Charles Proye

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.

Hypocalcemia following Thyroid Surgery: Incidence and Prediction of Outcome

Abstract. Postoperative hypocalcemia is a common and most often transient event after extensive thyroid surgery. It may reveal iatrogenic injury to the parathyroid glands and permanent hypoparathyroidism. We prospectively evaluated the incidence of hypocalcemia and permanent hypoparathyroidism following total or subtotal thyroidectomy in 1071 consecutive patients operated during 1990–1991. We then determined in a cross-sectional study which early clinical and biochemical characteristics of patients experiencing postoperative hypocalcemia correlated with the long-term outcome. Postoperative calcemia under 2 mmol/l was observed in 58 patients (5.4%). In 40 patients hypocalcemia was considered severe (confirmed for more than 2 days, symptomatic or both). At 1 year after surgery five patients (0.5%) had persistent hypocalcemia. We found that patients carried a high risk for permanent hypoparathyroidism if fewer than three parathyroid glands were preserved in situ during surgery or the early serum parathyroid hormone level was ≤ 12 pg/ml, the delayed serum calcium levels ≤ 8 mg/dl, or the delayed serum phosphorus level ≥ 4 mg/dl under oral calcium therapy. When one or more of these criteria are present, long-term follow-up should be enforced to check for chronic hypocalcemia and to avoid its severe complications by appropriate supplement therapy.

Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors.

The definitive diagnostic criteria for malignant adrenocortical tumors are distant metastasis and/or local invasion. The Weiss histopathologic system is the most commonly used method for assessing malignancy because of its simplicity and reliability. Unfortunately, its application remains subjective. This current retrospective study evaluated the Weiss system and assessed the value of MIB-1 labeling in the diagnosis of adrenocortical malignancy. Twenty-four malignant tumors with distant metastasis, gross local invasion, or recurrence were selected and matched on their functioning status to 25 benign tumors. Two independent observers delineated the Weiss criteria. An MIB-1 labeling index was determined. Presence of three or more Weiss microscopic criteria was related to malignancy (specificity 96%, sensitivity 100%), thus confirming the value of the Weiss system. Interobserver agreement for the Weiss system (total score) was excellent (r = 0.94). The lack of reliability for some Weiss criteria led us to propose a statistically modified system, based on the most reliable criteria (2.mitotic rate × 2.cytoplasm × abnormal mitoses × necrosis × capsular invasion) with a significant correlation with the Weiss system (r = 0.98). The MIB-1 labeling index was significantly higher in malignant tumors (p <0.0001). MIB1 could also help to differentiate malignant from benign adrenocortical tumors.

Germ-Line Mutation Analysis in Patients with Multiple Endocrine Neoplasia Type 1 and Related Disorders

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.

Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas

Objective:To analyze the penetrance and clinical course of isolated nonfunctioning tumors of the pancreas (NFTP) in MEN 1 patients, and to propose a strategy for managing them. Summary Background Data:Pancreaticoduodenal tumors develop in a majority of MEN 1 patients and are a major cause of death. The natural history of NFTP is poorly defined, and no clear-cut guidelines have been widely accepted regarding treatment. Methods:Data on 108 patients with isolated NFTP among 579 MEN 1 patients from the French Endocrine Tumor Study Group (GTE) were analyzed. Survival rates were calculated using the Kaplan-Meier method. Results:The penetrance of NFTP was 34% at age 50, making it the most frequent pancreaticoduodenal tumor in MEN 1 patients. Forty-three patients (40%) underwent surgery, 32 of them curatively. No patient died because of surgery. Average life expectancy for patients with NFTP was shorter than that for MEN 1 patients who did not have pancreaticoduodenal tumors. Thirteen patients died during follow-up, 10 due to NFTP. Tumor size was correlated with the risks of metastasis and death. These risks were low for patients with tumors ≤20 mm. Conclusions:NFTP are currently the most common tumors of the pancreaticoduodenal region in patients with MEN 1. Prevention of tumor spread by surgery should be balanced with potential operative mortality and morbidity. We do not recommend routine surgery for NFTP ≤20 mm.

Prognostic Factors in Patients With Zollinger-Ellison Syndrome and Multiple Endocrine Neoplasia Type 1

Abstract Background & Aims: Risk factors of metachronous liver metastases and death are not well known in patients with the Zollinger–Ellison syndrome and multiple endocrine neoplasia type 1. These factors were retrospectively determined in 77 patients. Methods: Data chart review was performed. Results: Median follow-up was 102 months (range, 12–366). Surgery was performed on 48 patients, including 9 of the 10 patients with large pancreatic tumors (≥3 cm). Liver metastases developed in 4 patients (40%) with large pancreatic tumors, in 3 (4.8%) without, and in 1 of the 4 patients with pancreatic tumors of unknown size; all had previously undergone surgery. The only independent factor associated with development of liver metastases identified by multivariate analysis was large pancreatic tumors (risk ratio, 29.0; 95% confidence interval [CI], 3.2–260.7). Surgery was not selected. The probability of being free of liver metastases in the 63 patients without large pancreatic tumors was 96% (95% CI, 88–100) at 10 and 15 years. Thirteen (16.9%) patients died. The only independent factors of death selected by multivariate analysis were Zollinger–Ellison syndrome diagnosis before 1980 (risk ratio, 8.2; 95% CI, 1.7–40.6) and age at diagnosis (risk ratio/year, 1.08; 95% CI, 1.03–1.14). Conclusions: Large pancreatic tumors are predictive of the development of metachronous liver metastases, and surgery does not seem to prevent them. GASTROENTEROLOGY 1999;116:286-293

Is Surgery Beneficial for MEN1 Patients with Small (≤2 cm), Nonfunctioning Pancreaticoduodenal Endocrine Tumor? An Analysis of 65 Patients from the GTE

BackgroundThe management of small, nonfunctioning pancreaticoduodenal endocrine tumors (NFPET) in multiple endocrine neoplasia type 1 (MEN1) patients is still controversial. We therefore investigated the effect of surgery on survival and tumor progression in MEN1 patients with NFPET ≤2 cm by analyzing data from the Groupe des Tumeurs Endocrines (GTE) registry.Materials and MethodsAmong 579 MEN1 patients in the registry, 65 had NFPET ≤ 2 cm. Fifteen (23%) underwent pancreatectomy, 9 at least segmental pancreatectomies and 6 biopsies or enucleations (the surgery group), and 50 (77%) were followed conservatively (the no surgery group). Age at MEN1 and NFPET diagnosis was similar in both groups, as was size of the primary tumor. Seven (10.8%) patients had metastases. Five metastases were synchronous, and 2 (one in each group) were metachronous. Tumor size was similar in patients with or without metastasis.ResultsThere was no perioperative mortality. The average follow-up time after NFPET diagnosis was 6.7 years in the surgery group and 3.3 years in the no surgery group. Three (4.6%) patients died during follow-up, 2 due to NFPET and 1 due to thymus tumor. The 2 patients who died of NFPET had undergone pancreatic surgery at the time of NFPET diagnosis. The 2 groups did not differ significantly with respect to tumor progression [5/15 (33%) vs 6/38 (16%), P = 0.16]. Overall life expectancy of patients with NFPET ≤2 cm was not different than that of the 229 MEN1 patients in the registry without any pancreaticoduodenal tumor (P = 0.33).ConclusionsThis study suggests that surgery may not be beneficial for MEN1 patients with NFPET ≤2 cm.

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.

Supernumerary Parathyroid Glands: Frequency and Surgical Significance in Treatment of Renal Hyperparathyroidism

Supernumerary parathyroid glands (SPGs) are found in 13% of random autopsies. The high incidence of SPGs could explain the persistence or trigger recurrence of renal hyperparathyroidism after surgery. The aim of this study was to assess the frequency and clinical relevance of SPG in patients operated on for renal hyperparathyroidism (HPT). In this retrospective study we reviewed the medical records of 290 patients with renal HPT who were initially treated in our department. We examined the anatomic and pathologic findings during cervical surgical exploration and the outcome of HPT during follow-up. SPGs were identified in 87 patients (30%) during the initial cervicotomy, corresponding to intrathymic parathyroid cell islets (one to four) in 70 cases and to extrathymic SPG in 17 patients. Among 260 patients available for follow-up, 11 experienced persistent HPT (4%), and 34 developed recurrent HPT (13%). A total of 25 patients were reoperated on, and SPGs were responsible for 4 of 8 cases of persistent HPT and 4 of 17 cases of recurrent HPT, representing an overall frequency of 32%. The anatomic distribution of SPGs found during reoperations included thymus, retroesophageal grove, carotid sheath, and mediastinum. SPGs are thus present in 30% of patients with renal HPT and are situated mainly in the thymus. Thymectomy should be performed routinely during the first surgical exploration to prevent recurrences arising from anterior mediastinal glands. SPGs were also responsible for 32% of persistent or recurrent HPT. In that setting, frankly ectopic SPGs are not rare, and preoperative imaging appears highly desirable prior to embarking on surgical reexploration.

Ductal Cyst Formation in Collagen-Embedded Adult Human Islet Preparations: A Means to the Reproduction of Nesidioblastosis In Vitro

Neogenesis of endocrine islets from ductal epithelium termed nesidioblastosis has been described in vivo after various experimental conditions (90% pancreatectomy or pancreas wrapping in the rodent) and in clinical pathologies. In the adult regenerating pancreas, a proliferation and organization of ductal epithelium into tubular structures precedes its differentiation into endocrine cells. Reproduction of nesidioblastosis in vitro may provide a novel approach to human islet propagation in vitro. With this aim, adult human islet preparations were cultured in diverse three-dimensional (3D) gels in the presence of serum. After 3–5 days in rat tail collagen gels, proliferating (bromodeoxyuridine-positive) cystic structures appeared associated with islets and as isolated spheres. Percentage labeling indexes of the cysts were 4.1, 18.7, 15.4, and 13.3% after 3, 5, 7, and 10 days of culture, respectively. Immunohistochemistry confirmed the ductal (carbohydrate antigen 19–9) and epithelial (keratin-1) nature of the cysts. No cysts were formed in agarose gels or Vitrogen 100, whereas the cyst number was increased by the quantity of serum (20% > 10%) and gels rich in extracellular matrix components and growth factors (Matrigel). The latter lead to tubular networks. Single endocrine islet cells were observed in the ductal cysts after 7 (2.8%) to 10 (5.6%) days in rat tail collagen. Our observations paralleled the changes characteristic of the regenerating pancreas in vivo. 3D culture may permit the identification of matrix and media constituents promoting the neogenesis of islets and may be the means to increase the mass of endocrine tissue obtained from adult cadaveric pancreases for transplantation.