Year : 2021 | Volume
: 4 | Issue : 2 | Page : 67--71
Award Clinical Neuro-Oncology
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. Award Clinical Neuro-Oncology.Int J Neurooncol 2021;4:67-71
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. Award Clinical Neuro-Oncology. Int J Neurooncol [serial online] 2021 [cited 2022 Jun 25 ];4:67-71
Available from: https://www.Internationaljneurooncology.com/text.asp?2021/4/2/67/343558
A clinicoradiological analysis of silent corticotroph adenomas after the introduction of pituitary specific transcription factors
Abhijit Goyal-Honavar, Sauradeep Sarkar, HS Asha, Nitin Kapoor, Rajesh Balakrishnan, Harshad Vanjare, Geeta Chacko, Ari G Chacko; Christian Medical College, Vellore, Tamil Nadu, India
Objectives: Silent corticotroph adenomas (SCAs) are a rare subtype of nonfunctional pituitary adenoma. Although it has been suggested that they are more aggressive and recur more frequently following excision, there is limited literature on the optimum treatment strategy for these tumors, especially with regard to the role of radiation therapy in incompletely resected tumors. We aimed to examine the clinical behavior of these enigmatic tumors, comparing them to a cohort of other nonfunctional adenomas, and the role of radiation in halting their inexorable progression.
Materials and Methods: We assimilated data from 62 SCAs, defined as per the WHO 2017 criteria that incorporate transcription factor analysis, operated between 2007 and 2019, comparing the clinicoradiological characteristics and outcomes to those of 249 nonfunctional adenomas of other subtypes (ONAs) operated during the same time. We also assessed the role of early adjuvant radiotherapy in the treatment of residual SCAs and the need for a differential strategy from other adenoma subtypes.
Results: Patients with SCAs present at a younger age than ONAs (43.9 years vs. 48.2 years, P = 0.014), with larger (14.9 cc vs. 9.7 cc, P = 0.006) and more invasive adenomas (61.2% vs. 45.8%, P = 0.021). SCAs are more likely to recur or progress (48.7% vs. 15.7%, P < 0.001) following excision than ONAs, with significantly poorer event-free survival (Log rank test P < 0.001). Multivariate analysis identified male gender (HR: 2.217; P = 0.017), MIB index ≥ 3% (HR: 2.116; P = 0.012), and SCA tumor pathology (HR: 3.787; P < 0.001) as factors predicting recurrence. Early adjuvant radiotherapy produces favorable outcomes among SCAs with postoperative residual tumor, on par with ONAs.
Conclusions: SCAs are an aggressive subtype of nonfunctional pituitary adenomas that are larger, more likely to be invasive, and tend to recur after a subtotal excision compared with other nonfunctional adenomas. A gross total resection must be attempted whenever possible and earlier adjuvant radiation is recommended when resurgery for residual tumor is difficult.
Advanced imaging attributes of H3K27M mutation in diffuse midline gliomas
Richa Singh Chauhan, Karthik K, Jitender Saini, Maya D Bhat, Vani Santosh, Shilpa Rao, Dwarkanath Srinivas, Alok Mohan Uppal; National Institute of Mental Health and Neurosciences (NIMHANS)
Objectives: Diffuse midline glioma (DMG), H3 K27M-mutant, is a newly described distinct class of clinically aggressive tumors categorized by 2016 WHO classification of the CNS tumors as grade IV irrespective of their histologic morphology. They carry an unfavorable outcome as compared to their wild-type counterpart. As the occurrence of H3 K27M-mutation may foresee an aggressive clinical course of the tumor while concurrently giving a prospect for new targeted treatment methods, the presence of these molecular alterations should be eagerly sought after. Our study aimed at evaluating the advanced MRI features (diffusion and perfusion) that might aid in differentiating H3 K27M-mutant from WT DMGs.
Materials and Methods: This was a retrospective, observational study, done in the Departments of Neuroimaging and Interventional Radiology and Neuropathology, NIMHANS, Bangalore. MRI features of 123 patients who satisfied the inclusion criteria (August 2016–April 2020) were evaluated after Institutional ethics committee approval. MRI was performed on 1.5/3.0T MR Scanners. Advanced MRI features based on diffusion-weighted imaging (tumoral ADC, peritumoral (PT) ADC, normalized tumoral and PT ADC, and fractional anisotropy) as well as perfusion-weighted imaging (rCBV, rCBF, normalized rCBV, normalized rCBF, uncorrected rCBV, normalized uncorrected CBV, corrected CBV and K2) were analyzed between two tumor groups. Statistical analysis was done using R software. A value of P <0.05 was taken as the level of statistical significance.
Results: Sixty-one patients out of total 123 cases harbored H3 K27M-mutant gliomas while 62 patients had WTDMGs. The mean age of patients with mutant DMGs was 24.13 ± 13.13 years while in the WT group was 35.79 ± 18.74 years (P = 0.016). Diffusion data were available in 94 cases (48 mutant and 46 WT) and perfusion data in 64 cases (34 mutant and 30 WT). On intergroup analysis of diffusion parameters, PTADC and normalized PTADC were significantly higher in WT group (P = 0.033 and 0.040, respectively). The normalized mean PT ADC was 1.64 × 10–3 mm2/s in mutant DMGs and 1.83 × 10–3 mm2/s in WT DMGs. Among various perfusion parameters, rCBV (25.17 ± 27.76 vs. 13.73 ± 14.83, P = 0.018), rCBF (266.15 ± 189.26 vs. 181.91 ± 167.97, P = 0.017), normalized rCBV (3.44 ± 2.16 vs. 2.39 ± 1.25, P = 0.05) and normalized uncorrected rCBV (3.5 ± 2.05 vs. 2.54 ± 1.56, P = 0.019) were significantly higher in the mutant compared to WT DMGs.
Conclusion: Advanced MRI features such as normalized tumoral and PTADC, rCBV, rCBF, normalized rCBV, normalized rCBF, uncorrected rCBV, normalized uncorrected CBV can discriminate between the H3K27M-mutant and WT DMGs. For DMGs bearing different phenotypic and imaging characteristics, these findings carry an important implication for designing future trials in this specific neoplasm group.
Encouraging experience of intensity-modulated proton beam therapy using pencil beam scanning (PBS IMPT) in craniospinal irradiation (CSI)
Utpal Gaikwad, Srinivas Chilukuri, Sapna Nangia, Dayananda Sharma, Naufal Mp, Rakesh Jalali; Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India
Introduction: The aim of this study was to review patients treated with CSI at our center, South East Asia’s first proton center. All patients were treated using IMPT. The aim is to share unique challenges faced during planning, plan implementation, dosimetric benefits, and acute toxicities experienced by patients.
Patients and Methods: Twenty-five patients (5 adults and 20 pediatric) received CSI using IMPT technique till December 31, 2020 included in this analysis. This group had 32% medulloblastoma, 32 % ependymoma, 12% pineoblastoma, 8% GCT, 8% PNET and 4% ATRT. Twenty-one were men and 4 were women. Of the 20 pediatric patients, 16 (80%) were 8 years or younger, only 4 of which required anesthesia. 4 (16%) patients received concurrent chemotherapy. Average PTV length was 68 cm and PTV volume 2509 cc. Contouring and planning were done using Raystation system Citrix version 9. IMPT plan generated using, 4 or 5 fields, SFO technique, and eight cm junctions with dose gradient technique. For dose calculations, Monte Carlo algorithm was used and robustness for 3 mm was evaluated. All patients underwent baseline neuropsychological and QOL assessment and then planned for subsequent assessment on follow-up.
Results: Dose prescribed for CSI was in the range of 19.8 GyE to 30.6GyE. Mean Conformity index 1.1 and mean Homogeneity index 1.02. Lens Dmean_avg 3.96 GyE, Parotid Dmean_avg 10.67 GyE, Bowel Bag Dmean_avg 0.18 GyE, Lung Dmean_avg 0.65 GyE, Kidney Dmean_avg 1.85 GyE, while heart, liver, and gonads receiving no dose. Compared to adult, in pediatric CSI doses to OARs were on higher side and among these 25 patients only first three pediatric patients (12%) experienced grade 3 mucosal toxicities and treatment gap prolonging OTT (No treatment gaps vs. 4 days gap). 60 % developed grade dermatitis, while 56% developed grade 2 alopecia. Four (16%) patients required plan adaptation. With modified contouring and planning approach we managed to limit radiation doses to OARs in pediatric patients. At median follow-up of 12 months (3–24), 96% are alive with local control rate of 86%.
Conclusion: With IMPT, it is practically feasible to achieve good homogenous conformal coverage and reduce radiation doses to OARs significantly, limiting acute and late effects, improving QOL and therapeutic ratio. It is important to adapt newer contouring guidelines for pediatric CSI and to plan dose gradient while radiating whole vertebrae, further limiting OAR doses.
Keywords: CSI, Monte Carlo, PBS-IMPT
Efficacy of arc-based radiation in children and young adults with medulloblastoma
Shija Merrin Mathew, Uday Krishna, Varathraj CV, V Lokesh; Kidwai Memorial Institute of Oncology
Objectives: The aim of this study was to compare doses to organs at risk and assess low dose radiation bath by Cranio Spinal Irradiation in Children and Young Adults with Medulloblastoma between different techniques.
Materials and Methods: Thirty patients (median Age: 8 [5–23], M:F = 2:1) with Medulloblastoma, planned for Craniospinal irradiation by arc-based radiotherapy (VMAT-Elekta) also had an alternative radiotherapy plan (IMRT/3DCRT) to compare radiation doses to critical OARs (Cochlea, Thyroid, Heart) and low dose radiation bath to Vertebral Body and supratentorial normal brain. Mean doses of organs in parallel, maximum doses of organs in series, and integral dose were compared. Preradiation vertebral body CT density (HU) and the absorbed dose to it at various levels were estimated for each patient on the TPS. With the PTV coverage being 95% to the volume, dosimetrically superior plan was chosen for therapy.
Results: The cohort had a risk stratum in the ratio 4:1 (standard:high). IHC-based molecular subtyping showed WNT, SHH and non-WNT/non-SHH subtype (3:1:2). For ease of analysis, the sample was divided among age groups into <8 years, 8–12 years, and >12 years. Among the various age groups, children < 8 years received the lowest dose of 21 Gy to thyroid via arc therapy ([25 Gy ± 4 Gy] vs. [31 Gy ± 3 Gy]). Children at 8–12 years received the lowest mean dose of 35 Gy with Arc plan to B/L Cochlea ([36 Gy ± 4 Gy] vs. 41 Gy ± 4 Gy]). Significant reduction of mean dose to the heart was noted in >12 years with arc ([8 Gy ± 1 Gy] vs. [10 Gy ± 2 Gy]). The mean CT density by HU of vertebral body (Thoraco-Lumbar) estimated was 145 HU, 195 HU, and 315 HU in three age groups. Mean doses to the vertebrae were significantly lower with VMAT in kids < 8 years ([3211 cGy ± 80 cGy] vs. [3397 cGy ± 70cGy]). Supratentorial brain (basi frontal) received an additional (373.9 cGy ± 0.2 Gy) vs. (425 cGy ± 0.3 Gy) during PF boost.
Conclusions: Arc therapy in medulloblastoma reduces in field normal tissue radiation dose (thyroid, cochlea, and heart) at respective ages of <8 years, 8–12 years, and > 12 years as well as the low-dose radiation bath to structures (vertebral body and supratentorial brain) beyond the target volume which may reduce long term complications in children and young adults.
Creating predictive markers for high-grade gliomas using deep learning on FLAIR images
Sumeet Shinde, Abhilasha Indoria, Jitender Saini, Manish Beniwal, Vani Santosh, Madhura Ingalhalikar; Symbiosis Center for Medical Image Analysis
Objectives: Based on 2016 World Health Organization (WHO) classification, gliomas are subcategorized based not only on the histopathologic appearance but also on well-established molecular parameters such as the presence of IDH mutation and 1p19q codeletion. These observations have been highlighted in the recent cIMPACT consortium recommendations. Additional biological markers are being identified to predict the biological behavior of these tumors. However, currently both grading molecular characteristics like IDH mutations are being used for classification of Gliomas. Despite these developments, earlier Glioma studies using quantitative MRI-based analysis such as radiomics or convolutional neural nets (CNNs) have focused only on a single aspect––either grade or IDH mutation. In this work, we propose a CNN-based model to classify the grade as well as IDH status for efficient delineation into WHO-based categories.
Materials and Methods: We combined a local dataset of 58 scans with 120 scans from The Cancer Genome Atlas (TCGA) dataset. This included 71 G3 scans (56 IDH-mutant, 15 IDH-wildtype) and 107 G4 scans (12 mutant, 95 wildtype). Our dataset included 24 adult patients (age = 48.8 ± 15.76 years, M: F = 11:13) with grade-4 gliomas and 34 adult patients (age 38.87 ± 10.98, M:F 21:13) with grade-3 gliomas (confirmed via histology). We restricted our analysis to fluid attenuation inversion recovery imaging (FLAIR: TR/TE/T1= 11000/125/2800 ms within the plane resolution of 0.5 mm × 0.5 mm). VGG-16 architecture was trained on boxed regions around tumors on 2D FLAIR images to distinguish between four classes namely G3-mutant, G3-wildtype, G4-mutant, and G4-wildtype. To increase the robustness of the model, image augmentation methods were used. Furthermore, to gain insights into the most discriminative regions in the tumor slices, we plot activation maps using HR-CAMs.
Results: VGG-16 model performed with a normalized accuracy of 93.54% and balanced class accuracy of 91.06%. The classifier was able to differentiate between the four classes with average precision score of 0.941 and average recall score of 0.910 across all classes. Area under ROC was calculated with the one vs. rest approach and was found to be 0.993 for the test dataset.
Conclusion: Our study focuses on the classification of high-grade gliomas based on the grade as well as their IDH status using an end-to-end deep learning model. CAMs provide significant insights about the areas on which the classification model focuses while giving its prediction probability for every class. This framework can potentially support preoperative clinical prognosis aiding in treatment planning.
Toxicity outcomes of hypofractionated image-guided pencil beam scanning proton beam therapy for spinal chordomas
Nagarjuna Burela, Srinivas Chilikuri, Adithyan R, Sapna Nangia, Utpal Gaikwad, Sham Sundar, Rishan Thimma, Dayananda Sharma S, Abubacker Sulaiman, Rakesh Jalali; Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India
Objective: The aim of this study was to evaluate acute and late toxicities in patients of chordoma treated with hypofractionated, image-guided pencil beam scanning proton beam therapy.
Materials and Methods: Consecutive patients diagnosed with spinal chordomas treated at our center with hypofractionated pencil beam scanning proton beam therapy (part of a prospective SCCORE-Sarcoma, Chordoma, Chondrosarcoma registry) were included in this study. Among all patients, high-risk CTV(CTV-HR) was treated to a dose of 70.4CGE/32fractions and intermediate-risk CTV(CTV-IR) was treated to a dose of 57.6-64CGE/32fractions. Patients underwent clinical, radiological (including metabolic-DCE MRI imaging), and QOL (EORTC QOL QC-30) evaluations at baseline and 6 monthly thereafter. Acute and late toxicities were recorded at each clinical visit as per CTCAE V4.0 and LENT SOMA scales, respectively. Clinical and radiological outcomes are being reported in this study.
Results: Consecutive 23 patients with a median age of 38 years (range 4–64 years) with histologically proven chordoma (20 classical chordomas, 1 chondroid chordomas, and 2 de-differentiated chordomas were analyzed. Among patients with skull base and dorsal chordomas (15 patients) all patients underwent surgery at least once, 21% underwent surgery twice, 14% underwent thrice and 7% underwent more than 3 times. Among patients with sacral chordomas (8 patients), 63% underwent surgery at least once and 50% underwent more than once. 17% of patients (2clival and 2sacral) underwent prior radiation with photons (IMRT technique) with 13% receiving more than once. Mean volumes of CTV HR and for skull base chordomas were 32.4cc(0.83-132cc) and for sacral chordomas was 855cc (96.1–1740cc). Two patients had acute grade 3 dermatitis, 1 patient had acute grade 3 oropharyngeal mucositis and 1 patient had acute grade 3 gastrointestinal mucositis. Approximately 28.5% of patients with Clival and 50% of patients with Sacral lesions had grade 2 acute toxicities. 1 patient had late grade 3 toxicity requiring tracheostomy. None of the patients had any late grade 2/3 gastrointestinal or genitourinary toxicities. With a median follow-up of 17 months (9–23 months), 21 patients (91%) remained radiologically stable with favorable metabolic response in all the 10 patients (43%) where metabolic imaging was available. Only one patient had in-field radiological progression and one patient had distant bone metastases.
Conclusion: Moderately hypofractionated pencil beam scanning proton beam therapy is feasible in patients with spinal chordomas in the context of daily image guidance. Despite high doses, large treatment volumes and a large number of patients receiving prior treatments, the acute and late toxicities were relatively low in this cohort.
Treatment outcome of glomus jugulare tumors with stereotactic radiotherapy and radiosurgery: A single-institute experience
Ezhil Sindhanai M Parvath, Selvamani B, Rajesh B, Rajkrishna B, Patricia S; Christian Medical College, Vellore, Tamil Nadu, India
Objectives: The aim of this study was to assess the safety, response, and patterns of failure of glomus jugular tumors after stereotactic radiation.
Materials and Methods: We analyzed 44 patients with glomus jugular paraganglioma treated with HFSRT (hypofractionated stereotactic radiotherapy––12 patients), SRT (stereotactic radiotherapy––8 patients), SRS (stereotactic radiosurgery––24 patients) at our institution between June 2008 and December 2019. Data were collected retrospectively from electronic medical records and treatment planning systems.
Results: Median age at presentation was 49.5 years (range: 19–77 years). The most common symptoms at initial diagnosis were hearing loss (n = 35, 79%), pulsatile tinnitus (n = 25, 56%), dysphonia (n = 18, 40%), and 17 (38%) had additional cranial nerve deficits. The total dose range for HFSRT was 25–36 Gy in 5–12 fractions; for SRT total dose of 54 Gy in 27–30 fractions and for SRS 11–16 Gy to 80%isodose. The median target volume was 18.63 cm3 for HFSRT, 13.44 cm3 for SRT, and 5.38 cm3 for SRS (range, 0.53–45.26 cm3). None had acute adverse events greater than RTOG Grade 1.
Seven patients were lost to follow-up and we had data of 37 patients for whom we analyzed the disease response and survival. The median follow-up was 13.5 months (range: 3–84 months). Clinical symptoms improved in 24 patients and stabilized in 13 patients. Follow-up imaging with MRI showed partial response in 5 patients, stable disease in 25 patients, disease progression in 2 patients and 5 had only clinical review without imaging. Progression was noted in 2 patients treated with SRS at 6 months and at 204 months following RT. One patient developed new-onset neurological deficit, 12th nerve paresis after SRT at 15 months which was managed conservatively and remained stable on follow-up.
Conclusion: Stereotactic radiosurgery and fractionated stereotactic radiotherapy are effective and well-tolerated noninvasive treatment for paraganglioma, with excellent tumor control rates and a low risk of morbidity.
MR tractography and intraoperative direct electrical stimulation in eloquent area glioma surgery
Sushant Kumar Sahoo; Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Objective: Surgical resection of eloquent area glioma is challenging owing to the adjacent white fiber tracts. Injury to these fibers may result in additional neurological deficits. Visualization of these tracts in the preoperative period and intra-operative assessment is essential. Here we have analyzed patients of eloquent region gliomas operated at our institute in the last 3 years. The impact of MR tactography, awake surgery, direct electrical stimulation on extent of resection and functional outcome was further studied.
Materials and Methods: Patients of eloquent area glioma operated between January 2018 and February 2021 were included in this study. The preoperative clinic- radiological findings were recorded. Contrast MRI with tractography was processed in the preoperative period. Intraoperatively awake mapping and ultrasound were used. In the postop period any focal neurological deficit was documented. Postcontrast MRI was obtained at 3 months follow-up to assess the extent of resection.
Results: Total 46 patients (22 insular, 13 peri-rolandic area, 4 thalamic, and 7 inferior parietal lobule gliomas) were included in this study. The commonest clinical feature was a seizure, headache followed by hemiparesis, and speech disturbances.
MRI showed contrast-enhancing lesion in 21 and nonenhancing lesion in 25 patients. White fiber tracts were displaced in all. The corticospinal tract was pushed medially and superiorly in all cases of insular and 3 cases of peri rolandic area glioma. In one case of posterior frontal glioma, it was poorly visible. In 8 cases of left insular glioma and 10 cases of right insular glioma, the inferior fronto occipital fibers (IFOF) was defined. In four cases of right insular glioma, the IFOF could not be processed. Out of these 18 cases where IFOF was visualized, it was pushed superiorly in 14 and inferiorly in 4 cases.
Language mapping was possible in all cases of insular glioma. Eight patients developed dysarthria and six had hemiparesis during surgery. All except three patients improved at 6 weeks. In 18 cases although IOUS showed residual tumor subtotal resection was planned due to adjacent white fiber stimulation. Postop radiology showed complete resection in 34 and subtotal resection in 12 cases.
Conclusion: White fiber tracts are mostly displaced in eloquent area gliomas. Fiber tracking with direct electrical stimulation allows maximal tumor resection with minimal neurological deficit.
Prognsotic impact of semantic MRI features on survival outcomes in medulloblastoma: Does it reflect or transcend radiogenomic correlation?
Babusha Kalra, Archya Dasgupta, Madan Maitre, Abhishek Chatterjee, Rahul Krishnatry, Goda Jayant Sastri, Neelam Shirsat, Sridhar Epari, Ayusi Sahay, Amit Janu, Sona Pungavkar, Girish Chinnaswamy, Aliasgar Moiyadi, Prakash Shetty, Rakesh Jalali, Tejpal Gupta; Tata Memorial Hospital
Background: Imaging features are known to reflect inherent disease biology in various solid cancers including brain tumors. We have previously reported the radiogenomic correlation of semantic MRI features with molecular subgrouping in medulloblastoma. Herein we report prognostic impact of these semantic MRI features on survival in an extended cohort of 171 medulloblastoma patients treated with appropriate risk-stratified adjuvant therapy between 2007 till 2018 at our institute.
Materials and Methods: Sixteen predefined semantic MRI features derived from pre- and postcontrast T1W, T2W, and diffusion-weighted imaging were analyzed. Descriptive analysis of patient and disease characteristics was done. Univariate analysis (UVA) and multivariate analysis (MVA) were performed to assess the correlation of semantic MRI features with relapse-free survival (RFS) and overall survival (OS).
Results: The study cohort comprised of 131 pediatric and 40 adult patients with predilection of male gender (3.6:1 ratio). Fifty-five percent of patients had high-risk disease by traditional risk-stratification criteria including metastatic disease at initial diagnosis in 32.1%. The most common histological subtype was classic (49.7%), followed by desmoplastic (23.4%) and large cell/anaplastic (11.7%). The distribution of molecular subgrouping into WNT, SHH, Group 3, and Group 4 was 19.8%, 35.1%, 20.5%, and 24.6%, respectively. At a median follow-up of 45 months (interquartile range 1–137 months), 55 patients had recurrent/progressive disease most commonly neuraxial metastases resulting in 44 deaths including one treatment-related death yielding 5-year RFS and OS of 64% and 72%, respectively. Semantic MRI features such as vertical location, brainstem involvement, contrast-uptake area, contrast heterogeneity, necrosis, calcification, and T2-homogeneity significantly influenced survival on UVA. Vertical location, brainstem involvement, and calcification correlated significantly with RFS and OS on MVA. Distinctive MRI features correlated with outcomes even within individual molecular subgroups of medulloblastoma, for example, vertical-location in SHH, contrast-uptake area and calcification in Group 3 tumors, and contrast-enhancement pattern and T2-homogeneity in Group 4 medulloblastoma.
Conclusion: Distinctive semantic MRI features significantly influence survival outcomes in medulloblastoma including within individual molecular subgroups reflecting their prognostic impact that transcends radiogenomic correlation.
Somatic USP8, USP48, and BRAF mutations in patients with Cushing�s disease and their genotype-phenotype correlation
Ananth P Abraham, Rekha Pai, Geeta Chacko, H S Asha, Simon Rajaratnam, Nitin Kapoor, Nihal Thomas, Ari G Chacko; Christian Medical College, Vellore, Tamil Nadu, India
Objectives: The aim of this work was to study the prevalence of USP8, USP48, and BRAF mutations in patients with Cushing’s disease (CD) and describe their genotype-phenotype correlation.
Materials and Methods: We prospectively recruited 46 patients with CD who underwent surgery between September 2015 and July 2019 at our institute. Fresh frozen tumor tissue was obtained in all patients. Using Sanger sequencing, the presence of somatic USP8 mutations was documented and the frequency of USP48 and BRAF mutations in USP8 wild-type corticotroph adenomas was determined. Clinical, hormonal, and surgical data were then compared between USP8-, USP48- and BRAF-variant carriers and patients with wild-type tumors.
Results: Signature USP8 mutations were detected in 17 (37%) patients. Of the 29 USP8¬ wild-type adenomas, 4 (13.8%) harbored USP48 mutations, one of them being a splice-site mutation that has previously not been described. BRAF mutations were not found in any of the 29 patients. Corticotroph adenomas with USP8 mutations had a higher incidence of Crooke’s hyaline change than wild-type tumors (70.6% vs. 37.9%, P = 0.032). Adenomas with USP48 mutations had a higher rate of cavernous sinus invasion than their wild-type counterparts (50% vs. 4%, P = 0.042). No other significant phenotypic difference could be established between mutant and wild-type tumors.
Conclusions: The prevalence of USP8 mutations in our series of patients with CD was 37%. The prevalence of USP48 mutations in USP8 wild-type adenomas was 13.8%, including a novel splice-site mutation. BRAF mutations were not found in any USP8 wild-type tumor. USP8-mutants showed significantly more Crooke’s hyaline change in the adjacent adenohypophysis and USP48-mutants were more likely to demonstrate cavernous sinus invasion.