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INTRODUCTION: Prolactinoma account to the most common pituitary adenomas and current therapy regime constitutes of dopamine agonist therapy (DA) and surgery in selected cases [17]. Due to tumor fibrosis induced by previous DA therapy, surgical removal can be challenging though. Therefore, this study investigates how preoperative DA usage influences perioperative treatment and surgical outcome in prolactinoma and aims to ascertain whether a specific subgroup of prolactinoma patients could derive greater benefit from exclusive surgical intervention. METHODS: We retrospectively analyzed n = 159 surgically treated and histologically confirmed prolactinomas in the sella region from 2013-2022 in our institution. Clinical, radiological and surgical features were analyzed. Univariate and multivariate analyses were performed. RESULTS: Out of total of 159 prolactinoma patients, 83.6% received previous treatment with DA followed by surgery, while only 16.4% received exclusive surgery. Both groups presented similar initial tumor volumes (1.9cm3 vs. 1.5cm3, p = 0.59) and equal preoperative prolactin levels (PRL) (199.7 µg/l vs. 191.0 µg/l, p = 0.44). Surgical procedures took significantly longer when patients received prior DA treatment (79 min. vs. 70 min., p = 0.0479). Six months after surgery, pretreated patients revealed significantly higher PRL compared to non-treated (107 g/l vs. 8.64 µg/, p = 0.0009). Additionally, untreated microprolactinoma presented a remission of 100%, whereas pretreated exhibited a remission rate of 88.75%. CONCLUSION: The current study demonstrates that prior DA treatment is associated with significantly longer surgeries, higher recurrence rates and lower rates of normalization of PRL levels after surgery, particularly in microprolactinomas and support the latest recommendations of the Pituitary Society's Consensus Statement 2023, which favors the option of surgery alone as first-line therapy for microprolactinomas.
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Agonistas de Dopamina , Neoplasias Hipofisarias , Prolactinoma , Humanos , Prolactinoma/tratamiento farmacológico , Prolactinoma/cirugía , Agonistas de Dopamina/uso terapéutico , Masculino , Estudios Retrospectivos , Femenino , Adulto , Neoplasias Hipofisarias/cirugía , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/patología , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven , Cuidados Preoperatorios/métodos , Anciano , Adolescente , Prolactina/sangreRESUMEN
Background and Objectives: Skull base reconstruction is a crucial step during transsphenoidal surgery. Sphenoid mucosa is a mucosal membrane located in the sphenoid sinus. Preservation and lateral shifting of sphenoid mucosa as sphenoid mucosal flap (SMF) during the transsphenoidal exposure of the sella may be important for later closure. This is the first systematic review to evaluate the utility of sphenoid mucosal flap for sellar reconstruction after transsphenoidal surgery. Materials and Methods: A systematic literature search was performed in January 2023: Cochrane, EMBASE, PubMed, Scopus, and Web of Science. The following keywords and their combinations were used: "sphenoid mucosa", "sphenoid sinus mucosa", "sphenoid mucosal flap", "sphenoid sinus mucosal flap". From a total number of 749 records, 10 articles involving 1671 patients were included in our systematic review. Results: Sphenoid sinus mucosa used to be applied for sellar reconstruction as either a vascularized pedicled flap or as a free flap. Three different types of mucosal flaps, an intersinus septal flap, a superiorly based flap and an inferiorly based flap, were described in the literature. Total SMF covering compared to partial or no SMF covering in sellar floor reconstruction resulted in fewer postoperative CSF leaks (p = 0.008) and a shorter duration of the postoperative lumbar drain (p = 0.003), if applied. Total or partial SMF resulted in fewer local complications (p = 0.012), such as fat graft necrosis, bone graft necrosis, sinusitis or fungal infection, in contrast to no SMF implementation. Conclusions: SMF seems to be an effective technique for skull base reconstruction after transsphenoidal surgery, as it can reduce the usage of avascular grafts such as fat along with the incidence of local complications, such as fat graft necrosis, bone graft necrosis, sinusitis and fungal infection, or it may improve the sinonasal quality of life by maintaining favorable wound healing through vascular flap and promote the normalization of the sphenoid sinus posterior wall. Further clinical studies evaluating sphenoid mucosal flap preservation and application in combination with other techniques, particularly for higher-grade CSF leaks, are required.
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Procedimientos de Cirugía Plástica , Seno Esfenoidal , Colgajos Quirúrgicos , Humanos , Seno Esfenoidal/cirugía , Procedimientos de Cirugía Plástica/métodos , Base del Cráneo/cirugía , Membrana Mucosa/cirugía , Complicaciones PosoperatoriasRESUMEN
Pituitary neuroendocrine tumors (PitNETs) are classified according to cell lineage, which requires immunohistochemistry for adenohypophyseal hormones and the transcription factors (TFs) PIT1, SF1, and TPIT. According to the current WHO 2022 classification, PitNETs with co-expression of multiple TFs are termed "plurihormonal". Previously, PIT1/SF1 co-expression was prevailingly reported in PitNETs, which otherwise correspond to the somatotroph lineage. However, little is known about such tumors and the WHO classification has not recognized their significance. We compiled an in-house case series of 100 tumors, previously diagnosed as somatotroph PitNETs. Following TF staining, histopathological features associated with PIT1/SF1 co-expression were assessed. Integration of in-house and publicly available sample data allowed for a meta-analysis of SF1-associated clinicopathological and molecular features across a total of 270 somatotroph PitNETs. The majority (74%, 52/70) of our densely granulated somatotroph PitNETs (DGST) unequivocally co-expressed PIT1 and SF1 (DGST-PIT1/SF1). None (0%, 0/30) of our sparsely granulated somatotroph PitNETs (SGST) stained positive for SF1 (SGST-PIT1). Among DGST, PIT1/SF1 co-expression was significantly associated with scarce FSH/LH expression and fewer fibrous bodies compared to DGST-PIT1. Integrated molecular analyses including publicly available samples confirmed that DGST-PIT1/SF1, DGST-PIT1 and SGST-PIT1 represent distinct tumor subtypes. Clinicopathological meta-analyses indicated that DGST-PIT1 respond more favorably towards treatment with somatostatin analogs compared to DGST-PIT1/SF1, while both these subtypes show an overall less aggressive clinical course than SGST-PIT1. In this study, we spotlight that DGST with co-expression of PIT1 and SF1 represent a common, yet underrecognized, distinct PitNET subtype. Our study questions the rationale of generally classifying such tumors as "plurihormonal", and calls for a refinement of the WHO classification. We propose the term "somatogonadotroph PitNET".
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Adenoma , Tumores Neuroendocrinos , Neoplasias Hipofisarias , Humanos , Linaje de la Célula , Tumores Neuroendocrinos/genética , Neoplasias Hipofisarias/genética , Factores de Transcripción , Factor Esteroidogénico 1/genética , Factor Esteroidogénico 1/metabolismoRESUMEN
OBJECTIVE: First-line prolactin-secreting tumor (PST) management typically involves treatment with dopamine agonists and the role of surgery remains to be further explored. We examined the international experience of 12 neurosurgical centers to assess the patient characteristics, safety profile, and effectiveness of surgery for PST management. METHODS: Patients surgically treated for PST from January 2017 through December 2020 were evaluated for surgical characteristics, outcomes, and safety. RESULTS: Among 272 patients identified (65.1% female), the mean age was 38.0 ± 14.3 years. Overall, 54.4% of PST were macroadenomas. Minor complications were seen in 39.3% of patients and major complications were in 4.4%. The most common major complications were epistaxis and worsened vision. Most minor complications involved electrolyte/sodium dysregulation. At 3-6 months, local control on imaging was achieved in 94.8% of cases and residual/recurrent tumor was seen in 19.3%. Reoperations were required for 2.9% of cases. On multivariate analysis, previous surgery was significantly predictive of intraoperative complications (6.14 OR, p < 0.01) and major complications (14.12 OR, p < 0.01). Previous pharmacotherapy (0.27 OR, p = 0.02) and cavernous sinus invasion (0.19 OR, p = 0.03) were significantly protective against early endocrinological cure. Knosp classification was highly predictive of residual tumor or PST recurrence on 6-month follow-up imaging (4.60 OR, p < 0.01). There was noted institutional variation in clinical factors and outcomes. CONCLUSION: Our results evaluate a modern, multicenter, global series of PST. These data can serve as a benchmark to compare with DA therapy and other surgical series. Further study and longer term outcomes could provide insight into how patients benefit from surgical treatment.
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Adenoma , Neoplasias Hipofisarias , Prolactinoma , Humanos , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Masculino , Adenoma/cirugía , Prolactina , Agonistas de Dopamina/uso terapéutico , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/cirugía , Neoplasias Hipofisarias/patología , Resultado del Tratamiento , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Estudios de Seguimiento , Prolactinoma/tratamiento farmacológico , Prolactinoma/cirugíaRESUMEN
BACKGROUND: Crooke cell adenomas (CCAs) are a rare, aggressive subset of secretory pituitary corticotroph adenomas (sCTAs) found in 5%-10% of patients with Cushing disease. Multiple studies support worse outcomes in CCAs but are limited by small sample size and single-institution databases. We compared outcomes in CCA and sCTA using a multicenter, international retrospective database of high-volume skull base centers. METHODS: Patients surgically treated for pituitary adenoma from January 2017 through December 2020 were included. RESULTS: Among 2826 patients from 12 international centers, 20 patients with CCA and 480 patients with sCTA were identified. No difference in baseline demographics, tumor characteristics, or postoperative complications was seen. Microsurgical approaches (60% CCA vs. 62.3% sCTA) were most common. Gross total resection was higher in CCA patients (100% vs. 83%, P = 0.05). Among patients with gross total resection according to intraoperative findings, fewer CCA patients had postoperative hormone normalization of pituitary function (50% vs. 77.8%, P < 0.01) and remission of hypersecretion by 3-6 months (75% vs. 84.3%, P < 0.01). This was the case despite CCA having better local control rates (100% vs. 96%, P < 0.01) and fewer patients with remnant on magnetic resonance imaging (0% vs. 7.2%, P < 0.01). A systematic literature review of 35 studies reporting on various treatment strategies reiterated the high rate of residual tumor, persistent hypercortisolism, and tumor-related mortality in CCA patients. CONCLUSIONS: This modern, multicenter series of patients with CCA reflects their poor prognosis and reduced postsurgical hormonal normalization. Further work is necessary to better understand the pathophysiology of CCA to devise more targeted treatment approaches.
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Adenoma Hipofisario Secretor de ACTH , Adenoma , Neoplasias Hipofisarias , Humanos , Adenoma Hipofisario Secretor de ACTH/cirugía , Adenoma Hipofisario Secretor de ACTH/complicaciones , Estudios Retrospectivos , Adenoma/diagnóstico por imagen , Adenoma/cirugía , Adenoma/complicaciones , Neoplasias Hipofisarias/patología , Hipófisis/cirugía , Hipófisis/patología , Resultado del Tratamiento , Estudios Multicéntricos como AsuntoRESUMEN
IMPORTANCE: Benchmarks aid in improve outcomes for surgical procedures. However, best achievable results that have been validated internationally for transsphenoidal surgery (TS) are not available. OBJECTIVE: We aimed to establish standardized outcome benchmarks for TS of pituitary adenomas. DESIGN: A total of 2685 transsphenoidal tumor resections from 9 expert centers in 3 continents were analyzed. SETTING: Patients were risk stratified, and the median values of each center's outcomes were established. The benchmark was defined as the 75th percentile of all median values for a particular outcome. The postoperative benchmark outcomes included surgical factors, endocrinology-specific values, and neurology-specific values. RESULTS: Of 2685 patients, 1149 (42.8%) defined the low-risk benchmark cohort. Within these benchmark cases, 831 (72.3%) patients underwent microscopic TS, and 308 (26.8%) patients underwent endoscopic endonasal resection. Of all tumors, 799 (29.8%) cases invaded the cavernous sinus. The postoperative complication rate was 19.6% with mortality between 0.0% and 0.8%. Benchmark cutoffs were ≤2.9% for reoperation rate, ≤1.9% for cerebrospinal fluid leak requiring intervention, and ≤15.5% for transient diabetes insipidus. At 6 months, benchmark cutoffs were calculated as follows: readmission rate: ≤6.9%, new hypopituitarism ≤6.0%, and tumor remnant ≤19.2%. CONCLUSIONS: This analysis defines benchmark values for TS targeting morbidity and mortality and represents the best outcomes in the best patients in expert centers. These cutoffs can be used to assess different centers, patient populations, and novel surgical techniques. It should be noted that the benchmark values may influence each other and must be evaluated in their own context.
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Adenoma , Neoplasias Hipofisarias , Humanos , Neoplasias Hipofisarias/cirugía , Benchmarking , Reoperación , Adenoma/cirugía , Complicaciones Posoperatorias/epidemiologíaRESUMEN
PURPOSE: While MRI has become the imaging modality of choice in the diagnosis of sellar tumors, no systematic attempt has yet been made to align radiological reporting of findings with the information needed by the various medical disciplines dealing with these patients. Therefore, we aimed to determine the prevailing preferences in this regard through a nationwide expert survey. METHODS: First, an interdisciplinary literature-based catalog of potential reporting elements for sellar tumor MRI examinations was created. Subsequently, a web-based survey regarding the clinical relevance of these items was conducted among board certified members of the German Society of Neurosurgery, German Society of Radiation Oncology, and the Pituitary Working Group of the German Society of Endocrinology. RESULTS: A total of 95 experts (40 neurosurgeons, 28 radiation oncologists, and 27 endocrinologists) completed the survey. The description of the exact tumor location, size, and involvement of the anatomic structures adjacent to the sella turcica (optic chiasm, cavernous sinus, and skull base), occlusive hydrocephalus, relationship to the pituitary gland and infundibulum, and certain structural characteristics of the mass (cyst formation, hemorrhage, and necrosis) was rated most important (> 75% agreement). In contrast, the characterization of anatomic features of the nasal cavity and sphenoid sinus as well as the findings of advanced MRI techniques (e.g., perfusion and diffusion imaging) was considered relevant by less than 50% of respondents. CONCLUSION: To optimally address the information needs of the interdisciplinary treatment team, MRI reports of sellar masses should primarily focus on the accurate description of tumor location, size, internal structure, and involvement of adjacent anatomic compartments.
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OBJECTIVE: A somatic mutational hotspot in the SF3B1 gene was reported in lactotroph tumours. The aim of our study was to examine the prevalence of driver SF3B1 variants in a multicentre independent cohort of patients with lactotroph tumours and correlate with clinical data. DESIGN AND METHODS: This was a retrospective, multicentre study involving 282 patients with lactotroph tumours (including 6 metastatic lactotroph tumours) from 8 European centres. We screened SF3B1 exon 14 hotspot for somatic variants using Sanger sequencing and correlated with clinicopathological data. RESULTS: We detected SF3B1 variants in seven patients with lactotroph tumours: c.1874G > A (p.Arg625His) (n = 4, 3 of which metastatic) and a previously undescribed in pituitary tumours variant c.1873C > T (p.Arg625Cys) (n = 3 aggressive pituitary tumours). In two metastatic lactotroph tumours with tissue available, the variant was detected in both primary tumour and metastasis. The overall prevalence of likely pathogenic SF3B1 variants in lactotroph tumours was 2.5%, but when we considered only metastatic cases, it reached the 50%. SF3B1 variants correlated with significantly larger tumour size; higher Ki67 proliferation index; multiple treatments, including radiotherapy and chemotherapy; increased disease-specific death; and shorter postoperative survival. CONCLUSIONS: SF3B1 variants are uncommon in lactotroph tumours but may be frequent in metastatic lactotroph tumours. When present, they associate with aggressive tumour behaviour and worse clinical outcome.
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Lactotrofos , Neoplasias Hipofisarias , Humanos , Neoplasias Hipofisarias/epidemiología , Neoplasias Hipofisarias/genética , Prevalencia , Estudios Retrospectivos , Factores de Transcripción , Factores de Empalme de ARN/genética , FosfoproteínasRESUMEN
BACKGROUND AND OBJECTIVES: There is considerable controversy as to which of the 2 operating modalities (microsurgical or endoscopic transnasal surgery) currently used to resect pituitary adenomas (PAs) is the safest and most effective intervention. We compared rates of clinical outcomes of patients with PAs who underwent resection by either microsurgical or endoscopic transnasal surgery. METHODS: To independently assess the outcomes of each modality type, we sought to isolate endoscopic and microscopic PA surgeries with a 1:1 tight-caliper (0.01) propensity score-matched analysis using a multicenter, neurosurgery-specific database. Surgeries were performed between 2017 and 2020, with data collected retrospectively from 12 international institutions on 4 continents. Matching was based on age, previous neurological deficit, American Society of Anesthesiologists (ASA) score, tumor functionality, tumor size, and Knosp score. Univariate and multivariate analyses were performed. RESULTS: Among a pool of 2826 patients, propensity score matching resulted in 600 patients from 9 surgery centers being analyzed. Multivariate analysis showed that microscopic surgery had a 1.91 odds ratio (OR) ( P = .03) of gross total resection (GTR) and shorter operative duration ( P < .01). However, microscopic surgery also had a 7.82 OR ( P < .01) for intensive care unit stay, 2.08 OR ( P < .01) for intraoperative cerebrospinal fluid (CSF) leak, 2.47 OR ( P = .02) for postoperative syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was an independent predictor for longer postoperative stay (ß = 2.01, P < .01). Overall, no differences in postoperative complications or 3- to 6-month outcomes were seen by surgical approach. CONCLUSION: Our international, multicenter matched analysis suggests microscopic approaches for pituitary tumor resection may offer better GTR rates, albeit with increased intensive care unit stay, CSF leak, SIADH, and hospital utilization. Better prospective studies can further validate these findings as matching patients for outcome analysis remains challenging. These results may provide insight into surgical benchmarks at different centers, offer room for further registry studies, and identify best practices.
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Adenoma , Síndrome de Secreción Inadecuada de ADH , Neoplasias Hipofisarias , Humanos , Neoplasias Hipofisarias/cirugía , Neoplasias Hipofisarias/patología , Estudios Retrospectivos , Estudios Prospectivos , Síndrome de Secreción Inadecuada de ADH/etiología , Puntaje de Propensión , Resultado del Tratamiento , Endoscopía/métodos , Pérdida de Líquido Cefalorraquídeo/etiología , Adenoma/cirugía , Adenoma/patologíaRESUMEN
OBJECTIVE: Craniopharyngiomas (CP) are rare malformational tumors. Clinical presentation and outcome of pediatric patients with CP with specific regard to age at diagnosis is not clear. The aim of this cohort study was to determine clinical presentation and outcome in these patients diagnosed at different ages at diagnosis. DESIGN: Seven hundred and nine patients diagnosed with CP were recruited from 1999 to 2021 in HIT-Endo and KRANIOPHARYNGEOM 2000/2007/Registry 2019 and prospectively observed. METHODS: Age at diagnosis was categorized as infants and toddlers (<2 years), early childhood (2-6 years), middle childhood (6-12 years), and early adolescence (12-18 years). Overall and event-free survival (EFS), functional capacity (FMH), and quality of life (QoL) (PEDQOL) were assessed. RESULTS: Severe obesity (body mass index [BMI] >3 standard deviation score [SDS]) was prevalent in 45.4% at last visit. A lower EFS but better QoL was observed in children with age at diagnosis <6 years compared with ≥6 years. Reduced functional capacity percentiles were associated with increased BMI-SDS at last visit (rho = -0.125, 95% confidence interval [CI; -0.21; -0.04]) and age at diagnosis <2 years. Posterior hypothalamic involvement and hypothalamic lesion (HL) were independent risk factors for reduced EFS (hazard ratio = 1.59, 95% CI [1.12-2.26]) and obesity at last visit (odds ratio = 2.94, 95% CI [1.73-5.08]). Age at diagnosis did not contribute to severe obesity and reduced QoL. CONCLUSIONS: Diagnosis of CP at age <6 years may help patients to adapt early to disabilities but may lead to a higher probability of CP relapse. Not age at diagnosis but posterior HL may be the contributing factor to severe obesity and a reduced QoL. CLINICAL TRIAL REGISTRATION NUMBERS: NCT00258453; NCT01272622; NCT04158284.
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Craneofaringioma , Obesidad Mórbida , Neoplasias Hipofisarias , Adolescente , Niño , Preescolar , Humanos , Lactante , Estudios de Cohortes , Craneofaringioma/complicaciones , Craneofaringioma/diagnóstico , Recurrencia Local de Neoplasia , Obesidad/complicaciones , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/epidemiología , Neoplasias Hipofisarias/complicaciones , Calidad de VidaRESUMEN
Cushing´s disease is a rare endocrinological disorder which is caused by an adrenocorticotropic hormone secreting pituitary adenoma. The condition is associated with an increased risk for venous thromboembolism. While there exist reports on symptomatic venous thromboses complicating Cushing's disease, the prevalence of incidental leg vein thromboses accompanying pituitary surgery for Cushing's disease is yet unknown. 30 consecutive patients (9 male; age 25-77 years) with histologically confirmed Cushing's disease underwent transsphenoidal adenomectomy between October 2018 and September 2019. All patients received perioperative pharmacological thromboprophylaxis. Whole leg compression ultrasound was performed within one week after surgery (median 2 days) to exclude leg vein thromboses (primary endpoint). Preoperative laboratory values including plasma cortisol and various coagulation parameters were evaluated as secondary outcome measures. A comparison was made between patients with and without thrombotic events (p value ≤ 0.05). A total of 2 out of 30 patients (6.7%; CI 0.8-24.1%) presented with asymptomatic perioperative deep vein thromboses of the lower legs. Thrombosis patients differed not significantly from their counterparts with respect to age, sex, and comorbidities, but preoperative morning plasma cortisol was significantly higher in patients with venous thromboses (421.0 ± 49.5 µg/l vs. 188.1 ± 78.2 µg/l; p = 0.01). Moreover, von Willebrand factor activity was markedly increased in one case (409.0%) compared to the mean value obtained from 28 patients without phlebothromboses (146.9 ± 60.7%; p < 0.01). Perioperative asymptomatic leg vein thrombosis can be found with the aid of compression ultrasound in a considerable proportion of patients undergoing transsphenoidal adenomectomy for Cushing's disease despite the administration of pharmacological thromboprophylaxis.
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Adenoma , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Neoplasias Hipofisarias , Tromboembolia Venosa , Trombosis de la Vena , Humanos , Masculino , Adulto , Persona de Mediana Edad , Anciano , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/tratamiento farmacológico , Anticoagulantes/uso terapéutico , Hidrocortisona , Prevalencia , Adenoma/patología , Neoplasias Hipofisarias/patología , Tromboembolia Venosa/tratamiento farmacológico , Trombosis de la Vena/complicaciones , Extremidad Inferior/patologíaRESUMEN
Silent corticotrophic adenomas (SCAs) represent a rare group of non-functioning adenomas with a potentially aggressive clinical course. Cystic component is a very common finding among SCAs, but its clinical relevance has not yet been investigated. The aim of this study was to analyze clinical features of cystic and non-cystic SCAs, perioperative complications after microscopic transsphenoidal surgery, clinical outcome after first and repeat surgery along with risk factors for recurrence. We conducted a retrospective analysis of 62 silent corticotrophic adenomas treated at our university medical center via microscopic transsphenoidal surgery between January 2008 and July 2019. Parameters investigated included histology, invasiveness, intratumoral haemorrhage or cystic component on MRI, perioperative alteration of visual field, tumor size, pre- and postoperative ACTH, FSH, GH, LH, TSH, prolactin, cortisol, free T4, free T3, IGF-1, estrogen and testosterone levels, perioperative complications, neoadjuvant and adjuvant therapy along with clinical outcomes. A total of 62 patients were analyzed. The mean follow up was 28.3 months. Tumors with a cystic component occur statistically significant more often among male than non-cystic (80.6% vs. 44.4%, p = 0.02) and display lower rates of cavernous sinus invasion and sphenoid sinus invasion were significantly lower for cystic lesions comparing to non-cystic tumors (42.3% vs. 69.4%, p = 0.04 and 3.8% vs. 47.2%, p < 0.001). GTR after MTS was not statistically significant higher by cystic SCAs (80% vs. 57.1%, p = 0.09). Cystic lesions were also associated with higher risk of hyperprolactinemia (19.4% vs. 2.8%, p = 0.02) and only densely granulated cystic SCAs presented with preoperative intratumoral hemorrhage (19.2% vs. 0%, p = 0.01). Mean duration of first surgery was significantly shorter for cystic SCAs (71.6(± 18.7) vs. 94.8(± 31.1) minutes, p = 0.01). Preoperative pituitary insufficiency (25% vs. 16.7%, p = 0.49), intraoperative CSF space opening (21.1% vs. 37.5%, p = 0.32), along with postoperative new pituitary insufficiency (15% vs. 10%, p = 0.67) or diabetes insipidus/SIADH (10% vs. 13.3%, p > 0.99) with histological markers such as Ki67 (21.1% vs. 13.8%, p = 0.70) and p53 expression (6.3% vs. 0%, p = 0.39) as well as mitotic rate (5.3% vs. 10.3%, p > 0.99) were comparable between both groups. The presence of cystic component did not affect the tumor recurrence (10% vs. 16%, p = 0.68). Mean duration of surgery was first surgeries was not statistically shorter than repeat surgeries (85.4 ± 29.1 vs. 93.8 ± 28 min, p = 0.15). Patients undergoing first surgery had a higher probability of gross total resection (74.4% vs. 30%, p = 0.01) and lower probability of intraoperative CSF space opening (26% vs. 58.3%, p = 0.04) as well as a lower rate of preoperative anterior pituitary insufficiency (20% vs. 58.3%, p = 0.01). The incidence of new postoperative anterior pituitary insufficiency (10% vs. 0%, p = 0.57) and transient diabetes insipidus/SIADH (12% vs. 8.3%, p > 0.99) between those groups were comparable. No statistical difference was observed between patients with remission and with recurrent tumor regarding cortisol and ACTH levels, incidence of different histological subgroups, invasively growing tumors and lesions with cystic components as well as the percentage of cases with increased Ki67 proliferation index, p53 expression and mitotic indices. Our study presents one of the largest available cohorts of SCAs after microscopic transsphenoidal surgery and first clinical analysis of cystic versus non-cystic SCAs so far. We also performed the first comparison of index and repeat surgeries for this tumor entity. Cystic tumors presented with characteristic clinical aspects like male predominance, higher risk of hyperprolactinemia as well as lower rates of cavernous sinus and sphenoid sinus invasion comparing to non-cystic lesions. Mean duration of first surgery was significantly shorter for cystic SCAs. Moreover preoperative intratumoral hemorrhage had 100% specificity and 60% sensitivity for densely granulated cystic SCAs. All these clinical hallmarks may suggest a novel subgroup of SCAs with distinct clinical and biological features, however further clinical and molecular investigations are required. Second surgeries are associated with a higher incidence of preoperative pituitary insufficiency, and a higher risk of subtotal resection, and a higher probability of CSF space opening intraoperatively compared to first surgeries. On the other hand, the risk of new postoperative pituitary insufficiency was higher after first surgeries. In our cohort of patients, no prognostic factor for recurrence among histological diagnosis, Ki67-proliferation index, p53 expression, number of mitoses, invasive growth or cystic lesions for SCAs could be detected.
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Adenoma , Hiperprolactinemia , Hipopituitarismo , Síndrome de Secreción Inadecuada de ADH , Neoplasias Hipofisarias , Humanos , Masculino , Femenino , Estudios Retrospectivos , Hidrocortisona , Antígeno Ki-67 , Proteína p53 Supresora de Tumor , Resultado del Tratamiento , Recurrencia Local de Neoplasia , Adenoma/cirugía , Adenoma/patología , Hormona Adrenocorticotrópica , Hipopituitarismo/etiología , Hemorragia , Neoplasias Hipofisarias/cirugía , Neoplasias Hipofisarias/patologíaRESUMEN
Microscopic and endoscopic transsphenoidal surgeries represent the standard treatment for Cushing's disease (CD). At our institution a new exoscopic approach was implemented. After proof of the general use for transsphenoidal pituitary surgery, the aim of this study was to compare the exoscopic 4K3D video microscope with the microscopic transsphenoidal surgery for patients with CD. We conducted a retrospective analysis on 388 patients with CD treated in our medical center via microscopic transsphenoidal surgery (MTS) between January 2008 and July 2019 or via exoscopic transsphenoidal surgery (ExTS) between May 2019 and May 2021. Parameters investigated included histology, pre- and postoperative MRI with tumor size, pre- and postoperative ACTH and cortisol levels, duration of surgery, perioperative and postoperative complications as well as clinical outcome. Patients who underwent ExTS in CD experienced a lower incidence of SIADH/diabetes insipidus (p = 0.0164), a higher rate of remission (p = 0.0422), and a shorter duration of surgery (p < 0.0001), compared to MTS. However, there was no significant difference regarding new postoperative pituitary insufficiency and intraoperative CSF space opening. We found that ExTS had multiple benefits compared to MTS for tumor resection in case of CD. These results are in line with our previous publication on the general applicability of an exoscope in pituitary surgery. To our knowledge, this is the first clinical study proving the superiority of ExTS in CD. These results are promising, nevertheless further studies comparing exoscopic with the endoscopic approach are necessary to finally evaluate the utility of the new technique.
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Neoplasias , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Neoplasias Hipofisarias , Humanos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/cirugía , Estudios Retrospectivos , Hipófisis/cirugía , Procedimientos Neuroquirúrgicos/métodos , Neoplasias/cirugía , Resultado del Tratamiento , Neoplasias Hipofisarias/cirugíaRESUMEN
Corticotroph macroadenomas are rare but difficult to manage intracranial neoplasms. Mutations in the two Cushing's disease mutational hotspots USP8 and USP48 are less frequent in corticotroph macroadenomas and invasive tumors. There is evidence that TP53 mutations are not as rare as previously thought in these tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph tumors, with emphasis on macroadenomas, and their possible association with clinical and tumor characteristics. To this end, the entire TP53 coding region was sequenced in 86 functional corticotroph tumors (61 USP8 wild type; 66 macroadenomas) and the clinical characteristics of patients with TP53 mutant tumors were compared with TP53/USP8 wild type and USP8 mutant tumors. We found pathogenic TP53 variants in 9 corticotroph tumors (all macroadenomas and USP8 wild type). TP53 mutant tumors represented 14% of all functional corticotroph macroadenomas and 24% of all invasive tumors, were significantly larger and invasive, and had higher Ki67 indices and Knosp grades compared to wild type tumors. Patients with TP53 mutant tumors had undergone more therapeutic interventions, including radiation and bilateral adrenalectomy. In conclusion, pathogenic TP53 variants are more frequent than expected, representing a relevant amount of functional corticotroph macroadenomas and invasive tumors. TP53 mutations associated with more aggressive tumor features and difficult to manage disease.
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Adenoma , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Adenoma/genética , Corticotrofos/patología , Humanos , Antígeno Ki-67 , Mutación/genética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , Proteína p53 Supresora de Tumor/genéticaRESUMEN
PURPOSE/OBJECTIVE: Multiple tumorous lesions in one pituitary gland are rare and mostly described in case reports. Their incidences and combinations are defined in larger collectives. Therefore, we analyzed our large collection for double tumors and combinations of tumors, cysts, and inflammation. METHODS: The German Registry of Pituitary Tumors, including cases from 1990 to 2018, served as the database. Our collection comprises a total of 16,283 cases up until the end of 2018. Of these cases, 12,673 originated from surgical and 3,610 from autopsy material. All specimens were fixed in formalin and embedded in paraffin. The sections were stained with hematoxylin-eosin and PAS. Monoclonal (prolactin, TSH, FSH, LH, and α subunit) or polyclonal (GH and ACTH) antibodies were used to detect pituitary hormones in the lesions. Since 2017, antibodies against the transcription factors Pit-1, T-Pit, and SF-1 have been used in difficult cases. The criteria of the 2017 WHO classification have been basic principles for classification since 2018 (Osamura et al. 2017). For differentiation of other sellar tumors, such as meningiomas, chordomas, or metastases, the use of additional antibodies was necessary. For these cases, it was possible to use a broad antibody spectrum. Autopsy pituitaries were generally studied by H&E and PAS sections. If any lesions were demonstrated in these specimens, additional immunostaining was performed. RESULTS: Multiple tumorous lesions with more than one pituitary neuroendocrine tumor (PitNET) respectively adenoma make up 1.4% (232 cases) in our collection. Within the selected cases, synchronous multiple pituitary neuroendocrine tumors (PitNETs) account for 17.3%, PANCH cases (pituitary adenoma with neuronal choristoma) for 14.7%, PitNETs and posterior lobe tumors for 2.2%, PitNETs and metastases for 5.2%, PitNETs and mesenchymal tumors for 2.6%, PitNETs and cysts for 52.2%, and PitNETs and primary inflammation for 6.0%. The mean patient age was 53.8 years, with a standard deviation of 18.5 years. A total of 55.3% of the patients were female and 44.7% were male. From 1990 to 2018, there was a continuous increase in the number of multiple tumorous lesions. CONCLUSION: From our studies, we conclude that considering possible tumorous double lesions during surgeries and in preoperative X-ray analyses is recommended.
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Adenoma , Quistes , Neoplasias Primarias Múltiples , Tumores Neuroendocrinos , Enfermedades de la Hipófisis , Neoplasias Hipofisarias , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/patología , Hipófisis/patología , Adenoma/patología , Tumores Neuroendocrinos/patología , Neoplasias Primarias Múltiples/patología , InflamaciónAsunto(s)
Adenoma Oxifílico , Neoplasias Hipofisarias , Epigenómica , Hemorragia , Humanos , HipófisisRESUMEN
Cushing's disease is a rare but devastating and difficult to manage condition. The somatostatin analogue pasireotide is the only pituitary-targeting pharmaceutical approved for the treatment of Cushing's disease but is accompanied by varying efficacy and potentially severe side effects. Finding means to predict which patients are more likely to benefit from this treatment may improve their management. More than half of corticotroph tumours harbour mutations in the USP8 gene, and there is evidence of higher somatostatin receptor 5 (SSTR5) expression in the USP8-mutant tumours. Pasireotide has a high affinity for SSTR5, indicating that these tumours may be more sensitive to treatment. To test this hypothesis, we examined the inhibitory action of pasireotide on adrenocorticotrophic hormone synthesis in primary cultures of human corticotroph tumour with assessed USP8 mutational status and in immortalized murine corticotroph tumour cells overexpressing human USP8 mutants frequent in Cushing's disease. Our in vitro results demonstrate that pasireotide exerts a higher antisecretory response in USP8-mutant corticotroph tumours. Overexpressing USP8 mutants in a murine corticotroph tumour cell model increased endogenous somatostatin receptor 5 (Sstr5) transcription. The murine Sstr5 promoter has two binding sites for the activating protein 1 (AP-1) and USP8 mutants possibly to mediate their action by stimulating AP-1 transcriptional activity. Our data corroborate the USP8 mutational status as a potential marker of pasireotide response and describe a potential mechanism through which USP8 mutants may regulate SSTR5 gene expression.
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Neoplasias , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Animales , Corticotrofos/metabolismo , Endopeptidasas/genética , Endopeptidasas/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Humanos , Ratones , Neoplasias/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/tratamiento farmacológico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Somatostatina/análogos & derivados , Somatostatina/farmacología , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción AP-1/uso terapéutico , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismoAsunto(s)
Adenoma Hipofisario Secretor de ACTH , Adenoma , Neoplasias Hipofisarias , Adenoma Hipofisario Secretor de ACTH/patología , Adenoma/patología , Hormona Adrenocorticotrópica/metabolismo , Neoplasias de la Mama , Carcinoma , Humanos , Mutación , Fosfohidrolasa PTEN/genética , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Proteína p53 Supresora de Tumor/genética , Proteína Nuclear Ligada al Cromosoma X/genéticaRESUMEN
PURPOSE: To analyze the expression of somatostatin receptor (SSTR)2a and 5 by immunohistochemistry (IHC) in surgically resected somatotrophic pituitary adenomas and to associate expression rates with tumor size and clinical, biochemical, and histological parameters and response to somatostatin analog (SA) therapy. METHODS: Forty-three microsurgically treated patients with histopathologically proven growth hormone (GH)-producing pituitary adenoma were included (WHO 2017). SSTR subtype expression was analyzed in adenoma tissues using monoclonal antibodies (Abcam, SSTR2a-UMB1, SSTR5-UMB4). Expression rates were classified as low (≤ 20% staining positivity), moderate (21-50%), and high (> 50%). Furthermore, biochemical parameters such as human growth hormone (hGH) and insulin-like growth factor-1 (IGF-1) levels were measured and clinical, biochemical, radiological, and histological data were evaluated. RESULTS: Of the 43 patients included in this study, 28 were female and 15 were male. The median age was 52 years (range 17-72 years). The median tumor size was 1.2 cm (range: 0.13-3.93 cm). All resected tumors showed positivity for somatotrophic hormone (STH). In all tissue samples, SSTR2a signal expression was detectable in immunohistochemistry, while only 39 samples were positive for SSTR5. Thirty-six samples had a high expression of SSTR2a, while three had a moderate and four a low SSTR2a signal. In comparison, SSTR5 signal was high in 26 out of 43 samples, while seven adenomas showed a moderate and six cases a low expression rate of SSTR5. The median IGF-1 was 714.2 µg/l and the median GH 19.6 mU/l (= 6.53 µg/l). The present study indicates that there is no significant relationship between the expression rates of receptor subtypes and the parameters we analyzed. However, our study revealed that smaller adenomas have a lower baseline GH level (p = 0.015), CONCLUSION: IHC with monoclonal antibodies appears to be a suitable method to determine the expression rates of SSTR2a and 5 at protein levels, as it is not possible to draw conclusions regarding receptor subtypes solely on the basis of the parameters analyzed.
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Acromegalia , Adenoma , Adenoma Hipofisario Secretor de Hormona del Crecimiento , Neoplasias Hipofisarias , Acromegalia/tratamiento farmacológico , Acromegalia/cirugía , Adenoma/tratamiento farmacológico , Adenoma/metabolismo , Adolescente , Adulto , Anciano , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/patología , Receptores de Somatostatina/metabolismo , Somatostatina/uso terapéutico , Adulto JovenRESUMEN
(1) Background: We identified screening parameters and associated factors for delayed, symptomatic hyponatremia (DSH) following inpatient discharge after transsphenoidal surgery (TSS). (2) Methods: In this prospective, monocentric study, 108 patients who underwent TSS for pituitary pathologies were included, provided with a questionnaire and instructed to document urine specific gravity, fluid intake/urine output, body weight and clinical symptoms for every of five days following discharge from hospital. (3) Results: The overall incidence of DSH within 14 days following discharge from the hospital was 14.8% (n = 9). Symptomatic patients presented on average 8.6 days after surgery. Mild DSH was present in 3.3% of the patients, moderate in 1.6% and severe hyponatremia in 9.8% of patients. Female sex (p = 0.02) and lower BMI (p = 0.02), as well as nausea (66.7%; p < 0.01) and emesis (33.3%; p < 0.05), were associated with DSH. A significant weight delta between morning and afternoon weight two days before the event of DSH between both groups (1.26 kg (n = 5) vs. 0.79 kg (n = 52), p < 0.05) was detected. (4) Conclusions: Handing out a symptom questionnaire at discharge seems to be an easy and feasible tool for the detection of DSH after hospital discharge.