Jean-François Henry

Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group

Because of the rarity of adrenocortical carcinoma, survival rates and the prognosis for patients who have undergone operation are not well known. The purpose of the French Association of Endocrine Surgery was to evaluate these factors over an 18-year period. A trend study was associated to assess changes in the clinical and biochemical presentations as well as the surgical evolution. A total of 253 patients (158 women, 95 men) with a mean age of 47 years were included. Cushing syndrome was the main clinical presentation (30%), and hormonal studies revealed secreting tumors in 66% of the cases. Altogether, 72% (n=182) of patients underwent resection for cure, and 41.5% (n=105) of them had an extensive resection because of metastatic cancer. A lymphadenectomy was performed in 32.5% (n=89) of the cases. The operative mortality was 5.5% (n=14). Patients were given mitotane as adjuvant therapy in 53.8% of the cases (n=135). The results of staging were stage I in 16 patients (6.3%), stage II (local disease) in 126 patients (49.8%), stage III (locoregional disease) in 57 patients (22.5%), and stage IV (metastases) in 54 patients (21.3%). Neither tumor staging nor the rate of curative surgery changed during the study period. More subcostal incisions were performed, and the use of mitotane increased significantly. The 5-year actuarial survival rates were 38% overall, 50% in the curative group, 66% for stage I, 58% for stage II, 24% for stage III, and 0% for stage IV. Multivariate analysis showed that mitotane benefited only the group of patients not operated on for cure. A better prognosis was found in patients operated on after 1988 (p=0.04), in those with precursor-secreting tumors (p=0.005), and in those at local stages of the disease (p=0.0003). Thus mitotane benefited only patients not operated on for cure. Curative resection, precursor secretion, recent diagnosis, and local stage were favorably associated with survival.RésuméIntroduction: La survie et le pronostic des patients opérés d’un corticosurrénalome restent mal connus car il s’agit d’une tumeur rare. L’Association Française de Chirurgie Endocrinienne s’est fix pour but d’évaluer ces facteurs pendant une période de 18 ans. Les changements de présentation clinique, biochimique et l’évolution de la prise en charge chirurgicale ont également fait l’objet d’une analyse. Méthode: Deux cent cinquante trois patients (158 femmes, 95 hommes), d’une moyenne d’âge de 47 ans. ont été étudiés. Un syndrome de Cushing a été la situation clinique la plus fréquente (30%), et les études hormonales ont montré une tumeur sécrétante dans 66% des cas. Soixante-douze pour cent (n=182) des patients ont bénéficié d’une chirurgie à visée curative et 41,5% (n=105) ont eu une résection étendue en raison des métastases. Un curage ganglionnaire a été réalisé dans 32,5% (n=89) des cas. La mortalité post-opératoire a été de 5,5% (n=14). Du mitotane a été utilisé dans 53,8% des cas (n=135). La classification tumorale a montré : 16 stades I (6,3%): 126 stades II (maladie locale) (49,8%), 57 stades III (maladie loco-régionale) (22,5%); et 54 stades IV (métastases) (21.3%). Résultats: Le stade des tumeurs et le pourcentage de chirurgie à visée curative n’ont pas évolué. II a été réalisé plus d’incisions sous-costales et l’utilisation du mitotane n’a cessé de croître de façon significative. La survie actuarielle à 5 ans a été de 38% : 50% dans le groupe opéré à visée curative, 66% dans les stades I, 58% dans les stades II, 24% dans les stades III, et 0% dans les stades IV. L’analyse multivariée a montré que le mitotane a apporté un bénéfice de survie au groupe de patients opérés à visée palliative. Une amélioration du pronostic a été notée après 1988 (p=0.04), chez les patients sécrétant des précurseurs (p=0,005) et dans les stades locaux (p=0,0003). Conclusion: Le mitotane n’a été profitable qu’aux patients opérés à visée palliative. Le caractère curatif de la chirurgie, le type de sécrétion hormonale, la période récente de diagnostic et le stade local ont été des facteurs favorables de survie.ResumenIntroducción: Dada la poca frecuencia del cáncer adreno-cortical el pronóstico y la supervivencia de los pacientes intervenidos no es bien conocido. La Asociación Francesa de Cirugía Endocrina se ha marcado como objetivo valorar estos factores durante un periodo de tiempo de 18 años. Además, pretendemos analizar los cambios clínicos y bioquímicos, así como la evolución del tratamiento quirúrgico. Método: Se estudiaron 253 pacientes (158 hembras y 95 varones) cuya edad media fue de 47 años. El cuadro clínico más frecuente fue el del síndrome de Cushing (30%) y los análisis hormonales demostraron la existencia de un tumor secretor en el 66% de los casos. El 72% (n=182) de los pacientes fueron intervenidos quirúrgicamente con fines curativos y en el 41.5% (n=105) hubieron de efectuarse resecciones ampliadas por metástasis. Una linfadenectomia se realizó en el 32.5% (n=89) de los casos. La mortalidad operatoria fue del 5.5% (n=14). El 53.8% (n=135) de los pacientes recibieron como terapia adyuvante Mitotane. La clasificación tumoral registra: 16 estadios I (6.3%); 126 estadios II (enfermedad local) (49.8%). 57 estadios III (enfermedad loco-regional) (22.5%) y 54 estadios IV (con metástasis) (21.3%). Resultados: El porcentaje de tumores en los diferentes estadios no se ha modificado, ni tampoco la cirugía con fines curativos. La vía de abordaje más frecuente ha sido la subcostal y el empleo, como terapia adyuvante, de Mitotane no ha cesado de aumentar significativamente. La supervivencia actuarial global a 5 años fue del 38%; 50% en el grupo operado con fines curativos: 66% en pacientes en estadio I, 58% en los del estadio II, 24% en los del estadio III y 0% en los del estadio IV. Un análisis multivariante ha demostrado los beneficiosos efectos del Mitotane, por lo que a la supervivencia se refiere, en el grupo de pacientes intervenidos con fines paliativos. El pronóstico ha mejorado desde 1988 (p=0.04), en los pacientes secretores de precursores (p=0.005) y en los pacientes con enfermedad local (p=0.0003). Conclusiones: El Mitotane sólo es útil en casos de cirugía paliativa. La cirugía radical, el tipo de secreción hormonal, el diagnóstico precoz y el estadio de enfermedad local, son los factores más favorables en cuanto a la supervivencia se refiere.

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.

Effectiveness and limits of preoperative imaging studies for the localisation of pheochromocytomas and paragangliomas: a review of 282 cases

OBJECTIVE To find out the optimal strategy for the preoperative location of pheochromocytomas and paragangliomas. DESIGN Retrospective study. PATIENTS 282 patients operated on for histologically confirmed pheochromocytoma in France between 1980 and 1991, the past decade. MAIN OUTCOME MEASURES The results of imaging procedures, i.e. computed tomography (CT), (131)I meta-iodobenzylguanidine scintigraphy (MIBG) and magnetic resonance imaging (MRI) were reviewed. RESULTS Pheochromocytomas were sporadic in 206 (73%). They were unilateral in 189 (67%), bilateral in 54 (19%) and extra-adrenal in 39 (14%). Overall sensitivity of the studies was 89% for CT, 98% for MRI, and 81% for (131)I-MIBG. In unilateral adrenal lesions sensitivity were 100% for CT and MRI, and 88% for (131)I-MIBG; in bilateral lesions 66% for CT, 100% for MRI, and 62% for (131)I-MIBG; in extra-adrenal lesions 64% for CT, 88% for MRI, and 64% for (131)I-MIBG. CONCLUSION The accuracy with which pheochromocytomas and paragangliomas can be visualized questions nowadays the routine use of abdominal approach. In selected cases of sporadic unilateral chromaffin tumours, a posterior, lateral, or even laparoscopic approach should be considered.

18F-FDG Avidity of Pheochromocytomas and Paragangliomas: A New Molecular Imaging Signature?

Our objective was to evaluate 18F-FDG PET uptake in patients with nonmetastatic and metastatic chromaffin-derived tumors. Methods: Twenty-eight consecutive unrelated patients with chromaffin tumors, including 9 patients with genetically determined disease, were studied. A combination of preoperative imaging work-up, surgical findings, and pathologic analyses was used to classify the patients into 2 groups: those with nonmetastatic disease (presumed benign, n = 18) and those with metastatic tumors (n = 10). 18F-FDG PET was performed in all cases. Visual and quantitative analyses were individually graded for each tumor. Somatic mutations of the succinate dehydrogenase subunits B and D and Von-Hippel Lindau genes were also evaluated in 6 benign sporadic tumor samples. Results: All but 2 patients showed significantly increased 18F-FDG uptake on visual analysis. The maximum standardized uptake value (SUVmax) ranged from 1.9 to 42 (mean ± SD, 8.2 ± 9.7; median, 4.6) in nonmetastatic tumors and 2.3 to 29.3 (mean ± SD, 9.7 ± 8.4; median, 7.4) in metastatic tumors. No statistical difference was observed between the groups (P = 0.44), but succinate dehydrogenase–related tumors were notable in being the most 18F-FDG–avid tumors (SUVmax, 42, 29.3, 21, 17, and 5.3). Succinate dehydrogenase and Von-Hippel Lindau–related tumors had a significantly higher SUVmax than did neurofibromatosis type 1 and multiple endocrine neoplasia type 2A syndrome–related tumors (P = 0.02). 18F-FDG PET was superior to 131I-metaiodobenzylguanidine in all metastatic patients but one. By contrast, 18F-FDG PET underestimated the extent of the disease, compared with 6-18F-fluorodopa PET, in 5 patients with metastatic pheochromocytoma. However, succinate dehydrogenase mutations (germline and somatic) and functional dedifferentiation do not adequately explain 18F-FDG uptake since most tumors were highly avid for 18F-FDG. Conclusion: 18F-FDG PET positivity is almost a constant feature of pheochromocytomas and paragangliomas. It may be considered a molecular signature of such tumors, although which aspect of the plethora of molecular changes associated with dedifferentiation, germline genetic defects, or the adaptive response to hypoxia is responsible for this characteristic requires further elucidation.

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.

Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type IIa: Retrospective French Multicentric Study

Abstract. Primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia (MEN) type IIa is rare, occurring in 20% to 30% of the patients. The aim of this study was to evaluate clinical findings, surgical therapy, and outcome for 56 patients affected by PHPT among 249 MEN-IIa patients collected from 84 families assembled by the Groupe d’Etude des Tumeurs á Calcitonine (GETC, French Calcitonin Tumors Study Group). This retrospective study was based on cases registered by the GETC (20 participating centers) from 1969 to 1994. Characteristics of PHPT in 56 patients (31 women, 25 men) with MEN-IIa were reviewed. All but two underwent cervicotomy. The median age at diagnosis was 37.6 years. PHPT was found concomitantly with medullary thyroid carcinoma (MTC) or pheochromocytoma in 43 patients (77%). PHPT was asymptomatic in 68% of the patients. Serum calcium levels ranged from 2.20 to 3.70 mmol/L (median 2.82 mmol/L; normal 2.10–2.60 mmol/L). The number of parathyroid glands removed at surgery was 0 (n = 2), 1 (n = 24), 2 (n = 5), > 2 (n = 12), 4 (n = 11). Pathology (initial surgery) consisted of 24 adenomas, 4 double adenomas, and 25 hyperplasia. Cure after initial surgery was obtained in 89%, including a 22% incidence of hypoparathyroidism. There were 6 cases (11%) with persistent PHPT. With a mean follow-up of 6.4 years, five patients (9%) had recurrent PHPT. The results indicate that MEN-IIa-related PHPT is generally associated with mild, often asymptomatic hypercalcemia. Despite recurrences encountered 5 to 15 years after the first cervicotomy, resection of only macroscopically enlarged glands generally appears sufficient. Subtotal or total parathyroidectomy with autotransplantation is associated with a high rate of hypoparathyroidism.

Thyroid surgery: postoperative hematoma—prevention and treatment

Background and aimsPostoperative haematoma formation is a fortunately rare but potentially life-threatening complication of thyroid surgery. This paper aims to identify potential aetiological factors, describe surgical techniques and newer haemostatic agents that may be used to minimise the risk of haematoma formation and propose surgical strategies to deal with haematoma formation.Materials and methodsAn extensive literature search as well as own considerable experience in a tertiary referral centre endocrine surgical unit was drawn upon to review this topic.ConclusionsPostoperative haematoma may have a multifactorial aetiology. Numerous manoeuvres and surgical haemostatic agents may be employed to minimise the risk of haematoma formation but are no substitute for meticulous haemostasis. In the event of haematoma formation, early surgical re-intervention is strongly advocated with due care given to at risk structures.

Endoscopic Parathyroid Surgery: Results of 365 Consecutive Procedures

In recent years, several series have documented the feasibility of endoscopic approaches for parathyroid diseases. We performed a retrospective study to evaluate the results of endoscopic parathyroidectomy (EP) in the management of our patients with primary hyperparathyroidism (PHPT). During a 5.5 year period (1998–2003), we operated on 644 patients with PHPT. EP was proposed for patients with sporadic PHPT, without associated goiter, and without previous neck surgery in whom a single adenoma was localized by means of sonography and sestamibi scanning. EP was performed by the lateral approach with insufflation for patients with an adenoma located deep in the neck and by a gasless midline approach for patients whose adenoma was located anteriorly. A quick parathyroid (QPTH) assay was used during the surgical procedures. Among 644 patients with PHPT, 279 (43.3%) were not eligible for EP for the following reasons: associated nodular goiter (116 cases), previous neck surgery (52 cases), suspicion of multiglandular disease (31 cases), lack of preoperative localization (61 cases), and miscellaneous causes (19 cases). EP was performed in 365 patients with sporadic PHPT: 339 lateral access, 25 midline access, and one thoracoscopy. The median operating time was 49 minutes (16–130 minutes). Conversion to conventional parathyroidectomy was required in 49 patients (13.4%) for these reasons: missed adenomas (14 cases), difficulty with the dissection (8 cases), multiglandular disease correctly predicted by QPTH (11 cases), false-negative QPTH assay results (4 cases), false-positive sestamibi scan results (11 cases), and 1 false-positive sonography result. One patient presented with definitive recurrent nerve palsy. Three patients remained hypercalcemic, and one other patient had recurrent hypercalcemia. In conclusion, EP can be proposed for more than half of the patients with PHPT. Immediate results of EP are similar to those obtained with conventional parathyroidectomy, but no conclusions can be drawn in terms of the influence of EP on the outcome of the patients operated on for PHPT.

Long-term Outcome following Laparoscopic Adrenalectomy for Large Solid Adrenal Cortex Tumors

IntroductionLaparoscopic adrenalectomy (LA) is the procedure of choice for small benign adrenal tumors. In the absence of local invasion or metastases, the preoperative diagnosis of an adrenocortical carcinoma (ACC) is difficult, often leaving size as the principal predictor of malignancy. Large tumors are resectable laparoscopically, but the long-term outcome and therefore appropriateness of LA for cortical tumors > 6 cm is not known.MethodsWe reviewed the LA experience in our institution since its introduction in June 1994. Patients who underwent LA for solid cortical tumors ≥ 60 mm in diameter without preoperative or intraoperative evidence of malignancy were reviewed. Follow-up data, including clinical examination, biochemical analysis, and repeat scans, were reviewed for evidence of local or systemic recurrent disease.ResultsBetween 1994 and 2004 a total of 462 adrenalectomies were performed, 391 of which were done laparoscopically. Among them, 19 were solid cortical tumors ≥ 60 mm in diameter with no overt malignant preoperative or intraoperative characteristics: 9 nonsecreting tumors, 8 Cushing’s syndrome tumors (including 2 virilizing variants), 1 virilizing tumor, and 1 aldosteronoma. The mean age of the patients was 49.9 years (range 22–77 years), and the mean tumor size was 69.0 mm (range 60–80 mm). Histology confirmed a cortical adenoma in eight patients, malignant tumors in three, and indeterminate tumors in eight. The mean follow-up was 34 months (range 4–108 months). Two patients died of systemic recurrent disease (liver metastases) at 10 and 19 months, respectively, following surgery; two other patients died 12 and 21 months, respectively following surgery owing to unrelated cardiovascular and cerebrovascular pathology. One patient underwent surgery for local recurrence 54 months after primary surgery; the remaining 14 patients are well with no clinical or radiologic evidence of recurrent disease.ConclusionsLaparoscopic adrenalectomy for large solid cortical tumors without pre- or intraoperative evidence of malignancy is not contraindicated, and it is unlikely to have a deleterious effect on long-term outcome. Each case should be considered individually. We provide an algorithm for the approach to adrenocortical tumors ≥ 6 cm.

latent subclinical medullary thyroid carcinoma: diagnosis and treatment

Abstract. Sporadic medullary thyroid carcinoma (SMTC) is usually diagnosed at a clinical stage often associated with lymph node involvement. Hence surgical treatment does not result in definitive cure in many patients. Studies have demonstrated that routine measurement of serum basal calcitonin (CT) in patients with nodular thyroid disease allows preoperative, early diagnosis of unsuspected SMTC. The aim of this work was to assess the results of surgery in patients operated on for subclinical SMTC detected preoperatively by measurement of serum CT. Results were compared with those obtained in patients with SMTCs diagnosed at a clinical stage and operated on during the same period. During a 4-year period (1993–1996) 24 SMTCs were diagnosed and treated in our department. They were diagnosed at a clinical stage in 13 patients (group 1): palpable thyroid tumor (n= 11), palpable metastatic lymph node (n= 6), distant metastases (n= 4). In nine cases the diagnosis was made by both fine-needle aspiration cytology and serum CT measurement. In the four other cases the initial cytology was incorrect, but the diagnosis was revised on the basis of elevated basal CT values. In 11 patients (group 2) presenting with nodular thyroid disease, SMTC was not clinically detectable. SMTC was preoperatively suspected by elevated CT levels: basal CT > 10 pg/ml and pentagastrin-stimulated CT peak > 100 pg/ml. One patient in group 1 with distant metastases was not operated on. All of the other 12 patients underwent total thyroidectomy and extensive lymph node dissection. The mean size of the tumors was 27 mm. Lymph node involvement was found in nine patients. After surgery, CT levels returned to normal in five patients but remained elevated in five others; the two remaining patients died of distant metastases. All 11 patients in group 2 underwent total thyroidectomy and central neck dissection. None of the 11 patients had nodal extension. All 11 patients are biochemically cured. It was concluded that routine measurement of basal serum CT in those with nodular thyroid disease allows early, preoperative diagnosis of subclinical SMTC and improves the results of surgery.