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Inserm U1052, CNRS UMR5286, Claude Bernard Lyon 1 University, Cancer Research Center of Lyon, Lyon, France
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Endocrinology Department, “C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania
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Purpose
The purpose of this work was toinvestigate the clinicopathological characteristics at the initial diagnosis of the pituitary tumor and at pituitary carcinoma (PC) diagnosis, alongside with the management and outcomes of PCs, and identify potential prognostic factors and therapeutic strategies associated with the clinical outcome.
Methods
PubMed was searched in May 2021 for articles in English and French reporting PCs, the diagnosis of which was made on the presence of metastases. The cases without histological proof and with either another cancer present or an atypical history for a pituitary tumor were excluded.
Results
One hundred and eighty-one articles reporting 207 cases were included, which included 38% corticotroph and 29% lactotroph carcinomas. An initial Ki67 index ≥10% was associated with shorter survival after the initial diagnosis (P = 0.01). Cases with early metastases were associated with both higher initial Ki67 index (P = 0.01) and shorter survival after PC diagnosis (P = 0.001). Interestingly, cases with short survival after PC diagnosis were associated with shorter time between the initial diagnosis and PC diagnosis (P = 0.0006) and had both higher initial Ki67 index (P = 0.003) and higher Ki67 index of the metastasis (P = 0.03). In addition, cases with long survival after PC diagnosis had received more frequently both systemic treatment after PC diagnosis (P = 0.0005) and local treatment for metastases (P < 0.0001).
Conclusions
An initial Ki67 index ≥10% is associated with worse outcome and appears as a promising early marker of future metastasis. Its presence should lead to an intensified surveillance and to a more timely management. Clinicians should not hesitate to use local treatment, independent of whether systemic treatment is used.
Inserm U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes-Université de Paris, Paris, France
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Department of Neurosurgery, Hôpital Universitaire Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France
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Department of Endocrinology, Center for Rare Adrenal Diseases, Hôpital Cochin APHP, Paris, France
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Lyon 1 University, Villeurbanne, France
Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France
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The classification of tumours of the pituitary gland has recently been revised in the 2021 5th edition World Health Organization (WHO) Classification of Central Nervous System Tumours (CNS5) and 2022 5th edition WHO Classification of Endocrine and Neuroendocrine Tumours (ENDO5). This brief review aims to appraise the most relevant changes and updates introduced in the two classifications. A new nomenclature has been introduced in CNS5 and ENDO5 to align adenohypophyseal tumours with the classification framework of neuroendocrine neoplasia. The term pituitary neuroendocrine tumour (PitNET) with subtype information has therefore been adopted and preferred to adenoma. Pituitary carcinoma has been replaced by metastatic PitNET. The ICD-O coding has been changed from benign to malignant in line with NETs from other organs. Histological typing and subtyping based on immunohistochemistry for lineage-restricted pituitary transcription factors are regarded as the cornerstone for accurate classification. Such an approach does not fully reflect the complexity and dynamics of pituitary tumorigenesis and the variability of transcription factors expression. ENDO5 does not support a grading and/or staging system and argues that histological typing and subtyping are more robust than proliferation rate and invasiveness to stratify tumours with low or high risk of recurrence. However, the prognostic and predictive relevance of histotype is not fully validated. Recent studies suggest the existence of clinically relevant molecular subgroups and emphasize the need for a standardized, histo-molecular integrated approach to the diagnosis of PitNETs to further our understanding of their biology and overcome the unsolved issue of grading and/or staging system.
Endocrinology Department, ‘C.I. Parhon’ National Institute of Endocrinology, Bucharest, Romania
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Pathology Department, Reference Center for Rare Pituitary Diseases HYPO, ‘Groupement Hospitalier Est’ Hospices Civils de Lyon, Bron, France
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Neurosurgery Department, Reference Center for Rare Pituitary Diseases HYPO, ‘Groupement Hospitalier Est’ Hospices Civils de Lyon, Bron, France
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Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, ‘Groupement Hospitalier Est’ Hospices Civils de Lyon, Bron, France
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Once temozolomide has failed, there is no recommended treatment option for pituitary carcinomas and aggressive pituitary tumors. Immune-checkpoint inhibitors (ICIs) represent the most recent therapeutic avenue, having raised hope with the publication of the first successful case in 2018. Here, we present an overview of immunotherapy in pituitary carcinomas and aggressive pituitary tumors, starting with the rationale for using ICIs and the implications of tumor-infiltrating lymphocytes in anterior pituitary tumors, followed by a systematic review of all published cases, analyzing both treatment response and potential predictors of response and finishing with research and clinical perspectives. Seven corticotroph and four lactotroph tumors have been so far treated with ICIs. Corticotroph tumors showed radiological partial response in 57% of cases, followed by stable disease in 29% of cases, which was accompanied by biochemical partial or complete response in 83% of cases. Half of lactotroph tumors showed radiological complete or partial response, accompanied by biochemical complete response in 33% of the cases. In the case of a dissociate response, continuation of immunotherapy combined with local treatment represents a good option. At this time, a high tumor mutational burden appears to be the most promising predictive marker of response. MMR deficiency does not guarantee a response. Negative PD-L1 staining should not preclude ICIs administration. Therefore, ICIs are a promising option after temozolomide failure. This review highlights key clinical aspects that can already be implemented into practice and also discusses tumor biology concepts and perspectives expected to improve immunotherapy outcomes.
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Endocrinology Department, “C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania
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Faculté de Médecine Lyon Est, Université Lyon 1, Lyon, France
Department of Endocrinology, Reference center for rare pituitary disease (HYPO), Groupement Hospitalier EST, Hospices Civils de Lyon, University of Lyon, Lyon, France
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Pituitary tumours are benign neoplasms that derive from hormone-producing cells of the pituitary gland. While medical treatments have emerged for most subtypes, gonadotroph tumours that express follicle-stimulating hormone (FSH) and/or luteinizing hormone still lack therapeutic options apart from surgery and radiotherapy. Activin ligands are physiological regulators of production and secretion of FSH by gonadotroph cells, but their role in gonadotroph tumourigenesis remains little explored. Using the LβT2 mouse gonadotroph cell line which produces FSH under activin stimulation, we first tested whether subcutaneous xenografts of LβT2 cells resulted in tumour formation in Rag2KO mice. Histological analysis confirmed the presence of LβT2 tumours with endothelial cells and macrophages in their microenvironment. FSH expression was found in a subset of clusters of LβT2 cells in the tumours. We subsequently addressed the consequences of targeting activin signalling via injection of a soluble activin decoy receptor (sActRIIB-Fc). sActRIIB-Fc treatment resulted in significantly decreased LβT2 tumour volume. Reduced Smad2 phosphorylation as well as inhibition of tumour-induced FSH production confirmed the efficient targeting of activin-downstream signalling in treated tumours. More interestingly, treated tumours showed significantly fewer endothelial cells associated with reduced Vegfa expression. In vitro treatment of LβT2 cells with sActRIIB-Fc had no effect on cell proliferation or apoptosis, but Vegfa expression was inhibited, pointing to a likely paracrine effect of LβT2 cells on endothelial cells through activin-mediated Vegfa regulation. Further in vitro and in vivo studies are now needed to pinpoint the exact roles of activin signalling in these processes prior to translating these observations to the clinic.
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Although most pituitary tumors are benign, some are invasive or aggressive. In the absence of specific markers of malignancy, only tumors with metastases are considered malignant. To identify markers of invasion and aggressiveness, we focused on prolactin (PRL) tumors in the human and rat. Using radiology and histological methods, we classified 25 human PRL tumors into three groups (non-invasive, invasive, and aggressive–invasive) and compared them with a model of transplantable rat PRL tumors with benign and malignant lineages. Combining histological(mitoses and labeling for Ki-67, P53, pituitary transforming tumor gene (PTTG), and polysialic acid neural cell adhesion molecule) and transcriptomic (microarrays and q-RTPCR) methods with clinical data (post-surgical outcome with case–control statistical analysis), we found nine genes implicated in invasion (ADAMTS6, CRMP1, and DCAMKL3) proliferation (PTTG, ASK, CCNB1, AURKB, and CENPE), or pituitary differentiation (PITX1) showing differential expression in the three groups of tumors (P = 0.015 to 0.0001). A case–control analysis, comparing patients in remission (9 controls) and patients with persistent or recurrent tumors (14 cases) revealed that eight out of the nine genes were differentially up- or downregulated (P = 0.05 to 0.002), with only PTTG showing no correlation with clinical course (P = 0.258). These combined histological and transcriptomic analyses improve the pathological diagnosis of PRL tumors, indicating a reliable procedure for predicting tumor aggressiveness and recurrence potential. The similar gene profiles found between non-invasive human and benign rat tumors, as well as between aggressive–invasive human and malignant rat tumors provide new insights into malignancy in human pituitary tumors.
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Responses of GH-secreting adenomas to multimodal management of acromegaly vary widely between patients. Understanding the behavioral patterns of GH-secreting adenomas by identifying factors predictive of their evolution is a research priority. The aim of this study was to clarify the relationship between the T2-weighted adenoma signal on diagnostic magnetic resonance imaging (MRI) in acromegaly and clinical and biological features at diagnosis. An international, multicenter, retrospective analysis was performed using a large population of 297 acromegalic patients recently diagnosed with available diagnostic MRI evaluations. The study was conducted at ten endocrine tertiary referral centers. Clinical and biochemical characteristics, and MRI signal findings were evaluated. T2-hypointense adenomas represented 52.9% of the series, were smaller than their T2-hyperintense and isointense counterparts (P<0.0001), were associated with higher IGF1 levels (P=0.0001), invaded the cavernous sinus less frequently (P=0.0002), and rarely caused optic chiasm compression (P<0.0001). Acromegalic men tended to be younger at diagnosis than women (P=0.067) and presented higher IGF1 values (P=0.01). Although in total, adenomas had a predominantly inferior extension in 45.8% of cases, in men this was more frequent (P<0.0001), whereas in women optic chiasm compression of macroadenomas occurred more often (P=0.0067). Most adenomas (45.1%) measured between 11 and 20 mm in maximal diameter and bigger adenomas were diagnosed at younger ages (P=0.0001). The T2-weighted signal differentiates GH-secreting adenomas into subgroups with particular behaviors. This raises the question of whether the T2-weighted signal could represent a factor in the classification of acromegalic patients in future studies.
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GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso- and hyper-intense groups (8% and 3%, respectively; P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001, r = 0.22), IGF-1 (P < 0.0001, r = 0.14) and adenoma volume (P < 0.0001, r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.
