The Treatment of Refractory Pituitary Adenomas

Dai, Congxin; Liu, Xiaohai; Ma, Wenbin; Wang, Renzhi

doi:10.3389/fendo.2019.00334

Cited by 30 publications

(30 citation statements)

References 110 publications

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“…Although the understanding of the molecular pathogenesis of PCs has progressed rapidly, the early identification of PC is difficult until the presence of metastatic lesions. Refractory PAs lie between benign adenomas and true malignant PC and are defined as aggressive-invasive PAs characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments, including temozolomide (TMZ) (10,11). Therefore, both refractory PAs and PCs are very difficult to manage due to the lack of effective treatment, and they are associated with increased morbidity and mortality (12).…”

Section: Introductionmentioning

confidence: 99%

The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas

et al. 2020

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Most pituitary adenomas (PAs) are considered benign tumors, but approximately 0.2% can present metastasis and are classified as pituitary carcinomas (PCs). Refractory PAs lie between benign adenomas and true malignant PC and are defined as aggressive-invasive PAs characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments, including temozolomide. It is notoriously difficult to manage refractory PAs and PC because of the limited therapeutic options. As a promising therapeutic approach, cancer immunotherapy has been experimentally used for the treatment of many tumors, including pituitary tumors. The purpose of this review is to report the progress of immunotherapy in pituitary tumors, including refractory PAs and PCs. The tumor immune microenvironment has been recognized as a key contributor to tumorigenesis, progression, and prognosis. One study indicated that the number of CD68+ macrophages was positively correlated with tumor size and Knosp classification grade for tumor invasiveness. The infiltration of CD4+ and CD8+ T cells was relatively scant in these adenomas, but pituitary growth hormone (GH) adenomas exhibited significantly more CD4+ and CD8+ T cells than non-GH adenomas. These results suggest an association of CD68+ macrophage infiltration with an increase in pituitary tumor size and invasiveness. Another study suggested that a lower number of CD8+ lymphocytes is associated with cavernous sinus invasion and resistance to treatment with first-generation somatostatin analogs in acromegaly patients, highlighting a potential role of the tumor immune microenvironment in determining the prognosis of somatotroph pituitary tumors. Preclinical studies have indicated that widely varying degrees of programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) are found among different subtypes. Functional PAs and aggressive PAs express significantly higher levels of PD-L1 and TILs than other subtypes, indicating that PD-1 blockade might be a promising alternative therapy for patients with aggressive PAs. PD-L1 transcript and protein levels were found to be significantly increased in functioning (GH and prolactin-expressing) pituitary tumors compared to nonfunctioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary tumors harbored higher levels of PD-L1 mRNA than recurrent tumors. These findings suggest the possibility of considering checkpoint blockade immunotherapy for functioning pituitary tumors refractory to conventional management. Animal models of Cushing’s disease also demonstrated PD-L1 and TIL expression in cultured tumors and murine models, as well as the effectiveness of checkpoint blockade therapy in reducing the tumor mass, decreasing hormone secretion, and increasing the survival rate. Clinical studies show that immunotherapy may be an effective treatment in patients with pituitary tumors. One corticotroph carcinoma patient showed a significant reduction in hormone levels and shrinkage of the tumor size of primary and metastatic lesions immediately after investigational treatment with ipilimumab and nivolumab. However, another patient with corticotroph adenoma progressed rapidly after four cycles of anti-PD-1 (pembrolizumab) treatment. To date, there are two registered clinical trials of immunotherapy for pituitary tumors. One of them is the phase II clinical trial of nivolumab combined with ipilimumab for patients with aggressive pituitary tumors (NCT04042753). The other one is also a phase II clinical trial of the combination of nivolumab and ipilimumab for rare tumors, including pituitary tumors (NCT02834013). Both clinical trials are in the stage of recruiting patients and have not been completed. In summary, the results from preclinical research and clinical studies indicated that immunotherapy might be a promising alternative therapy for PCs and refractory PAs resistant to conventional treatments. The combination of immunotherapy and radiotherapy or temozolomide may have synergistic effects compared to a single treatment. More preclinical and clinical studies are needed to further indicate the exact efficacy of immunotherapy in pituitary tumors.

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Section: Introductionmentioning

confidence: 99%

The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas

et al. 2020

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“…Other transcriptomic studies that could be compared to our results are reports that have assessed the invasiveness of the PitNETs. The invasiveness could also be related to increased cell growth, and in PitNETs, it has been demonstrated that resistance to SSA is accompanied with reduced tumor shrinkage ( 51 ). In the transcriptome studies comparing invasive and non-invasive PitNETs, there are various candidates identified that are related to cell proliferation, growth, apoptosis pathways, but still rarely these candidates overlap between the studies ( 49 , 50 , 52 – 58 ) ( Supplementary Material Table 5 ).…”

Section: Discussionmentioning

confidence: 99%

Medication for Acromegaly Reduces Expression of MUC16, MACC1 and GRHL2 in Pituitary Neuroendocrine Tumour Tissue

et al. 2021

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Acromegaly is a disease mainly caused by pituitary neuroendocrine tumor (PitNET) overproducing growth hormone. First-line medication for this condition is the use of somatostatin analogs (SSAs), that decrease tumor mass and induce antiproliferative effects on PitNET cells. Dopamine agonists (DAs) can also be used if SSA treatment is not effective. This study aimed to determine differences in transcriptome signatures induced by SSA/DA therapy in PitNET tissue. We selected tumor tissue from twelve patients with somatotropinomas, with half of the patients receiving SSA/DA treatment before surgery and the other half treatment naive. Transcriptome sequencing was then carried out to identify differentially expressed genes (DEGs) and their protein–protein interactions, using pathway analyses. We found 34 upregulated and six downregulated DEGs in patients with SSA/DA treatment. Three tumor development promoting factors MUC16, MACC1, and GRHL2, were significantly downregulated in therapy administered PitNET tissue; this finding was supported by functional studies in GH3 cells. Protein–protein interactions and pathway analyses revealed extracellular matrix involvement in the antiproliferative effects of this type of the drug treatment, with pronounced alterations in collagen regulation. Here, we have demonstrated that somatotropinomas can be distinguished based on their transcriptional profiles following SSA/DA therapy, and SSA/DA treatment does indeed cause changes in gene expression. Treatment with SSA/DA significantly downregulated several factors involved in tumorigenesis, including MUC16, MACC1, and GRHL2. Genes that were upregulated, however, did not have a direct influence on antiproliferative function in the PitNET cells. These findings suggested that SSA/DA treatment acted in a tumor suppressive manner and furthermore, collagen related interactions and pathways were enriched, implicating extracellular matrix involvement in this anti-tumor effect of drug treatment.

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“…This definition was derived by summarizing the clinical characteristics and pathological findings of a group of patients with refractory PAs from Peking Union Medical College Hospital (PUMCH). The diagnostic criteria for refractory PAs were also proposed as follows: 1) tumor infiltration of adjacent structures according to radiological results or intraoperative findings; 2) Ki-67 index greater than 3%, and growth velocity greater than 2% per month; 3) failure of current treatments to control tumor growth and/or hormonal hypersecretion; and 4) tumor recurrence within 6 months after surgery ( 37 ). Although the term “refractory” has caused some controversy ( 38 ), it does provide a more accurate definition and more objective diagnostic criteria for these invasive-aggressive PAs.…”

Section: Controversies In the Classification And Definition Of Pituitmentioning

confidence: 99%

How to Classify and Define Pituitary Tumors: Recent Advances and Current Controversies

et al. 2021

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Pituitary tumors are very complex and heterogeneous and have a very wide range of proliferative and aggressive behaviors, and how to define and classify these tumors remains controversial. This review summarizes the epidemiology and progress in the classification and definition of pituitary tumors, as well as controversial issues. Based on the results of radiologic and autopsy studies, the prevalence of pituitary tumors has recently increased significantly. However, the majority of pituitary tumors are incidentally discovered and asymptomatic, and such tumors are called pituitary incidentalomas. Most of these incidentalomas do not induce symptoms, remain stable in size, and do not need treatment. The recent revised classification strategies mainly depend on immunohistochemistry (IHC) to detect pituitary hormones and pituitary transcription factors; therefore, the accuracy of diagnosing pituitary tumors has improved. Although new classification strategies and definitions for pituitary tumors have been presented, there are still some controversies. The term pituitary neuroendocrine tumor (PitNET) was proposed by the International Pituitary Pathology Club, and this terminology can encompass the unpredictable malignant behavior seen in the subset of aggressive pituitary adenomas (PAs). However, some endocrinologists who oppose this change in terminology have argued that the use of tumor in the terminology is misleading, as it gives PAs a harmful connotation when the majority are not aggressive. Such terminology may add new ambiguity to the origin of PAs and unnecessary anxiety and frustration for the majority of patients with benign PAs. The classification of aggressive PAs mainly relies on subjective judgment of clinical behavior and lacks objective biomarkers and unified diagnostic criteria. However, the term “refractory” could more accurately represent the characteristics of these tumors, including their clinical behaviors, radiological features, and pathologic characteristics. Moreover, the diagnostic criteria for refractory PAs are stricter, more objective, and more accurate than those for aggressive PAs. Early identification of patients with these tumors through recognition and increased awareness of the definition of refractory PAs will encourage the early use of aggressive therapeutic strategies.

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The Treatment of Refractory Pituitary Adenomas

Cited by 30 publications

References 110 publications

The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas

The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas

Medication for Acromegaly Reduces Expression of MUC16, MACC1 and GRHL2 in Pituitary Neuroendocrine Tumour Tissue

How to Classify and Define Pituitary Tumors: Recent Advances and Current Controversies

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