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The Journal of Clinical Endocrinology... May 2022Although most tumors in patients with acromegaly are benign and are cured or controlled by surgery and/or first-generation somatostatin receptor ligands therapy, some...
Although most tumors in patients with acromegaly are benign and are cured or controlled by surgery and/or first-generation somatostatin receptor ligands therapy, some can behave more aggressively and are resistant to these standard therapies. Acromegaly, if left untreated, is a rare and chronic disorder, commonly caused by a GH-producing pituitary adenoma and is associated with significant comorbidities and an increased mortality. Transsphenoidal surgery is considered the mainstay of acromegaly management, but medical therapy has an increasingly important role. However, disease activity is not fully controlled in a significant number of patients treated with surgery and/or high-dose first-generation somatostatin receptor ligand monotherapy. In these circumstances, therefore, repeated surgery, second-line medical therapy, and radiotherapy, alone or combined as multimodal therapeutic strategies should be considered, in a patient-centered perspective.
Topics: Acromegaly; Human Growth Hormone; Humans; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin
PubMed: 35090028
DOI: 10.1210/clinem/dgac037 -
Romanian Journal of Morphology and... 2023Acromegaly is a rare endocrine disorder, which despite the recent advances in diagnosis and management, remains a significant burden in terms of morbidity and mortality... (Review)
Review
Acromegaly is a rare endocrine disorder, which despite the recent advances in diagnosis and management, remains a significant burden in terms of morbidity and mortality for patients because of the frequent aggressive evolution and lack of response to available first-line pharmacological therapy. A switch from the classical "trial and error" management to a personalized therapy approach has been proposed through early identification of biomarkers that could predict treatment response and biological behavior. Several such molecular markers have been extensively studied through immunohistochemistry (IHC), among them the somatostatin receptors type 2 (SSTR-2) and type 5 (SSTR-5), which are known to correlate with response to somatostatin analogues treatment, the SSTR-2 negative tumors usually being resistant to first-generation analogues, while SSTR-5 potentially being a predictive marker for the novel agent, Pasireotide. Based on cytokeratin (CK) immunostaining pattern, somatotropinomas have been classified into densely granulated adenomas (DGAs), which present a milder evolution and favorable outcomes after therapy, and sparsely granulated adenomas (SGAs), known to be more aggressive and frequently resistant to first-line treatment options. Other novel markers, such as the E-cadherin cell-adhesion protein, the aryl hydrocarbon receptor-interacting protein (AIP), the cytoskeleton molecule filamin A (FLNA) and the Ki-67 nuclear antigen have also been the highlight of IHC studies on growth hormone (GH)-producing tumors, with promising results regarding their predictive roles for the outcome of acromegalic patients. In this review, we aimed to summarize the current knowledge on the role of IHC for acromegaly, highlighting the most important biomarkers that could offer valuable information for predicting treatment response, biological behavior, and prognosis.
Topics: Humans; Acromegaly; Adenoma; Pituitary Neoplasms; Biomarkers; Intracellular Signaling Peptides and Proteins
PubMed: 37128788
DOI: 10.47162/RJME.64.1.03 -
Current Oncology (Toronto, Ont.) Mar 2022Craniopharyngiomas (CPs) are slow growing, histologically benign intracranial tumors located in the sellar-suprasellar region. Although known to have low mortality,... (Review)
Review
Craniopharyngiomas (CPs) are slow growing, histologically benign intracranial tumors located in the sellar-suprasellar region. Although known to have low mortality, their location and relationship to the adjacent neural structures results in patients having significant neurologic, endocrine, and visual comorbidities. The invasive nature of this tumor makes complete resection a challenge and contributes to its recurrence. Additionally, these tumors are bimodally distributed, being treated with surgery, and are followed by other adjuncts, such as focused radiation therapy, e.g., Gamma knife. Advances in surgical techniques, imaging tools, and instrumentations have resulted in the evolution of surgery using endoscopic techniques, with residual components being treated by radiotherapy to target the residual tumor. Advances in molecular biology have elucidated the main pathways involved in tumor development and recurrence, but presently, no other treatments are offered to patients, besides surgery, radiation, and endocrine management, as the disease and tumor evolve. We review the contemporary management of these tumors, from the evolution of surgical treatments, utilizing standard open microscopic approaches to the more recent endoscopic surgery, and discuss the current recommendations for care of these patients. We discuss the developments in radiation therapy, such as radiosurgery, being used as treatment strategies for craniopharyngioma, highlighting their beneficial effects on tumor resections while decreasing the rates of adverse outcomes. We also outline the recent chemotherapy modalities, which help control tumor growth, and the immune landscape on craniopharyngiomas that allow the development of novel immunotherapies.
Topics: Adult; Craniopharyngioma; Humans; Pituitary Neoplasms; Radiosurgery; Retrospective Studies; Treatment Outcome
PubMed: 35323338
DOI: 10.3390/curroncol29030138 -
The Lancet. Oncology May 2023Compared with photon therapy, proton therapy reduces exposure of normal brain tissue in patients with craniopharyngioma, which might reduce cognitive deficits associated...
BACKGROUND
Compared with photon therapy, proton therapy reduces exposure of normal brain tissue in patients with craniopharyngioma, which might reduce cognitive deficits associated with radiotherapy. Because there are known physical differences between the two methods of radiotherapy, we aimed to estimate progression-free survival and overall survival distributions for paediatric and adolescent patients with craniopharyngioma treated with limited surgery and proton therapy, while monitoring for excessive CNS toxicity.
METHODS
In this single-arm, phase 2 study, patients with craniopharyngioma at St Jude Children's Research Hospital (Memphis TN, USA) and University of Florida Health Proton Therapy Institute (Jacksonville, FL, USA) were recruited. Patients were eligible if they were aged 0-21 years at the time of enrolment and had not been treated with previous radiotherapeutic or intracystic therapies. Eligible patients were treated using passively scattered proton beams, 54 Gy (relative biological effect), and a 0·5 cm clinical target volume margin. Surgical treatment was individualised before proton therapy and included no surgery, single procedures with catheter and Ommaya reservoir placement through a burr hole or craniotomy, endoscopic resection, trans-sphenoidal resection, craniotomy, or multiple procedure types. After completing treatment, patients were evaluated clinically and by neuroimaging for tumour progression and evidence of necrosis, vasculopathy, permanent neurological deficits, vision loss, and endocrinopathy. Neurocognitive tests were administered at baseline and once a year for 5 years. Outcomes were compared with a historical cohort treated with surgery and photon therapy. The coprimary endpoints were progression-free survival and overall survival. Progression was defined as an increase in tumour dimensions on successive imaging evaluations more than 2 years after treatment. Survival and safety were also assessed in all patients who received photon therapy and limited surgery. This study is registered with ClinicalTrials.gov, NCT01419067.
FINDINGS
Between Aug 22, 2011, and Jan 19, 2016, 94 patients were enrolled and treated with surgery and proton therapy, of whom 49 (52%) were female, 45 (48%) were male, 62 (66%) were White, 16 (17%) were Black, two (2%) were Asian, and 14 (15%) were other races, and median age was 9·39 years (IQR 6·39-13·38) at the time of radiotherapy. As of data cutoff (Feb 2, 2022), median follow-up was 7·52 years (IQR 6·28-8·53) for patients who did not have progression and 7·62 years (IQR 6·48-8·54) for the full cohort of 94 patients. 3-year progression-free survival was 96·8% (95% CI 90·4-99·0; p=0·89), with progression occurring in three of 94 patients. No deaths occurred at 3 years, such that overall survival was 100%. At 5 years, necrosis had occurred in two (2%) of 94 patients, severe vasculopathy in four (4%), and permanent neurological conditions in three (3%); decline in vision from normal to abnormal occurred in four (7%) of 54 patients with normal vision at baseline. The most common grade 3-4 adverse events were headache (six [6%] of 94 patients), seizure (five [5%]), and vascular disorders (six [6%]). No deaths occurred as of data cutoff.
INTERPRETATION
Proton therapy did not improve survival outcomes in paediatric and adolescent patients with craniopharyngioma compared with a historical cohort, and severe complication rates were similar. However, cognitive outcomes with proton therapy were improved over photon therapy. Children and adolescents treated for craniopharyngioma using limited surgery and post-operative proton therapy have a high rate of tumour control and low rate of severe complications. The outcomes achieved with this treatment represent a new benchmark to which other regimens can be compared.
FUNDING
American Lebanese Syrian Associated Charities, American Cancer Society, the US National Cancer Institute, and Research to Prevent Blindness.
Topics: Child; Humans; Male; Adolescent; Female; United States; Craniopharyngioma; Proton Therapy; Endocrine System Diseases; Progression-Free Survival; Pituitary Neoplasms
PubMed: 37084748
DOI: 10.1016/S1470-2045(23)00146-8 -
Human Pathology Aug 2021Follicular cells (FCs) are thought to be agranular, non-hormone-producing stellate cells distributed throughout the adenohypophysis, occasionally arranged around...
Follicular cells (FCs) are thought to be agranular, non-hormone-producing stellate cells distributed throughout the adenohypophysis, occasionally arranged around colloid-filled follicles, and thought to be more prominent in the vicinity of necrosis and apoptotic cells. A distinct but similar cell type, the folliculostellate cell (FSC), is a sustentacular cell that is negative for keratins and stains for S100, GFAP, and SOX10. While several studies have examined FSCs in pituitary neuroendocrine tumors (PitNETs), the distribution and derivation of FCs in these lesions is unclear. We examined the presence and distribution of FCs in 104 PitNETs obtained by trans-sphenoidal surgery, using immunohistochemistry for keratins as well as the full complement of immunohistochemical stains for tumor characterization. The tumors included 9 somatotroph, 5 mammosomatotroph, 7 lactotroph, 7 immature PIT1-lineage, 2 acidophil stem cell, 17 corticotroph, 53 gonadotroph, 2 null cell, and 2 unusual plurihormonal tumors. CK-positive FCs were only identified in gonadotroph PitNETs and were found in 12 (23%) of those tumors; all other tumor types were negative for FCs. FCs express keratins identified by CAM5.2, AE1/AE3, CK18, and CK19 antibodies. FCs were identified scattered singly among hormone-producing neuroendocrine cells, in small clusters of 3-5 cells and surrounding colloid-filled follicles, as well as linearly along intratumoral blood vessels. Sequential stains showed that FCs express nuclear SF1 and GATA3, transcription factors of gonadotrophs, and multiplex immunohistochemistry confirmed colocalization of SF1 in the nucleus of keratin-positive FCs. In this series, FCs were exclusively found in gonadotroph PitNETs and occurred in 23% of those tumors. Co-expression of gonadotroph transcription factors in FCs supports the concept of cellular plasticity and transformation of neoplastic hormone-producing neuroendocrine cells to FCs. Further studies are required to determine if and why gonadotrophs alone undergo this transformation, the function of these cells and whether they have prognostic value.
Topics: Biomarkers, Tumor; Cell Plasticity; Humans; Immunohistochemistry; Neuroendocrine Tumors; Phenotype; Pituitary Neoplasms; Prognosis; Retrospective Studies
PubMed: 33991528
DOI: 10.1016/j.humpath.2021.05.002 -
Frontiers in Endocrinology 2021Pituitary 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... (Review)
Review
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.
Topics: Adenoma; Diagnostic Techniques, Endocrine; Humans; Neuroendocrine Tumors; Pituitary Neoplasms; Practice Guidelines as Topic
PubMed: 33815274
DOI: 10.3389/fendo.2021.604644 -
Brain Pathology (Zurich, Switzerland) Sep 2020Advances in our understanding of the biological basis and molecular characteristics of ependymal tumors since the latest iteration of the World Health Organization (WHO)... (Review)
Review
Advances in our understanding of the biological basis and molecular characteristics of ependymal tumors since the latest iteration of the World Health Organization (WHO) classification of CNS tumors (2016) have prompted the cIMPACT-NOW group to recommend a new classification. Separation of ependymal tumors by anatomic site is an important principle of the new classification and was prompted by methylome profiling data to indicate that molecular groups of ependymal tumors in the posterior fossa and supratentorial and spinal compartments are distinct. Common recurrent genetic or epigenetic alterations found in tumors belonging to the main molecular groups have been used to define tumor types at intracranial sites; C11orf95 and YAP1 fusion genes for supratentorial tumors and two types of posterior fossa ependymoma defined by methylation group, PFA and PFB. A recently described type of aggressive spinal ependymoma with MYCN amplification has also been included. Myxopapillary ependymoma and subependymoma have been retained as histopathologically defined tumor types, but the classification has dropped the distinction between classic and anaplastic ependymoma. While the cIMPACT-NOW group considered that data to inform assignment of grade to molecularly defined ependymomas are insufficiently mature, it recommends assigning WHO grade 2 to myxopapillary ependymoma and allows grade 2 or grade 3 to be assigned to ependymomas not defined by molecular status.
Topics: Brain Neoplasms; Central Nervous System Neoplasms; Ependyma; Ependymoma; Glioma; Humans; Supratentorial Neoplasms
PubMed: 32502305
DOI: 10.1111/bpa.12866 -
The Journal of Clinical Endocrinology... Jun 2023Aggressive pituitary tumors (APTs) and pituitary carcinomas (PCs) are heterogeneous with regard to clinical presentation, proliferative markers, clinical course, and...
Aggressive pituitary tumors (APTs) and pituitary carcinomas (PCs) are heterogeneous with regard to clinical presentation, proliferative markers, clinical course, and response to therapy. Half of them show an aggressive course only many years after the first apparently benign presentation. APTs and PCs share several properties, but a Ki67 index greater than or equal to 10% and extensive p53 expression are more prevalent in PCs. Mutations in TP53 and ATRX are the most common genetic alterations; their detection might be of value for early identification of aggressiveness. Treatment requires a multimodal approach including surgery, radiotherapy, and drugs. Temozolomide is the recommended first-line chemotherapy, with response rates of about 40%. Immune checkpoint inhibitors have emerged as second-line treatment in PCs, with currently no evidence for a superior effect of dual therapy compared to monotherapy with PD-1 blockers. Bevacizumab has resulted in partial response (PR) in few patients; tyrosine kinase inhibitors and everolimus have generally not been useful. The effect of peptide receptor radionuclide therapy is limited as well. Management of APT/PC is challenging and should be discussed within an expert team with consideration of clinical and pathological findings, age, and general condition of the patient. Considering that APT/PCs are rare, new therapies should preferably be evaluated in shared standardized protocols. Prognostic and predictive markers to guide treatment decisions are needed and are the scope of ongoing research.
Topics: Humans; Pituitary Neoplasms; Temozolomide; Bevacizumab
PubMed: 36856733
DOI: 10.1210/clinem/dgad098 -
European Neurology 2022Pituitary adenomas (PAs) account for the top three primary intracranial tumors in terms of total incidence rate. PAs can cause severe endocrine disorders and even... (Review)
Review
Pituitary adenomas (PAs) account for the top three primary intracranial tumors in terms of total incidence rate. PAs can cause severe endocrine disorders and even malignant features, such as invasion, metastasis, and recurrence. Therefore, the early diagnosis and accurate prognosis would be greatly beneficial for clinical treatment of PAs. MicroRNAs (miRNAs) are small, protein-noncoding RNAs that regulate gene expression posttranscriptionally. They regulate essential physiological processes, including proliferation, growth, and apoptosis, and also they involve in the invasion and metastasis of malignant tumors. At the tissue level, differential miRNA expression in endocrine malignancies including PAs has been reported. When miRNAs have been successfully detected in various biofluids and cell-free environments, their important roles as potential screening or prognostic biomarkers have been extensively investigated. The current work reviews recent studies on the emerging roles of miRNAs in PAs and the clinical significance.
Topics: Adenoma; Humans; MicroRNAs; Pituitary Neoplasms; Prognosis
PubMed: 35034033
DOI: 10.1159/000521388 -
Journal of Veterinary Internal Medicine 2023Radiotherapy (RT) is an effective treatment for dogs presented with neurologic signs caused by pituitary tumors. However, its impact on the outcome of concurrent...
BACKGROUND
Radiotherapy (RT) is an effective treatment for dogs presented with neurologic signs caused by pituitary tumors. However, its impact on the outcome of concurrent pituitary-dependent hypercortisolism (PDH) is controversial.
OBJECTIVES
Determine whether dogs with PDH have longer survival after pituitary RT compared with dogs with nonhormonally active pituitary masses and to evaluate whether clinical, imaging, and RT variables affect survival.
ANIMALS
Ninety-four dogs divided into 2 groups: PDH and non-PDH, based on the presence of hypercortisolism. Forty-seven dogs were allocated to the PDH group and 47 to the non-PDH group.
METHODS
Retrospective cohort study in which clinical records of dogs undergoing RT for pituitary macroadenomas between 2008 and 2018 at 5 referral centers were retrospectively evaluated.
RESULTS
Survival was not statistically different between PDH and non-PDH groups (median survival time [MST], 590 days; 95% confidence interval [CI], 0-830 days and 738 days; 95% CI, 373-1103 days, respectively; P = .4). A definitive RT protocol was statistically associated with longer survival compared with a palliative protocol (MST 605 vs 262 days, P = .05). The only factor statistically associated with survival from multivariate Cox proportional hazard analysis was total radiation dose (Gy) delivered (P < .01).
CONCLUSIONS AND CLINICAL IMPORTANCE
No statistical difference in survival was identified between the PDH and non-PDH groups, and longer survival was associated with higher Gy delivered.
Topics: Humans; Dogs; Animals; Pituitary Neoplasms; Retrospective Studies; Cushing Syndrome; Pituitary ACTH Hypersecretion; Adrenocortical Hyperfunction; Treatment Outcome; Dog Diseases
PubMed: 37218395
DOI: 10.1111/jvim.16724