Search

Objective: This study investigated the effect of various histotripsy dosages on tumor cell kill and associated bleeding in two murine brain tumor models (glioma [Gl261] and lung metastasis [LL/2-Luc2])., Methods and Materials: GL261 or LL/2-Luc2 cells were cultured and implanted into the brains of C57BL/6 mice. Histotripsy (1-cycle pulses, 5 Hz PRF, 30 MPa-P) was performed using a 1 MHz transducer for five different dosages for each cell line: 5, 20 or 200 pulses per location (PPL) at a single treatment point, or 5 or 10-20 PPL at multiple treatment points. MRI, bioluminescence imaging and histology were used to assess tumor ablation and treatment effects within 4-6 h post-treatment., Results: All treatment groups resulted in a reduction of BLI intensity for the LL/2-Luc2 tumors, with significant signal reductions for the multi-point groups. The average pre-/post-treatment BLI flux (photons/s, ×10 8 ) for the different treatment groups were: 4.39/2.19 (5 PPL single-point), 5.49/1.80 (20 PPL single-point), 3.86/1.73 (200 PPL single-point), 2.44/1.11 (5 PPL multi-point) and 5.85/0.80 (10 PPL multi-point). MRI and H&E staining showed increased tumor damage and hemorrhagic effects with increasing histotripsy dose for both GL261 and LL/2-Luc2 tumors, but the increase in tumor damage was diminished beyond 10-20 PPL for single-point treatments and outweighed by increased hemorrhage. In general, hemorrhage was confined to be within 1 mm of the treatment boundary for all groups., Conclusions: Our results suggest that a lower number of histotripsy pulses at fewer focal locations can achieve substantial tumor kill while minimizing hemorrhage.

Accurate intraoperative diagnosis is essential for providing safe and effective care during brain tumor surgery. Our standard-of-care diagnostic methods are time, resource, and labor intensive, which restricts access to optimal surgical treatments. To address these limitations, we propose an alternative workflow that combines stimulated Raman histology (SRH), a rapid optical imaging method, with deep learning-based automated interpretation of SRH images for intraoperative brain tumor diagnosis and real-time surgical decision support. Here, we present OpenSRH , the first public dataset of clinical SRH images from 300+ brain tumors patients and 1300+ unique whole slide optical images. OpenSRH contains data from the most common brain tumors diagnoses, full pathologic annotations, whole slide tumor segmentations, raw and processed optical imaging data for end-to-end model development and validation. We provide a framework for patch-based whole slide SRH classification and inference using weak (i.e. patient-level) diagnostic labels. Finally, we benchmark two computer vision tasks: multiclass histologic brain tumor classification and patch-based contrastive representation learning. We hope OpenSRH will facilitate the clinical translation of rapid optical imaging and real-time ML-based surgical decision support in order to improve the access, safety, and efficacy of cancer surgery in the era of precision medicine. Dataset access, code, and benchmarks are available at https://opensrh.mlins.org., Competing Interests: Competing interests: C.W.F. is an employee and shareholder of Invenio Imaging, Inc., a company developing SRH microscopy systems. D.A.O. is an advisor and shareholder of Invenio Imaging, Inc, and T.C.H. is a shareholder of Invenio Imaging, Inc.

The World Health Organization (WHO) published the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5) in 2021, as an update of the WHO central nervous system (CNS) classification system published in 2016. WHO CNS5 was drafted on the basis of recommendations from the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) and expounds the classification scheme of the previous edition, which emphasized the importance of genetic and molecular changes in the characteristics of CNS tumors. Multiple newly recognized tumor types, including those for which there is limited knowledge regarding neuroimaging features, are detailed in WHO CNS5. The authors describe the major changes introduced in WHO CNS5, including revisions to tumor nomenclature. For example, WHO grade IV tumors in the fourth edition are equivalent to CNS WHO grade 4 tumors in the fifth edition, and diffuse midline glioma, H3 K27M -mutant, is equivalent to midline glioma, H3 K27 -altered. With regard to tumor typing, isocitrate dehydrogenase (IDH)-mutant glioblastoma has been modified to IDH -mutant astrocytoma. In tumor grading, IDH -mutant astrocytomas are now graded according to the presence or absence of homozygous CDKN2A/B deletion. Moreover, the molecular mechanisms of tumorigenesis, as well as the clinical characteristics and imaging features of the tumor types newly recognized in WHO CNS5, are summarized. Given that WHO CNS5 has become the foundation for daily practice, radiologists need to be familiar with this new edition of the WHO CNS tumor classification system. Online supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article. © RSNA, 2022.

In this inaugural clinicopathological conference, the invited experts discussed the diagnostic approach to central nervous system infections in immunocompromised hosts. The case presented involved a pancreas-kidney transplant recipient with multiple brain abscesses caused by Bartonella henselae. CSF metagenomic next-generation sequencing played a significant role in the diagnosis. Bartonella henselae is a gram-negative zoonotic pathogen that causes cat-scratch disease, which can be transmitted to humans through cat bites or scratches. Symptoms can vary in severity, correlating with the patient's immune status. Visceral organ involvement, ocular involvement, and neurological manifestations have been reported in immunocompromised patients, but brain abscesses are rare., (© 2022 Wiley Periodicals LLC.)

Background: Accurate specimen analysis of skull base tumors is essential for providing personalized surgical treatment strategies. Intraoperative specimen interpretation can be challenging because of the wide range of skull base pathologies and lack of intraoperative pathology resources., Objective: To develop an independent and parallel intraoperative workflow that can provide rapid and accurate skull base tumor specimen analysis using label-free optical imaging and artificial intelligence., Methods: We used a fiber laser-based, label-free, nonconsumptive, high-resolution microscopy method (<60 seconds per 1 × 1 mm2), called stimulated Raman histology (SRH), to image a consecutive, multicenter cohort of patients with skull base tumor. SRH images were then used to train a convolutional neural network model using 3 representation learning strategies: cross-entropy, self-supervised contrastive learning, and supervised contrastive learning. Our trained convolutional neural network models were tested on a held-out, multicenter SRH data set., Results: SRH was able to image the diagnostic features of both benign and malignant skull base tumors. Of the 3 representation learning strategies, supervised contrastive learning most effectively learned the distinctive and diagnostic SRH image features for each of the skull base tumor types. In our multicenter testing set, cross-entropy achieved an overall diagnostic accuracy of 91.5%, self-supervised contrastive learning 83.9%, and supervised contrastive learning 96.6%. Our trained model was able to segment tumor-normal margins and detect regions of microscopic tumor infiltration in meningioma SRH images., Conclusion: SRH with trained artificial intelligence models can provide rapid and accurate intraoperative analysis of skull base tumor specimens to inform surgical decision-making., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Histotripsy has been previously applied to target various cranial locations in vitro through an excised human skull. Recently, a transcranial magnetic resonance (MR)-guided histotripsy (tcMRgHt) system was developed, enabling pre-clinical investigations of tcMRgHt for brain surgery. To determine the feasibility of in vivo transcranial histotripsy, tcMRgHt treatment was delivered to eight pigs using a 700-kHz, 128-element, MR-compatible phased-array transducer inside a 3-T magnetic resonance imaging (MRI) scanner. After craniotomy to open an acoustic window to the brain, histotripsy was applied through an excised human calvarium to target the inside of the pig brain based on pre-treatment MRI and fiducial markers. MR images were acquired pre-treatment, immediately post-treatment and 2-4 h post-treatment to evaluate the acute treatment outcome. Successful histotripsy ablation was observed in all pigs. The MR-evident lesions were well confined within the targeted volume, without evidence of excessive brain edema or hemorrhage outside of the target zone. Histology revealed tissue homogenization in the ablation zones with a sharp demarcation between destroyed and unaffected tissue, which correlated well with the radiographic treatment zones on MRI. These results are the first to support the in vivo feasibility of tcMRgHt in the pig brain, enabling further investigation of the use of tcMRgHt for brain surgery., Competing Interests: Conflict of interest disclosure Z.X. and T.H. have financial and/or other relationships with HistoSonics Inc. The University of Michigan has a financial interest in Histosonics Inc., (Copyright © 2021. Published by Elsevier Inc.)

Background: Neuro-oncology has grown tremendously since 2010, marked by increasing society membership, specialized clinical expertise, and new journals. Yet, modest improvement in racial/ethnic diversity amongst clinical trial participants, researchers, and clinicians led us to conduct a survey to identify opportunities to enhance diversity and inclusiveness amongst neuro-oncology professionals., Methods: In summer 2020, the Women and Diversity Committee of the Society for Neuro-Oncology (SNO) distributed an anonymous online survey to members and affiliates including the European Association of Neuro-Oncology (EANO), Asian Society for Neuro-Oncology (ASNO), Society for Neuro-Oncology Latin America (SNOLA) and Society for Neuro-Oncology Sub-Saharan Africa (SNOSSA). The survey captured personal and professional characteristics, biases, effective mentorship qualities, career service metrics, and suggested field/society changes. Results were analyzed by geography, profession, age, racial/ethnic, and sexual identity. Standard descriptive statistics characterized the study population., Results: The 386 respondents were predominantly female (58%) with a median age range of 40-49 years (31%), White (65%), and SNO members (97%). Most worked in North America (77%) in a research profession (67%). A majority of White respondents reported never experiencing biases (64%), while the majority of non-White respondents reported unconscious biases/microaggressions, followed by a lack of/limited mentorship. Qualitative assessments showcased that personal/professional success metrics were linked to needed improvements in diversity and inclusion efforts within the neuro-oncology field., Conclusions: The prevalence of racial/ethnic biases and poor mentorship rates amongst underrepresented groups in neuro-oncology is high and potentially linked to the limited diverse representation amongst members and affiliates. These findings warrant a swift implementation of equity and inclusion practices within the neuro-oncology field., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2021.)

Background: Allergic fungal rhinosinusitis (AFRS) is a common condition in which sinusitis develops as an IgE-mediated response to common sinonasal fungal organisms. If that response leads to blockage of sinus ostia, bone expansion and erosion by expansive cysts containing dense inspissated debris may occur with the potential for critical neurovascular compression including damage to the anterior visual pathway., Methods: Review of clinical and imaging features of 2 patients who sustained catastrophic clinical outcomes., Results: The first patient had pansinusitis with massive mucocele-like cysts expanding the sphenoid sinus and cranial base and causing compression of the anterior visual pathway that led to persistent severe vision loss despite extensive sinus surgery. The second patient developed sphenoethmoidal expansion with a marked inflammatory response and presumed conversion to invasive fungal sinusitis that caused anterior visual pathway vision loss, bilateral ocular motor palsies from extension into the cavernous sinuses, and death from a large middle cerebral artery stroke., Conclusions: Although AFRS is most often benign and treatable, it may rarely produce catastrophic outcomes, especially if the sphenoid sinus is involved. Irreversible vision loss may occur from compression, and ocular motor palsies and death from conversion to invasive fungal disease. Close ophthalmologic and imaging monitoring is necessary in patients with expanded sinuses, and prophylactic sinus surgery may be indicated in certain cases.

Undiagnosed significant hydrocephalus is an uncommon finding at forensic autopsy as many cases present in life with complex neurological symptoms. We present a case of a 46-year-old man with no neurological deficits or history of head trauma that was incidentally found to have a massive hydrocephalus at autopsy. This was found to be associated with an unruptured arteriovenous malformation completely confined to the choroid plexus as well as complete agenesis of the corpus callosum. The arteriovenous malformation was found to form a calcified obstruction at the foramen of Monro analogous to a mass lesion, such as a colloid cyst of the third ventricle. The association of this malformation and agenesis of the corpus callosum has never been described. Histologic examination of the brain confirmed significant loss of white matter tracts and thinning of the cortical ribbon due to pressure atrophy of the ependymal lining without significant gliosis, cortical dysplasia, or evidence of other developmental malformations. Autopsy is a vital tool in the evaluation of such rare cases, enhances epidemiologic data, and increases the understanding of these pathophysiological associations.

Histiocytosis syndromes (HS) are group of heterogeneous disorders characterized by abnormal accumulation and infiltration of histiocytes, cells derived from hematopoietic cells of monocyte/macrophage lineage. Overall these disorders are rare. When they do occur they involve many organ systems including the central nervous system (CNS). While imaging findings can provide important clues, diagnosis of this disorder is challenging and definitive diagnosis often necessitates pathologic examination. In this review, we describe imaging features of HS involving the CNS, with the aim to increase our understanding of these disorders. The entities discussed in this review will include: Langerhans cell histiocytosis (LCH), Rosai-Dorfman Disease (RDD), Erdheim Chester Disease (ECD), hemophagocytic lymphohistiocytosis (HLH), and crystal-storing histiocytosis (CSH)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We present a case of a 22-year-old man who died unexpectedly after a seizure due to a previously undiagnosed calcifying pseudoneoplasm of the neuraxis (CAPNON). Calcifying pseudoneoplasm of the neuraxis is a rare entity, and this is, to our knowledge, the first described case of sudden death due to CAPNON. Sudden death due to undiagnosed central nervous system mass lesions is rare, and most cases are attributable to hemorrhage, hydrocephalus, or increased intracranial pressure due to mass effect. Seizure is a rare cause of sudden death due to central nervous system mass lesions. This case highlights that mass lesions may cause sudden death due to seizure, even without other pathologic evidence of a cause of death, such as hemorrhage or edema. Furthermore, benign, reactive, and low-grade mass lesions may cause sudden death due to seizure. Seizure should remain in the autopsy differential as a cause of death, even where there is no pathologically evident mechanism by which a mass lesion caused death.

Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery 1 . The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive 2,3 . Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce 4 . In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH) 5-7 , a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min) 2 . In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.

Background: Chromosomal instability is associated with earlier progression in isocitrate dehydrogenase (IDH)-mutated astrocytomas. Here we evaluated the prognostic significance of polysomy in gliomas tested for 1p/19q status., Methods: We analyzed 412 histologic oligodendroglial tumors with use of 1p/19q testing at 8 institutions from 1996 to 2013; fluorescence in situ hybridization (FISH) for 1p/19q was performed. Polysomy was defined as more than two 1q and 19p signals in cells. Tumors were divided into groups on the basis of their 1p/19q status and polysomy and were compared for progression-free survival (PFS) and overall survival (OS)., Results: In our cohort, 333 tumors (81%) had 1p/19q loss; of these, 195 (59%) had concurrent polysomy and 138 (41%) lacked polysomy, 79 (19%) had 1p/19q maintenance; of these, 30 (38%) had concurrent polysomy and 49 (62%) lacked polysomy. In agreement with prior studies, the group with 1p/19q loss had significantly better PFS and OS than did the group with 1p/19q maintenance (P < 0.0001 each). Patients with 1p/19q loss and polysomy showed significantly shorter PFS survival than patients with 1p/19q codeletion only (P < 0.0001), but longer PFS and OS than patients with 1p/19q maintenance (P < 0.01 and P < 0.0001). There was no difference in survival between tumors with >30% polysomic cells and those with <30% polysomic cells. Polysomy had no prognostic significance on PFS or OS in patients with 1p/19q maintenance., Conclusions: The presence of polysomy in oligodendroglial tumors with codeletion of 1p/19q predicts early recurrence and short survival in patients with 1p/19q codeleted tumors., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Familial adenomatous polyposis (FAP) is a cancer predisposition syndrome driven by germline loss-of-function of the APC gene and phenotypically manifests with intestinal polyposis and a variety of extra-intestinal bone and soft tissue tumors. Craniopharyngioma is not a well-described FAP-associated tumor, however, six cases have been reported in adults, all demonstrating ectopic location and adamantinomatous histology. We report the first case of craniopharyngioma associated with FAP in a pediatric patient. A seven-year-old girl who presented with headache and vomiting was found on magnetic resonance imaging to have a suprasellar mass with cystic extension to the pre-pontine space. The tumor represented an adamantinomatous craniopharyngioma (aCP) with nuclear β-catenin expression. Whole exome sequencing confirmed a CTNNB1 activating point mutation and a germline APC frameshift variant. This case represents the first FAP-associated craniopharyngioma in childhood…. expanding our understanding of the molecular underpinnings driving tumorigenesis in this unique patient.

Objective: Histotripsy is an ultrasound-based treatment modality relying on the generation of targeted cavitation bubble clouds, which mechanically fractionate tissue. The purpose of the current study was to investigate the in vivo feasibility, including dosage requirements and safety, of generating well-confined destructive lesions within the porcine brain utilizing histotripsy technology., Methods: Following a craniectomy to open an acoustic window to the brain, histotripsy pulses were delivered to generate lesions in the porcine cortex. Large lesions with a major dimension of up to 1 cm were generated to demonstrate the efficacy of histotripsy lesioning in the brain. Gyrus-confined lesions were generated at different applied dosages and under ultrasound imaging guidance to ensure that they were accurately targeted and contained within individual gyri. Clinical evaluation as well as MRI and histological outcomes were assessed in the acute (≤ 6 hours) and subacute (≤ 72 hours) phases of recovery., Results: Histotripsy was able to generate lesions with a major dimension of up to 1 cm in the cortex. Histotripsy lesions were seen to be well demarcated with sharp boundaries between treated and untreated tissues, with histological evidence of injuries extending ≤ 200 µm from their boundaries in all cases. In animals with lesions confined to the gyrus, no major hemorrhage or other complications resulting from treatment were observed. At 72 hours, MRI revealed minimal to no edema and no radiographic evidence of inflammatory changes in the perilesional area. Histological evaluation revealed the histotripsy lesions to be similar to subacute infarcts., Conclusions: Histotripsy can be used to generate sharply defined lesions of arbitrary shapes and sizes in the swine cortex. Lesions confined to within the gyri did not lead to significant hemorrhage or edema responses at the treatment site in the acute or subacute time intervals.

Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant tumor that is commonly associated with biallelic alterations of SMARCB1. Recurrent or refractory AT/RT has not been molecularly characterized as well. We present the case of a child with recurrent AT/RT who underwent clinically integrated molecular profiling (germline DNA and tumor DNA/RNA sequencing). This demonstrated a somatic lesion in CDKN1C alongside hallmark loss of SMARCB1. This data allowed us to explore potential personalized therapies for this patient and expose a molecular driver that may be involved in similar cases.

Targeted chemotherapeutics provide a promising new treatment option in neuro-oncology. The ability of these compounds to penetrate the blood-brain barrier is crucial for their successful incorporation into patient care. "CNS Targeted Agent Prediction" (CNS-TAP) is a multi-institutional and multidisciplinary translational program established at the University of Michigan for evaluating the central nervous system (CNS) activity of targeted therapies in neuro-oncology. In this report, we present the methodology of CNS-TAP in a series of pediatric and adolescent patients with high-risk brain tumors, for which molecular profiling (academic and commercial) was sought and targeted agents were incorporated. Four of five of the patients had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). We further describe the specific drug properties of each agent chosen and discuss characteristics relevant in their evaluation for therapeutic suitability. Finally, we summarize both tumor and drug characteristics that impact the ability to successfully incorporate targeted therapies into CNS malignancy management., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cerebral air embolism is a recognized life-threatening complication, sometimes iatrogenic. Its timely diagnosis is essential because it can result in neurologic deficits or death. We report a case of a 58-year-old man who died from cerebral air embolism diagnosed by nonenhanced computed tomography scan of the head after a cardiac bypass surgery with Biventricular Assist Device and multiple vascular line placements. Autopsy revealed extensive subcutaneous emphysema, intravascular and perivascular air bubbles in the central nervous system and associated cerebral and cerebellar hemorrhagic infarction. The autopsy was helpful in documenting the extent of the air embolism and its appearance in soft tissue and central nervous system.

Purpose: To evaluate the tolerability and efficacy of gemcitabine plus radiation therapy (RT) in this phase 1 study of patients with newly diagnosed malignant glioma (HGG)., Patients and Methods: Between 2004 and 2012, 29 adults with HGG were enrolled. After any extent of resection, RT (60 Gy over 6 weeks) was given concurrent with escalating doses of weekly gemcitabine. Using a time-to-event continual reassessment method, 5 dose levels were evaluated starting at 500 mg/m(2) during the last 2 weeks of RT and advanced stepwise into earlier weeks. The primary objective was to determine the recommended phase 2 dose of gemcitabine plus RT. Secondary objectives included progression-free survival, overall survival (OS), and long-term toxicity., Results: Median follow-up was 38.1 months (range, 8.9-117.5 months); 24 patients were evaluable for toxicity. After 2005 when standard practice changed, patients with World Health Organization grade 4 tumors were no longer enrolled. Median progression-free survival for 22 patients with grade 3 tumors was 26.0 months (95% confidence interval [CI] 15.6-inestimable), and OS was 48.5 months (95% CI 26.8-inestimable). In 4 IDH mutated, 1p/19q codeleted patients, no failures occurred, with all but 1 alive at time of last follow-up. Seven with IDH mutated, non-codeleted tumors with ATRX loss had intermediate OS of 73.5 months (95% CI 32.8-inestimable). Six nonmutated, non-codeleted patients had a median OS of 26.5 months (95% CI 25.4-inestimable). The recommended phase 2 dose of gemcitabine plus RT was 750 mg/m(2)/wk given the last 4 weeks of RT. Dose reductions were most commonly due to grade 3 neutropenia; no grade 4 or 5 toxicities were seen., Conclusions: Gemcitabine concurrent with RT is well-tolerated and yields promising outcomes, including in patients with adverse molecular features. It is a candidate for further study, particularly for poor-prognosis patient subgroups with HGG., (Published by Elsevier Inc.)

Background: The diagnosis of ectopic pituitary hormone secretion requires abnormally high circulating hormone levels, absence of a pituitary tumor, and localization of the hormone in question to the extrapituitary malignant neoplasm. No case of a malignant solid tumor producing prolactin has been documented thus far., Case Report: A 47-year-old woman presented with amenorrhea and galactorrhea of 3-year duration. Serum prolactin ranged from 300 to > 900 ng/mL, and other pituitary and thyroid indices were normal, including testing for macroprolactinemia. Pituitary magnetic resonance imaging revealed a partially empty sella but no tumor. Cabergoline 0.5 mg twice weekly did not affect her prolactinemia (1700 to 1900 ng/mL), and the medication was stopped. In the meantime, she developed abdominal pain, and a computed tomography scan showed a 17 × 13 × 8-cm mass abutting the distal stomach, proximal duodenum, and right colon. After the tumor was excised, her galactorrhea resolved, menstrual periodicity resumed within the first month, and serum prolactin fell to 5 ng/mL. Pathological examination of the excised tumor was consistent with perivascular epithelioid cell tumor. Between 5 and 10% of the tumor cells were strongly positive for prolactin on immunohistochemistry. RT-PCR detected prolactin mRNA in the tumor cell extract, confirming the diagnosis of ectopic prolactin synthesis and secretion., Conclusion: We present the first example of massive and symptomatic hyperprolactinemia due to ectopic prolactin production by a solid extrapituitary mesenchymal tumor confirmed with both mRNA analysis and immunohistochemistry. Ectopic prolactin secretion should be suspected in patients with a prolactin >200 ng/mL and negative sellar MRI.

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.