Maurizio Iacobone

Results of Laparoscopic Adrenalectomy for Large and Potentially Malignant Tumors

ndoscopic adrenalectomy is the procedure of choice for patients with small functioning adrenal tumors. For most surgeons invasive adrenal carcinoma is an absolute contraindication for laparoscopic adrenalectomy (LA). Whether LA should be proposed for large (> 6 cm), potentially malignant tumors is questionable. The aim of this study was to evaluate the risks and outcome of LA performed in our department in patients with tumors > 6 cm and potentially malignant. We performed a retrospective study of 216 patients who underwent 233 LAs in our department from 1994 to 2000. We selected 19 patients with a tumor > 6 cm and potentially malignant: 8 nonfunctional tumors, 4 cortisol-secreting tumors, 1 virilizing tumor, and 6 pheochromocytomas. In none of these patients did preoperative investigations demonstrated invasive carcinoma. The median tumor size was 70 mm. LA was performed by a transperitoneal flank approach. Conversion to open adrenalectomy was performed in two patients owing to intraoperative evidence of invasive carcinoma. The median operating time was 150 minutes (range 95–240 minutes). Capsular disruption occurred during the dissection of two pheochromocytomas. There was no postoperative morbidity. Six patients had an adrenocortical carcinoma on pathologic diagnosis: three of the eight nonfunctional tumors, one of the four cortisol-secreting tumors, and one virilizing tumor. One patient presented with liver metastases 6 months after surgery and died. The five other patients are disease-free with a follow-up ranging from 8 to 83 months. The 13 patients with benign lesions (6 cortical adenomas, 1 ganglioneuroma, 6 pheochromocytomas) are disease-free with a median follow-up of 47 months (range 10–81 months). In experienced hands LA can be proposed for large, potentially malignant tumors. Conversion to open adrenalectomy should be performed if local invasion is observed during surgery. At present the risk of intraabdominal recurrence is unknown.

Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas.

CONTEXT Pheochromocytomas and paragangliomas are genetically heterogeneous neural crest-derived neoplasms. We recently identified germline mutations of the novel transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromocytomas consistent with a tumor suppressor effect. OBJECTIVES To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. DESIGN, SETTING, AND PARTICIPANTS We sequenced the FP/TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without mutations in other susceptibility genes from 8 independent worldwide referral centers between January 2009 and June 2010. A multiplex polymerase chain reaction-based method was developed to screen for large gene deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant proteins was used to determine their subcellular localization. MAIN OUTCOME MEASURES The frequency and type of FP/TMEM127 mutation or deletion was assessed and correlated with clinical variables; the subcellular localization of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein. RESULTS We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers had adrenal tumors, including 7 bilateral (P = 2.7 × 10(-4)) and/or with familial disease (5 of 20 samples; P = .005). The median age at disease onset in the FP/TMEM127 mutation group was similar to that of patients without a mutation (41.5 vs 45 years, respectively; P = .54). The most common presentation was that of a single benign adrenal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse localization of the mutant proteins in contrast with the discrete multiorganelle distribution of wild-type TMEM127. CONCLUSIONS Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occurred in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein.

Can sporadic medullary thyroid carcinoma be biochemically predicted? Prospective analysis of 66 operated patients with elevated serum calcitonin levels.

Measuring serum calcitonin (CT) in patients with thyroid diseases allows preoperative diagnoses of sporadic medullary thyroid carcinoma (MTC) and C-cell hyperplasia (CCH). The aim of this prospective study was to distinguish biochemically between CCH and MTC. Basal CT (bCT) was determined in 7276 consecutive patients referred for thyroid disease. Patients with recurrent, persistent, or familial MTC were excluded. When bCT was > 10 pg/ml a pentagastrin-stimulated CT (sCT) assay was performed. Patients were routinely operated on when bCT > 30 pg/ml or sCT > 100 pg/ml or when other indications for surgery were present. An extensive search for CCH or microscopic MTC was conducted by immunochemistry. Pathologic findings were correlated with the bCT and sCT values. In this study 66 patients were included. No morphologic alterations of C-cells were observed in 5 patients; 16 patients presented with CCH and 45 with MTC. Statistical analysis revealed a correlation of sCT and overall bCT with tumor size and staging (p <0.001). Considering cutoff values for bCT of ≤ 30 pg/ml and for sCT of ≤ 200 pg/ml, the positive predictive value of the test to detect MTC was 100% and the negative predictive value 63%. No patients with MTC at stage 2 to 4 had bCT <30 pg/ml or sCT <200 pg/ml. A bCT value of ≤ 30 pg/ml or sCT ≤ 200 pg/ml (or both) is highly predictive of MTC, requiring total thyroidectomy with lymph node dissection. Values of bCT <30 pg/ml and sCT <200 pg/ml do not distinguish between CCH and MTC at stage 1. In this case total thyroidectomy at least is recommended, and the role of nodal dissection might be discussed.

Adrenalectomy may improve cardiovascular and metabolic impairment and ameliorate quality of life in patients with adrenal incidentalomas and subclinical Cushing's syndrome

BACKGROUND Adrenalectomy represents the definitive treatment in clinically evident Cushings syndrome; however, the most appropriate treatment for patients with subclinical Cushings syndrome (SCS) with an adrenal incidentaloma remains controversial. This study was aimed to assess whether adrenalectomy may improve cardiovascular and metabolic impairment and quality of life compared with conservative management. METHODS Twenty patients with adrenal incidentaloma underwent laparoscopic adrenalectomy for SCS, whereas 15 were managed conservatively. Hormonal laboratory parameters of corticosteroid secretion, arterial blood pressure (BP), glycometabolic profile, and quality of life (by the SF-36 questionnaire) were compared at baseline and the end of follow-up. RESULTS The 2 groups were equivalent concerning all the examined parameters at baseline. In the operative group, laboratory corticosteroid parameters normalized in all patients but not in the conservative-management group (P < .001). In operated patients, a decrease in BP occurred in 53% of patients, glycometabolic control improved in 50%, and body mass index decreased; in contrast, no improvement or some worsening occurred in the conservative-management group (P < .01). SF-36 evaluation improved in the operative group (P < .05). CONCLUSION Adrenalectomy can be more beneficial than conservative management in SCS and may achieve remission of laboratory hormonal abnormalities and improve BP, glycemic control, body mass index, and quality of life.

Surgical strategy for sporadic primary hyperparathyroidism an evidence-based approach to surgical strategy, patient selection, surgical access, and reoperations

PurposeProgress in parathyroid imaging has brought substantial changes in the surgical strategy to approach patients with sporadic primary hyperparathyroidism (pHPT). The present review is focused on the safety and efficacy of limited parathyroid exploration.Materials and methodsReview of the literature focused on studies dealing with unilateral (two-gland exploration) or selective parathyroidectomy (one-gland exploration) in selected patients with pHPT and on the classification of published reports according to the degree of evidence.ResultsParathyroid exploration limited to a solitary parathyroid adenoma can be considered a minimally invasive procedure that can be performed by the minicervicotomy, video-assisted, or endoscopic approaches. In properly selected patients, it affords results comparable to those of four-gland bilateral exploration in terms of cure and recurrence. It causes less postoperative hypocalcemia.ConclusionsSelective parathyroidectomy is an option for patients with positive preoperative localization tests undergoing first-time surgery who have no family history of pHPT, no goiter for which surgical therapy is proposed, and are not on lithium therapy.

Performance of salivary cortisol in the diagnosis of Cushing's syndrome, adrenal incidentaloma, and adrenal insufficiency.

OBJECTIVE Salivary cortisol has recently been suggested for studies on the hypothalamic-pituitary-adrenal (HPA) axis. The lack of circadian rhythm is a marker of Cushings syndrome (CS), and some authors have reported that low salivary cortisol levels may be a marker of adrenal insufficiency. The aim of our study was to define the role of salivary cortisol in specific diagnostic settings of HPA axis disease. SUBJECTS AND METHODS We analyzed morning salivary cortisol (MSC) and late-night salivary CORTISOL (LNSC) levels in 406 SUBJECTS: 52 patients with Cushings disease (CD), 13 with ectopic CS, 17 with adrenal CS, 27 with CD in remission (a mean follow-up of 66±39 months), 45 with adrenal incidentaloma, 73 assessed as having CS and then ruled out for endogenous hypercortisolism, 75 with adrenal insufficiency, and 104 healthy subjects. RESULTS A LNSC value above 5.24  ng/ml differentiated CS patients from controls with high sensitivity (96.3%) and specificity (97.1%); we found higher LNSC levels in ectopic CS patients than in CD patients. We found no difference in MSC and LNSC levels between patients with CD in remission and healthy subjects. Both MSC and LNSC levels were higher in patients with adrenal incidentaloma than in healthy controls. A MSC value below 2.65 ng/ml distinguished patients with adrenal insufficiency from controls with high sensitivity (97.1%) and specificity (93.3%). CONCLUSIONS Salivary cortisol is a useful tool to assess endogenous cortisol excess or adrenal insufficiency and to evaluate stable CD in remission.

Adrenalectomy for solid tumor metastases: Results of a multicenter European study

BACKGROUND We assessed the results of adrenalectomy for solid tumor metastases in 317 patients recruited from 30 European centers. METHODS Patients with histologically proven adrenal metastatic disease and undergoing complete removal(s) of the affected gland(s) were eligible. RESULTS Non-small cell lung cancer (NSCLC) was the most frequent tumor type followed by colorectal and renal cell carcinoma. Adrenal metastases were synchronous (≤6 months) in 73 (23%) patients and isolated in 213 (67%). The median disease-free interval was 18.5 months. Laparoscopic resection was used in 46% of patients. Surgery was limited to the adrenal gland in 73% of patients and R0 resection was achieved in 86% of cases. The median overall survival was 29 months (95% confidence interval, 24.69-33.30). The survival rates at 1, 2, 3, and 5 years were 80%, 61%, 42%, and 35%, respectively. Patients with renal cancer showed a median survival of 84 months, patients with NSCLC 26 months, and patients with colorectal cancer 29 months (P = .017). Differences in survival between metachronous and synchronous lesions were also significant (30 vs. 23 months; P = .038). CONCLUSION Surgical removal of adrenal metastasis is associated with long-term survival in selected patients.

Leçons retenues après 274 surrénalectomies laparoscopiques

Aims: To define the role of minimally invasive videoassisted surgery in the surgical management of adrenal disease and discuss the respective indications of the trans and retroperitoneal video assisted approaches. Materials and Methods: During the last 8 years (1994–2001), 330 adrenalectomies were performed in 305 patients: 274 (83%) laparoscopic approaches and 56 (17%) open approach. Open surgery was reserved for patients presenting with large or malignant tumours (29 cases), multiple and/or extraadrenal phaeochromocytomas (13 cases), previous intraabdominal intestinal surgery (10 cases), and in those requiring concomitant intraabdominal surgery (4 cases). Laparoscopic adrenalectomy was performed using the lateral transperitoneal approach for 89 Conn’s syndrome, 67 Cushing’s syndrome, 2 virilising tumours, 51 phaeochromocytomas and 65 non secretory tumours greater than 4 cm in diameter. Nineteen patients underwent bilateral adrenalectomy. Results: There were no deaths. Twenty patients (7.3%) had a complication. Eleven cases required open conversion (4%) because of difficulties with dissection (8 cases), peroperative suspicion of malignancy (2 cases), and one pneumothorax. The average size of tumours was 34 mm (7–110 mm). There were 18 malignant tumours (6.5%): 8 adrenocortical carcinomas, 1 leiomyosarcoma, and 9 metastases. All patients with hormonally secreting tumours were cured of their endocrinopathy. There was 1 death secondary to hepatic metastases in a patient with an adrenocortical carcinoma. Conclusion: Most adrenal tumours are suitable for video assisted excision. The only absolute contraindication is an invasive carcinoma requiring an extended excision. The lateral, transperitoneal approach is the most suitable for tumours greater than 5–6 cm in diameter. Both the transperitoneal or retroperitoneal approaches are suitable for smaller tumours depending on operator choice and experience. However in the presence of a large right lobe of liver or previous intraabdominal surgery the retroperitoneal approach may be preferable.

Mild hyperparathyroidism: a novel surgically correctable feature of primary aldosteronism.

Background: The parathyroid hormone (PTH) stimulates aldosterone secretion and cell proliferation in human adrenocortical cells; moreover, in rats hyperaldosteronism was associated with hyperparathyroidism. Hence, PTH could drive aldosterone excess in human primary aldosteronism. Method: To test this hypothesis, we recruited 105 consecutive hypertensive patients, of whom 44 had primary aldosteronism due to an aldosterone-producing adenoma (APA) and 61 had primary (essential) hypertension. We measured the plasma levels of (1-84)-PTH, 25(OH)D, 1,25(OH)2D, and serum Ca2+ (total and ionized), inorganic P, Mg2+, K+, and the 24-h urinary excretion of Ca2+, P, and deoxypyridinoline. In primary aldosteronism patients, these measurements were repeated after adrenalectomy or mineralocorticoid receptor blockade. We also sought for PTH receptor (PTHR-1) mRNA and protein in APA tissue. Results: Compared with primary (essential) hypertension patients, those with primary aldosteronism showed significantly higher plasma PTH (+31%), despite comparable urinary Ca2+ excretion and similarly deficient 25(OH) vitamin D levels. In APA patients, who showed the PTHR-1 transcript and protein in tumor tissue, adrenalectomy normalized PTH levels (from 118 ± 13 to 76 ± 12 ng/l; P = 0.002) and increased ionized Ca2+(from 1.17 ± 0.04 to 1.22 ± 0.03 mmol/l; P < 0.001). The slope of the inverse PTH/ionized Ca2+ relationship was steeper in primary aldosteronism than in primary (essential) hypertension, but normalized after adrenalectomy. Conclusion: Hence, in primary aldosteronism an increased sensitivity of parathyroid cells to Ca2+ lowering leads to an increase of PTH. This subtle hyperparathyroidism by acting on PTHR-1 in APA might contribute to maintaining hyperaldosteronism despite suppression of angiotensin II formation.

Clinical, genetic, and histopathologic investigation of CDC73-related familial hyperparathyroidism

CDC73 (HRPT2) germline mutations are responsible for more than half of cases of hyperparathyroidism-jaw tumor syndrome (HPT-JT) and for a subset of familial isolated HPT (FIHP). We performed a clinical, genetic, and histopathologic study in three unrelated Italian kindreds with HPT-JT and FIHP. We identified three germline inactivating mutations of the CDC73 gene in the probands and affected patients of the three kindreds, but also in some asymptomatic subjects. HPT-JT and FIHP patients had similar laboratory, clinical, and demographic features and shared primary HPT and other neoplasms, the most common of which was uterine polyposis. Genetic analysis of tumor samples demonstrated a second somatic CDC73 mutation only in a parathyroid adenoma and no cases with the loss of the wild-type allele or methylation of the CDC73 promoter, even though immunohistochemical analysis demonstrated the loss of nuclear parafibromin expression in all tumors, including a uterine polyp. In conclusion, our results indicate that FIHP and HPT-JT associated with CDC73 mutations do not have distinct clinical, genetic, and histopathologic features, but may represent variants of the same genetic disease. This study also confirms that uterine involvement represents a clinical manifestation of the syndrome.