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pnet-like features of synovial sarcoma of the lung: A pitfall in the cytologic diagnosis of soft-tissue tumors

DIAGNOSTIC CYTOPATHOLOGY 2001年第4期24卷 283-288页

作者： Hummel, P Yang, GCH Kumar, A Cohen, JM Winkler, B Melamed, J Scholes, JV Jagirdar, J NYU Med Ctr Dept Pathol New York NY 10016 USA

Fine-needle aspiration (FNA) cytology of soft-tissue tumors is evolving. As more experience is gained, we are becoming aware of potential pitfalls. We describe 2 cases of synovial sarcoma of the lung, primary and metastatic, in patients who had FNA biopsy performed on a lung mass. The cytologic smears showed extremely cellular groups of malignant small round cells, intersected by small blood vessels, with numerous loose single cells, in a background of macrophages and mature lymphocytes. The tumors displayed monomorphic cells forming rosettes and displaying occasional mitoses. A diagnosis of neuroendocrine tumor/primitive neuroepithelial tumor (pnet) was suspected. Furthermore, this suspicion was supported by immunohistochemical stains, which showed positivity for a neuroendocrine marker, Leu 7 (case 1), and for a neural marker, CD 99 (O 13 or HBA 71) (both cases);and negativity for cytokeratins (case 1). The resection specimen of case 1 had mostly tightly packed small round cells, with occasional rosettes, similar to the FNA biopsy, and focal areas composed of spindle cells, organized in a focal fibrosarcoma-like and hemangiopericytoma-like pattern. A balanced translocation between chromosomes X and 18, demonstrated by both karyotyping and fluorescent in situ hybridization (FISH), enabled us to make a diagnosis of synovial sarcoma, which was histologically classified as poorly differentiated. Case 2 was a metastatic biphasic synovial sarcoma of the arm, with a prominent epithelial component. Synovial sarcoma, when composed mainly of small round cells on cytologic smears, is a great mimicker of neuroendocrine/pnet tumors, with light microscopic and immunohistochemical overlap. Awareness of this potential pitfall may aid in preventing a misdiagnosis. Its recognition is of major concern, especially for the poorly differentiated variant, because it is associated with a worse prognosis. (C) 2001 Wiley-Liss, Inc.

关键词： synovial sarcoma lung fine-needle aspiration biopsy pnet neuroendocrine pitfalls

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Improving the budburst phenology subroutine in the forest carbon model pnet

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ECOLOGICAL MODELLING 2007年第3-4期205卷 515-526页

作者： Chiang, Jyh-Min Brown, Kim J. Ohio Univ Dept Environm & Plant Biol Athens OH 45701 USA

The timing of leaf expansion in spring and leaf senescence in fall determines growing season length;hence leaf phenology is important in modelling carbon production. Previous work monitoring net ecosystem exchange using eddy flux technology found phenological timing to be a key factor determining ecosystem carbon balance. Growing degree days (GDD;the sum of daily mean temperature above 0 degrees C) have long been used to track tree phenological behavior. Ecosystem carbon balance simulations should employ models that reliably track leaf phenological activities. Our goals for this study were to evaluate the GDD-based phenological algorithm for the forest carbon simulation model pnet and to develop a robust budburst model for the implementation of pnet in the forests of Ohio. We obtained 11 years (1990-2000) of leaf budburst phenology data from Harvard Forest, MA and found large interannual variations on the date of budburst. Contrary to the previous sensitivity analysis on GDD, we used the observed range in the data to inform our new GDD sensitivity analyses. In fact the broad inter- annual variation of the budburst phenology had substantial impacts on the annual net primary production. Moreover, GDD did not provide reliable prediction on the date of budburst although it was employed by the pnet family of models. The predictions of budburst dates were largely improved by incorporating a chilling factor, with 16 of 17 deciduous tree species showing significant linear relationships between predicted and observed dates of budburst. However, this updated phenology model showed geographic specificity that is not suitable for our simulations in southern Ohio. For successful development of a more comprehensive phenological model, locally developed and long-term leaf phenology records are required. (c) 2007 Elsevier B.V All rights reserved.

关键词： budburst Acer chilling Liriodendron NPP phenology pnet Quercus

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Metastatic pancreatic neuroendocrine tumors (pnet): Placing current findings into perspective

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CANCER TREATMENT REVIEWS 2013年第1期39卷 3-9页

作者： Phan, Alexandria T. Univ Texas MD Anderson Canc Ctr Dept GI Med Oncol Houston TX 77030 USA

Progress during the past 3 decades in the treatment of advanced neuroendocrine tumors (NET) has been slow, despite a substantial increase in the incidence of NET at all primary sites and stages of disease. In the United States, the annual incidence of pancreatic NET (pnet) was estimated as 0.32 per 100,000 people in 2004. Until recently, there were few available therapies for the treatment of patients with advanced pnet. Nonetheless, substantial strides have been made within the past several years. In 2011, 2 new systemic therapies (everolimus and sunitinib) were approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced pnet, based on recently published results from 2 phase III studies. Additions to the pnet treatment arsenal significantly expanded options for clinicians who treat these patients. However, important differences between the key clinical studies existed, preventing optimal direct comparison of the study results. Therefore, the clinical implications of these study results continue to be debated. The following commentary briefly summarizes the background of NET and provides an overview of available options, highlighting the important findings of the 2 pivotal studies. In this review, the data supporting the use of everolimus and sunitinib in advanced pnet are reviewed, and the incorporation of these targeted therapies into a pnet treatment algorithm is further discussed. (C) 2012 Elsevier Ltd. All rights reserved.

关键词： Pancreatic neuroendocrine tumors pnet Everolimus Sunitinib Chemotherapy

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KIT expression and methylation in medulloblastoma and pnet cell lines and tumors

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JOURNAL OF NEURO-ONCOLOGY 2011年第2期103卷 247-253页

作者： Enguita-German, Monica Gurrea, Mikel Schiapparelli, Paula Zhu, Thant S. Crowley, Jessica G. Hamm, Lisa L. Costello, Mark A. He, Xiaobing Talsma, Caroline E. Flack, Callie G. Hervey-Jumper, Shawn L. Heth, Jason A. Muraszko, Karin M. Rey, Juan A. Fan, Xing Castresana, Javier S. Univ Navarra Sch Sci Brain Tumor Biol Unit CIFA Pamplona 31008 Spain Univ Michigan Sch Med Dept Neurosurg Ann Arbor MI 48109 USA Univ Michigan Sch Med Dept Cell & Dev Biol Ann Arbor MI 48109 USA La Paz Univ Hosp Res Unit Madrid Spain

The stem cell factor/kit tyrosine kinase receptor pathway is related to tumor growth and progression in several cancers including Ewing sarcoma, a peripheral pnet (ppnet). Identifying additional groups of tumors that may use the pathway is important as they might be responsive to imatinib mesylate treatment. MB and central pnet (cpnet) are embryonal tumors of the CNS that share similar undifferentiated morphology with Ewing sarcomas and display aggressive clinical behavior. cpnet outcome is significantly lower than MB outcome, even for localized tumors treated with high-risk MB therapy. The elucidation of signaling pathways involved in MB and cpnet pathogenesis, and the discovery of new therapeutic targets is necessary to improve the treatment of these neoplasms. We analyzed KIT expression in 2 MB, one ppnet, one cpnet and 2 rhabdomyosarcoma (RMS) cell lines. Also, in 13 tumor samples (12 MB and one cpnet), we found KIT overexpression in the most aggressive cell lines (metastatic MB and ppnet). Hypermethylation of KIT was clear in the RMS non-expressing cell lines. Among MB tumors, we could see variable levels of KIT expression;a subset of them (25%) might be related in its growth pattern to KIT up-regulation. No methylated KIT was detected in the tumors expressing the lowest levels of KIT. Our results point to methylation as an epigenetic regulatory mechanism for KIT inhibition only in the KIT non-expressing RMS cell lines, and neither in the rest of the cell lines nor in the tumor samples.

关键词： KIT Stem cell factor Medulloblastoma pnet Methylation

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Treatment Options for Medulloblastoma and CNS Primitive Neuroectodermal Tumor (pnet)

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CURRENT TREATMENT OPTIONS IN NEUROLOGY 2013年第5期15卷 593-606页

作者： De Braganca, Kevin C. Packer, Roger J. Mem Sloan Kettering Canc Ctr New York NY 10065 USA George Washington Univ Sch Med & Hlth Sci Washington DC 20052 USA Childrens Natl Med Ctr CNR Washington DC 20010 USA

Medulloblastoma and central nervous system (CNS) primitive neuroectodermal tumor (pnet) are primary pediatric brain tumors that require multidisciplinary therapies. Although often treated similarly in clinical trials, they are biologically different diseases. Even within medulloblastomas and CNS pnets, there are molecularly distinct subgroups with differing presentations and prognoses. Overall, prognosis is better for medulloblastomas. Specific treatments for these types of cancer are continuously evolving to maximize survival and minimize long-term sequelae of treatment. Patients should be treated on a clinical trial, if eligible, as they may gain benefit with minimal risk over current standard of care. The amount of residual disease after surgery better correlates with survival for medulloblastomas than for CNS pnets. Maximal surgical resection of tumor should be done, only if additional permanent, neurologic deficits can be spared. Patients should have a staging work-up to assess the extent of disease. This includes postoperative magnetic resonance imaging (MRI) of the brain, MRI of the entire spine and lumbar cerebrospinal fluid (CSF) sampling for cytological examination, if deemed safe. Radiation therapy to the entire CNS axis is required, with a greater dose (boost) given to the region of the primary site or any bulky residual disease for older children. Adjuvant chemotherapy must be given even if no evidence of disease after radiation therapy exists, as the risk of relapse is substantial after radiation alone. Subsets of younger children with medulloblastoma, arbitrarily defined as those younger than 3 years of age in some studies and 4 or even 5 years in other studies, can be effectively treated with chemotherapy alone. Recent genomic studies have revealed further subtypes of disease than previously recognized. Clinical trials to exploit these biologic differences are required to assess potential efficacy of targeted agents. The treatment of medulloblastoma

关键词： Medulloblastoma Primitive neuroectodermal tumor CNS pnet pnet Treatment Radiation Surgery Chemotherapy Molecular subgroups Pharmacologic treatment Physical therapy Speech therapy

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Ewing sarcoma/pnet: 27 years of experience in Slovenia

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PEDIATRIC HEMATOLOGY AND ONCOLOGY 2006年第4期23卷 355-367页

作者： Marinsek, Ziva Pohar Kavalar, Rajko Jereb, Berta Inst Oncol Dept Cytopathol Ljubljana 1000 Slovenia Maribor Teaching Hosp Dept Pathol Maribor Slovenia Inst Oncol Dept Radiotherapy Ljubljana 1000 Slovenia

The study includes 91 patients treated for Ewing sarcoma between 1972 and 2002. Forty were younger and 51 were older than 16. The overall 5-year survival was 36%: 53.5% in the younger and 22.5% in the older age group. Among patients with localized disease, 5-year survival was 58% in younger and 25.5% in the older. Survival was similar whether patients received three treatment modalities or chemotherapy combined with either surgery or radiotherapy. Recurrence was noted in 47 out of 75 patients with localized disease, most commonly as local recurrence or lung metastases. Among 18 evaluated patients, 14 had minor physical defects and 4 had severe late treatment effects (sterility in 3 and secondary osteogenic sarcoma in 1).

关键词： ewing pnet survival therapy prognosis

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Primary pulmonary primitive neuroectodermal tumor (pnet) - A case report

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PATHOLOGY RESEARCH AND PRACTICE 2001年第2期197卷 113-119页

作者： Mikami, Y Nakajima, M Hashimoto, H Irei, I Matsushima, T Kawabata, S Manabe, T Kawasaki Med Sch Hosp Dept Pathol Okayama 7010192 Japan Kawasaki Med Sch Hosp Dept Resp Dis Okayama 7010192 Japan Univ Occupat & Environm Hlth Dept Pathol & Oncol Kitakyushu Fukuoka 807 Japan

We describe a rare case of a primary primitive neuroectodermal tumor (pnet) in the lung of a 17-year-oId girl. Grossly, the tumor, located in the right lower lobe, was relatively well-circumscribed and whitish to yellowish in color with scattered hemorrhagic necrosis. Microscopically, the tumor was composed of ovoid to polygonal cells with a high nuclear to cytoplasmic ratio and relatively scant cytoplasm, arranged in solid sheets with intervening fine fibrovascular stroma. Immunohistochemically, the tumor was positive for the MIC2 gene product, whereas AE1/AE3, CAM5.2, and a variety of neuroendocrine markers such as chromogranin A, synaptophysin, and ProGRP, were negative. Three months after the lobectomy, recurrent tumors were noted in the mediastinum and right thoracic wall, and she died despite combined chemotherapy and radiation therapy. In this case cytogenetic analysis showed a hypertriploid karyotype with multiple numerical and structural chromosomal aberrations, but failed to disclose distinct evidence of translocation between chromosome 11 and 22. However, the reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated EWS/FLI-1 fusion transcripts, confirming;the histopathologic diagnosis of pnet. This case indicates that the primary pulmonary pnet is a highly aggressive neoplasm occurring at a young age, and should prompt combined systemic chemotherapy, even though it is organ-confined.

关键词： pnet lung pathology PCR

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Ewing's Sarcoma/Peripheral Primitive Neuroectodermal Tumor (ES/pnet) Differentiation in Endometrial Serous Carcinomas

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REPRODUCTIVE SCIENCES 2009年第6期16卷 591-595页

作者： Quddus, M. Ruhul Rashid, Lanita Sung, James Steinhoff, Margaret M. Zhang, Cunxian Lawrence, V. Dwayne Brown Univ Warrant Alpert Med Sch Dept Pathol Providence RI 02905 USA Brown Univ Women & Infants Hosp Dept Pathol & Lab Med Providence RI 02905 USA

The association of Ewing's sarcoma/peripheral neuroectodermal tumor and endometrioid type endometrial carcinoma has been reported relatively recently. We have recently identified Ewing's sarcoma/peripheral neuroectodermal tumor differentiation in uterine serous carcinomas and undertook this study to evaluate the frequency of both serous and endometrioid carcinomas expressing Ewing's sarcoma/peripheral neuroectodermal tumor differentiation. Seventy cases of uterine serous carcinoma were retrieved from the archival files and stained with antibodies to CD99. Positive and negative control slides were am with each staining batch. Perinuclear dot-like and/or membranous staining was regarded as positive. The frequency of Ewing's sarcoma/peripheral neuroectodermal tumor differentiation in 56 FIGO grade 3 endometrioid carcinomas was also determined and 7% uterine serous and 12.5% of FIGO grade 3 endometrioid endometrial carcinomas showed Ewing's sarcoma/peripheral neuroectodermal tumor differentiation. Given the worse prognosis associated with Ewing's sarcoma/peripheral neuroectodermal tumor differentiation, even in neoplasms already at high risk for recurrence and metastasis, a high index of suspicion for Ewing's sarcoma/peripheral neuroectodermal tumor should be maintained in high-grade uterine serous carcinomas.

关键词： Endometrial serous carcinoma pnet Ewing's sarcoma

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A phase II study of sapanisertib (TAK-228) a mTORC1/2 inhibitor in rapalog-resistant advanced pancreatic neuroendocrine tumors (pnet): ECOG-ACRIN EA2161

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INVESTIGATIONAL NEW DRUGS 2022年第6期40卷 1306-1314页

作者： Rajdev, Lakshmi Lee, Ju-Whei Libutti, Steven K. Benson, Al B. Fisher, George A., Jr. Kunz, Pamela L. Hendifar, Andrew E. Catalano, Paul O'Dwyer, Peter J. Zucker Sch Med Hofstra Hempstead NY 11549 USA Dana Farber Canc Inst ECOG ACRIN Biostat Ctr Boston MA 02115 USA Rutgers Canc Inst New Jersey New Brunswick NJ USA Northwestern Univ Evanston IL USA Stanford Univ Stanford CA 94305 USA Yale Sch Med New Haven CT USA Cedars Sinai Med Ctr Los Angeles CA 90048 USA Univ Penn Abramson Canc Ctr Philadelphia PA 19104 USA

This was a two-stage phase II trial of a mTORC1/2 inhibitor (mTORC: mammalian target of rapamycin complex) Sapanisertib (TAK228) in patients with rapalog-resistant pancreatic neuroendocrine tumors (pnets) (NCT02893930). Approved rapalogs such as everolimus inhibit mTORC1 and have limited clinical activity, possibly due to compensatory feedback loops. Sapanisertib addresses the potential for incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2, and thus to reverse resistance to earlier rapamycin analogues. In stage 1, patients received sapanisertib 3 mg by mouth once daily on a continuous dosing schedule in 28-day cycle. This trial adopted a two-stage design with the primary objective of evaluating objective tumor response. The first stage would recruit 13 patients in order to accrue 12 eligible and treated patients. If among the 12 eligible patients at least 1 patient had an objective response to therapy, the study would move to the second stage of accrual where 25 eligible and treated patients would be enrolled. This study activated on February 1, 2017, the required pre-determined number of patients (n = 13) had entered by November 5, 2018 for the first stage response evaluation. The accrual of this trial was formally terminated on December 27, 2019 as no response had been observed after the first stage accrual. Treatment-related grade 3 adverse events were reported in eight (61%) patients with hyperglycemia being the most frequent, in three patients (23%). Other toxicities noted in the trial included fatigue, rash diarrhea, nausea, and vomiting. The median PFS was 5.19 months (95% CI [3.84, 9.30]) and the median OS was 20.44 months (95% CI [5.65, 22.54]). Due to the lack of responses in Stage 1 of the study, the study did not proceed to stage 2. Thus the potential to reverse resistance was not evident.

关键词： pnet mTORC1 2 inhibitor Sapanisertib

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CD133+cells from medulloblastoma and pnet cell lines are more resistant to cyclopamine inhibition of the sonic hedgehog signaling pathway than CD133-cells

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TUMOR BIOLOGY 2010年第5期31卷 381-390页

作者： Enguita-German, Monica Schiapparelli, Paula Rey, Juan A. Castresana, Javier S. Univ Navarra CIFA Unidad Biol Tumores Cerebrales Pamplona 31008 Spain Univ Navarra Sch Sci Brain Tumor Biol Unit Pamplona 31008 Spain La Paz Univ Hosp Res Unit Madrid Spain

CD133 has recently been used as a reliable marker for brain tumor stem cells isolation. Sonic hedgehog (SHH) is implicated in medulloblastoma and central primitive neuroectodermal tumor (cpnet) formation. It has recently been suggested a role for the EWS/FLI1 fusion protein-typical of ppnet-in the upregulation of GLI1 and PTCH1 genes. Cyclopamine inhibits the SHH pathway in medulloblastoma cell lines, but its effect on cpnet and ppnet cell lines has not been well established yet. Our purpose was to study the effect of cyclopamine on medulloblastoma and pnet cell lines and to analyze whether CD133 expression might be able to modify this effect. We analyzed gene expression, cell viability, apoptosis, and tumorigenic capability before and after cyclopamine treatment in CD133 high-expressing and CD133 low-expressing cell lines. All medulloblastoma and pnet cell lines displayed an inhibitory effect on the expression of SHH pathway genes, on viability, and on tumorigenic potential after treatment. Nevertheless, CD133 expression made the cells more resistant to cyclopamine inhibition. These results open new doors to the understanding of CD133+ cancer stem cells as residual cells that might be responsible for treatment resistance.

关键词： Sonic hedgehog Cyclopamine CD133 Medulloblastoma pnet EWS/FLI1

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