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A Ciofu, E Baudin, P Chanson, AF Cailleux, E Comoy, JC Sabourin, M Ducreux, G Schaison and M Schlumberger

OBJECTIVE: Amine precursor uptake and decarboxylation is a classical feature of gastroenteropancreatic (GEP) neuroendocrine tumors (NET). Production of catecholamines was studied in GEP NET and non-NET patients. DESIGN: A cross-sectional study was undertaken. METHODS: We studied catecholamine and metabolite secretion in 115 consecutive GEP NET patients and in 20 patients with non-NET. After specific extraction, vanilmandelic acid, homovanilic acid, catecholamines (norepinephrine, epinephrine, dopamine) and methoxylated derivates (metanephrine, normetanephrine, methoxytyramine) in urinary extracts were analyzed by high performance liquid chromatography. Results were indexed to the 24-h urinary creatinine levels. RESULTS: Among the 115 patients with NET, 9 (8%) had an increase of at least one urinary catecholamine or metabolite; in 7 out of the 9 the increase was slight being less than twice the upper value of the normal range. Elevated urinary dopamine (3 patients), methoxytyramine (6 patients), norepinephrine (2 patients) and normetanephrine (2 patients) were found. No increased urinary excretion of epinephrine nor metanephrine was observed. An adrenal mass existed in one of these nine patients but metaiodobenzylguanidine scintigraphy was negative as was immunohistochemistry for epithelial markers. None of the 20 patients with non-NET demonstrated an increased excretion of catecholamine or metabolites. No relationships were found between catecholamine and metabolite excretions and patients' tumor and treatment characteristics. CONCLUSION: Production of catecholamines and metabolites is a rare event in GEP NET patients. Histological results, including positive immunohistochemistry for epithelial markers may help to diagnose GEP NET.

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S Leboulleux, E Baudin, J Young, B Caillou, V Lazar, G Pellegriti, M Ducreux, G Schaison and M Schlumberger

Neuroendocrine tumors (NET) of the thyroid gland are rare. Apart from medullary thyroid carcinoma (MTC), metastases of gastroenteropancreatic (GEP) NET may also occur. Features of six patients (five men, one female: age range, 39-67 years) with thyroid metastases from a GEP-NET are described. Thyroid metastases were bilateral in all patients and were associated with enlarged neck lymph nodes in five. In four cases, the thyroid tumor was either the first sign of the disease (n = 2) or was an isolated site of recurrence (n = 2). The tumors were well (n = 3) or poorly differentiated (n = 3). Five tumors for which the primary site could be determined corresponded to foregut-derived tumors (3 lungs, 1 thymus and 1 pancreatic NET). One tumor demonstrated calcitonin (CT) production as shown by immunohistochemistry and elevated plasma CT levels. However, the disease history and the clinical features strongly favored a metastasizing GEP-NET. No tumoral RET proto-oncogene mutation was found in this patient. The differential diagnosis between metastatic GEP-NET and MTC is crucial because prognosis, work-up, and treatment differ greatly.

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P Niccoli-Sire, A Murat, E Baudin, JF Henry, C Proye, JC Bigorgne, B Bstandig, E Modigliani, S Morange, M Schlumberger and B Conte-Devolx

BACKGROUND: Once genetic testing accurately identifies MEN 2 gene carriers, affected children are given the opportunity to undergo thyroidectomy at the earliest stages of the C-cell disease. OBJECTIVE: To define reliable parameters by which to identify the best moment for thyroidectomy in patients who are carriers of the MEN 2 gene. PATIENTS AND METHODS: Seventy-one MEN 2/FMTC gene carriers, collected through the national register of the French Calcitonin Tumours Study Group, were evaluated. All the patients included were younger than 20 years of age and underwent total thyroidectomy. Basal and pentagastrin-stimulated calcitonin were assayed using an immunoradiometric method (sensitivity less than 2pg/ml). Calcitonin measurement was evaluated on the basis of histopathological findings in surgical thyroid specimens. RESULTS: We found C-cell hyperplasia or medullary thyroid carcinoma in all the 71 gene carriers - even for the youngest patients - and nodal metastases were present in four cases. Calcitonin measurement (basal or pentagastrin-stimulated) detected C-cell disease preoperatively in all patients. Six of the 71 patients were not surgically cured: one had nodal metastases, one had an advanced staged disease and four had an incomplete nodal dissection or had not undergone lymph node surgery. CONCLUSIONS: Determination of calcitonin forms an integral part of the management of MEN 2 gene carriers. Thyroidectomy is undisputably indicated when basal calcitonin is abnormal. When basal calcitonin is undetectable, a pentagastrin-stimulated increase in calcitonin to more than 10 pg/ml indicates an early thyroidectomy to cure the patient.

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S Leboulleux, D Deandreis, C Escourrou, A Al Ghuzlan, F Bidault, A Aupérin, J P Travagli, J Lumbroso, M Schlumberger and E Baudin

Objective

To make the specificity of fluorodesoxyglucose (18FDG) positron emission tomography (PET) precise, in the follow-up of patients with adrenal cancer.

Design

This single centre retrospective study assessed the frequency and outcome of 18FDG uptake in the remaining adrenal glands after adrenalectomy for adrenocortical carcinoma (ACC) or malignant phaeochromocytoma (PH).

Results

Two hundred and ten 18FDG PET scans in 62 ACC patients, all under 1,ortho-1,para′-dichloro-diphenyl-dichloro-ethane (o,p′-DDD) treatment, and 30 18FDG PET scans in 8 PH patients were reviewed. Abnormal 18FDG uptake in the remaining adrenal glands was found in 19 (8%) 18FDG PET scans, in 10 (16%) ACC patients and in none of the PH patients. 18FDG uptake was found in 4% of the patients before the onset of o,p′-DDD, in 29% of the patients 0–6 months after the onset of o,p′-DDD (P=0.05), in 26% of the patients 6–12 months (P=0.072) after the onset of o,p′-DDD and in 14% of the patients 12–24 months after the onset of o,p′-DDD. It was never found later than 24 months after the onset of o,p′-DDD. Adrenal glands with 18FDG uptake were normal on computed tomography scans with i.v. contrast agent in all cases. 18FDG uptake in the remaining adrenal glands decreased and disappeared on subsequent FDG PET imaging in eight of the patients with follow-up available.

Conclusions

18FDG uptake in the remaining adrenal glands occurred in 14–29% of the patients followed for ACC within 24 months after adrenalectomy and onset of o,p′-DDD. This uptake is transient and should not be considered as suspicious for malignancy.

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G Hajje, I Borget, S Leboulleux, C Chougnet, A Al Ghuzlan, H Mirghani, C Caramella, D Hartl, M Schlumberger and E Baudin

Introduction

The prognostic value of serum calcitonin (CT) and carcinoembryonic antigen (CEA) doubling time has been recently demonstrated in medullary thyroid carcinoma (MTC) patients. No study has yet validated the surrogate role of these markers for survival during treatment. The aim of this study was to evaluate, in patients with advanced MTC treated with cytotoxic chemotherapy, the relationship between early changes of serum CT or CEA levels and progression-free survival (PFS).

Patients and methods

The files of 28 consecutive metastatic MTC patients with progressive disease, treated with cytotoxic chemotherapy in a single tertiary referral center between 2000 and 2010, were retrospectively reviewed. Serum CT and CEA measurements and radiological Response Evaluation Criteria in Solid Tumors (RECIST) evaluations were collected every 3 months. The relationship between changes in serum CT and CEA levels at 3 months, defined by an increase or a decrease of at least 20%, and PFS according to RECIST 1.0, was estimated using Kaplan–Meier curves and log-rank test.

Results

The median follow-up for the 28 patients was 68 months. According to RECIST, a partial response, a stabilization or a progression was observed in 14, 43, and 43% of cases respectively. Median PFS from the initiation of cytotoxic chemotherapy was 4.5 months. Median PFS among patients with and without significant CT increase at 3 months was 4.6 and 3.3 months respectively (P=0.75). Median PFS among patients with a significant CEA increase at 3 months was 2.7 months, whereas it was 19.1 months in patients in whom CEA did not increase (P=0.02).

Conclusion

At 3 months, an increase of serum CEA but not of CT levels appears as a valuable surrogate marker of short PFS in MTC patients treated with cytotoxic chemotherapy. A prospective validation is expected.

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N Boulle, E Baudin, C Gicquel, A Logie, J Bertherat, A Penfornis, X Bertagna, JP Luton, M Schlumberger and Y Le Bouc

OBJECTIVE: Recent studies have pointed to the role of the IGF system in the pathogenesis of adrenocortical tumors, and it was shown recently that malignant adrenocortical tumors exhibit a high insulin-like growth factor binding protein (IGFBP)-2 content. Circulating markers specific for adrenocortical carcinoma are needed and the aim of this study was to evaluate plasma IGFBP-2 as a marker for these malignant tumors. METHODS: Plasma IGFBP-2 was determined in 51 patients referred to our institutions for adrenocortical tumors. Fifteen patients were in complete remission (group 1), eight patients had preoperative localized tumors (group 2) and 28 patients had metastatic tumors (group 3). Thirty-six healthy volunteers constituted a control group. RESULTS: There was no significant difference in plasma IGFBP-2 concentration between healthy controls and patients with complete remission or localized tumors. In contrast, patients with metastatic disease had significantly higher IGFBP-2 plasma levels than the control group (P<0.001). IGFBP-2 levels in patients with metastatic disease were inversely correlated with survival (R2=0.308; P=0.0026). In patients with localized tumors, there was no correlation between plasma IGFBP-2 concentration and tumor size or histological features. Analysis of individual IGFBP-2 concentrations showed that five patients (17.8%) with metastatic tumors had normal IGFBP-2 levels and two patients (13.3%) in complete remission had high plasma IGFBP-2 levels. The influence of nutrition, hormone secretion and treatment on IGFBP-2 levels was examined. Nutritional status was evaluated by determining IGF-I levels and was found to be normal in 16 patients (61.5%) with high IGFBP-2 levels, suggesting that malnutrition was not responsible for the high IGFBP-2 concentrations in these patients. IGFBP-2 levels did not differ significantly according to tumor secretion or mitotane treatment. In a follow-up study, plasma IGFBP-2 concentration remained stable in patients with complete remission or stabilized disease and was a late marker of tumor progression in patients with progressive metastatic disease. CONCLUSIONS: These results indicate that plasma IGFBP-2 is elevated in patients with malignant adrenocortical tumors and that the major factor affecting IGFBP-2 levels in these patients is tumor stage. However, plasma IGFBP-2 was less sensitive than expected for a tumor marker, which may limit its value in the diagnosis and follow-up of adrenocortical carcinoma.

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C Nascimento, I Borget, F Troalen, A Al Ghuzlan, D Deandreis, D Hartl, J Lumbroso, C N Chougnet, E Baudin, M Schlumberger and S Leboulleux

Context

Thyroglobulin (Tg) measurement is a major tool for the follow-up of differentiated thyroid cancer (DTC) patients; however, in patients who do not undergo radioactive iodine (RAI) ablation, normal ultrasensitive Tg levels measured under levothyroxine treatment (usTg/l-T4) are not well defined.

Objective and design

This single-center retrospective study assessed usTg/l-T4 level in 86 consecutive patients treated with total thyroidectomy without RAI ablation for low-risk DTC (n=77) or for tumors of uncertain malignant potential (TUMP) (n=9).

Results

DTCs were classified as pT1, pT2, and pT3 in 75, 1, and 1 case respectively and pN0, pN1, and pNx in 40, 6, and 31 respectively. Following surgery, ten patients had Tg antibodies (TgAb). Among those without TgAb, the first usTg/l-T4 determination obtained at a mean time of 9 months after surgery was ≤0.1 ng/ml in 62% of cases, ≤0.3 ng/ml in 82% of cases, ≤1 ng/ml in 91%, and ≤2 ng/ml in 96% of cases. After a median follow-up of 2.5 years (range: 0.6–7.2 years), one patient had persistent disease with an usTg/l-T4 at 11 ng/ml and an abnormal neck ultrasonography (US) and two patients had usTg/l-T4 level >2 ng/ml (3.9 and 4.9 ng/ml) with a normal neck US. Within the first 2 years following total thyroidectomy without RAI ablation, usTg/l-T4 level is ≤2 ng/ml in 96% of the cases.

Conclusion

After total thyroidectomy, sensitive serum Tg/l-T4 level is ≤2 ng/ml in most patients and can be used for patient follow-up.

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M Terzolo, A E Baudin, A Ardito, M Kroiss, S Leboulleux, F Daffara, P Perotti, R A Feelders, J H deVries, B Zaggia, S De Francia, M Volante, H R Haak, B Allolio, A Al Ghuzlan, M Fassnacht and A Berruti

Context

Mitotane plasma concentrations ≥14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC). A correlation between mitotane concentrations and patient outcome has not been demonstrated in an adjuvant setting.

Objective

To compare recurrence-free survival (RFS) in patients who reached and maintained mitotane concentrations ≥14 mg/l vs patients who did not.

Design and setting

Retrospective analysis at six referral European centers.

Patients

Patients with ACC who were radically resected between 1995 and 2009 and were treated adjuvantly with mitotane targeting concentrations of 14–20 mg/l.

Main outcome measures

RFS (primary) and overall survival (secondary).

Results

Of the 122 patients included, 63 patients (52%) reached and maintained during a median follow-up of 36 months the target mitotane concentrations (group 1) and 59 patients (48%) did not (group 2). ACC recurrence was observed in 22 patients of group 1 (35%) and 36 patients in group 2 (61%). In multivariable analysis, the maintenance of target mitotane concentrations was associated with a significantly prolonged RFS (hazard ratio (HR) of recurrence: 0.418, 0.22–0.79; P=0.007), while the risk of death was not significantly altered (HR: 0.59, 0.26–1.34; P=0.20). Grades 3–4 toxicity was observed in 11 patients (9%) and was managed with temporary mitotane discontinuation. None of the patients discontinued mitotane definitively for toxicity.

Conclusions

Mitotane concentrations ≥14 mg/l predict response to adjuvant treatment being associated with a prolonged RFS. A monitored adjuvant mitotane treatment may benefit patients after radical removal of ACC.

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S Leboulleux, D Deandreis, A Al Ghuzlan, A Aupérin, D Goéré, C Dromain, D Elias, B Caillou, J P Travagli, T De Baere, J Lumbroso, J Young, M Schlumberger and E Baudin

Context

Peritoneal carcinomatosis (PC) is a rare site of distant metastases in patients with adrenocortical cancer (ACC). One preliminary study suggests an increased risk of PC after laparoscopic adrenalectomy (LA) for ACC.

Objective

The objective of the study was to search for risk factors of PC including surgical approach.

Design

This was a retrospective cohort study conducted in an institutional practice.

Patients

Sixty-four consecutive patients with ACC seen at our institution between 2003 and 2009 were included. Mean tumor size was 132 mm. Patients had stage I disease in 2 cases, stage II disease in 32 cases, stage III disease in 7 cases, stage IV disease in 21 cases, and unknown stage disease in 2 cases. Surgery was open in 58 cases and laparoscopic in 6 cases.

Main outcome

The main outcome was the risk factors of PC.

Results

PC occurred in 18 (28%) patients. It was present at initial diagnosis in three cases and occurred during follow-up in 15 cases. The only risk factor of PC occurring during follow-up was the surgical approach with a 4-year rate of PC of 67% (95% confidence interval (CI), 30–90%) for LA and 27% (95% CI, 15–44%) for open adrenalectomy (P=0.016). Neither tumor size, stage, functional status, completeness of surgery, nor plasma level of op'DDD was associated with the occurrence of PC.

Conclusion

We found an increased risk of PC after LA for ACC. Whether this is related to an inappropriate surgical approach or to insufficient experience in ACC surgery should be clarified by a prospective program.