed recurrent disease despite undergoing either segmental resection or pancreaticoduodenectomy. Like other carcinoid tumors, the duodenal carcinoids were associated with second malignancies in one-third of patients. REFERENCES 1. LoGerfo P. Local/regional anesthesia for thyroidectomy: Evaluation as an outpatient procedure. Surgery 1998;124:975–979.
J Am Coll Surg
2. Specht MC, Romero M, Barden CB, et al. Characteristics of patients having thyroid surgery under regional anesthesia. J Am Coll Surg 2001;193:367–372. 3. Miccoli P, Berti P, Raffaelli M, et al. Comparison between minimally invasive video-assisted thyroidectomy and conventional thyroidectomy: A prospective randomized study. Surgery 2001; 130:1039–1043. 4. Hermann M, Alk G, Roka R, et al. Laryngeal nerve injury in surgery for benign thyroid diseases: Effect of nerve dissection and impact of individual surgeon in more than 27,000 nerves at risk. Ann Surg 2002;235:261–268. 5. McHenry CR. Patient volumes and complications in thyroid surgery. Br J Surg (in press). 6. Birkmeyer JD, Finlayson EV, Birkmeyer CM. Volume standards for high-risk surgical procedures: Potential benefits of the Leapfrog initiative. Surgery 2001;130:415–422. 7. Sosa JA, Bowman HM, Tielsoti JM, et al. The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann Surg 1998;228:320–330. 8. LaMade W, Renz K, Willeke F, et al. Effect of training on the incidence of nerve damage in thyroid surgery. Br J Surg 1999; 86:388–391. 9. Mishra A, Agarwal G, Agarwal A, et al. Safety and efficacy of total thyroidectomy in hands of endocrine surgery trainees. Am J Surg 1999;178:377–380. 10. McHenry SR, Slusarczyk S, Ascari AT, et al. Refined use of scintigraphy in the evaluation of nodular thyroid disease. Surgery 1998;124:656–662. 11. Mittendorf EA, Tamarkin SW, McHenry CR. The results of ultrasound-guided fine-needle aspiration biopsy for evaluation of nodular thyroid disease. Surgery (in press). 12. Van den Bruel A, Maes A, DePotler T, et al. Clinical relevance of thyroid fluorodeoxyglucose-whole body positron emission tomography incidentaloma. J Clin Endocrinol Metab 2002;87: 1517–1520. 13. Cohen MS, Arslan N, Dehdashti F, et al. Risk of malignancy in thyroid incidentalomas identified by fluorodeoxyglucosepositron emission tomography. Surgery 2001;130:941–946. 14. Jemal A, Thomas A, Murray T, et al. Cancer statistics, 2002. CA Cancer J Clin 2002;52:23–47. 15. Kitamara Y, Shimizuk K, Nagahama M, et al. Immediate causes of death in thyroid carcinoma: Clinicopathological analysis of 161 fatal cases. J Clin Endocrinol Metab 1999;84:4043–4049. 16. Mazzaferri EL, Kloos R. Is diagnostic iodine-131 scanning with recombinant human TSH useful in the follow-up of differentiated thyroid cancer after thyroid ablation? J Clin Endocrinol Metab 2002;87:1490–1498. 17. Zarnegar R, Brunaud L, Kanauchi H, et al. Increasing the effectiveness of radioactive iodine therapy in the treatment of thyroid cancer using Trichostatin A (TSA), a histine deacetylase (HDAC) inhibitor. Surgery (in press). 18. Moley JF. Invited commentary: Are specific inherited mutations important in clinical management of hereditary cancer syndromes? Surgery 2002;131:382–383. 19. Ukkat J, Lorenz K, Hinze R, et al. Importance of early screening and prophylactic thyroidectomy in asymptomatic nonindex RET germline carriers. World J Surg 2001;25:713–717. 20. NIH Conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement. Ann Intern Med 1991;114:593–597. 21. Sywak MS, Knowlton ST, Pasieka JL, et al. Do the National Institutes of Health Consensus Guidelines for parathyroidec-
Vol. 195, No. 3, September 2002
22. 23. 24. 25.
26. 27. 28.
29.
30. 31. 32. 33. 34.
tomy predict symptom severity and surgical outcome in patients with primary hyperparathyroidism? Surgery (In Press). Sivula A, Pelkonen R. Long-term health risk of primary hyperparathyroidism: the effect of surgery. Ann Med 1996;28:95– 100. Hedback G, Tisell LE, Bengtsson BA, et al. Premature death in patients operated on for primary hyperparathyroidism. World J Surg 1990;14:839–836. Palmer M, Adami HO, Berstrom R, et al. Survival and renal function in untreated hypercalcemia. Population-based cohort study with 14 years of follow-up. Lancet 1987;1:59–62. Stefenilli T, Mayr H, Bergler-Klein J, et al. Primary hyperparathyroidism: incidence of cardiac abnormalities and partial reversibility after successful parathyroidectomy. Am J Med 1993; 95:197–202. Hedback G, Oden A, Tisell LE. The influence of surgery on the risk of death in patients with primary hyperparathyroidism. World J Surg 1991;15:399–407. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 2002;235:665–672. Mittendorf EA, McHenry CR. Persistent parathyroid hormone elevation following curative parathyroidectomy for primary hyperparathyroidism. Arch Otolaryngol Head Neck Surg 2002; 128:275–279. Goudet P, Cougard P, Verges B, et al. Hyperparathyroidism in multiple endocrine neoplasia Type I: Surgical trends and results of 256-patient series from Groupe d’Etude des Neoplasies Endocriniennes Multiples Study Group. World J Surg 2001;25: 886–890. Kivlin MH, Bartlett DL, Libutti SK, et al. Reoperations for hyperparathyroidism in multiple endocrine neoplasia type I. Surgery 2001;130:991–998. Decker PA, Cohen EP, Doffek KM, et al. Subtotal parathyroidectomy in renal failure: still needed after all these years. World J Surg 2001;25:708–712. McHenry CR, Wilhelm SM, Ricanati E. Refractory renal hyperparathyroidism: clinical features and outcome of surgical therapy. Am Surg 2001;67:310–317. Chou FF, Chen JB, Lee CH, et al. Parathyroidectomy can improve bone mineral density in patients with symptomatic secondary hyperparathyroidism. Arch Surg 2001;136:1064–1068. Yasunaga C, Matsuo K, Yanagida T, et al. Early effects of parathyroidectomy on erythropoietin production in secondary hyperparathyroidism. Am J Surg 2002;183:199–204.
McHenry
What’s New in General Surgery: Endocrine
371
35. Gordon RD, Stowasser M. Rutherford JC. Primary aldosteronism: Are we diagnosing and operating on too few patients? World J Surg 2001;25:941–947. 36. Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile and molecular biology. J Clin Endocrine Metab 2000; 85:1863–1867. 37. Li ML, Fitzgerald PA, Price DC, et al. Iatrogenic pheochromocytomatosis: A previously unreported result of laparoscopic adrenalectomy. Surgery 2001;130:1072–1077. 38. Lenders JWM, Pacak K, McClellan WM, et al. Biochemical diagnosis of pheochromocytoma: Which test is best? JAMA 2002;287:1427–1434. 39. Eisenhofer G. Biochemical diagnosis of pheochromocytoma. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 2001;134:317– 320. 40. Neumann HPH, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002;346:1459–1466. 41. Brunt LM, Lairmore TC, Doherty GM, et al. Adrenalectomy for familial pheochromocytoma in the laparoscopic era. Ann Surg 2002;235:713–721. 42. Hiramoto JS, Feldstein VA, LaBerge JM, et al. Intraoperative ultrasound and preoperative localization detects all occult insulinomas. Arch Surg 2001;136:1020–1026. 43. Richards ML, Gauger PG, Thompson NW, et al. Pitfalls in the surgical treatment of insulinoma. Surgery (in press). 44. Iihara M, Kanbe M, Okamoto T, et al. Laparoscopic ultrasonography for resection of insulinomas. Surgery 2001;130:1086– 1091. 45. Carneiro DM, Levi JU, Irvin GL. Rapid insulin assay for intraoperative confirmation of complete resection of insulinomas. Surgery (in press). 46. Proye CA, Pattou F, Carnaille B, et al. Intraoperative insulin measurement during surgical management of insulinomas. World J Surg 1998;22:1218–1224. 47. Amikura K, Nakamura R, Arai K, et al. Role of intraoperative insulin monitoring in surgical management of insulinoma. J Lap Adv Surg Tech 2001;11:193–199. 48. Zyromski NJ, Kendrick ML, Nagorney DM, et al. Duodenal carcinoid tumors: How aggressive should we be? J Gastrointest Surg 2002;5:588–593.