Discrepancy in the Ki67 labeling index of brain and orbital metastatic lesions from gastrointestinal neuroendocrine tumors: A case report

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Presentación de un caso y revisión de la literatura" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 797 "Ancho" => 1505 "Tamanyo" => 308123 ] ] "descripcion" => array:1 [ "en" => "(A) Immunostaining for CD45 stains non-neoplastic bystander lymphoid cells, whereas the neoplastic RS cells remain unlabelled (↑). (B) CD30 is typically present in a membrane pattern, with accentuation in the Golgi area of the cytoplasm (↑) (perinuclear dot-like staining). (C) CD15 is selectively expressed in neoplastic cells (▴). (D) Immunostaining for PAX5 labels the nuclei of the RS cells (▴ and those of the non-neoplastic by-stander B cells (↑). (E) Ki-67 is positive in RS cells. 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"Gemma" "apellidos" => "Mateu Esquerda" ] 3 => array:2 [ "nombre" => "Jordi" "apellidos" => "de Manuel-Rimbau Muñoz" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2529849622000582?idApp=UINPBA00004B" "url" => "/25298496/0000003300000006/v3_202212060641/S2529849622000582/v3_202212060641/en/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "Case Report" "titulo" => "Discrepancy in the Ki67 labeling index of brain and orbital metastatic lesions from gastrointestinal neuroendocrine tumors: A case report" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "345" "paginaFinal" => "349" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Satoshi Matsuo, Toshiyuki Amano, Yuichiro Miyamatsu, Daisuke Hayashi, Sojiro Yamashita, Seiya Momosaki, Ken Kawabe, Akira Nakamizo" "autores" => array:8 [ 0 => array:4 [ "nombre" => "Satoshi" "apellidos" => "Matsuo" "email" => array:1 [ 0 => "smatsuo1979@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "1" "identificador" => "fn0005" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Toshiyuki" "apellidos" => "Amano" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Yuichiro" "apellidos" => "Miyamatsu" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Daisuke" "apellidos" => "Hayashi" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "2" "identificador" => "fn0010" ] ] ] 4 => array:3 [ "nombre" => "Sojiro" "apellidos" => "Yamashita" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "3" "identificador" => "fn0015" ] ] ] 5 => array:3 [ "nombre" => "Seiya" "apellidos" => "Momosaki" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 6 => array:3 [ "nombre" => "Ken" "apellidos" => "Kawabe" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 7 => array:3 [ "nombre" => "Akira" "apellidos" => "Nakamizo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Neurosurgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Pathology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Gastroenterology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Discrepancia en el índice de etiquetado Ki67 de las lesiones metastásicas cerebrales y orbitales de los tumores neuroendocrinos gastrointestinales: Un informe de caso" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 427 "Ancho" => 1405 "Tamanyo" => 190583 ] ] "descripcion" => array:1 [ "en" => "Histopathological examination of the resected brain (A–E) and orbital (F–J) tumor. Hematoxylin–eosin staining. Proliferating monotonous cells with round and bland nuclei in cord, nest, rosette, or tubular structures along with fibrous stroma are observed (A). The tumor cells are positive for CD56 (B), synaptophysin (C), and chromogranin A (D). The Ki67 labeling index is 8% (E). (F) Hematoxylin–eosin staining. Invasive proliferation of atypical small cells with hyperchromatic nuclei and scant cytoplasm arranged in a solid nest are observed. The tumor cells are positive for CD56 (G) and synaptophysin (H) and negative for chromogranin A (I). The Ki67 labeling index is 22% (J)." ] ] ] "textoCompleto" => "IntroductionGastrointestinal tract neuroendocrine tumors (GI-NETs), which are NETs arising from the GI tract, usually grow slowly, and metastasis is the leading cause of death in these patients.<a class="elsevierStyleCrossRef" href="#bib0080">1</a> Approximately 10% of GI-NETs have metastatic lesions, and the most frequent site is the liver, followed by the lung and bone.<a class="elsevierStyleCrossRefs" href="#bib0080">1,2</a> The brain and orbit are considered rare metastatic sites.<a class="elsevierStyleCrossRefs" href="#bib0085">2–8</a> Brain metastasis is estimated to occur in 1.5–5.0% of patients with NETs.<a class="elsevierStyleCrossRef" href="#bib0090">3</a> According to the most recent report,<a class="elsevierStyleCrossRef" href="#bib0085">2</a> only 0.18% of patients with GI-NETs had brain metastasis. Regarding orbital metastasis from NETs, the incidence remains unknown because only a few case series have been reported to date.<a class="elsevierStyleCrossRefs" href="#bib0105">6–8</a>Typically, only one tumor site is biopsied or removed to determine the histological features of the tumor. However, intra-patient heterogeneity in cellular markers among metastatic tumor sites in patients with NETs have been reported.<a class="elsevierStyleCrossRef" href="#bib0120">9</a> In addition, considering the variability in the Ki67-LI in patients with NETs over time,<a class="elsevierStyleCrossRef" href="#bib0125">10</a> sampling only one NET tumor site may result in an inaccurate evaluation of the histological features.We report a case of orbital and brain metastases from a GI-NET with different Ki67-LIs. This case suggests that sampling multiple lesions is required for the optimal evaluation of the proliferative activity of GI-NETs.Clinical caseA 71-year-old woman presenting with a 1-month history of headaches, right exophthalmos, and pain in her right eye was referred to our department. She had a colon carcinoid tumor treated by colonoscopy in her 40s. Approximately 5 years before admission, she was diagnosed with multiple liver tumors, and a liver tumor biopsy was performed. She was then diagnosed with a GI-NET [World Health Organization (WHO) Grade 1] and liver, bone, and lymph node metastases. Although she received systemic therapy, including octreotide, the mTOR inhibitor everolimus, and streptozocin, in this order, each for approximately one year before admission, her metastatic lesions grew slowly but progressively. On admission, her head magnetic resonance image (MRI) revealed the presence of a 3-cm mass accompanied with edema in the left occipital lobe and a heterogeneously enhanced well-circumscribed 2.5-cm mass in the right inferior part of the orbit (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). We diagnosed her with metastatic brain and orbital tumors from the GI-NET. She manifested a headache, possibly due to the intracranial pressure elevation and exophthalmos of the right eye. We then performed the surgical removal of both lesions. The gross total resection of both tumors was performed successfully, and they were pathologically diagnosed as metastatic tumors from the GI-NET (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Immunohistochemical studies revealed that tumor cells in the occipital lesion were positive for CD56, synaptophysin, and chromogranin A (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B–D). The Ki67-LI was 8% (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>E). Tumor cells in the right orbital lesion were positive for CD56 and synaptophysin but negative for chromogranin A (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>G–I), and the Ki67-LI was 22% (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>J). Although the patient was doing well after surgery, a follow-up MRI showed mass lesions in the right orbit involving the medial rectus muscle and left internal auditory canal, both of which were diagnosed as metastatic tumors (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Approximately 12 months after the surgery, we administered radiation therapy for these newly developed lesions. The patient continued to respond well for 10 months after the radiation therapy but was found to have progression of the metastatic liver tumors. Therefore, we inducted palliative care.<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>DiscussionIn patients with NETs, the incidence of brain metastasis is estimated to be 1.5–5.0%.<a class="elsevierStyleCrossRef" href="#bib0090">3</a> NETs arising from the lung appear to be the dominant source of brain metastasis.<a class="elsevierStyleCrossRefs" href="#bib0090">3–5</a> According to previous reports, 47.0–83.9% of primary lesions in patients with brain metastasis are lung NETs.<a class="elsevierStyleCrossRefs" href="#bib0090">3–5</a> In contrast, only 0.18% of patients with GI-NETs had brain metastasis.<a class="elsevierStyleCrossRef" href="#bib0085">2</a> Among GI-NETs, esophageal NETs have the highest rate of brain metastasis.<a class="elsevierStyleCrossRef" href="#bib0085">2</a> According to previous reports,<a class="elsevierStyleCrossRefs" href="#bib0095">4,5</a> no unique imaging patterns were observed. Therefore, single or multiple lesions and nodular or cystic formation can be manifested on neuroradiological examinations. Non-lung NETs tended to have multiple lesions.<a class="elsevierStyleCrossRef" href="#bib0095">4</a> Dural-based metastasis, as shown in our case, can occur.<a class="elsevierStyleCrossRef" href="#bib0100">5</a> Regarding the therapy for metastatic brain lesions, no definitive treatment guideline is available because of the rare incidence of these metastases. Currently, treatment is decided on the basis of comprehensive evaluation of patient conditions, clinical course of the primary site of the tumor, and symptoms. Surgical removal followed by whole-brain radiation therapy appears to be an appropriate strategy whenever the condition of the patient permits it.<a class="elsevierStyleCrossRef" href="#bib0100">5</a> We decided to surgically remove the brain metastases because the patient was symptomatic. In our case, after the complete removal of the tumor, local control was achieved for more than 1 year, but a new lesion requiring radiation therapy later developed. Although long-term survivors have been reported, the median survival time from diagnosis of the brain tumor remains unsatisfactory at only 8–10 months.<a class="elsevierStyleCrossRefs" href="#bib0090">3–5</a> The most common cause of death is systemic disease progression,<a class="elsevierStyleCrossRef" href="#bib0095">4</a> as shown in our case.Similar to brain metastases from NETs, limited studies have reported orbital metastasis.<a class="elsevierStyleCrossRefs" href="#bib0105">6–8</a> In contrast to brain metastases from NETs, orbital metastases tend to arise from GI-NETs rather than lung NETs.<a class="elsevierStyleCrossRef" href="#bib0105">6</a> For diagnosis, MR imaging is the gold standard. Usually, the tumor demonstrates well-circumscribed mass lesions with contrast enhancement on MRIs.<a class="elsevierStyleCrossRef" href="#bib0110">7</a> The rectus muscle involvement, as shown in our case, is a common finding.<a class="elsevierStyleCrossRef" href="#bib0115">8</a> No bias in the side of the orbit or frequent site of the quadrant in the orbit is observed.<a class="elsevierStyleCrossRef" href="#bib0105">6</a> Although the unilateral lesion is predominant, bilateral involvement can occur.<a class="elsevierStyleCrossRef" href="#bib0115">8</a> Similar to brain metastasis, no treatment guidelines are available. Radiation with or without systemic therapy appears to be a mainstay of therapy.<a class="elsevierStyleCrossRefs" href="#bib0105">6–8</a> Because of the effectiveness of radiation therapy, surgery plays a limited role. Therefore, the current standards of management for orbital metastases include a diagnosis by biopsy followed by local radiotherapy with systemic chemotherapy.<a class="elsevierStyleCrossRefs" href="#bib0105">6–8</a> In our case, we completely removed the lesion because it caused ocular pain and exophthalmos. She was doing well after surgery, but then a new progressively growing orbital metastatic tumor involving the medial rectus muscle was found during follow-up. We performed radiation therapy, and local control was achieved. Recently, Das et al. reported that a surgical biopsy of the orbital lesion is not necessary for diagnosis and that empiric therapy can be administered to patients who have a history of a NET with other systemic metastases and characteristic MRI findings showing that the orbital lesion involves the rectus muscles.<a class="elsevierStyleCrossRef" href="#bib0115">8</a> Because of improvements in high sensitivity somatostatin-receptor based imaging modalities, such as Gallium-68-labeled dodecanetetraacetic acid-tyrosine-3-octreotate positron emission tomography/computed tomography scan, their strategy appeared reasonable. However, we should keep it in mind that the incidence of secondary tumors following NETs has increased, especially among those diagnosed at age 70 or order.<a class="elsevierStyleCrossRef" href="#bib0130">11</a> Thus, we partially agree with their strategy but suggest that the metastatic orbital tumor from secondary cancer should be ruled out, especially in elderly patients.The current WHO classification of NETs includes three grades based on the Ki67-LI and the mitotic count.<a class="elsevierStyleCrossRef" href="#bib0135">12</a> This grading is considered a key factor in planning the management of this disease. The guidelines recommended systemic treatment with somatostatin analogs, targeted drugs, and peptide receptor radionuclide therapy for NET WHO Grades 1 and 2, whereas more aggressive therapy, such as chemotherapy with cisplatin and etoposide, is recommended for NET Grade 3 under certain conditions, including rapidly progressive disease and/or failure of other therapies.<a class="elsevierStyleCrossRef" href="#bib0140">13</a> Panzuto et al.<a class="elsevierStyleCrossRef" href="#bib0145">14</a> and Singh et al.<a class="elsevierStyleCrossRef" href="#bib0125">10</a> reported that the proliferative activity of NETs varied over time. Therefore, the reassessment of the Ki67-LI plays a pivotal role in deciding the therapeutic strategy, especially when disease progression occurs.<a class="elsevierStyleCrossRefs" href="#bib0125">10,14</a> However, whether the intra-patient discrepancy in the Ki67-LI among metastatic tumor sites exists is unknown. Lindholm et al. assessed the heterogeneity in the expression of common cellular markers, including the Ki67-LI, in primary and metastatic NETs and reported that sampling multiple tumor sites provides an optimal evaluation of the tumor characteristics.<a class="elsevierStyleCrossRef" href="#bib0120">9</a> According to them, the maximum intra-patient difference in the Ki67-LI was only 5%, whereas that of chromogranin A was 90%.<a class="elsevierStyleCrossRef" href="#bib0120">9</a> In our case, we found a discrepancy in both of the Ki67-LI and chromogranin A staining between brain and orbital metastatic tumors. Although the exact mechanisms for this discrepancy among metastatic sites remain elusive, variability in the Ki67-LI among tumor sites over time may exist. Alternatively, as Von Hoff et al. reported, heterogeneity in drug sensitivities among tumor sites might be related.<a class="elsevierStyleCrossRef" href="#bib0150">15</a> Regardless of the reasons, our case indicates that sampling only one metastatic site in patients with GI-NETs may potentially lead to an underestimation of the Ki67-LI.ConclusionThe Ki67-LI can vary among metastatic sites in patients with a GI-NET. Therefore, the sampling of multiple metastatic tumor sites may be recommended to accurately evaluate the tumor proliferative activity, which may help in the selection of the most effective treatment strategy.Informed consentInformed consent was obtained from the patient for presenting images for academic purposes.FundingPart of this work was supported by JSPS KAKENHI Grant Number 19K18411.Conflict of interestNone." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1814921" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1584563" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1814920" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1584564" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Clinical case" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conclusion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Informed consent" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interest" ] 11 => array:2 [ "identificador" => "xack640361" "titulo" => "Acknowledgements" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-03-10" "fechaAceptado" => "2021-04-25" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1584563" "palabras" => array:4 [ 0 => "Brain metastasis" 1 => "Orbital metastasis" 2 => "Neuroendocrine tumor" 3 => "Ki67 labeling index" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1584564" "palabras" => array:4 [ 0 => "Metástasis cerebral" 1 => "Metástasis orbital" 2 => "Tumor neuroendocrino" 3 => "Índice de etiquetado Ki67" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Proliferative activity examined by Ki67 labeling index (LI) plays pivotal role for managing gastrointestinal neuroendocrine tumor (GI-NET). Few reports indicated the intra-patient heterogeneity of Ki67-LI among metastatic tumor sites. We report a case of brain and orbital metastases from GI-NET that showed discrepancy of the Ki67-LI. A 71 year-old woman who was diagnosed as GI-NET with liver and bone metastases and performed medical therapy, had headache, right exophthalmos, and pain of right eye and was referred to our department. Magnetic resonance image revealed that tumors in the left occipital region and right orbit. We diagnosed as metastatic brain and orbital tumors from GI-NET. Surgical removal of both symptomatic lesions was performed and the diagnosis was pathologically confirmed. Immunohistochemical studies revealed the discrepancy of the Ki67-LI of the lesions (brain tumor: 8% versus orbital tumor: 22%). Sampling of multiple metastatic sites may prevent underestimate tumor proliferative activity." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La actividad proliferativa examinada por el índice de etiquetado Ki67 (LI) desempeña un papel fundamental en el tratamiento del tumor neuroendocrino gastrointestinal (GI-NET). Pocos informes indican la heterogeneidad intrapaciente del Ki67-LI entre las localizaciones de los tumores metastásicos. Presentamos un caso de metástasis cerebrales y orbitales de GI-NET que mostró discrepancia del Ki67-LI. Una mujer de 71 años a la que se le diagnosticó un GI-NET con metástasis hepáticas y óseas y que realizó tratamiento médico, presentó cefalea, exoftalmos derecho y dolor de ojo derecho, y fue remitida a nuestro departamento. La imagen de resonancia magnética reveló que los tumores en la región occipital izquierda y la órbita derecha. Diagnosticamos como metástasis tumores cerebrales y orbitales de GI-NET. Se realizó la extirpación quirúrgica de ambas lesiones sintomáticas y se confirmó patológicamente el diagnóstico. Los estudios inmunohistoquímicos revelaron la discrepancia del Ki67-LI de las lesiones (tumor cerebral: 8% frente a tumor orbitario: 22%). El muestreo de múltiples focos metastásicos puede evitar que se subestime la actividad proliferativa del tumor." ] ] "NotaPie" => array:3 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "Present address: Department of Neurosurgery, Hamanomachi Hospital, Fukuoka, Japan." "identificador" => "fn0005" ] 1 => array:3 [ "etiqueta" => "2" "nota" => "Present address: Department of Neurosurgery, Iizuka Hospital, Fukuoka, Japan." "identificador" => "fn0010" ] 2 => array:3 [ "etiqueta" => "3" "nota" => "Present address: Department of Neurosurgery, Graduate School of Medical Sciences Kyushu University, Fukuoka, Japan." "identificador" => "fn0015" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1175 "Ancho" => 1305 "Tamanyo" => 199133 ] ] "descripcion" => array:1 [ "en" => "Head magnetic resonance images on admission. Axial T1-weighted postcontrast magnetic resonance image (MRI) shows an enhanced tumor in the left occipital region (A). Axial fluid-attenuated inversion-recovery image shows peritumoral edema (B). Axial T1-weighted postcontrast MRI shows a heterogeneously enhanced tumor in the right retrobulbar region (C). Coronal T1-weighted postcontrast MRI shows a tumor involving the inferior rectus muscle (D)." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 427 "Ancho" => 1405 "Tamanyo" => 190583 ] ] "descripcion" => array:1 [ "en" => "Histopathological examination of the resected brain (A–E) and orbital (F–J) tumor. Hematoxylin–eosin staining. Proliferating monotonous cells with round and bland nuclei in cord, nest, rosette, or tubular structures along with fibrous stroma are observed (A). The tumor cells are positive for CD56 (B), synaptophysin (C), and chromogranin A (D). The Ki67 labeling index is 8% (E). (F) Hematoxylin–eosin staining. Invasive proliferation of atypical small cells with hyperchromatic nuclei and scant cytoplasm arranged in a solid nest are observed. The tumor cells are positive for CD56 (G) and synaptophysin (H) and negative for chromogranin A (I). The Ki67 labeling index is 22% (J)." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 984 "Ancho" => 905 "Tamanyo" => 118984 ] ] "descripcion" => array:1 [ "en" => "Head magnetic resonance images on follow-up. Axial T1-weighted postcontrast magnetic resonance image (MRI) shows an enhanced tumor in the right orbit involving the medial rectus muscle (A). 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Merola" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pone.0179445" "Revista" => array:4 [ "tituloSerie" => "PLOS ONE" "fecha" => "2017" "volumen" => "12" "paginaInicial" => "e0179445" ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0150" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Simultaneous in vitro drug sensitivity testing on tumors from different sites in the same patient" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "D.D. Von Hoff" 1 => "G.M. Clark" 2 => "B.J. Forseth" 3 => "J.D. Cowan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/1097-0142(19860901)58:5<1007::aid-cncr2820580503>3.0.co;2-#" "Revista" => array:6 [ "tituloSerie" => "Cancer" "fecha" => "1986" "volumen" => "58" "paginaInicial" => "1007" "paginaFinal" => "1013" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3731033" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack640361" "titulo" => "Acknowledgements" "texto" => "We thank Melissa Crawford, PhD, from Edanz Group (<a target="_blank" href="https://en-author-services.edanzgroup.com/ac">https://en-author-services.edanzgroup.com/ac</a>) for editing a draft of this manuscript." 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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Histopathological examination of the resected brain &#40;A&#8211;E&#41; and orbital &#40;F&#8211;J&#41; tumor&#46; Hematoxylin&#8211;eosin staining&#46; Proliferating monotonous cells with round and bland nuclei in cord&#44; nest&#44; rosette&#44; or tubular structures along with fibrous stroma are observed &#40;A&#41;&#46; The tumor cells are positive for CD56 &#40;B&#41;&#44; synaptophysin &#40;C&#41;&#44; and chromogranin A &#40;D&#41;&#46; The Ki67 labeling index is 8&#37; &#40;E&#41;&#46; &#40;F&#41; Hematoxylin&#8211;eosin staining&#46; Invasive proliferation of atypical small cells with hyperchromatic nuclei and scant cytoplasm arranged in a solid nest are observed&#46; The tumor cells are positive for CD56 &#40;G&#41; and synaptophysin &#40;H&#41; and negative for chromogranin A &#40;I&#41;&#46; The Ki67 labeling index is 22&#37; &#40;J&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Gastrointestinal tract neuroendocrine tumors &#40;GI-NETs&#41;&#44; which are NETs arising from the GI tract&#44; usually grow slowly&#44; and metastasis is the leading cause of death in these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> Approximately 10&#37; of GI-NETs have metastatic lesions&#44; and the most frequent site is the liver&#44; followed by the lung and bone&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1&#44;2</span></a> The brain and orbit are considered rare metastatic sites&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">2&#8211;8</span></a> Brain metastasis is estimated to occur in 1&#46;5&#8211;5&#46;0&#37; of patients with NETs&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a> According to the most recent report&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> only 0&#46;18&#37; of patients with GI-NETs had brain metastasis&#46; Regarding orbital metastasis from NETs&#44; the incidence remains unknown because only a few case series have been reported to date&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">6&#8211;8</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Typically&#44; only one tumor site is biopsied or removed to determine the histological features of the tumor&#46; However&#44; intra-patient heterogeneity in cellular markers among metastatic tumor sites in patients with NETs have been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> In addition&#44; considering the variability in the Ki67-LI in patients with NETs over time&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a> sampling only one NET tumor site may result in an inaccurate evaluation of the histological features&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">We report a case of orbital and brain metastases from a GI-NET with different Ki67-LIs&#46; This case suggests that sampling multiple lesions is required for the optimal evaluation of the proliferative activity of GI-NETs&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Clinical case</span><p id="par0020" class="elsevierStylePara elsevierViewall">A 71-year-old woman presenting with a 1-month history of headaches&#44; right exophthalmos&#44; and pain in her right eye was referred to our department&#46; She had a colon carcinoid tumor treated by colonoscopy in her 40s&#46; Approximately 5 years before admission&#44; she was diagnosed with multiple liver tumors&#44; and a liver tumor biopsy was performed&#46; She was then diagnosed with a GI-NET &#91;World Health Organization &#40;WHO&#41; Grade 1&#93; and liver&#44; bone&#44; and lymph node metastases&#46; Although she received systemic therapy&#44; including octreotide&#44; the mTOR inhibitor everolimus&#44; and streptozocin&#44; in this order&#44; each for approximately one year before admission&#44; her metastatic lesions grew slowly but progressively&#46; On admission&#44; her head magnetic resonance image &#40;MRI&#41; revealed the presence of a 3-cm mass accompanied with edema in the left occipital lobe and a heterogeneously enhanced well-circumscribed 2&#46;5-cm mass in the right inferior part of the orbit &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; We diagnosed her with metastatic brain and orbital tumors from the GI-NET&#46; She manifested a headache&#44; possibly due to the intracranial pressure elevation and exophthalmos of the right eye&#46; We then performed the surgical removal of both lesions&#46; The gross total resection of both tumors was performed successfully&#44; and they were pathologically diagnosed as metastatic tumors from the GI-NET &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Immunohistochemical studies revealed that tumor cells in the occipital lesion were positive for CD56&#44; synaptophysin&#44; and chromogranin A &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#8211;D&#41;&#46; The Ki67-LI was 8&#37; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>E&#41;&#46; Tumor cells in the right orbital lesion were positive for CD56 and synaptophysin but negative for chromogranin A &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>G&#8211;I&#41;&#44; and the Ki67-LI was 22&#37; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>J&#41;&#46; Although the patient was doing well after surgery&#44; a follow-up MRI showed mass lesions in the right orbit involving the medial rectus muscle and left internal auditory canal&#44; both of which were diagnosed as metastatic tumors &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Approximately 12 months after the surgery&#44; we administered radiation therapy for these newly developed lesions&#46; The patient continued to respond well for 10 months after the radiation therapy but was found to have progression of the metastatic liver tumors&#46; Therefore&#44; we inducted palliative care&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">In patients with NETs&#44; the incidence of brain metastasis is estimated to be 1&#46;5&#8211;5&#46;0&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a> NETs arising from the lung appear to be the dominant source of brain metastasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3&#8211;5</span></a> According to previous reports&#44; 47&#46;0&#8211;83&#46;9&#37; of primary lesions in patients with brain metastasis are lung NETs&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3&#8211;5</span></a> In contrast&#44; only 0&#46;18&#37; of patients with GI-NETs had brain metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> Among GI-NETs&#44; esophageal NETs have the highest rate of brain metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> According to previous reports&#44;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">4&#44;5</span></a> no unique imaging patterns were observed&#46; Therefore&#44; single or multiple lesions and nodular or cystic formation can be manifested on neuroradiological examinations&#46; Non-lung NETs tended to have multiple lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a> Dural-based metastasis&#44; as shown in our case&#44; can occur&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a> Regarding the therapy for metastatic brain lesions&#44; no definitive treatment guideline is available because of the rare incidence of these metastases&#46; Currently&#44; treatment is decided on the basis of comprehensive evaluation of patient conditions&#44; clinical course of the primary site of the tumor&#44; and symptoms&#46; Surgical removal followed by whole-brain radiation therapy appears to be an appropriate strategy whenever the condition of the patient permits it&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a> We decided to surgically remove the brain metastases because the patient was symptomatic&#46; In our case&#44; after the complete removal of the tumor&#44; local control was achieved for more than 1 year&#44; but a new lesion requiring radiation therapy later developed&#46; Although long-term survivors have been reported&#44; the median survival time from diagnosis of the brain tumor remains unsatisfactory at only 8&#8211;10 months&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3&#8211;5</span></a> The most common cause of death is systemic disease progression&#44;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a> as shown in our case&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Similar to brain metastases from NETs&#44; limited studies have reported orbital metastasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">6&#8211;8</span></a> In contrast to brain metastases from NETs&#44; orbital metastases tend to arise from GI-NETs rather than lung NETs&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> For diagnosis&#44; MR imaging is the gold standard&#46; Usually&#44; the tumor demonstrates well-circumscribed mass lesions with contrast enhancement on MRIs&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">7</span></a> The rectus muscle involvement&#44; as shown in our case&#44; is a common finding&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> No bias in the side of the orbit or frequent site of the quadrant in the orbit is observed&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> Although the unilateral lesion is predominant&#44; bilateral involvement can occur&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> Similar to brain metastasis&#44; no treatment guidelines are available&#46; Radiation with or without systemic therapy appears to be a mainstay of therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">6&#8211;8</span></a> Because of the effectiveness of radiation therapy&#44; surgery plays a limited role&#46; Therefore&#44; the current standards of management for orbital metastases include a diagnosis by biopsy followed by local radiotherapy with systemic chemotherapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">6&#8211;8</span></a> In our case&#44; we completely removed the lesion because it caused ocular pain and exophthalmos&#46; She was doing well after surgery&#44; but then a new progressively growing orbital metastatic tumor involving the medial rectus muscle was found during follow-up&#46; We performed radiation therapy&#44; and local control was achieved&#46; Recently&#44; Das et al&#46; reported that a surgical biopsy of the orbital lesion is not necessary for diagnosis and that empiric therapy can be administered to patients who have a history of a NET with other systemic metastases and characteristic MRI findings showing that the orbital lesion involves the rectus muscles&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> Because of improvements in high sensitivity somatostatin-receptor based imaging modalities&#44; such as Gallium-68-labeled dodecanetetraacetic acid-tyrosine-3-octreotate positron emission tomography&#47;computed tomography scan&#44; their strategy appeared reasonable&#46; However&#44; we should keep it in mind that the incidence of secondary tumors following NETs has increased&#44; especially among those diagnosed at age 70 or order&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a> Thus&#44; we partially agree with their strategy but suggest that the metastatic orbital tumor from secondary cancer should be ruled out&#44; especially in elderly patients&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The current WHO classification of NETs includes three grades based on the Ki67-LI and the mitotic count&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a> This grading is considered a key factor in planning the management of this disease&#46; The guidelines recommended systemic treatment with somatostatin analogs&#44; targeted drugs&#44; and peptide receptor radionuclide therapy for NET WHO Grades 1 and 2&#44; whereas more aggressive therapy&#44; such as chemotherapy with cisplatin and etoposide&#44; is recommended for NET Grade 3 under certain conditions&#44; including rapidly progressive disease and&#47;or failure of other therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> Panzuto et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a> and Singh et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a> reported that the proliferative activity of NETs varied over time&#46; Therefore&#44; the reassessment of the Ki67-LI plays a pivotal role in deciding the therapeutic strategy&#44; especially when disease progression occurs&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">10&#44;14</span></a> However&#44; whether the intra-patient discrepancy in the Ki67-LI among metastatic tumor sites exists is unknown&#46; Lindholm et al&#46; assessed the heterogeneity in the expression of common cellular markers&#44; including the Ki67-LI&#44; in primary and metastatic NETs and reported that sampling multiple tumor sites provides an optimal evaluation of the tumor characteristics&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> According to them&#44; the maximum intra-patient difference in the Ki67-LI was only 5&#37;&#44; whereas that of chromogranin A was 90&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> In our case&#44; we found a discrepancy in both of the Ki67-LI and chromogranin A staining between brain and orbital metastatic tumors&#46; Although the exact mechanisms for this discrepancy among metastatic sites remain elusive&#44; variability in the Ki67-LI among tumor sites over time may exist&#46; Alternatively&#44; as Von Hoff et al&#46; reported&#44; heterogeneity in drug sensitivities among tumor sites might be related&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> Regardless of the reasons&#44; our case indicates that sampling only one metastatic site in patients with GI-NETs may potentially lead to an underestimation of the Ki67-LI&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusion</span><p id="par0040" class="elsevierStylePara elsevierViewall">The Ki67-LI can vary among metastatic sites in patients with a GI-NET&#46; Therefore&#44; the sampling of multiple metastatic tumor sites may be recommended to accurately evaluate the tumor proliferative activity&#44; which may help in the selection of the most effective treatment strategy&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Informed consent</span><p id="par0045" class="elsevierStylePara elsevierViewall">Informed consent was obtained from the patient for presenting images for academic purposes&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Funding</span><p id="par0050" class="elsevierStylePara elsevierViewall">Part of this work was supported by <span class="elsevierStyleGrantSponsor" id="gs1">JSPS KAKENHI</span> Grant Number <span class="elsevierStyleGrantNumber" refid="gs1">19K18411</span>&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conflict of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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          "titulo" => "Acknowledgements"
        ]
        12 => array:1 [
          "titulo" => "References"
        ]
      ]
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2021-03-10"
    "fechaAceptado" => "2021-04-25"
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      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1584563"
          "palabras" => array:4 [
            0 => "Brain metastasis"
            1 => "Orbital metastasis"
            2 => "Neuroendocrine tumor"
            3 => "Ki67 labeling index"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1584564"
          "palabras" => array:4 [
            0 => "Met&#225;stasis cerebral"
            1 => "Met&#225;stasis orbital"
            2 => "Tumor neuroendocrino"
            3 => "&#205;ndice de etiquetado Ki67"
          ]
        ]
      ]
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Proliferative activity examined by Ki67 labeling index &#40;LI&#41; plays pivotal role for managing gastrointestinal neuroendocrine tumor &#40;GI-NET&#41;&#46; Few reports indicated the intra-patient heterogeneity of Ki67-LI among metastatic tumor sites&#46; We report a case of brain and orbital metastases from GI-NET that showed discrepancy of the Ki67-LI&#46; A 71 year-old woman who was diagnosed as GI-NET with liver and bone metastases and performed medical therapy&#44; had headache&#44; right exophthalmos&#44; and pain of right eye and was referred to our department&#46; Magnetic resonance image revealed that tumors in the left occipital region and right orbit&#46; We diagnosed as metastatic brain and orbital tumors from GI-NET&#46; Surgical removal of both symptomatic lesions was performed and the diagnosis was pathologically confirmed&#46; Immunohistochemical studies revealed the discrepancy of the Ki67-LI of the lesions &#40;brain tumor&#58; 8&#37; versus orbital tumor&#58; 22&#37;&#41;&#46; Sampling of multiple metastatic sites may prevent underestimate tumor proliferative activity&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La actividad proliferativa examinada por el &#237;ndice de etiquetado Ki67 &#40;LI&#41; desempe&#241;a un papel fundamental en el tratamiento del tumor neuroendocrino gastrointestinal &#40;GI-NET&#41;&#46; Pocos informes indican la heterogeneidad intrapaciente del Ki67-LI entre las localizaciones de los tumores metast&#225;sicos&#46; Presentamos un caso de met&#225;stasis cerebrales y orbitales de GI-NET que mostr&#243; discrepancia del Ki67-LI&#46; Una mujer de 71 a&#241;os a la que se le diagnostic&#243; un GI-NET con met&#225;stasis hep&#225;ticas y &#243;seas y que realiz&#243; tratamiento m&#233;dico&#44; present&#243; cefalea&#44; exoftalmos derecho y dolor de ojo derecho&#44; y fue remitida a nuestro departamento&#46; La imagen de resonancia magn&#233;tica revel&#243; que los tumores en la regi&#243;n occipital izquierda y la &#243;rbita derecha&#46; Diagnosticamos como met&#225;stasis tumores cerebrales y orbitales de GI-NET&#46; Se realiz&#243; la extirpaci&#243;n quir&#250;rgica de ambas lesiones sintom&#225;ticas y se confirm&#243; patol&#243;gicamente el diagn&#243;stico&#46; Los estudios inmunohistoqu&#237;micos revelaron la discrepancia del Ki67-LI de las lesiones &#40;tumor cerebral&#58; 8&#37; frente a tumor orbitario&#58; 22&#37;&#41;&#46; El muestreo de m&#250;ltiples focos metast&#225;sicos puede evitar que se subestime la actividad proliferativa del tumor&#46;</p></span>"
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      0 => array:3 [
        "etiqueta" => "1"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Present address&#58; Department of Neurosurgery&#44; Hamanomachi Hospital&#44; Fukuoka&#44; Japan&#46;</p>"
        "identificador" => "fn0005"
      ]
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        "etiqueta" => "2"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Present address&#58; Department of Neurosurgery&#44; Iizuka Hospital&#44; Fukuoka&#44; Japan&#46;</p>"
        "identificador" => "fn0010"
      ]
      2 => array:3 [
        "etiqueta" => "3"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Present address&#58; Department of Neurosurgery&#44; Graduate School of Medical Sciences Kyushu University&#44; Fukuoka&#44; Japan&#46;</p>"
        "identificador" => "fn0015"
      ]
    ]
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      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
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          0 => array:4 [
            "imagen" => "gr1.jpeg"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Head magnetic resonance images on admission&#46; Axial T1-weighted postcontrast magnetic resonance image &#40;MRI&#41; shows an enhanced tumor in the left occipital region &#40;A&#41;&#46; Axial fluid-attenuated inversion-recovery image shows peritumoral edema &#40;B&#41;&#46; Axial T1-weighted postcontrast MRI shows a heterogeneously enhanced tumor in the right retrobulbar region &#40;C&#41;&#46; Coronal T1-weighted postcontrast MRI shows a tumor involving the inferior rectus muscle &#40;D&#41;&#46;</p>"
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        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
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          0 => array:4 [
            "imagen" => "gr2.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Histopathological examination of the resected brain &#40;A&#8211;E&#41; and orbital &#40;F&#8211;J&#41; tumor&#46; Hematoxylin&#8211;eosin staining&#46; Proliferating monotonous cells with round and bland nuclei in cord&#44; nest&#44; rosette&#44; or tubular structures along with fibrous stroma are observed &#40;A&#41;&#46; The tumor cells are positive for CD56 &#40;B&#41;&#44; synaptophysin &#40;C&#41;&#44; and chromogranin A &#40;D&#41;&#46; The Ki67 labeling index is 8&#37; &#40;E&#41;&#46; &#40;F&#41; Hematoxylin&#8211;eosin staining&#46; Invasive proliferation of atypical small cells with hyperchromatic nuclei and scant cytoplasm arranged in a solid nest are observed&#46; The tumor cells are positive for CD56 &#40;G&#41; and synaptophysin &#40;H&#41; and negative for chromogranin A &#40;I&#41;&#46; The Ki67 labeling index is 22&#37; &#40;J&#41;&#46;</p>"
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        "etiqueta" => "Fig&#46; 3"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Head magnetic resonance images on follow-up&#46; Axial T1-weighted postcontrast magnetic resonance image &#40;MRI&#41; shows an enhanced tumor in the right orbit involving the medial rectus muscle &#40;A&#41;&#46; Axial constructive interference in steady-state MRI shows a tumor in the left internal acoustic canal &#40;B&#41;&#46;</p>"
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      ]
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