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Background: The surgical management and follow-up strategy in patients with medullary thyroid carcinoma (MTC) remain controversial because of the lack of data on the natural history of these tumors and their patterns of progression., Methods: We reviewed the records of all patients who underwent a cervical operation for MTC between 1991 and 2002. Compartment-oriented surgery (COS) was performed to minimize the risk of cervical recurrence., Results: We identified 92 consecutive patients who underwent a cervical operation for MTC: 80 had invasive MTC, and 12 had C-cell hyperplasia after prophylactic thyroidectomy for familial MTC. Ten (13%) of the 80 patients with invasive MTC presented with distant metastases and underwent COS to achieve local-regional control; cervical recurrence developed in none, but three have died of MTC. The remaining 70 patients underwent COS for primary (n=23) or recurrent (n=47) MTC. Disease recurred in 18 (26%) of these 70 patients at a median follow-up of 35 months, with 10 (14%) of the recurrences being cervical. Recurrent disease was associated with a basal calcitonin level of >250 pg/mL in all but four patients, two of whom showed tumor dedifferentiation. In contrast, only 5 (11%) patients without evidence of recurrence had basal calcitonin levels of >250 pg/mL at last follow-up., Conclusions: Complete COS minimizes cervical recurrence. Radiographic evidence of recurrent disease is unlikely when the calcitonin level is < or =250 pg/mL. These data could be used to develop a logical, cost-effective treatment and follow-up strategy for patients with MTC.

Background: Preoperative localization is essential for successful directed, minimally invasive or reoperative parathyroidectomy. Standard technetium Tc 99m-sestamibi imaging is the most sensitive modality for localization. We reviewed our experience with (99m)Tc-sestamibi imaging and specifically investigated the effect of thyroid suppression on repeat imaging of patients who had initially nonlocalizing scans., Methods: . The records of patients who underwent (99m)Tc-sestamibi imaging during evaluation for primary hyperparathyroidism were reviewed. A subset of patients with initially nonlocalizing scans underwent thyroid suppression with either thyroxin or liothyronine and then had their scans repeated., Results: Ninety-nine patients with primary hyperparathyroidism underwent (99m)Tc-sestamibi imaging followed by parathyroidectomy (initial operation, 78; reoperation, 21). Successful parathyroid localization was obtained on standard imaging in 67 patients. Fourteen of 32 patients who had nonlocalizing (99m)Tc-sestamibi imaging studies underwent an additional scan after thyroid suppression. In 10 of 14 patients (71%), repeat (99m)Tc-sestamibi imaging after thyroid suppression successfully localized abnormal parathyroid tissue., Conclusions: Thyroid suppression may improve the yield of (99m)Tc-sestamibi imaging in patients with hyperparathyroidism who have an initially nonlocalizing study. This diagnostic strategy may be helpful in patients motivated to undergo a directed, minimally invasive operation, as well as in the evaluation of patients for reoperative parathyroidectomy.

Background: The natural history of nonfunctioning islet cell carcinoma of the pancreas is poorly defined. We therefore reviewed our institutional experience during a period of 12 years to define more clearly the natural history of this disease as a basis for individual therapeutic recommendations., Methods: The records of all patients who had histologically or cytologically confirmed nonfunctioning islet cell carcinoma of the pancreas were retrospectively reviewed. Patients were grouped by extent of disease at diagnosis and by initial treatment. Survival distributions were estimated by Kaplan-Meier analysis., Results: One hundred sixty-three patients with nonfunctioning islet cell carcinoma of the pancreas were identified. The overall median survival duration was 3.2 years. The median survival was 7.1 years in patients with localized disease who underwent a potentially curative resection and 5.2 years in those with locally advanced, unresectable, nonmetastatic disease (P = .04). Patients with metastatic disease that could not be resected had a median survival of 2.1 years., Conclusions: Patients with completely resected localized disease had a long median survival. Patients with nonmetastatic but unresectable locally advanced disease also had a surprisingly long median survival; major treatment-related morbidity may be hard to justify in this subgroup. The short median survival in patients with metastatic disease suggests that the frequent practice of observation in this patient subgroup needs to be reexamined and that continued investigation of regional and systemic therapies with novel agents is warranted.

Background: Adrenal abnormalities are often identified on imaging studies performed during the staging of patients presenting with a new malignancy or restaging of patients with a history of a malignancy., Methods: We reviewed the records of patients who underwent surgical resection of an adrenal mass identified in the setting of previously or newly diagnosed extra-adrenal malignancy., Results: Eighty-one patients with an adrenal mass and recently diagnosed malignancy (n = 24) or history of a malignancy (n = 57) underwent adrenalectomy. In 42 patients (52%) the adrenal mass was a metastasis. In 39 patients (48%) the adrenal mass was an additional primary adrenal tumor process: 19 pheochromocytomas, (14 syndrome-associated, 5 sporadic), 13 cortical adenomas, 3 adrenocortical carcinomas, 2 ganglioneuromas, and 2 cases of nodular hyperplasia., Conclusions: In this series nearly half of the patients with cancer and an adrenal mass had adrenal pathologic condition independent of their primary malignancy. Despite the presence of a newly diagnosed malignancy or history of malignancy, all patients with an adrenal mass should undergo a standard hormone evaluation to confirm that the mass is not a functional neoplasm. An assumption that the adrenal mass is metastatic disease will be wrong in up to 50% of such patients.

Background: Size has been considered to be the single best predictor of malignancy in adrenal neoplasms that have been identified incidentally. However, small adrenal cortical cancers have been reported from multiple centers., Methods: We retrospectively evaluated the value of tumor size and other clinical parameters in the prediction of the presence of adrenal malignancy., Results: The records of 117 patients who underwent evaluation for tumors of the adrenal gland were reviewed. The median tumor size of the adrenal cortical carcinomas (n = 38 carcinomas) was 9.2 cm (range, 1.7-30 cm); 5 cancers (13.5%) were smaller than 5.0 cm. The median overall size of the benign tumors, excluding pheochromocytomas, was 4.0 cm (n = 38 carcinomas); 10 benign tumors (26%) were larger than 5.0 cm. The imaging features of 4 of 5 small adrenal cancers predicted malignancy; the remaining patients had hormonally functioning tumors. The imaging features of 7 of 10 large benign adrenal tumors predicted benign histologic features, including 5 of 5 myelolipomas., Conclusions: Although size remains a good predictor of the histologic features and clinical behavior of adrenal neoplasms, both small adrenal cortical cancers and large benign tumors occur with measurable frequency. High-quality imaging studies may be helpful in the identification of relatively small adrenal cancers and of characteristic benign lesions that may be selectively followed.

Background: Most patients from typical multiple endocrine neoplasia type 1 (MEN1) kindreds harbor mutations in the MEN-1 gene, MEN1. We hypothesized that some patients with atypical endocrine neoplasia would also have mutations in MEN1., Methods: DNA sequencing analysis of mutations in the coding region of MEN1 was performed with genomic DNA obtained from peripheral blood lymphocytes in a total of 21 patients who had: typical MEN1 (n = 8), clinical features suggestive of MEN1 but without a family history of endocrinopathy (n = 7), and atypical endocrine neoplasia and a family history of endocrinopathy suggestive of MEN1 (n = 6)., Results: All 8 patients with typical MEN1 had mutations in MEN1. None of the 7 patients with features of MEN1, but without a family history of endocrinopathy, had a MEN1 mutation. In contrast, 4 of 6 patients with atypical endocrine neoplasia that included components of MEN1 and a family history of endocrinopathy had mutations in MEN1, including 2 patients with pheochromocytoma., Conclusions: Genomic mutations in MEN1 may frequently be identified in patients with atypical endocrine neoplasia, especially in the setting of a family history of endocrinopathy. Atypical presentations of MEN1 may include pheochromocytoma.

Background: Fine-needle aspiration biopsy to identify adrenal metastasis from an occult primary malignancy has been recommended as part of the evaluation of the patient who presents with an incidentally discovered adrenal mass. This recommendation was assessed by examining the frequency of adrenal involvement in patients with suspected unknown primary cancer., Methods: Data from 1715 patients referred for evaluation of suspected unknown primary cancer were retrospectively reviewed., Results: Of 1639 patients found to have cancer, the adrenal gland was identified as a site of involvement at presentation in 95 (5.8%). Involvement was limited to the adrenal gland in 4 patients (0.2%). All 4 patients had large (> or = 6 cm) adrenal tumors, 3 of 4 had bilateral involvement, and all had symptoms that otherwise mandated evaluation for an occult malignancy; none had a true adrenal incidentaloma., Conclusions: Although cancer of an unknown primary site occasionally involves the adrenal gland, metastatic cancer presenting as a true adrenal incidentaloma is extremely rare. Therefore, in the absence of a history of prior malignancy or symptoms, physical examination findings, radiographic findings, or laboratory findings suggestive of an occult malignancy, we do not recommend fine-needle aspiration biopsy as part of the diagnostic evaluation of the patient who presents with a unilateral adrenal mass.

Background: Bilateral pheochromocytomas are common in patients with multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau disease (VHL). In an effort to avoid long-term steroid dependence and Addisonian crisis, we have performed cortical-sparing adrenalectomy in this patient population., Methods: Retrospective chart review was completed for patients with MEN 2- or VHL-related pheochromocytomas who underwent laparotomy at our institution for intended cortical-sparing adrenalectomy between June 1965 and March 1995., Results: Fifteen patients (MEN 2A [10], MEN 2B [2], VHL [3]) underwent laparotomy for cortical-sparing adrenalectomy. None of the tumors were malignant. Cortical-sparing adrenalectomy was possible in 14 (93%). Thirteen of these 14 patients (93%) had normal postoperative plasma cortisol measurements and did not require steroid hormone supplementation. At a median follow-up of 138 months, two patients had died of metastatic medullary thyroid cancer, no patient had suffered Addisonian crisis, and three patients (21%) had recurrent pheochromocytomas (at 118, 176, and 324 months after operation). The remaining nine patients were alive without pheochromocytomas., Conclusions: Cortical-sparing adrenalectomy can be performed successfully in MEN 2 or VHL patients with bilateral pheochromocytomas, avoiding chronic steroid hormone replacement and the risk of Addisonian crisis in most patients. Long-term follow-up is necessary because recurrence may develop many years after operation.

Background: Surgical resection is the only potentially curative treatment for adrenal cortical carcinoma, yet the value of extended resection, palliative resection, and tumor DNA analysis remains unclear., Methods: The records of 23 patients with adrenal cortical carcinoma who underwent primary surgical resection at our institution were retrospectively reviewed. Flow cytometric DNA analysis was performed on primary tumor tissue from 14 patients., Results: Sixteen of 23 patients underwent complete resection. For these 16 patients the median follow-up was 43 months, the actuarial median survival was 46 months, and the actuarial 5-year survival rate was 46%. The seven patients who underwent incomplete resection all died of disease with a median survival of 8.5 months. Isolated local recurrence as the first site of failure occurred in two patients. Only completeness of resection (p = 0.004) and stage at presentation (p = 0.006) were significant prognostic indicators. None of the following predicted a poor prognosis in patients who underwent complete resection: (1) need for extended resection, (2) presence of renal vein or inferior vena cava tumor thrombus, or (3) tumor aneuploidy (14 of 14 tumors were aneuploid)., Conclusions: Long-term survival is possible in patients with adrenal cortical carcinoma if complete, margin-negative tumor resection can be achieved. Isolated local recurrence is uncommon after complete resection. Because adrenal cortical carcinomas are consistently aneuploid, tumor DNA content is not a useful prognostic factor.

Background: Nonfunctioning islet cell carcinoma of the pancreas has a variable and often indolent natural history, which has resulted in a wide range of treatment recommendations. To more clearly define the natural history and appropriate treatment of this disease, we reviewed our institutional experience over the last 39 years., Methods: The records of all patients confirmed to have a nonfunctioning islet cell carcinoma of the pancreas were retrospectively reviewed. Kaplan-Meier life tables were constructed and log-rank comparisons were performed., Results: The 73 patients studied had an overall 5-year actuarial survival rate of 50%. Patients with localized disease at presentation (n = 39) had a significantly higher survival rate (p = 0.03) compared with patients with metastatic disease (n = 34). The 19 patients who underwent a potentially curative resection of the primary tumor had a significantly higher survival rate (p = 0.03) compared with the 20 patients with locally advanced, unresectable, nonmetastatic disease. Nine of these 20 patients died of complications of the primary tumor. In contrast, only 2 of 22 cancer-related deaths in the 34 patients with metastatic disease at diagnosis were due to the primary tumor., Conclusions: (1) Surgical resection should be performed in patients with resectable nonmetastatic disease. (2) Resection of the primary tumor in the presence of metastatic disease is rarely indicated. (3) Innovative treatment strategies are needed for patients with locally advanced, unresectable, nonmetastatic tumors of the pancreatic head.