What’s New in General Surgery: Endocrine Surgery
Janice L. Pasieka, MD, FRCSC, FACS
“What’s New in Surgery” evolves from the contributions of leaders in each of the fields 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.
Adrenal
In 1911, Dr Harvey Cushing said, “I would like to see the day when somebody would be appointed surgeon somewhere who had no hands, for the operative part is the least part of the work.” In no area of endocrine surgery is this more true than in the diagnostic workup and surgical planning of patients with adrenal pathol- ogy. The past year saw the publication of a consensus conference on diagnosis and treatment of Cushing’s syn- drome.1 Although only 20% of Cushing’s syndrome pa- tients have ACTH-independent Cushing’s resulting from an adrenal source, the article provides an excellent consensus statement on the diagnostic criteria needed in the workup of these complex and often challenging patients.
Another important area for the endocrine surgeon is the laboratory diagnosis of pheochromocytomas. Au- thors from the Mayo Clinic compared their experience before the use of fractionated, plasma-free metanephrine (1978 to 1996) with current data obtained after the introduction of such testing.2 Plasma metanephrines had a sensitivity of 96%, yet a specificity of only 85%. Their experience demonstrated that biochemical testing for pheochromocytomas should be directed by the de- gree of clinical suspicion. Fractionated, plasma-free metanephrines were ideal in patients with a high pretest probability of the disease, such as familial patients (MEN IIa, IIb, von Hippel-Lindau [VHL], neurofibro- matosis type 1, or familial paraganglion syndrome) or patients in whom urinary collection is problematic (pe- diatric population). In the more common scenarios, those with incidentalomas, or patients with poorly con-
Correspondence address: Janice L Pasieka, MD, FACS, University of Calgary and the Calgary Health Region, 1403-29th St NW, Calgary, Alberta, Canada T2N 2T9.
trolled hypertension, 24-hour urinary metanephrines and catecholamines are recommended for screening because of their high specificity (99%) and acceptable sensitivity (88%). So 24-hour urinary metanephrine remains the best screening test for suspected pheochromocytomas.
Since Neumann and colleagues’3 report in 2001 dem- onstrating that 23% of sporadic pheochromocytomas carry mutations in either RET, VHL, SDHD, or SDHB genes, the 10% rule for pheochromocytomas continues to be challenged. Opocher and associates,4 in their series of 91 pheochromocytoma patients, found that 19% of the patients had bilateral disease and 30% proved to be familial. Although this might be because of the referral basis of the center, as we learn more about pheochromo- cytomas and improve our diagnostic accuracy, the 10% rule will likely need modification. With the growing support that genetic causes make up a greater proportion of pheochromocytomas than once believed, recommen- dations now are that genetic counseling and potential genetic testing should be offered to all patients diag- nosed with pheochromocytoma before the age of 50.5
Pheochromocytomas are not the only adrenal lesions that investigators are studying at a molecular level. In their paper from the Karolinska Institute, Enberg and coworkers6 used mRNA gene expression to study adre- nal adenoma from patients with hyperaldosteronism and Cushing’s syndrome. The gene CYP11B2 encodes the steroid synthesis enzymes for aldosterone produc- tion, and the genes CYP11B1 and CYP17 are needed for cortisol production. Adenomas from patients with Conn’s syndrome showed considerable variation in ex- pression of CYP11B2; patients with Cushing’s syn- drome have strong expression for CYP11B1 and CYP17. Four patients with hyperaldosteronism had oc- cult nodules in the adrenal gland detected by expression of CYP11B2 gene when the adrenal mass seen on CT
| Abbreviations and Acronyms | |
|---|---|
| ACC | = adrenal cortical carcinoma |
| 18F-FDG-PET = fluorine-18-fluorodeoxyglucose positron emission tomography | |
| HPT | = hyperparathyroidism |
| iPHT | = intraoperative parathyroid hormone |
| MEN1 | = multiple endocrine neoplasia type 1 |
| MIBG | = metaiodobenzylguanidine |
| MIBI | = technetium 99m Sestamibi |
| NET | = neuroendocrine tumors |
| PTC | = papillary thyroid cancer |
| rhTSH | = recombinant human thyroid-stimulating hormone |
| SPECT | = single photon emission CT |
| VHL | = von Hippel-Lindau |
| WDTC | = well-differentiated thyroid cancer |
scan in these patients expressed CYP11B1 and CYP17, suggesting cortisol production in the visible nodule. This study emphasized the value of functional studies in the workup of patients with primary hyperaldosteron- ism, because it is likely that these occult nodules were responsible for the aldosterone production in these pa- tients. This study also brought into question increasing reports of partial adrenalectomies being done in patients with aldosterone-producing tumors.7 Adenomas in a background of microscopic hyperplasia are seen in 33% to 43% of patients with primary aldosterone-producing tumors.8,9 The clinical significance of this background hyperplasia is unclear, yet studies like Enberg’s should help clarify the degree of function from the nodules and/or the hyperplastic cortex in the future.
The importance of functional assessment in the form of selective venous sampling in patients with hyperaldo- steronism was illustrated in Young and colleagues’ recent paper from the Mayo Clinic.1º In their study of 203 patients, if CT findings alone were used to determine whether the patient suffered from idiopathic adrenal hy- perplasia or aldosterone-producing adenoma, 22% would have been incorrectly excluded as candidates for adrenalectomy and 25% might have had an inappropri- ate adrenalectomy. This study, with Enberg’s, demon- strates the increasing need for functional assessment af- ter biochemical and anatomic assessment of patients with hyperaldosteronism in the era of incidentalomas. Laparoscopic adrenalectomy is still considered the treat- ment of choice in patients with unilateral aldosterone- producing disease. But medical management of these patients has been suggested if mineralocorticoid recep-
tor blockade is used.11 Up until recently, spironolactone has been the drug of choice, but it is not a selective aldosterone receptor antagonist. It has many undesirable side effects related to antagonism of the testosterone re- ceptors that have limited its longterm use, especially in otherwise healthy males. Eplerenone is a competitive selective aldosterone antagonist that has become avail- able this past year and appears to be well tolerated. Whether we will see increased use of the drug as opposed to adrenalectomy in these patients remains to be seen.
Unfortunately, there is very little new to report on the treatment of adrenal cortical carcinoma (ACC). This rare and universally fatal disease was reviewed by Ng and Libertino.12 Using data from 7 institutions, they re- viewed 602 patients with ACC and found that 62% of ACC were functional at presentation and that stage at diagnosis is the most significant prognostic factor. Com- plete resection was the only effective treatment modality, with the median survival of patients with completely resected disease ranging from 13 to 28 months; patients with unresected disease survived from 3 to 9 months. Wood and associates13 reported on a novel approach using radiofrequency ablation (RFA) of adrenal tumors that were unresectable or in patients who were poor surgical candidates. They found that percutaneous ra- diofrequency ablation was a safe and well-tolerated pro- cedure most effective for tumors less than 5 cm. This unfortunately limits its use in ACC, which tend to be greater than 10 cm, but it does warrant further study in the use of recurrence or unresectable tumors.
Finally, the role of adrenalectomy for isolated solitary adrenal metastasis was evaluated in 41 patients from Memorial Sloan-Kettering Cancer Center.14 This study found that a disease-free interval greater than 6 months (metachronous lesions) was the only significant predic- tor of improved survival. Although limited in the num- ber of patients, their data also suggested that there was no oncologic disadvantage to removing the metastases laparoscopically in properly selected patients. So pa- tients with solitary metastatic disease to the adrenal gland should be assessed for possible surgical resection.
Parathyroid
Hyperparathyroidism (HPT) is one of the most com- mon causes of hypercalcemia. The prevalence is esti- mated to be as high as 2% of menopausal women. The surgical approach to HPT has evolved over the last de- cade partly because of the introduction of minimal-
access surgery and the use of preoperative imaging and intraoperative parathyroid hormone (iPHT) monitor- ing. Imaging studies are neither sensitive nor specific enough to make or confirm the diagnosis of HPT, but they have allowed many surgeons to use image-directed parathyroidectomy in selected patients. Most series in the literature report a sensitivity of 60% to 70% for technetium 99m Sestamibi scan (MIBI), and this in- creases with the use of single photon emission CT (SPECT) to 90%.15,16 Not all practicing clinicians have experienced this degree of accuracy with the use of pla- nar MIBI imaging. This led to the report by Gotthardt and colleagues15 assessing the clinical value of parathy- roid scintigraphy, with a review of their clinical data and a metaanalysis of the literature. In their retrospective review of their own clinical data, they found the sensi- tivity of MIBI to be 45% and the specificity 94% in primary HPT and a sensitivity and specificity of only 40% in secondary HPT. In the metaanalysis of 52 stud- ies, the median sensitivity of MIBI was 72% (range 39% to 93%), although the quality of the studies analyzed was variable. Their study illustrates the need for a well- designed prospective study assessing the accuracy of MIBI in both academic and nonacademic centers.
Preoperative use of CT-MIBI image fusion could be on the horizon. A small series by Profanter and associ- ates17 found that CT-MIBI image fusion appeared to be superior compared with SPECT imaging alone. CT- MIBI image fusion had a sensitivity of 93% and a spec- ificity of 100% compared with a sensitivity of 31% and a specificity of 87% with SPECT imaging alone. The authors pointed out that any center capable of doing CT and SPECT imaging would be able to adopt this tech- nique, so this might be a new modality worth exploring.
Since 1996, more than 200 articles have been pub- lished on the use of iPTH to help guide the surgeon during parathyroidectomy. Many endocrine surgeons use iPTH to predict the successful outcomes of patients undergoing image-directed or minimal parathyroidec- tomy; others have used it in reoperative surgery and to assess adequacy of resection in patients with hyperplasia. To improve the specificity and decrease the cost of iPTH, several criteria have been used to predict com- pleteness of resection. Carneiro and coworkers18 did a nice job of comparing sensitivity, specificity, and overall accuracy of 5 different criteria in 341 patients. They found that a 50% or greater decrease in the iPTH result from preexcision values at 10 minutes had a 1% false-
negative and a 2.6% false-positive rate. Although the specificities of the other criteria were higher, this was at a cost of decreased accuracy. In patients with parathyroid hyperplasia, the criteria for iPTH are less clearly defined. Recently, Weber and colleagues19 reported their results on 46 patients with sporadic parathyroid hyperplasia and found more rigid criteria are required when inter- rupting iPTH values. In contast to solitary adenoma disease, a drop in iPTH values to less than 35 pg/mL or a greater than 90% drop from baseline was predictive of success in 89% of patients with parathyroid hyperplasia.
Not all surgeons have adopted the routine use of iPTH in parathyroidectomy. Many centers and health- care agencies fail to find the cost benefit of such technol- ogy when the standard four-gland exploration provides a 95% to 98% cure rate without it.20,21 Siperstein and colleagues,22 in a prospective study of 350 sporadic HPT patients, demonstrated that in patients with both con- cordant MIBI and ultrasonographic scans and appropri- ate iPTH drop, additional abnormal parathyroid glands were found after complete exploration in 15% of pa- tients. This would mean that if a focused parathyroidec- tomy was carried out in these patients, 15% of the time abnormal parathyroid tissue would be left behind. The definition of multigland disease was based on the weight and size of the parathyroid glands, and some would ar- gue whether these abnormally enlarged glands would or would not become hypersecreting in the future. Need- less to say, the study does demonstrate the need for a longterm followup of patients treated with image- directed parathyroidectomy to see if the rate of recur- rence equals the reported rates of missed multigland dis- ease seen in this and other studies. This study also calls for a randomized study comparing image-directed par- athyroidectomy with iPTH to a four-gland exploration.
Propofol is a sedative-hypnotic agent used commonly in outpatient surgical procedures. It is not used fre- quently in parathyroidectomies because reports have shown there is an interference in the iPTH assay in vitro. Sippel and colleagues23 presented a randomized trial studying the effect of propofol on iPTH levels in pa- tients with secondary hyperparathyroidism undergoing dialysis access surgery. The authors found no difference in iPTH levels measured throughout the procedure re- gardless of whether they received propofol or not. They concluded that iPTH assay can be safely used during propofol sedation in parathyroidectomies.
The use of iPTH has been expanded beyond parathy-
roid surgery. Lombardi and associates24 demonstrated that iPTH levels below the normal range (<10 pg/mL) 4 and 6 hours after total thyroidectomy were predictors of postoperative hypocalcemia. Their study of 53 con- secutive patients found that this criterion had a specific- ity of 100%, a sensitivity of 94%, and an overall accu- racy of 98%. This novel use of iPTH would identify patients at risk for hypocalcemia, allowing directed re- placement therapy and determining those eligible for early discharge.
Clinicians continue to debate the role of parathyroid- ectomy in the treatment of mild HPT. Throughout the years, surgeons have illustrated the benefits of parathy- roidectomy, not only in correcting the metabolic abnor- mities in calcium and PTH, but by also alleviating many of the symptoms these patients suffer from and improv- ing their quality of life. At the recent American Associ- ation of Endocrine Surgeons meeting, Bondeson and coworkers25 demonstrated, in a randomized trial, the effects of early parathyroidectomy on hip bone mineral density in patients with mild HPT. Although parathy- roidectomy done early (at the time of diagnosis) or de- layed for 1 year improved bone mineral density in the spine equally, only in the early intervention group did the bone density of the hip improve significantly. They concluded that prolonged exposure to mild HPT is a risk factor for hip fractures.
Several studies in the past from Sweden and Germany have found an increased risk of death from cardiovascu- lar disease in patients with HPT, but this increased mor- tality has not been borne out in North American studies. In the past year, a group from Denmark reported an increase in mortality in patients hospitalized with pri- mary HPT. In their study, Ogard and associates26 found that patients receiving a hospital diagnosis of HPT be- tween 1977 and 1993 had a significantly increased risk of premature death from cardiovascular disease and can- cer compared with that of the rest of the Danish popu- lation. They also found a tendency toward a lower stan- dard mortality ratio in the cohort of women operated on for HPT compared with women who were not oper- ated on. This lowering of the standard mortality ratio with surgical intervention was not seen in the male population.
Parathyroid carcinoma is a rare disease accounting for 1% to 3% of all cases of primary HPT. Histologic fea- tures of parathyroid carcinoma have included sheets of cells arranged in lobulated fashion with fibrous trabecu-
lae, capsular or vascular invasion, and mitotic figures. In a retrospective study from MD Anderson, these “classi- cal” pathologic features were not always present. Fibrous bands were seen in 37% of their patients, capsular inva- sion was observed in 26%, and trabeculae and lymphatic invasion in only 11%.27 Of interest, although retrospec- tive in nature, their study indicated that local recurrence rates were lower if adjuvant radiation was used after sur- gical resection, independent of the type of operation or stage of disease. Their 5-year survival rate was similar to that in the literature, at 85%, yet the 10-year survival was somewhat higher than previously reported, at 77%. In an attempt to facilitate the diagnosis of benign versus malignant parathyroid tumors, Stojadinovic and coau- thors28 studied 45 patients with adenomas, 8 with atyp- ical adenoma, and 20 patients with parathyroid carci- noma using immunohistochemistry carried out on tissue microarrays. They found that molecular markers Ki 67 and p27 may distinguish parathyroid carcinomas from adenoma because the molecular phenotype p27(+)Bcl-2(+)Ki67(-)mdm2(+) appears to be unique to nonmalignant parathyroid tumors.
Mutations of the recently cloned HRPT2 gene are seen in familial hyperparathyroidism-jaw tumor syn- drome patients, who are known to carry an increased risk of parathyroid cancer. Shattuck and colleagues29 found 10 of 15 parathyroid carcinomas had heterozy- gosity at HRPT2. They also found three supposedly sporadic patients had germ-line mutations in the HRPT2 gene. They concluded that certain patients with apparently sporadic parathyroid carcinoma carry germ- line mutations in HRPT2 and might have a phenotypic variant to hyperparathyroidism-jaw tumor syndrome. This study raises the question as to whether all patients with parathyroid carcinoma should be genetically screened for HRPT2 mutations.
Neuroendocrine tumors
Neuroendocrine tumors (NET) are rare tumors that originate from endocrine cell types. These tumors are also called carcinoids, a historical term first used by Oberndorfer to describe a “carcinomalike” tumor with a less aggressive behavior than adenocarcinoma of the gas- trointestinal tract. Although these tumors are considered rare and biologically indolent in nature, Modlin and colleagues’30 recent analysis of 13,715 carcinoid tumors brought into question these beliefs. In this large epide- miologic series from three national databases, they
found that the incidence of NET has increased over the past three decades. Whether this reflects a true in vivo change in this disease or an improvement in diagnosis is unclear. The data did question the widely held belief that the majority of these tumors behave in a benign fashion. They found that the overall 5-year survival for all NET, regardless of site, was 67.2%. They concluded that cur- rent therapeutic strategies for NET should be based on an appreciation of the obvious malignant, yet somewhat restrained, biologic behavior of these tumors.
Therapeutic options for patients with metastatic mid- gut carcinoids continue to evolve around surgical resec- tion and debulking of the tumor. In a retrospective anal- ysis of the effect of surgery on the outcomes of midgut carcinoid disease in patients with lymph node and liver metastases, Hellman and colleagues31 found that pa- tients whose primary tumor had been resected had a longer median survival than patients in whom the pri- mary was unresected (7.4 years versus 4 years [p < 0.01]). They also found that resection of the pri- mary tumor and the mesenteric lymph nodes led to a significant reduction in tumor-related symptoms, sup- porting the role of aggressive surgical resection of the primary tumor and regional nodes, even in the face of liver metastases. For patients with widespread NET dis- ease, several studies have demonstrated biochemical re- sponse in 40% to 50% and symptomatic response in 40% to 70% of patients treated with interferon-alpha.32 In a recent prospective randomized study in which pa- tients were randomized to either octreotide alone or in combination with interferon, there was no difference in the 5-year survival rates (37% versus 57%).33 But the authors did find that patients in the interferon/ octreotide arm had a significantly reduced risk of tumor progression and concluded that the addition of inter- feron to octreotide may retard tumor growth in patients with midgut carcinoids. The majority of patients with NET benefit from somatostatin analogue therapy, with a median duration of effect lasting 12 months. A new somatostatin analogue SOM 230 has been developed. It has a longer half-life (24 hours) and a higher affinity to somatostatin receptors 1, 2, 3, and 5 than the currently used analogues.32 The phase 1 clinical trial currently un- derway using SOM 230 will hopefully address the ques- tion of whether somatostatin receptor subtypes 1 and 3, which display antitumor effects, will be of clinical sig- nificance in the treatment of NET.
Other novel approaches to metastatic NET have been
explored. The use of isolated hepatic perfusion with mel- phalan was reported by the NIH group at the recent American Association of Endocrine Surgeons meeting.34 Half of their patients demonstrated a partial response for a mean duration of 12 months. Unfortunately, this form of treatment was associated with significant morbidity and long operative times, minimizing its universal use by most surgeons. Another less invasive approach to dis- seminated NET is the use of radionuclide therapies in- cluding 111 In-octreotide and 131I metaiodobenzylguani- dine (mIBG). In a retrospective cohort study done in our own center, we compared survival outcomes of pa- tients with metastatic midgut carcinoid tumors treated with or without the addition of 131I mIBG. 35 The 3- and 5-year survival rates were 77% and 63%, respectively, in the mIBG-treated group compared with survival rates of 56% and 47%, respectively, in the group treated with standard therapy only (p = 0.1). Although retrospective in nature, the addition of 131I mIBG might improve survival, and this treatment modality warrants more study. Whether radionuclide therapy will improve sur- vival in these patients or not, at the present time, thera- peutic use of 111 In-octreotide and 131I mIBG provided good palliation for patients with progressive NET, as shown in two recently reported series.36,37 The majority of NET will take up octreotide, yet because of the lim- ited particle penetration that 111 In provides, many re- search groups have developed somatostatin analogues that can be linked to therapeutic radionuclides that emit beta particles with longer particle ranges, such as 177 lu- tetium (177Lu) and 9ºyttrium (9ºYu). Preliminary results from these radionucleotides are encouraging.38,39 The fu- ture of radionuclide therapies will depend on the im- provement of existing peptide analogues and on the de- velopment of new peptide analogues and combination analogues, labeled with different radionuclides.
Multiple endocrine neoplasia type 1 (MEN I) contin- ues to fascinate the endocrine surgeon. Only a few cen- ters have a large experience with these tumors and it is from these centers that we have gained our current un- derstanding of the spectrum of the disease. Gibril’s group40 at the NIH was able to identify a number of clinical and laboratory features of MEN I patients with Zollinger-Ellison syndrome that were not previously ap- preciated, in their prospective study of 107 patients. Specifically, approximately 25% of MEN I/Zollinger- Ellison syndrome patients have no family history; pitu- itary disease, when looked for, is seen in 60% of patients,
much more common than the reported 30% for previ- ous studies; and carcinoid tumors are commonly seen in up to 30% of these patients. Surgical management of the MEN I pancreas remains controversial. Many centers have adopted an aggressive surgical approach designed to control functional syndromes and reduce the malig- nant potential of these tumors. At the recent American Association of Endocrine Surgeons meeting, the group from the University of Michigan reviewed their experi- ence with aggressive surgical resection of NET within the pancreas, duodenum, and the regional lymph nodes, known as a Thompson procedure.41 Followup data on 39 MEN I patients revealed that recurrence rates were high (77%), with the mean time to recurrence of 4 years. Although malignant growth was seen in 56% of their patients, only 2 (5%) have died as a result of malignant disease.
Thyroid
Thyroid surgery continues to be the most common op- eration performed by endocrine surgeons. Complica- tions from thyroidectomy continue to fuel the debate about the best surgical therapy for low-risk, well- differentiated thyroid cancer (WDTC). Although there are many case series from experienced surgeons report- ing the incidence of complications after thyroidectomy, there are few large cohort series that illustrate the risk of this procedure to the population at large. In a retrospec- tive analysis from Italy, 14,934 patients who underwent thyroid surgery were reviewed over a 5-year followup.42 The authors reported a transient hypoparathyroidism rate of 8.3% and a permanent rate of 1.7%. Recurrent laryngeal nerve injury, documented on direct laryngos- copy, was found transiently in 2% and permanent in an additional 1% of patients. The superior laryngeal nerve was damaged in 3.7% of the patients, and significant neck hematomas occurred in 1.2% of all patients. The extent of the procedure did influence the risk of these complications.
Papillary thyroid cancer (PTC) is the most common cancer arising in the thyroid. The treatment of PTC remains controversial because there are no randomized controlled studies to guide the surgeon. Part of the prob- lem is that the majority of patients with PTC have an excellent prognosis, with 10-year survival rates exceed- ing 90%. But there is a group of patients with PTC that has a more aggressive biologic behavior. Various prog- nostic risk classifications, such as AGES, AMES, and
MACIS, have been devised in an attempt to distinguish the low-risk patient from the more aggressive high-risk patient. The prognostic value of lymph node metatases, especially in young patients, remains controversial. Su- gitani and colleagues43 devised a novel classification sys- tem for PTC that included large (>3 cm) nodal metas- tases. Their series demonstrated that in older patients (>50 years), important prognostic factors included dis- tant metastases (risk ratio 6.7), large nodal metastasis (risk ratio 5.3), and extrathyroidal invasion (risk ratio 2.4). In particular, the authors found a high incidence of distant disease, and local and regional recurrence in pa- tients with large nodal metastases, disputing previous reports that stated the presence of nodal disease did not adversely affect outcomes of the patients.
Although these clinical prognostic scoring systems have helped provide some understanding of the biologic behavior of WDTC, it is likely that true prognosis of a tumor will be dictated by the molecular genetic makeup of the tumor. Recently developed genomic technologies help provide molecular profiles of these tumors in hopes of defining which tumors are more prone to metastasis, distinguishing prognostic outcomes from morphologi- cally identical tumors and perhaps predicting response to therapy. For example, Finley’s group44 from Cornell recently reported the genetic profiling of Hurthle cell tumors and found that both Hurthle cell adenomas and carcinomas displayed molecular profiles different from those of benign lesions or PTC, yet similar to follicular carcinomas. Although the Hurthle cell tumor profiles were similar to follicular carcinomas, when Hurthle cell adenomas were compared with Hurthle cell carcinomas, two distinct profiles emerged. This study supports the clinical observation that Hurthle cell carcinomas behave clinically more like follicular carcinomas than PTC, and it suggests that Hurthle cell adenomas may be the pre- cursors to Hurthle cell carcinomas.
Over the last several years, pathways involved in the development and progression of thyroid cancer have be- gun to be elucidated. Uncontrolled activation or overex- pression of receptor tyrosine kinases and downstream signaling molecules, and inhibition of apoptosis, have all been demonstrated in thyroid cancers. Several new agents directed at these mechanisms are currently being tested in vitro and in clinical studies.45 In their article, Braga-Basaria and Ringel45 reviewed potential new ther- apeutic approaches to thyroid cancer, including drugs targeted against the Ras pathway such as R115777
(Tipifarnib, Zarnestra; Johnson & Johnson); drugs that target receptor tyrosine kinases such as antivascular en- dothelial growth factor antibodies like bevacizumab (Avastin; Genetech Inc); anti-Her2/neu antibodies (Herceptin; Genetech Inc); and drugs targeted against the apoptotic pathways such as tumor necrosis factor- related, apoptosis-inducing ligands. It is likely that these or similar compounds will play a primary role in the treatment of thyroid cancer as our understanding of the disease increases.
At present, most clinicians continue to treat WDTC with surgical resection followed by radioiodine and thy- roid stimulating hormone (TSH) suppression. Al- though the debate about the best surgical treatment for WDTC will continue for decades to come, a new debate is emerging about the best followup for these patients in the era of recombinant human TSH (rhTSH). A num- ber of recently published studies using rhTSH and thy- roglobulin levels have proposed a variety of optimal sur- veillance strategies for patients with WDTC.46 In an effort to formulate from the literature a cost-efficient postoperative strategy for patients with WDTC who have no clinical evidence of disease after undergoing a total thyroidectomy and 131I thyroid remnant ablation, a consensus panel was devised.47 The panel believed that hypothyroid and euthyroid rhTSH-stimulated serum thyroglobulin levels are similar in detecting metastatic disease when a cutoff of 2 ug/L is used. They also con- cluded that TSH-stimulated thyroglobulin alone was sufficient for followup in low-risk patients with no clin- ical evidence of disease and suppressed thyroglobulin level during TSH suppression. Little information is gained by performing whole body scans in these pa- tients. The authors proposed surveillance guidelines us- ing TSH-stimulated thyroglobulin levels only for low- risk WDTC patients undergoing total thyroidectomy and 131I ablation, with no clinical evidence of residual disease and serum thyroglobulin level undetectable on TSH suppression.
Imaging modalities continue to evolve, adding a new dimension to the workup of thyroid nodules. Fluorine- 18-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is a noninvasive means of screening the whole body for various kinds of malignancies. Thyroid incidentalomas are seen on up to 50% of ultrasounds, yet have a low risk of cancer (1.5% to 10%). In contrast, 18F-FDG-PET studies have demonstrated an incidence of thyroid incidentalomas of 2.3%, with 47% demon-
strating malignancy.48 Kang and coauthors49 confirmed the prevalence of thyroid nodules on 18F-FDG-PET scan to be 2.2%, and this prevalence was not different in healthy subjects or those evaluated for metastasis of can- cer. More importantly, they demonstrated that focal thy- roid nodules carry a high risk of malignancy, especially in patients with high standard uptake values. In the pre- operative evaluation of thyroid nodules, Kresnik and associates5º found similar results. Standard uptake values greater than 2 were found in all thyroid carcinomas and Hurthle cell adenomas; follicular adenoma and degen- erative cysts had standard uptake values less than 2. These studies suggest that 18F-FDG-PET may be help- ful in selecting patients for surgery when cytology is inconclusive. 18F-FDG-PET may also be effective in the detection of recurrent or metastatic WDTC, particularly in patients with negative radioiodine scan and elevated thyroglobulin level.51 PET imaging with rhTSH stimu- lation may increase its sensitivity, but more studies are required to establish this clinically.
In summary, this year brought new advances to our understanding of endocrine surgical diseases. We con- tinue to expand our knowledge of the genetic profile of not only adrenal tumors, but also parathyroid carcino- mas and thyroid tumors. Understanding the genetic phenotype of these tumors will, in the future, change our current classification of these tumors and likely di- rect our treatment strategies. As we continue to use min- imally invasive surgical techniques in the treatment of HPT, development of better preoperative imaging and refinement of iPTH will become important in the fu- ture. Large national databases for tumors such as NET have allowed us to gain a better understanding of the biologic behavior of these rare tumors. Novel treatment modalities, such as targeted radiation, appear to play an important role in the palliation of patients with dissem- inated NET. As imaging modalities and biologic mark- ers continue to evolve, so will the ability of the clinician to follow and detect recurrence of disease at an early stage. Hopefully, this will allow for earlier intervention and improved survival.
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