Although usually benign, anterior pituitary tumours occasionally exhibit aggressive behaviour, with invasion of surrounding tissues, rapid growth, resistance to conventional treatments and multiple ...recurrences. In very rare cases, they metastasize and are termed pituitary carcinomas. The time between a 'classical' pituitary tumour and a pituitary carcinoma can be years, which means that monitoring should be performed regularly in patients with clinical (invasion and/or tumour growth) or pathological (Ki67 index, mitotic count and/or p53 detection) markers suggesting aggressiveness. However, although both invasion and proliferation have prognostic value, such parameters cannot predict outcome or malignancy without metastasis. Future research should focus on the biology of both tumour cells and their microenvironment, hopefully with improved therapeutic outcomes. Currently, the initial therapeutic approach for aggressive pituitary tumours is generally to repeat surgery or radiotherapy in expert centres. Standard medical treatments usually have no effect on tumour progression but they can be maintained on a long-term basis to, at least partly, control hypersecretion. In cases where standard treatments prove ineffective, temozolomide, the sole formally recommended treatment, is effective in only one-third of patients. Personalized use of emerging therapies, including peptide receptor radionuclide therapy, angiogenesis-targeted therapy and immunotherapy, will hopefully improve the outcomes of patients with this severe condition.
Few data are published on the long-term follow-up of ipilimumab-induced hypophysitis, a cytotoxic T-lymphocyte antigen 4 antibody. We characterized hypophysitis in terms of clinical signs, ...endocrinological profile, and imaging at diagnosis and during a long-term follow-up.
Fifteen patients, treated for malignant melanoma and who presented ipilimumab-induced hypophysitis, were observed between June 2006 and August 2012 in Timone Hospital, Marseille.
Symptoms, pituitary function, and pituitary imaging at diagnosis of hypophysitis and during the follow-up were recorded.
Of 131 patients treated with ipilimumab or a placebo, 15 patients (10 mg/kg in 11/15) presented with hypophysitis (≥11.5%) at 9.5±5.9 weeks (mean±s.d.) after treatment start, occurring in 66% after the third infusion. The main initial symptoms were headache (n=13) and asthenia (n=11). All patients but one had at least one hormonal defect: thyrotroph (n=13), gonadotroph (n=12), or corticotroph (n=11) deficiencies. None had diabetes insipidus. Pituitary imaging showed a moderately enlarged gland in 12 patients. Clinical symptoms improved rapidly on high-dose glucocorticoids (n=11) or physiological replacement doses (n=4). At the end of follow-up (median 33.6 months, range 7-53.5), corticotroph deficiency remained in 13 patients, 11 recovered thyrotroph and ten gonadotroph functions. Pituitary imaging remained abnormal in 11 patients.
Ipilimumab-induced hypophysitis is a common side-effect with frequent hormonal deficiencies at diagnosis. Usually, hormonal deficiencies improved, except for corticotroph function. Patients receiving these immunomodulatory therapies should be closely monitored especially by systematic baseline hormone measurements after the third infusion and remain at a risk of adrenal insufficiency in the long-term.
: Phaeochromocytoma and paraganglioma (PPGL) are chromaffin cell tumours that require timely diagnosis because of their potentially serious cardiovascular and sometimes life- threatening sequelae. ...Tremendous progress in biochemical testing, imaging, genetics and pathophysiological understanding of the tumours has far-reaching implications for physicians dealing with hypertension and more importantly affected patients. Because hypertension is a classical clinical clue for PPGL, physicians involved in hypertension care are those who are often the first to consider this diagnosis. However, there have been profound changes in how PPGLs are discovered; this is often now based on incidental findings of adrenal or other masses during imaging and increasingly during surveillance based on rapidly emerging new hereditary causes of PPGL. We therefore address the relevant genetic causes of PPGLs and outline how genetic testing can be incorporated within clinical care. In addition to conventional imaging (computed tomography, MRI), new functional imaging approaches are evaluated. The novel knowledge of genotype-phenotype relationships, linking distinct genetic causes of disease to clinical behaviour and biochemical phenotype, provides the rationale for patient-tailored strategies for diagnosis, follow-up and surveillance. Most appropriate preoperative evaluation and preparation of patients are reviewed, as is minimally invasive surgery. Finally, we discuss risk factors for developing metastatic disease and how they may facilitate personalised follow-up. Experts from the European Society of Hypertension have prepared this position document that summarizes the current knowledge in epidemiology, genetics, diagnosis, treatment and surveillance of PPGL.
MEN2B is a very rare autosomal dominant hereditary tumor syndrome associated with medullary thyroid carcinoma (MTC) in 100% cases, pheochromocytoma in 50% cases and multiple extra-endocrine features, ...many of which can be quite disabling. Only few data are available in the literature. The aim of this review is to try to give further insights into the natural history of the disease and to point out the missing evidence that would help clinicians optimize the management of such patients. MEN2B is mainly characterized by the early occurrence of MTC, which led the American Thyroid Association to recommend preventive thyroidectomy before the age of 1 year. However, as the majority of mutations are
, improved knowledge of the nonendocrine signs would help to lower the age of diagnosis and improve long-term outcomes. Future large-scale studies will be aimed at characterizing more in detail the main characteristics and outcomes of MEN2B.
Transsphenoidal surgery is the first‐line treatment of Cushing's disease. However, medical treatment can be given in a high proportion of patients with this rare condition. This is especially the ...case in severe hypercortisolism for which medical treatment will be given for a short period of time to prepare the patient for surgery, or on a long‐term basis after failed transsphenoidal surgery, or when waiting for the maximal beneficial effect of radiation techniques. These different situations all require that hypercortisolism be perfectly controlled. Severe hypercortisolism is frequently treated by a block and replace approach during which a substitutive treatment is given after the induction of adrenal insufficiency. Mild hypercortisolism, the most frequent situation, is usually treated with a titration approach with a progressive dose increase. This approach requires certainty of eucortisolism because patients may be treated for a prolonged period. This review details the main situations during which medical treatment should be considered, as well as the way in which to monitor them to avoid the long‐term consequences of mild hypo‐ or hypercortisolism.
Proposed algorithm of monitoring cortisol‐lowering drugs in Cushing's syndrome. UFC, urinary free cortisol; LSNC, late night salivary cortisol
Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. ...We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival.
Multicenter retrospective study by members of the French Society of Endocrinology.
Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (
= 23) or lactotroph (
= 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment.
The median treatment duration was 6.5 cycles (range 2-24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0-72). Overall survival was significantly higher among responders (
= 0.002); however, ten patients relapsed 5 months (0-57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success.
Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.
Abstract Objective The study aimed to analyze complications of endoscopic transsphenoidal surgery (ETS) for nonfunctioning pituitary adenomas (NFPAs). Methods A retrospective study of 300 NFPAs was ...carried out. Complications and factors that could influence these complications were analyzed. Results Visual and pituitary functions worsened in 2.4% and 13.7% of cases, respectively. Postoperative diabetes insipidus was permanent in 6.2% of cases. Postoperative meningitis occurred in 3.3% of patients. It was strongly associated with intraoperative cerebrospinal fluid (CSF) leaks ( p = 0.01), postoperative CSF leaks ( p = 0.0001), and operation times of more than 1 hour ( p = 0.023). Detection of Staphylococcus aureus and preoperative treatment with mupirocin in the nostrils did not impact the occurrence of meningitis. Two patients with meningitis died (unique cause of death). Postoperative CSF leaks occurred in 2.7% of cases and were associated with intraoperative CSF leaks ( p = 0.007) and permanent diabetes insipidus ( p = 0.028). The rate of CSF leak fell from 4% to 0.8% ( p = 0.01) after we moved from a soft to hard reconstruction of the sella. The rate of postoperative epistaxis fell from 6.7% to 1.25% after we stopped using the monopolar coagulation ( p = 0.013). Conclusions ETS permits a wide view, allowing good conditions for a satisfactory resection in the majority of NFPAs. Some pitfalls of endoscopy can lead to complications that improve with modification of the operative technique (i.e., CSF leak and postoperative epistaxis). This study confirms an acceptable rate of complications associated with ETS.
Multiple endocrine neoplasia type 2 (MEN2) is a rare hereditary syndrome due to mutations of the proto-oncogene REarranged during Transfection (RET), defined by the association of medullary thyroid ...carcinoma (MTC) in almost 100% cases, and pheochromocytoma in roughly 50% (primary hyperparathyroidism can be seen in 10–20% of patients with MEN2A). Early thyroidectomy and the efficacy of novel tyrosine kinase inhibitors modified the natural history of MTC, with possibilities of cure or long-term control. The second main compound, pheochromocytoma, is reported with a variable penetrance, from 10 to 80% cases, depending on the mutation of
RET
. Pheochromocytoma constitutes the main disease to screen in patients with
RET
mutations. Pheochromocytoma clinical and biochemical diagnosis, as well as the way to treat it are thus crucial. This review will thus focus on the epidemiological specificities of MEN2-related pheochromocytoma, the genotype/phenotype relationship, the modern imaging modalities necessary to confirm the diagnosis in this hereditary context, as well as the optimal management and the possibilities of adrenal sparing surgery. Additional information will include the natural history of MEN2B-pheochromocytoma, the rare cases of malignant pheochromocytoma, and the factors that could modify the penetrance between individuals carrying the same mutation, especially in the same family.
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