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Gerald Raverot, Emmanuel Jouanneau, and Jacqueline Trouillas

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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Laura Chinezu, Alexandre Vasiljevic, Jacqueline Trouillas, Marion Lapoirie, Emmanuel Jouanneau, and Gérald Raverot

Background

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).

Results

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).

Conclusions

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.

Free access

Etienne Delgrange, Alexandre Vasiljevic, Anne Wierinckx, Patrick François, Emmanuel Jouanneau, Gérald Raverot, and Jacqueline Trouillas

Context

A sex difference in the progression of prolactin (PRL) tumors has been disputed for years.

Objective

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.

Results

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.

Conclusions

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.

Free access

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.

Free access

Gérald Raverot, Anne Wierinckx, Emmanuel Jouanneau, Carole Auger, Françoise Borson-Chazot, Joël Lachuer, Michel Pugeat, and Jacqueline Trouillas

Objective

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.

Methods

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.

Results

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).

Conclusions

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.

Free access

Gerald Raverot, Pia Burman, Ann McCormack, Anthony Heaney, Stephan Petersenn, Vera Popovic, Jacqueline Trouillas, Olaf M Dekkers, and The European Society of Endocrinology

Background

Pituitary tumours are common and easily treated by surgery or medical treatment in most cases. However, a small subset of pituitary tumours does not respond to standard medical treatment and presents with multiple local recurrences (aggressive pituitary tumours) and in rare occasion with metastases (pituitary carcinoma). The present European Society of Endocrinology (ESE) guideline aims to provide clinical guidance on diagnosis, treatment and follow-up in aggressive pituitary tumours and carcinomas.

Methods

We decided upfront, while acknowledging that literature on aggressive pituitary tumours and carcinomas is scarce, to systematically review the literature according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The review focused primarily on first- and second-line treatment in aggressive pituitary tumours and carcinomas. We included 14 single-arm cohort studies (total number of patients = 116) most on temozolomide treatment (n = 11 studies, total number of patients = 106). A positive treatment effect was seen in 47% (95% CI: 36–58%) of temozolomide treated. Data from the recently performed ESE survey on aggressive pituitary tumours and carcinomas (165 patients) were also used as backbone for the guideline.

Selected recommendation

(i) Patients with aggressive pituitary tumours should be managed by a multidisciplinary expert team. (ii) Histopathological analyses including pituitary hormones and proliferative markers are needed for correct tumour classification. (iii) Temozolomide monotherapy is the first-line chemotherapy for aggressive pituitary tumours and pituitary carcinomas after failure of standard therapies; treatment evaluation after 3 cycles allows identification of responder and non-responder patients. (iv) In patients responding to first-line temozolomide, we suggest continuing treatment for at least 6 months in total. Furthermore, the guideline offers recommendations for patients who recurred after temozolomide treatment, for those who did not respond to temozolomide and for patients with systemic metastasis.

Free access

Ann McCormack, Olaf M Dekkers, Stephan Petersenn, Vera Popovic, Jacqueline Trouillas, Gerald Raverot, Pia Burman, and ESE survey collaborators

Objective

To collect outcome data in a large cohort of patients with aggressive pituitary tumours (APT)/carcinomas (PC) and specifically report effects of temozolomide (TMZ) treatment.

Design

Electronic survey to ESE members Dec 2015–Nov 2016.

Results

Reports on 166 patients (40 PC, 125 APT, 1 unclassified) were obtained. Median age at diagnosis was 43 (range 4–79) years. 69% of the tumours were clinically functioning, and the most frequent immunohistochemical subtype were corticotroph tumours (45%). Ki-67 index did not distinguish APT from PC, median 7% and 10% respectively. TMZ was first-line chemotherapy in 157 patients. At the end of the treatment (median 9 cycles), radiological evaluation showed complete response (CR) in 6%, partial response (PR) in 31%, stable disease (SD) in 33% and progressive disease in 30%. Response was more frequent in patients receiving concomitant radiotherapy and TMZ. CR was seen only in patients with low MGMT expression. Clinically functioning tumours were more likely to respond than non-functioning tumours, independent of MGMT status. Of patients with CR, PR and SD, 25, 40 and 48% respectively progressed after a median of 12-month follow-up. Other oncological drugs given as primary treatment and to TMZ failures resulted in PR in 20%.

Conclusion

This survey confirms that TMZ is established as first-line chemotherapeutic treatment of APT/PC. Clinically functioning tumours, low MGMT and concurrent radiotherapy were associated with a better response. The limited long-term effect of TMZ and the poor efficacy of other drugs highlight the need to identify additional effective therapies.

Open access

Pia Burman, Jacqueline Trouillas, Marco Losa, Ann McCormack, Stephan Petersenn, Vera Popovic, Marily Theodoropoulou, Gerald Raverot, Olaf M Dekkers, and

Objective

To describe clinical and pathological characteristics and treatment outcomes in a large cohort of aggressive pituitary tumours (APT)/pituitary carcinomas (PC).

Design

Electronic survey August 2020–May 2021.

Results

96% of 171 (121 APT, 50 PC), initially presented as macro/giant tumours, 6 were microadenomas (5 corticotroph). Ninety-seven tumours, initially considered clinically benign, demonstrated aggressive behaviour after 5.5 years (IQR: 2.8–12). Of the patients, 63% were men. Adrenocorticotrophic hormone (ACTH)-secreting tumours constituted 30% of the APT/PC, and the gonadotroph subtypes were under-represented. Five out of 13 silent corticotroph tumours and 2/6 silent somatotroph tumours became secreting. Metastases were observed after median 6.3 years (IQR 3.7–12.1) from diagnosis. At the first surgery, the Ki67 index was ≥3% in 74/93 (80%) and ≥10% in 38/93 (41%) tumours. An absolute increase of Ki67 ≥ 10% after median of 6 years from the first surgery occurred in 18/49 examined tumours. Tumours with an aggressive course from outset had higher Ki67, mitotic counts, and p53. Temozolomide treatment in 156/171 patients resulted in complete response in 9.6%, partial response in 30.1%, stable disease in 28.1%, and progressive disease in 32.2% of the patients. Treatment with bevacizumab, immune checkpoint inhibitors, and peptide receptor radionuclide therapy resulted in partial regression in 1/10, 1/6, and 3/11, respectively. Median survival in APT and PC was 17.2 and 11.3 years, respectively. Tumours with Ki67 ≥ 10% and ACTH-secretion were associated with worse prognosis.

Conclusion

APT/PCs exhibit a wide and challenging spectrum of behaviour. Temozolomide is the first-line chemotherapy, and other oncological therapies are emerging. Treatment response continues to be difficult to predict with currently studied biomarkers.