VIPomas are rare-functioning neuroendocrine tumors (NETs). Overproduction of vasointestinal peptide (VIP) leads to the Verner–Morrison syndrome, whose management is challenging when refractory to somatostatin analogs. Two patients with progressive metastatic pancreatic NETs and refractory VIPoma symptoms were treated with sunitinib. This led to fast and sustained total relief of VIPoma symptoms, enabling earlier discharge from hospital and improvement in their quality of life. In both cases, sunitinib discontinuation led to the quick recurrence of watery diarrhea, which resolved within a few days after reintroducing sunitinib. The anti-secretory effect of sunitinib on VIPoma syndrome was probably not related to any anti-tumor effect. These observations agree with the rare reported cases of anti-secretory effects with targeted therapies. The sunitinib-driven inhibition of multiple-tyrosine kinase receptors might act on secretory pathways and describe sunitinib's ability to improve VIPoma symptoms. Sunitinib could be a therapeutic option to control refractory VIPoma symptoms in patients with NETs.
Louis de Mestier, Thomas Walter, Hedia Brixi, Catherine Lombard-Bohas, and Guillaume Cadiot
Thomas Walter, Laurence Chardon, Valérie Hervieu, Richard Cohen, Jean-Alain Chayvialle, Jean-Yves Scoazec, and Catherine Lombard-Bohas
We aimed to gain insight into the functional consequences of ghrelin overproduction in patients with neuroendocrine tumors and its relations with disease characteristics and evolution.
We retrospectively analyzed three cases of neuroendocrine carcinomas associated with very high levels of circulating ghrelin.
Between February and October 2007, serum ghrelin levels were determined in all patients with well-differentiated endocrine carcinoma referred to our center (n=72). Three patients were found to have circulating ghrelin levels >10-fold the upper limit of normal. The clinical, biochemical, and pathological characteristics of these three patients were reviewed. The ratio between circulating acyl and total ghrelin was determined, and tumor tissue expression of ghrelin was assayed by immunohistochemistry.
The three patients had massive hyperghrelinemia (respectively 49 028, 63 711, and 101 996 pg/ml), with <10% of acyl ghrelin. The corresponding primary tumors were located in the pancreas, rectum, and gallbladder; all were metastatic. There was no acromegaly; there was a decrease in appetite; and body mass index was low. Serum GH levels were only slightly increased and serum IGF1 levels were normal. Immunoreactive ghrelin was detected in the tumor tissue in the two cases in which tissue material was available. All three patients died before 12 months after the diagnosis of hyperghrelinemia.
Well-differentiated neuroendocrine carcinomas of various origins may produce markedly high levels of circulating ghrelin, without evidence of clinical or functional consequences.
Cécile Nozières, Laurence Chardon, Bernard Goichot, Françoise Borson-Chazot, Valérie Hervieu, Karim Chikh, Catherine Lombard-Bohas, and Thomas Walter
Inappropriate calcitonin (CT) release, a major feature of medullary thyroid cancer (MTC), may occur in neuroendocrine tumors (NETs). The aims of this retrospective study were to assess i) the characteristics and prognosis of CT-producing NETs, and ii) the value of CT monitoring during follow-up.
All patients with NETs in whom serum CT was assayed between 2010 and 2012 were included. MTCs were excluded. Clinical, biological, and histological characteristics were studied.
Twenty-one (12%) of 176 patients in whom serum CT was systematically assayed had concentrations >100 ng/l, with tumours predominantly of bronchial or pancreatic origin (P<0.0001), and of high grade (P=0.0006). Poor prognosis was linked to high CT levels, poor differentiation, and grade 3. In a total group of 24 patients with serum CT >100 ng/l, symptoms potentially attributable to CT were recorded in eight, with occasional overlap with the carcinoid syndrome among other secretory syndromes. Immunohistochemistry could be performed in six tumor specimens, CT being detected in five. In 11 patients with five or more successive CT assays, hormone levels were fairly well correlated with clinical courses.
Serum CT levels may be raised in some patients with NETs, especially from foregut origin, and of high grade. The suggested value of CT monitoring during follow-up must be confirmed in further studies.
Philippe A Cassier, Sawsan Abou-Amara-Olivieri, Pascal Artru, Marie-George Lapalus, Jean-Paul Riou, and Catherine Lombard-Bohas
Ectopic adrenocorticotropin secretion (EAS) remains a therapeutic challenge whenever the tumor responsible for the syndrome is not amenable to curative resection. Two cases of EAS related to metastatic foregut-derived endocrine carcinomas led us to use mifepristone, an antagonist of both progesterone and glucocorticoids. Mifepristone clearly improved skin lesions and diabetes associated with hypercorticism. The beneficial effect lasted for about 10 months. In both cases, recurrent hypertension and hypokalemia eventually required adrenalectomy.
Cécile Nozières, Thomas Walter, Marie-Odile Joly, Sophie Giraud, Jean-Yves Scoazec, Françoise Borson-Chazot, Chantal Simon, Jean-Paul Riou, and Catherine Lombard-Bohas
Ten percent of paragangliomas are malignant and one-third occurs in a genetic background. We report a case of succinate dehydrogenase subunit B (SDHB)-related malignant paraganglioma with dramatic response to temozolomide and capecitabine regimen (decrease in tumor size of 70% with RECIST criteria). Tumor cells harbored a new mutation in SDHB gene and showed aberrant hypermethylation of O6-methylguanine-DNA-methyltransferase promoter. Our report suggests the importance of molecular predictive factors of response for the selection of chemotherapeutic as well as targeted agents. This observation points to a possible genotype response to treatment relationships, which could help to design tailor-made treatments in the future.
Valérie Bernard, Catherine Lombard-Bohas, Marie-Caroline Taquet, François-Xavier Caroli-Bosc, Philippe Ruszniewski, Patricia Niccoli, Rosine Guimbaud, Cécile N Chougnet, Bernard Goichot, Vincent Rohmer, Françoise Borson-Chazot, Eric Baudin, and for the French Group of Endocrine Tumors
Refractory hypoglycemia in patients with metastatic insulinoma is an important cause of morbidity and mortality. Everolimus could be a new therapeutic option.
Within the French Group, we conducted a retrospective, multicentric study of endocrine tumors to evaluate the time to the first recurrence of symptomatic hypoglycemia, after everolimus initiation, in patients with metastatic insulinoma and refractory hypoglycemia. Ongoing hyperglycemic medical options, tumor response, and safety information were recorded.
Twelve patients with metastatic insulinoma and refractory hypoglycemia who were treated with everolimus between May 2007 and June 2011 were reviewed. Everolimus (starting dose, 10 mg/day, except in one patient, 5 mg/day) was given after a median of four previous therapeutic lines. Medication aimed at normalizing blood glucose levels in 11 patients. After a median duration of 6.5 months (range 1–35+ months), median time to the first recurrence of symptomatic hypoglycemia was 6.5 months (range 0 to 35+ months). Three patients discontinued everolimus because of cardiac and/or pulmonary adverse events at 1, 1.5, and 7 months after initiation, which led to two deaths. Three patients discontinued everolimus because of tumor progression at 2, 3, and 10 months after initiation, without recurrence of hypoglycemia.
Everolimus appears to be a new effective treatment for patients with metastatic insulinoma and refractory hypoglycemia. Tolerance should be carefully monitored.
Juliette Maurel, Rosine Guimbaud, Thierry Lecomte, Astrid Lièvre, Vincent Hautefeuille, Philip Robinson, Laurent Francois, Catherine Lombard-Bohas, Julien Forestier, Laurent Milot, Fabien Subtil, and Thomas Walter
Literature on patient-reported outcomes (PRO) of carcinoid syndrome symptoms (CSS) is scarce. We used a patient-reported outcome measure (PROM) to evaluate CSS, the domains of daily life impacted by CSS, the main symptoms that affect daily life, its change according to clinical, biological and morphological evolution, and the risk factors for a poor PRO-CSS score.
Patients completed the PRO-CSS, EORTC-QLQ30, and GI-NET21 questionnaires at the time of their clinical, laboratory, and morphological assessments in a multicentre French cohort study from February 2019 to May 2020.
In total, 147 patients with metastatic ileal (n =126), lung (n =20), or unknown primitive neuroendocrine tumour but high 5-hydroxyindole-3-acetic acid level (n =1) were included; 42 (32%) received an above-label dose of somatostatin analogues. Fifty-one (35%) patients had a poor PRO-CSS score. Travelling and food restriction were the two main domains affected. Diarrhoea (mean: 2.3/5 on Likert scale), imperiousness (mean of 2.5/5), fatigue (2.2/5), abdominal pain (1.7/5), and flushing episodes (1.5/5) were the main symptoms affecting daily life. The PRO-CSS score was not correlated to the clinical assessment performed by physicians at the baseline and during the follow-up. Patients with a poor PRO-CSS score had a higher tumour burden.
PROM-CSS may help physicians make an objective assessment of CSS and its impact in daily practice; this tool could become a key evaluation criterion in clinical trials focusing on CSS.