Outcomes analysis in patients undergoing laparoscopic adrenalectomy for hormonally active adrenal tumors.

BACKGROUND: Laparoscopic adrenalectomy (LA) has become the preferred method of removal of most adrenal neoplasms, but few studies have evaluated the functional outcomes of this approach. The purpose of this study was to analyze our operative results and the clinical and biochemical responses to LA in patients with various hormonally active adrenal tumors. METHODS: From 1993 through November 2000, 72 patients with functional adrenal tumors underwent attempted LA. Data were obtained retrospectively by review of medical records, during routine follow-up, and by patient questionnaire. RESULTS: Indications for adrenalectomy were pheochromocytoma (n = 35), aldosteronoma (n = 29), cortisol-producing adenoma (n = 5), and adrenocorticotropic hormone-dependent Cushing's syndrome (n = 3). LA was completed in 70 of 72 patients, with 2 conversions (3%) to open adrenalectomy. Mean operative time for unilateral LA was 176 +/- 60 minutes, and postoperative length of hospital stay averaged 3.0 +/- 1.7 days. Complications, most of which were minor, occurred in 19% of patients; there were no serious complications or perioperative deaths. Two patients were unavailable for follow-up. At a mean follow-up interval of 37.6 months after LA (range, 2-90 months), resolution of clinical and biochemical signs of adrenal hyperfunction was accomplished in 34 of 34 patients with pheochromocytomas, 25 of 26 patients with aldosteronomas, 5 of 5 patients with cortisol-producing adenomas, and 3 of 3 patients with andrenocorticotropic hormone-dependent Cushing's syndrome. Two patients with multiple endocrine neoplasia (MEN) type 2 had contralateral pheochromocytomas removed 4 and 5 years after the initial surgery. Persistent hypertension necessitating medication was present in 72% of patients with aldosteronomas, although 92% of these patients had improved blood pressure control after LA. Recurrent hypokalemia developed in 1 patient (4%) with a cortical nodule in the contralateral adrenal. No local or distant tumor recurrences have occurred. CONCLUSIONS: LA results in an excellent clinical outcome in patients with various functional endocrine tumors. LA is associated with few major complications, and clinical and biochemical cure rates are comparable with those of open adrenalectomy during long-term follow-up.

Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1.

OBJECTIVE: To review the authors' 7-year experience with a surgical approach for pancreatic and duodenal neuroendocrine tumors (NETs) in patients with multiple endocrine neoplasia type 1 (MEN 1) designed to remove all gross tumor with limited complications, preserving pancreatic function. SUMMARY BACKGROUND DATA: MEN 1 is an autosomal dominant familial neoplasia syndrome characterized by the development of NETs of the duodenum and pancreas. Some tumors are clinically insignificant or follow a benign course, although a subset pursues a malignant, lethal natural history; the risk of surgical management must be appropriate to the disease course. METHODS: The clinical, biochemical, genetic, and pathologic data were retrospectively reviewed for 21 consecutive MEN 1 patients undergoing pancreatic resection for NETs between 1993 and 1999 at one institution. Age at operation, presenting symptoms, results of preoperative and intraoperative localization studies, major and minor complications, and pathology, including metastases, were analyzed. RESULTS: The surgical approach was selected based on the location and size of the tumors. Five patients required pancreaticoduodenectomy, 11 patients underwent non-Whipple pancreatic resections, and 5 underwent simple enucleation of benign NETs. The incidence of regional lymph node metastases was 33%. CONCLUSIONS: Major pancreatic procedures can be performed safely in most patients with MEN 1 and NETs. Because NETs are the most common MEN 1-related cause of death in the authors' kindreds, an aggressive surgical approach, including early intervention before malignant spread and major pancreatic resection where indicated, appears justified.

Preservation of the recurrent laryngeal nerves in thyroid and parathyroid reoperations.

BACKGROUND: The recurrent laryngeal nerve (RLN) is vulnerable to injury in thyroid and parathyroid reoperations because of the presence of scar tissue and displacement of the nerve from its normal position. METHODS: Since 1993, we have performed 132 reoperations for recurrence of thyroid or parathyroid carcinoma (102 cases), persistent hyperparathyroidism (21 cases), and recurrent goiter (9 cases). One or both RLNs were identified in all cases (208 nerves). Exposure of the nerve was accomplished by a lateral approach (159 nerves), a low anterior approach (41 nerves), or the identification of the nerve between the larynx and the upper pole of the thyroid, in parathyroid reoperations (8 nerves). Dissection was then done while the nerve was kept in view at all times. RESULTS: Preoperatively, unilateral vocal cord paralysis was noted in 6 patients. Resection of a functioning RLN encased with a tumor was intentionally carried out in 5 patients. The RLNs were identified and preserved in all other cases. Among these 121 patients, transient hoarseness lasting up to a month occurred in 12 patients. CONCLUSIONS: Careful identification and exposure of the RLN through a previously undissected area can be done safely in thyroid and parathyroid reoperations and resulted in no permanent recurrent nerve injuries in our experience.

Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection.

OBJECTIVE: To establish the frequency, pattern and location of cervical lymph node metastases from palpable medullary thyroid carcinoma (MTC). Recommendations are made regarding the extent of surgery for this tumor. SUMMARY BACKGROUND DATA: Medullary thyroid carcinoma is a tumor of neuroendocrine origin that does not concentrate iodine. Surgical extirpation of the thyroid tumor and cervical node metastases is the only potentially curative therapeutic option. Patterns of node metastases in the neck and guidelines for the extent of dissection for palpable MTC are not well established. METHODS: Seventy-three patients underwent thyroidectomy for palpable MTC with immediate or delayed central and bilateral functional neck dissections. The number and location of lymph node metastases in the central (levels VI and VII) and bilateral (levels II to V) nodal groups were noted and were correlated with the size and location of the primary thyroid tumor. Intraoperative assessment of nodal status by palpation and inspection by the surgeon was correlated with results of histologic examination. RESULTS: Patients with unilateral intrathyroid tumors had lymph node metastases in 81% of central node dissections, 81% of ipsilateral functional (levels II to V) dissections, and 44% of contralateral functional (levels II to V) dissections. In patients with bilateral intrathyroid tumors, nodal metastases were present in 78% of central node dissections, 71% of functional (levels II to V) node dissections ipsilateral to the largest intrathyroid tumor, and 49% of functional (levels II to V) node dissections contralateral to the largest thyroid tumor. The sensitivity of the surgeon's intraoperative assessment for nodal metastases was 64%, and the specificity was 71%. CONCLUSION: In this series, >75% of patients with palpable MTC had associated nodal metastases, which often were not apparent to the surgeon. Routine central and bilateral functional neck dissections should be considered in all patients with palpable MTC.

Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects.

Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome characterized by parathyroid hyperplasia, pituitary adenomas, and neuroendocrine tumors of the pancreas and duodenum. In 1997, the MEN1 tumor suppressor gene was identified, and numerous germline mutations have been reported to be distributed throughout the gene. We used single strand conformational variant (SSCV) analysis to search for germline mutations in the members of 33 kindreds with a confirmed diagnosis of MEN 1. SSCV analysis revealed 25 conformational variants representing germline mutations that are predicted to result in loss of normal menin function. Twenty different disease-associated mutations were identified: five resulting in potential abnormal RNA splicing, two missense mutations, seven nonsense mutations, and six frameshift mutations. The aberrant splice products were identified and confirmed by RT-PCR and direct sequence analysis for two of the five splice mutations. Sixteen of the 20 (80%) mutations identified have not been previously reported. Mutations were not identified in eight kindreds with signs and symptoms consistent with MEN 1. The SSCV analysis revealed mutations in 76% (25 of 33) of the kindreds investigated, thus showing SSCV analysis to be a reliable mutation detection strategy. One-fifth of the mutations identified in this study involve intron sequences, therefore, highlighting the importance of including intron sequences in the search for germline mutations in the MEN1 gene. The need to investigate the entire gene when characterizing new MEN 1 families presents challenges in the translation of genetic studies to efficient clinical diagnostic tests.

Prospective study of the utility of somatostatin-receptor scintigraphy in the evaluation of patients with multiple endocrine neoplasia type 1.

BACKGROUND: Neuroendocrine tumors (NETs) are a potentially lethal component of multiple endocrine neoplasia type 1 (MEN 1). Somatostatin receptor scintigraphy (SRS) can be used to localize NETs and evaluate patients for extraduodenopancreatic disease; its utility in managing MEN 1 is undefined. METHODS: All patients with MEN 1 evaluated by SRS from April 1994 to November 1997 are reported. SRS findings were correlated with other imaging studies and operative findings. RESULTS: Thirty-seven SRS studies were performed in 29 patients with MEN 1. SRS identified occult tumor in 36% (4/11) of patients with only biochemical evidence of NET; 2 patients went on to resection. SRS showed tumor in 79% (15/19) of patients with computed tomography (CT)-demonstrated tumor; 30% (6/20) of the SRS lesions were occult on CT. Conversely, 55% (16/29) of CT-identified lesions were occult on SRS. SRS found distant disease in 21% (6/29) of patients. In patients who had previous operations, SRS found tumor in 40% (4/10) of patients, again with both new positive and false-negative results compared with other imaging. SRS also had 3 important false-positive results, including 1 patient who had laparotomy with no tumor identified. CONCLUSIONS: SRS is useful in identifying otherwise occult NETs in patients with MEN 1 and can substantially alter management. However, SRS also has significant false-positive and false-negative results that demand correlation with other studies.

Surgical management of patients with persistent or recurrent medullary thyroid cancer.

Residual or recurrent medullary thyroid carcinoma (MTC), manifested by elevated calcitonin levels, occurs commonly following primary treatment of MTC. Re-operation in appropriately selected patients is the only treatment modality which consistently and reliably reduces stimulated calcitonin levels, and results in excellent local disease control. We report improved results of surgical management of recurrent MTC in two consecutive series of patients. In our most recent series (1992-96), 38% of patients (17 out of 45) had normal postoperative stimulated calcitonin levels, compared to 28% (nine of 32) in our first series (1990-92). In the most recent series, only 13% (six of 45) of patients had no decrease in calcitonin levels following re-operation, compared to 31% (10 of 32) in our first series (P = 0.07, Fisher's exact test). This improvement has mainly occurred through better preoperative selection of patients, and the institution of routine laparoscopic liver examination preoperatively, which identified metastases in 10 patients, nine of whom had normal CT or MRI imaging.

Improved results of cervical reoperation for medullary thyroid carcinoma.

OBJECTIVE: The purpose of the study is to determine whether reoperation for medullary thyroid carcinoma (MTC), performed with low morbidity in carefully selected patients, consistently results in improvement as determined by lowering of stimulated calcitonin levels. BACKGROUND: Persistent or recurrent elevation of stimulated plasma calcitonin levels occurs in > 50% of patients after primary operation for MTC. Success of reoperation with clearance of metastatic cervical nodal disease has been hampered by failure to identify patients with distant metastases and by inadequate removal of involved nodal groups. METHODS: Since 1992, the authors have evaluated 115 patients with recurrent or residual MTC. Fifty-three patients have not undergone operation because of extent of disease, previous extensive treatment, medical condition, or patient choice. Sixty-two patients underwent surgery. Ten patients had laparoscopic or open examination of the liver, the results of which showed liver metastases. Seven patients had palliative debulking of cervical tumor. In 45 patients without evidence of distant metastases, cervical operation was carried out with curative intent. Removal of central, upper mediastinal, and lateral nodes (levels II, III, IV, VI, and VII) was done. RESULTS: Seven of eight patients who had palliative resections are alive without symptoms. In patients who underwent curative resections, postoperative stimulated calcitonin levels were in the normal range in 17 patients (38%) and were not significantly lowered in 6 patients (13%). There were no deaths, and no transfusions were used. CONCLUSIONS: These results are a significant improvement over the authors' previous series and reflect better preoperative identification of patients with disease confined to the neck and improved operative strategy based on knowledge of the pattern of nodal spread of MTC.

Heterotopic autotransplantation of parathyroid tissue in children undergoing total thyroidectomy.

AIM: The purpose of this study was to examine the efficacy of parathyroid autotransplantation in children undergoing total thyroidectomy. METHODS: We have prospectively evaluated 32 cases of total thyroidectomy in children. The ages ranged from 1 year to 15.7 years, and the mean was 8.9 years. In 31 cases, the indication for surgery was a diagnosis of MEN2A or 2B based on direct DNA testing. One child had suspected sporadic medullary thyroid carcinoma. All of the patients underwent heterotopic autotransplantation of parathyroid gland tissue. In 26 cases, the parathyroid tissue was placed in the nondominant forearm, while in 6 children it was autotransplanted into the sternocleidomastoid muscle. RESULTS: In 31 of 32 children (97%), the serum calcium level transiently decreased in the immediate postoperative period. All of the patients were placed on oral calcium carbonate and vitamin D supplementation, and the serum calcium levels became normal within several days. The supplemental medications were then weaned as tolerated. Within 3 months of their procedure, 30 patients (94%) had adequate parathyroid tissue engraftment, and the calcium and vitamin D medications were discontinued. One child required 9 months of calcium and vitamin D medications before she could be weaned from the medications. One child has been treated more recently, and is currently being weaned from supplemental calcium and vitamin D. Serum PTH levels in 22 patients who had placement of the tissue into their forearms were measured, and in each there was increased PTH in the grafted arm compared with the nongrafted arm. In five children who had parathyroid tissue grafted into the sternocleidomastoid muscle, the peripheral serum PTH levels were in the normal range. CONCLUSION: The heterotopic autotransplantation of resected parathyroid tissue is safe and effective in preventing permanent hypoparathyroidism.

Pancreatic polypeptide is a useful plasma marker for radiographically evident pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1.

BACKGROUND: The usefulness of human pancreatic polypeptide (hPP) as a plasma marker for islet cell neoplasms is controversial. We sought to determine the relation between fasting plasma hPP levels and radiographically detectable pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1 (MEN 1). METHODS: Fasting plasma hPP levels were measured prospectively in 202 individuals from 31 independent kindreds with MEN 1. Plasma levels greater than 3.0 times the normal age-specific values were defined as elevated. Patients with elevated plasma hPP levels were evaluated with computed tomographic scanning and magnetic resonance imaging, octreotide scanning, or selective angiography. RESULTS: Twenty-two patients had elevated fasting plasma hPP levels, and 20 of these patients were evaluated radiographically. Pancreatic lesions were detected in 19 patients. A group of eight patients with normal basal fasting plasma hPP levels were evaluated with computed tomography, magnetic resonance imaging, octreotide scanning, or selective angiography based on clinical presentation. One patient in this group had an imaging study that was positive for a pancreatic lesion. CONCLUSIONS: The presence of a markedly elevated fasting plasma hPP level in patients with MEN 1 is 95% sensitive and 88% specific for the presence of radiographically detectable pancreatic islet cell tumors.

Parathyroid autotransplantation during thyroidectomy. Results of long-term follow-up.

SUMMARY BACKGROUND DATA: Permanent hypoparathyroidism is a recognized complication of thyroidectomy. Operative strategies to prevent this complication include preservation of parathyroid glands in situ and autotransplantation of parathyroid glands resected or devascularized during thyroidectomy. METHODS: An analysis of 194 patients having thyroidectomy and simultaneous parathyroid autotransplantation at Barnes Hospital from 1990 to 1994 was performed. Data were collected regarding patient demographics, indication for thyroidectomy, operative procedure, pathologic diagnoses, and postoperative course, including biochemical assessment of parathyroid autograft function. RESULTS: Of 194 patients having either total, subtotal, or completion thyroidectomy, 104 (54%) experienced a [Ca(+2)]nadir less than or equal to 8.0 mg/dL and had symptoms and signs of hypocalcemia. Parathyroid autotransplantation was successful in 103 (99%) of these 104 cases and resulted in a 1.0% incidence of hypoparathyroidism in this series. CONCLUSIONS: Although preservation of parathyroid glands in situ is desirable, routine parathyroid autotransplantation during thyroidectomy virtually eliminates postoperative hypoparathyroidism. Normal parathyroid glands resected or devascularized during thyroidectomy for well-differentiated thyroid carcinoma or benign disease should be transplanted in the sternocleidomastoid muscle. Patients with Multiple Endocrine Neoplasia type 2A should have parathyroid glands resected at the time of thyroidectomy for medullary thyroid carcinoma and transplanted in the nondominant forearm. Postoperative management in most patients after thyroidectomy and parathyroid autotransplantation involves temporary calcium and vitamin D replacement and close biochemical evaluation. This precautionary measure of parathyroid autotransplantation markedly reduces the incidence of permanent postoperative hypoparathyroidism.

Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B.

Recently it has become possible to identify persons who have multiple endocrine neoplasia (MEN) syndrome types 2A and 2B based on the presence of missense mutations in the RET protooncogene. Kindred members who have inherited these syndromes can be identified before clinical or biochemical evidence of medullary thyroid carcinoma (MTC) develops, the malignancy that occurs in all affected patients. It is not known whether prophylactic removal of the thyroid gland early in childhood, based on a positive genetic test result, has a better clinical outcome than that associated with thyroidectomy after MTC is diagnosed clinically or biochemically. The authors' goal was to determine the long-term outcome for patients with MEN 2A and 2B who had thyroidectomy for MTC during childhood. These results were compared with those of patients who had prophylactic removal of the thyroid gland after the genetic diagnosis of MEN 2A was established. The hospital records of 49 children with MEN 2A or 2B were reviewed. Each patient had thyroidectomy for MTC before 16 years of age. The mean age at the time of operation was 10 years, and the mean follow-up period for those who had surgery before the availability of direct DNA genetic testing was 9.8 years. The indications for surgery included an elevated basal or stimulated plasma calcitonin level, a positive genetic test result, a thyroid mass, family history of MTC, or a phenotype diagnostic of MEN 2B. All children for whom the diagnosis of MEN 2A was established by direct genetic testing had thyroidectomy within the last 2 years. Of the 11 patients with MEN 2B who underwent thyroidectomy during childhood, 10 had MTC, and only 3 (27%) remain free of disease after the mean follow-up period of 11 years. One patient died, and seven are alive with persistent MTC. Among the 24 patients with MEN 2A who had their thyroid glands removed because of a family history of MTC or because of biochemical evidence of the disease, 5 (21%) have persistent or recurrent MTC after the mean follow-up period of 9.3 years. In four of these, the MTC was confined to the thyroid gland at the time of thyroidectomy. Of the 14 children who had thyroidectomy based on direct DNA testing, MTC was present in 11. Only four had elevated levels of stimulated plasma calcitonin before surgery. None had lymph node metastasis or surgical complications. The authors conclude that a significant number of patients with MEN 2A or 2B who undergo thyroidectomy in childhood for MTC have persistent or recurrent disease long-term. The genetic diagnosis of patients with these syndromes may allow for prophylactic surgery before the development of biochemical or clinical evidence of MTC. This approach is safe, but longer clinical follow-up will be necessary to confirm that MTC has been cured.

Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A.

BACKGROUND: Missense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy. METHODS: A polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing. RESULTS: Direct DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal. CONCLUSION: The PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.