Elizabeth G. Grubbs

A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma

CONTEXT Pheochromocytomas and paragangliomas (PHEO/PGL) are neuroendocrine tumors that arise from sympathetic and parasympathetic paraganglia. Diagnosed rarely during childhood, PHEO/PGL are nonetheless important clinical entities, particularly given our evolving understanding of their pathophysiology. EVIDENCE ACQUISITION We identified articles through the U.S. National Library of Medicine by using the search terms pheochromocytoma and paraganglioma. Results were narrowed to manuscripts that included children and studies related to the genetics of PHEO/PGL. Web-based resources for genetic disorders were also used. For all articles, we performed subsequent reference searches and verification of source data. EVIDENCE SYNTHESIS Up to 20% of PHEO/PGL are diagnosed in children. Most are functional tumors, and clinical presentation includes symptoms related to catecholamine hypersecretion and/or tumor mass effect. Increasingly, PHEO/PGL are identified during presymptomatic screening in children with genetic syndromes associated with PHEO/PGL (multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and the paraganglioma syndromes). Plasma and/or urine metanephrines are the best diagnostic test for a functional tumor, and the management of pediatric patients is similar to adults. Genetic counseling should be undertaken in all cases. Although most pediatric PHEO/PGL are benign, these tumors can occasionally metastasize, a condition for which no curative treatment exists. CONCLUSIONS Although PHEO/PGL are rarely diagnosed during childhood, the pediatric provider should be able to recognize and screen for such tumors, particularly in the context of a known genetic predisposition. Optimal care of these children includes a multidisciplinary team approach at centers experienced in the evaluation and treatment of these uncommon yet fascinating endocrine neoplasms.

Robot assisted transaxillary surgery (RATS) for the removal of thyroid and parathyroid glands

BACKGROUND Robotic assisted transaxillary surgery (RATS) is a minimally invasive approach for the removal of the thyroid and/or parathyroid glands through the axilla. This anatomically directed technique, popularized by Chung, eliminates a visible scar and affords excellent high definition optics of the cervical anatomy. We report an initial series of single access RATS in the U.S. METHODS The prospective endocrine surgery database at a tertiary care center was used to capture all patients who underwent RATS between October 2009 and March 2010. All procedures were performed using a single transaxillary incision. RESULTS Fourteen operations were performed on 13 patients. Indications for RATS were indeterminate thyroid nodules in 11 patients, the need for completion thyroidectomy in 1 patient, and primary hyperparathyroidism in 2 patients. For patients who underwent robotic assisted thyroid lobectomy, the median thyroid nodule size was 2.1 cm (range, 0.8-2.8 cm), and the median body mass index was 25.33 (range, 21.3-34.4). Mean and median total operative times for robotic assisted thyroid lobectomies were 142 minutes and 137 minutes respectively (range, 113-192 minutes). Operative time for the 2 patients who underwent robotic assisted parathyroidectomy was 115 and 102 minutes. Minor complications occurred in 4 patients (28.5%), with no significant perioperative morbidity or mortality. CONCLUSION RATS is feasible. We believe that further study of the RATS technique for removing thyroid lobes and parathyroid glands is warranted. This initial series suggests that careful, continued investigation is necessary prior to routine implementation into clinical practice across the U.S.

Posterior retroperitoneoscopic adrenalectomy: Preferred technique for removal of benign tumors and isolated metastases

Objective:Posterior retroperitoneoscopic adrenalectomy (PRA) is a minimally invasive approach to removal of the adrenal gland. This anatomically direct approach, popularized by Walz, minimizes dissection and affords early access to the adrenal vein. We report the largest experience to date of PRA in the United States. Methods:The prospective endocrine surgery database at a tertiary care center was used to capture all patients who underwent PRA between October 2005 and February 2008. All PRA procedures were performed using a 3-trocar technique with the patient in a prone jackknife position. Results:Sixty-eight PRAs were performed in 62 patients; there were 6 conversions (3 video-assisted and 3 open). Indications for adrenalectomy were functional tumors in 43 patients (20 pheochromocytomas, 13 Cushing disease or syndrome, and 10 others), nonfunctional cortical adenomas in 4, and isolated adrenal metastases in 15. Mean tumor size was 3.4 cm. Complications occurred in 11 patients (16%), with no perioperative deaths. In 34 (55%) patients, there was a relative contraindication to an anterior approach. Additionally, 20 patients (38%) had a body mass index greater than 30. Median operating time was 121 minutes. Conclusion:PRA is safe, avoids intra-abdominal adjacent organ mobilization, is unaffected by the presence of intra-abdominal adhesions, and is possible in obese patients. PRA may be the preferred technique for removing benign adrenal tumors and isolated metastases.

Preoperative vitamin D replacement therapy in primary hyperparathyroidism: safe and beneficial?

BACKGROUND The significance of vitamin D deficiency with primary hyperparathyroidism (PHPT) remains unclear. The safety and value of preoperative vitamin D (Vit D) replacement is unknown. METHODS A prospective surgical database of PHPT patients was queried to identify those who were vitamin D sufficient, deficient, and deficient but repleted. Biochemical parameters were measured preoperatively, after vitamin D replacement, at 1-month follow-up, and at 6-months follow-up. RESULTS Of 301 patients, 118 (39%) had a vitamin D level of 30 ng/mL or more; 71 patients (24%) were deficient, and 112 patients (37%) were vitamin D deficient but underwent repletion. The median duration of replacement was 28 days, and the dose of ergocalciferol was 400,000 U. Among the 112 patients who underwent repletion, the mean serum calcium remained relatively unchanged or decreased in 91 patients (81%). The gland size was smallest in patients with a preoperative sufficiency and largest in those deficient and not repleted. Postoperative PTH values at 1 month and at 6 months in the baseline-normal group were significantly less than in the other 2 groups (P = .05 and = .009, respectively), with no differences observed between the deficient and the deficient-repleted groups. CONCLUSION Preoperative Vit D replacement therapy was safe in PHPT patients and did not increase serum calcium levels. Vit D status affects gland size and postoperative PTH elevation. Repletion in this population is not durable.

Posterior retroperitoneoscopic adrenalectomy is a safe and effective alternative to transabdominal laparoscopic adrenalectomy for pheochromocytoma

INTRODUCTION Laparoscopic adrenalectomy (LA) is a safe minimally invasive approach for treatment of pheochromocytoma (PHEO). Posterior retroperitoneoscopic adrenalectomy (PRA) is an alternative minimally invasive technique; however, there is a lack of data regarding the appropriateness of this approach in patients with PHEO. METHODS Our endocrine surgery database was queried to identify patients who underwent LA or PRA for PHEO. Patient and tumor characteristics, as well as operative details and postoperative course were compared between the 2 groups. RESULTS LA or PRA was attempted in 46 patients with PHEO (23 LA, 23 PRA). There were no differences in age, BMI, or tumor size between these groups. PRA was associated with significantly reduced operative times (99 min vs 145 min, P < .001), estimated blood loss (8.4 cc vs 123.8 cc, P = .02), and postoperative length of stay (1.9 nights vs 3.1 nights, P < .01). There was no significant difference in rates of conversion to an open procedure or perioperative complications between these groups. CONCLUSION LA and PRA are both safe and effective approaches in patients with PHEO. In our experience, PRA results in decreased operative times, blood loss, and postoperative length of stay compared with LA. PRA has become our preferred approach for patients with PHEO.

Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation

BACKGROUND Most cases of multiple endocrine neoplasia type 2B (MEN-2B) are attributable to a germline methionine to threonine mutation at codon 918 (M918T) of the RET proto-oncogene; very few cases of a germline alanine to phenylalanine mutation at codon 883 (A883F) are reported without a clear description of the clinical course. Nevertheless, RET-A883F is currently considered to be among the highest risk mutations, and prophylactic thyroidectomy is recommended as early as 6 months of life. Further characterization of the clinical behavior of RET-A883F mutation is warranted. We present the clinical data for a family with MEN-2B associated with RET-A883F mutation. SUMMARY The proband, a 39-year-old woman, had multifocal medullary thyroid carcinoma (MTC) with cervical lymphadenopathy, but no evidence of distant metastases. She was disease free after surgical resection. She also had bilateral pheochromocytomas and mucosal neuromas leading to the clinical diagnosis of MEN-2B. Genetic testing showed that the woman and her three children (3-5 years old) had the RET-A883F mutation. The children had near-normal calcitonin levels, and none had sonographic evidence of suspicious thyroid nodules or cervical lymphadenopathy. CONCLUSION A family with MEN-2B due to RET-A883F mutation displayed a less aggressive form of MTC than what is usually seen in patients with RET-M918T mutation. RET-A883F mutation could be a lower-risk mutation than previously thought and the current recommendation of prophylactic thyroidectomy in the first year of life may not be warranted. Further reports will help clarify the natural history of MTC caused by this mutation.

A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma.

CONTEXT Adrenocortical carcinoma (ACC) is a rare malignancy with high recurrence and mortality rates. The role of adjuvant radiation therapy (RT) to improve outcome remains unclear. OBJECTIVE The aim of this study was to evaluate the impact of adjuvant RT on overall survival and recurrence rates of ACC patients. DESIGN We conducted a retrospective cohort study of select ACC patients who were seen at The University of Texas MD Anderson Cancer Center (MDACC) between 1998 and 2011. All patients in this study underwent primary tumor resection and received adjuvant RT within 3 months of primary surgical resection prior to referral to the MDACC. We compared patients who had surgery and adjuvant RT with patients who had surgery alone. RESULTS Baseline characteristics and adjuvant mitotane use were not significantly different between the adjuvant RT group (n = 16) and the non-RT group (n = 32). Local recurrence occurred in seven patients (43.8%) who received RT and 10 patients (31.3%) in the control group. At 5 yr, the estimated local recurrence-free rate (95% confidence interval) was 53% (32-87%) in the RT group and 67% (52-86%) in the non-RT group (P = 0.53). The distributions of time to distant recurrence and recurrence-free survival were not significantly different between the two groups. Using a multivariate Cox proportional hazards model for overall survival, the hazard ratio for RT use was 1.593 (95% confidence interval, 0.707-3.589; P = 0.26) after adjusting for stage and adjuvant mitotane therapy. CONCLUSIONS ACC has high rates of recurrence. In our study, RT did not improve clinical outcomes in patients who received their initial care in the community. We believe there is a need for a collaborative, multicenter, prospective randomized trial to evaluate the role of adjuvant treatments (both mitotane and RT) to assess their impact on recurrence patterns and survival.

Long-Term Outcomes of Surgical Treatment for Hereditary Pheochromocytoma

BACKGROUND The ideal surgical management of hereditary pheochromocytomas includes planning for a potential metachronous bilateral presentation and the possibility of lifelong steroid dependence if bilateral adrenalectomy is needed. An intact and viable cortical remnant after bilateral pheochromocytoma resection can eliminate the necessity for steroid dependency, but can increase the risk of pheochromocytoma recurrence. STUDY DESIGN We retrospectively reviewed outcomes of all patients with a diagnosis of hereditary pheochromocytomas treated at our tertiary cancer institution from 1962-2011, with subset analysis of patients undergoing a cortical-sparing procedure in the setting of bilateral adrenalectomy. RESULTS Of the ninety-six patients who underwent adrenalectomy for hereditary pheochromocytomas, 47 presented with bilateral disease. In 15 of the 49 patients (30%) who originally underwent unilateral adrenalectomy, pheochromocytoma developed in the contralateral gland at a median of 8.2 years (range 1 to 20 years) after the initial diagnosis. There were 4 recurrences in 55 cortical-sparing remnants (7%) and 3 recurrences in the adrenal bed after 101 intended total adrenal resections (3%) (p = 0.24). Total bilateral adrenalectomy was performed in 25 patients and acute adrenal insufficiency developed in 5 (20%) of those patients. An intended cortical-sparing adrenalectomy was performed in 39 patients and acute adrenal insufficiency developed in 1 (3%). Of these patients with adequate follow-up, 21 of 27 (78%) were steroid independent at 3-year follow-up. Sex, median age, adrenal vein preservation, metachronous adrenal resection, and bilateral cortical-sparing procedures did not predict steroid independence at 3 years. CONCLUSIONS Cortical-sparing adrenalectomy avoids long-term corticosteroid dependence in the majority of patients with hereditary pheochromocytoma with minimal risk of acute adrenal insufficiency. Recurrence occurs in approximately 7% of adrenal remnants.

Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine.

This study investigated whether the therapeutic index of regional melanoma therapy using parenteral temozolomide could be improved by chemomodulation with O6-benzylguanine (O6BG), an inhibitor of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT). Using a nude rat s.c. human melanoma xenograft model of the extremity, tumors were analyzed for AGT level 2 to 3 hours after the i.p. injection of 3.5 to 70.0 mg/kg O6BG to inhibit AGT activity. Survival studies were conducted using animals that were treated with a 15-minute isolated limb infusion with 10% DMSO in PBS (control), temozolomide alone, or temozolomide in conjunction with single or multiple doses of i.p. O6BG. Tumor volume and toxicity level were monitored every other day. Administration of 3.5 mg/kg O6BG depleted tumor AGT activity by 93.5% (P < 0.01). Groups treated with regional temozolomide alone (350 mg/kg), systemic temozolomide with O6BG, or vehicle combined with O6BG showed no significant tumor responses compared with controls. Whereas use of regional temozolomide alone at a higher dose (750 mg/kg) showed some degree of tumor response, regional temozolomide given in conjunction with multiple dosages of O6BG showed a marked (P < 0.01) reduction in tumor growth with minimal toxicity. Our findings suggest that AGT modulation by the administration of O6BG in combination with temozolomide regional chemotherapy leads to a significant improvement in melanoma antitumor responses. Clinical trials using chemotherapy modulation may improve response rates in future regional infusion and perfusion drug trials. [Mol Cancer Ther 2006;5(3):732–8]

Bilateral Robotic-Assisted Transaxillary Surgery

HYPOTHESIS Robotic-assisted transaxillary surgery (RATS) for the removal of thyroid glands is feasible by surgeons in the United States. DESIGN Case report. SETTING Academic research. Patient A 53-year-old woman. INTERVENTION Total thyroidectomy via the transaxillary approach. MAIN OUTCOME MEASURE Successful completion thyroidectomy using bilateral RATS. RESULTS Right thyroid lobectomy was performed via RATS to remove a 2.2-cm Hurthle cell neoplasm of the thyroid gland per cytologic analysis. Final pathologic analysis was consistent with minimally invasive follicular thyroid carcinoma. The patient then underwent completion thyroidectomy via left-sided RATS. There were no complications. CONCLUSIONS Bilateral RATS to perform total thyroidectomy is a feasible option in properly selected patients. To our knowledge, this is the first reported use of this technique in the United States.