Pituitary tumours, the most frequent intracranial tumour, are historically considered benign. However, various pieces of clinical evidence and recent advances in pathological and molecular analyses suggest the need to consider these tumours as more than an endocrinological disease, despite the low incidence of metastasis. Recently, we proposed a new prognostic clinicopathological classification of these pituitary tumours, according to the tumour size (micro, macro and giant), type (prolactin, GH, FSH/LH, ACTH and TSH) and grade (grade 1a, non-invasive; 1b, non-invasive and proliferative; 2a, invasive; 2b, invasive and proliferative and 3, metastatic). In addition to this classification, numerous molecular prognostic markers have been identified, allowing a better characterisation of tumour behaviour and prognosis. Moreover, clinical and preclinical studies have demonstrated that pituitary tumours could be treated by some chemotherapeutic drugs or new targeted therapies. Our improved classification of these tumours should now allow the identification of prognosis markers and help the clinician to propose personalised therapies to selected patients presenting tumours with a high risk of recurrence.
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Gerald Raverot, Emmanuel Jouanneau, and Jacqueline Trouillas
Lucile Parlant-Pinet, Catherine Harthé, Florence Roucher, Yves Morel, Françoise Borson-Chazot, Gérald Raverot, and Véronique Raverot
Gel filtration chromatography (GFC), the gold standard for macroprolactinaemia (MPRL) diagnosis, is a slow, costly and labour-intensive method. To limit the number of GFC required, we evaluated two screening tests for MPRL: prolactin (PRL) recovery after polyethylene glycol (PEG) precipitation and PRL concentration ratio, derived from two assays, each having different big-big-PRL cross-reactivities.
In some patients, MPRL is characterised by clinical symptoms which can be associated with an excess of monomeric PRL. We compared the monomeric PRL concentration obtained from GFC with the PRL concentration i) on a cobas e 601 analyser and ii) in the supernatant after PEG precipitation.
Design and methods
We studied hyperprolactinaemic sera subjected to physician-ordered GFC, between February 2013 and July 2014. We performed PEG precipitation (to evaluate the PRL concentration and rate of recovery in the supernatant) and two PRL assays: RIA and electrochemiluminescent assay (ECLIA), on a Roche cobas e 601 analyser, and calculated the RIA/ECLIA ratio.
Among the 222 sera, we were able to diagnose or exclude MPRL in 72.1% of cases, based solely on the ratio and/or recovery. In the remaining cases, GFC was necessary for making a diagnosis. Elevated monomeric PRL was present in 10.9% of macroprolactinaemic sera. In the case of MPRL, both PRL measurements on the cobas analyser and in the supernatant weakly correlated with monomeric PRL values obtained from GFC.
The combination of PEG and RIA/ECLIA ratio analysis reduced the number of necessary GFC. However, GFC is essential in MPRL cases to evaluate the monomeric PRL concentration.
Michel Pugeat, Ingrid Plotton, Aude Brac de la Perrière, Gérald Raverot, Henri Déchaud, and Véronique Raverot
Measuring total testosterone level is the first-line approach in assessing androgen excess in women. The main pitfalls in measuring testosterone relate to its low concentration and to the structural similarity between circulating androgens and testosterone, requiring accurate techniques with high specificity and sensitivity. These goals can be achieved by immunoassay using a specific anti-testosterone monoclonal antibody, ideally after an extraction step. Liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) will be commonly used for measuring testosterone, providing optimal accuracy with a low limit of detection. Yet, the pitfalls of these two techniques are well identified and must be recognized and systematically addressed. In general, laboratories using direct testosterone immunoassay and mass spectrometry need to operate within a quality framework and be actively engaged in external quality control processes and standardization, so as to ensure appropriate interpretation irrespective of the particular laboratory. Circulating testosterone is strongly bound to sex-hormone-binding globulin (SHBG), and SHBG levels are typically low in overweight hyperandrogenic patients. Thus, low SHBG may decrease circulating testosterone to normal values, which will mask androgen excess status. One way to avoid this pitfall, awaiting direct free testosterone assays that are yet to be developed, is to measure SHBG and calculate free testosterone. A few other pitfalls will be discussed in this review, including those of adrenal androgen exploration, with the aim of helping clinicians to better handle laboratory investigation of androgen excess disorders in women.
Etienne Delgrange, Alexandre Vasiljevic, Anne Wierinckx, Patrick François, Emmanuel Jouanneau, Gérald Raverot, and Jacqueline Trouillas
A sex difference in the progression of prolactin (PRL) tumors has been disputed for years.
To compare tumor characteristics and postoperative clinical course between men and women, and correlate data with estrogen receptor alpha (ERα (ESR1)) expression status.
Design, patients, and methods
Eighty-nine patients (59 women and 30 men) operated on for a prolactinoma and followed for at least 5 years were selected. Tumors were classified into five grades according to their size, invasion, and proliferation characteristics. The ERα expression was detected by immunohistochemistry and a score (0–12) calculated as the product of the percentage of positive nuclei and the staining intensity.
We found a significant preponderance of high-grade tumors among men and a lower surgical cure rate in men (23%) than in women (71%). Patients resistant to medical treatment were mainly men (7/8), six of whom showed tumor progression despite postoperative medical treatment, which led to multiple therapies and eventually death in three. The median score for ERα expression was 1 in men (range, 0–8) and 8 in women (range, 0–12) (P<0.0001). The expression of ERα was inversely correlated with tumor size (r=−0.59; P<0.0001) and proliferative activity. All dopamine agonist-resistant tumors and all grade 2b (invasive and proliferative) tumors (from ten men and four women) were characterized by low ERα expression.
PRL tumors in men are characterized by lower ERα expression, which is related to higher tumor grades, resistance to treatment, and an overall worse prognosis.
Laura Chinezu, Alexandre Vasiljevic, Jacqueline Trouillas, Marion Lapoirie, Emmanuel Jouanneau, and Gérald Raverot
Silent somatotroph tumours are growth hormone (GH) immunoreactive (IR) pituitary tumours without clinical and biological signs of acromegaly. Their better characterisation is required to improve the diagnosis.
Materials and methods
Twenty-one silent somatotroph tumours were compared to 59 somatotroph tumours with acromegaly. Tumours in each group were classified into GH and plurihormonal (GH/prolactin (PRL)/±thyroid-stimulating hormone (TSH)) and into densely granulated (DG) and sparsely granulated (SG) types. The two groups were then compared with regards to proliferation (Ki-67, p53 indexes and mitotic count), differentiation (expression of somatostatin receptors SSTR2A–SSTR5 and transcription factor Pit-1) and secretory activity (% of GH- and PRL-IR cells).
The silent somatotroph tumours represented 2% of all tested pituitary tumours combined. They were more frequent in women than in men (P = 0.002), more frequently plurihormonal and SG (P < 0.01), with a lower percentage of GH-IR cells (P < 0.0001) compared to those with acromegaly. They all expressed SSTR2A, SSTR5 and Pit-1. The plurihormonal (GH/PRL/±TSH) tumours were mostly observed in women (sex ratio: 3/1) and in patients who were generally younger than those with acromegaly (P < 0.001). They were larger (P < 0.001) with a higher Ki-67 index (P = 0.007).
The silent somatotroph tumours are not uncommon. Their pathological diagnosis requires the immunodetection of GH and Pit-1. They are more frequently plurihormonal and more proliferative than those with acromegaly. A low secretory activity of these tumours might explain the normal plasma values for GH and insulin-like growth factor 1 (IGF1) and the absence of clinical signs of acromegaly.
Jacqueline Trouillas, Pia Burman, Ann McCormack, Stephan Petersenn, Vera Popovic, Olaf Dekkers, and Gerald Raverot
The European Society of Endocrinology (ESE) survey reported on the largest cohort of 125 aggressive pituitary tumours (APT) and 40 pituitary carcinomas (PC). Whilst the survey focused on treatment effectiveness, all pathological data were not explored in detail. Here, we comment on some interesting pathological findings, notably the difference between APT and PC.
Gerald Raverot, Alexandre Vasiljevic, Emmanuel Jouanneau, and Hélène Lasolle
Recent publications suggested that pasireotide could be a good therapeutic option in some dopamine-resistant or aggressive prolactinomas. We discussed the two published cases and describe another case of poorly differentiated plurihormonal PIT-1-positive adenoma with moderate SSTR2 expression and intense STTR5 expression successfully treated with PAS-LAR 40 mg/month.
Mirela Diana Ilie, Véronique Raverot, François Tronc, Alexandre Vasiljevic, Françoise Borson-Chazot, and Gérald Raverot
Cabergoline has been shown to have some effect in the treatment of moderate Cushing’s disease, but its effectiveness in Cushing’s syndrome of ectopic or occult origin remains to be investigated.
In this case series, cabergoline was used in combination with steroidogenesis inhibitors in nine patients with severe Cushing’s syndrome of ectopic or occult origin. Cabergoline’s effectiveness enabled rapid withdrawal of the steroidogenesis inhibitors and long-term control of the hypercortisolism in three of the cases.
Review of the literature
In the literature, we found only 11 cases of ectopic or occult Cushing’s syndrome treated with dopamine receptor agonists, alone or in combination. Yet of these 11 cases, 10 responded.
Although limited, the existing experience highlights the potential value of cabergoline in the treatment of ectopic or occult Cushing’s syndrome.
Gérald Raverot, Anne Wierinckx, Emmanuel Jouanneau, Carole Auger, Françoise Borson-Chazot, Joël Lachuer, Michel Pugeat, and Jacqueline Trouillas
Silent corticotroph adenomas (SCAs) are rare pituitary tumours immunoreactive for ACTH, but without clinical evidence of Cushing's disease. We characterized SCAs based on clinical, hormonal and molecular data, and compared the characteristics of these tumours with those of macro (MCA)- and micro (mCA)-ACTH adenomas with Cushing's disease.
Fifty ACTH adenomas (14 SCAs, 15 MCAs and 21 mCAs) with complete corresponding clinical, radiological and biochemical data were selected. Histological corticotroph differentiation; immunostaining for ACTH, β-endorphin and β-LPH; and mRNA expression levels of TPIT, POMC, GR α, prohormone convertase 1/3 (PC1/3) and galectin-3 were compared in 21 representative tumours.
Despite the absence of clinical hypercortisolism in patients with SCA, elevated plasma ACTH levels that were similar to those associated with mCA were observed. The cortisol/ACTH ratio was similar between SCA and MCA groups and lower than that found with mCA (P<0.05). This dissociation could be explained by lower expression of PC1/3 in SCA and MCA than in mCA (P<0.05). After an i.v. dexamethasone suppression test, ACTH levels were significantly higher in patients with MCA than in those with mCA (P<0.05). Cytological and immunocytochemical analyses as well as mRNA expression levels of TPIT, POMC and GR α confirmed corticotroph differentiation in both mCAs and MCAs and in half of the SCAs, with a strong correlation between TPIT and POMC mRNA expression levels in SCAs (R 2=0.72; P<0.01) and in MCAs (R 2=0.65; P<0.05).
Despite the absence of hypercortisolism, SCAs exhibit histological, biochemical and molecular corticotroph differentiation. SCA and MCA show hormonal and molecular similarities differentiating them from mCA.
Etienne Delgrange, Gerald Raverot, Marie Bex, Pia Burman, Bénédicte Decoudier, France Devuyst, Ulla Feldt-Rasmussen, Marianne Andersen, and Dominique Maiter
To characterise distinctive clinical features of giant prolactinomas in women.
A multicentre, retrospective case series and literature review.
We collected data from 15 female patients with a pituitary tumour larger than 4 cm and prolactin levels above 1000 μg/l and identified 19 similar cases from the literature; a gender-based comparison of the frequency and age distribution was obtained from a literature review.
The initial PubMed search using the term ‘giant prolactinomas’ identified 125 patients (13 women) responding to the inclusion criteria. The female:male ratio was 1:9. Another six female patients were found by extending the literature search, while our own series added 15 patients. The median age at diagnosis was 44 years in women compared with 35 years in men (P<0.05). All cases diagnosed before the age of 15 years were boys. In women (n=34), we observed a minor peak incidence during the third decade of life and a major peak during the fifth decade. Amenorrhoea was a constant feature with seven cases of primary amenorrhoea. In eight women with onset of secondary amenorrhoea before the age of 40 years, the diagnosis was made 2–31 years later (median 9 years) and in all but one because of tumour pressure symptoms. The prolactin levels were above 10 000 μg/l in 15/34 and misdiagnosis due to ‘hook effect’ occurred in two of them. Eighteen patients were treated with cabergoline; standard doses (<2.0 mg/week) were able to normalise prolactin in only 4/18 patients, and 7/18 patients were resistant to weekly doses ranging from 3.0 to 7.0 mg.
Giant prolactinomas are rare in women, often resistant to dopamine agonists and seem to be distributed in two age groups, with a larger late-onset peak.