Accepted Manuscript Multiple brain metastases from pancreatic adenocarcinoma presenting with simultaneous intratumoral hemorrhages: A case report Satoshi Matsuo, MD, PhD, Toshiyuki Amano, MD, PhD, Shigeto Kawauchi, MD, PhD, Akira Nakamizo, MD, PhD PII: S1878-8750(18)32859-6 DOI: https://doi.org/10.1016/j.wneu.2018.12.036 Reference: WNEU 10982 To appear in: World Neurosurgery Received Date: 10 October 2018 Accepted Date: 5 December 2018 Please cite this article as: Matsuo S, Amano T, Kawauchi S, Nakamizo A, Multiple brain metastases from pancreatic adenocarcinoma presenting with simultaneous intratumoral hemorrhages: A case report, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2018.12.036. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Matsuo ACCEPTED MANUSCRIPT 1 Multiple brain metastases from pancreatic adenocarcinoma presenting with simultaneous intratumoral hemorrhages: A case report RI PT Satoshi Matsuo, MD, PhDa, Toshiyuki Amano, MD, PhDa, Shigeto Kawauchi, MD, PhDb, Akira Nakamizo, SC MD, PhDa Kyushu Medical Center, Fukuoka, Japan TE D Declarations of interest: None. M AN U Departments of aNeurosurgery and bPathology, Clinical Research Institute, National Hospital Organization Address all correspondence to: Satoshi Matsuo, MD, PhD EP Department of Neurosurgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical AC C Center, 1-8-1 Jigyo-hama, Fukuoka 810-8563, Japan TEL: +81-92-852-0700; FAX: +81-92-846-8485; E-mail: smatsuo1979@gmail.com Keywords: Intratumoral hemorrhage, Metastatic brain tumor, Pancreatic adenocarcinoma Abbreviation List: CT, computed tomography; MRI, magnetic resonance imaging Matsuo ACCEPTED MANUSCRIPT 2 Abstract Background RI PT Pancreatic adenocarcinoma rarely metastasizes to the brain, and the clinical features of brain metastasis in such cases remain elusive. To the best of our knowledge, only 21 cases of brain metastasis from pancreatic adenocarcinoma have been previously reported in the English-language literature. SC Case Description M AN U One year 4 months before the current admission, a 61-year-old woman was diagnosed with pancreatic adenocarcinoma and began chemotherapy. Three days before the current admission, she developed acute dysarthria. She was referred to a cancer center, where neuroradiological examination revealed multiple TE D metastatic brain tumors, including a 30-mm-diameter tumor in the right cerebellar region. She was transferred to our institute. Three days after admission, she developed sudden-onset disturbance of consciousness and left hemiparesis. Head computed tomography and magnetic resonance imaging showed EP that the multiple metastatic lesions had increased in size with the development of intratumoral hemorrhage AC C and obstructive hydrocephalus. She underwent urgent removal of the tumor in the cerebellum. The obstructive hydrocephalus was relieved and her consciousness improved immediately after the surgery. She was transferred to the palliative care unit of the cancer center and died under hospice care 3 weeks after the surgery. Conclusions This case demonstrates that brain metastases from pancreatic adenocarcinoma can enlarge suddenly and Matsuo ACCEPTED MANUSCRIPT 3 simultaneously by intratumoral hemorrhage even without coagulation disorders, resulting in neurological deterioration in a short time. Surgical resection of metastatic brain lesions from pancreatic adenocarcinoma AC C EP TE D M AN U SC improve the patient’s quality of life in selected cases. RI PT has an extremely limited role, but such treatment can remove the neurological symptoms and temporarily Matsuo ACCEPTED MANUSCRIPT 4 Introduction Pancreatic adenocarcinoma is a relentlessly progressive and fatal disease with an overall 5-year survival RI PT rate of <5%.1 Because of the absence of early signs or characteristic symptoms, most patients with pancreatic adenocarcinoma present with metastatic disease involving the lymph nodes, liver, peritoneum, lungs, or bone at the time of diagnosis.1,2 Pancreatic adenocarcinoma can metastasize to the central SC nervous system, but this is quite rare.2,3 Due to recent advancements in the treatment of pancreatic cancer, M AN U the incidence of brain metastasis in such patients may be increasing.4 We herein describe a case of multiple brain metastases from pancreatic adenocarcinoma that progressively enlarged by intratumoral hemorrhage and were treated surgically. To our knowledge, this is TE D the first report of a patient with multiple hemorrhagic brain metastases that progressively and Case report EP simultaneously enlarged within a short time. AC C One year 4 months before the present admission, a 61-year-old woman was found to have a tumor in the tail of the pancreas with ascites. Cytological analysis of the ascites led to a diagnosis of pancreatic adenocarcinoma. She underwent multi-agent systemic chemotherapy regimens involving gemcitabine, nab-paclitaxel, and S-1 (tegafur, gimeracil, and oteracil potassium). Three months before the present admission, she developed difficulty breathing, and chest computed tomography (CT) showed that the pleural effusion was due to carcinomatous pleurisy. After the patient underwent a modified FOLFIRINOX Matsuo ACCEPTED MANUSCRIPT 5 regimen, her pleural effusion resolved and her dyspnea was relieved. Three days before the current admission, she presented to an emergency department with acute onset of dysarthria. Head CT and RI PT magnetic resonance imaging (MRI) showed multiple lesions, including a 3-cm cerebellar lesion (Fig. 1). A prognosis of at least a few months was predicted despite the presence of carcinomatous peritonitis and pleurisy and liver and brain metastases. Palliative whole-brain radiation was planned; however, the patient SC and her family expressed their desire to pursue treatment as long as she could tolerate it. On admission, her M AN U mental status was alert and she exhibited mild dysarthria. Laboratory data revealed no thrombocytopenia or blood coagulation disorders (platelet count, 299 × 103/L; activated partial thromboplastin time, 22.8 s; prothrombin time–international normalized ratio, 1.11). Suboccipital craniotomy with resection of the TE D tumors in the cerebellum was planned to avoid obstructive hydrocephalus and brain stem compression induced by the enlargement of the lesions. Three days after admission, she developed a sudden disturbance of consciousness (Glasgow coma scale score of E3V3M6) and left hemiparesis. CT and MRI showed that EP the multiple metastatic lesions in the initial imaging studies had increased in size with intratumor AC C hemorrhage and obstructive hydrocephalus (Fig. 2). After a lengthy discussion regarding the extent of her disease and the prognosis, the patient’s family expressed their desire to pursue treatment as long as she could tolerate it. She underwent removal of the tumors in the cerebellum through a suboccipital craniotomy, and the obstructive hydrocephalus was improved (Fig. 3). Histopathological analysis revealed moderately to highly differentiated tubular adenocarcinoma, which was consistent with metastasis from the pancreatic adenocarcinoma (Fig. 4). Her disturbance of consciousness recovered immediately after the surgery, and Matsuo ACCEPTED MANUSCRIPT 6 she could communicate with her family. Although removal of the supratentorial lesions was planned, the patient declined the additional surgery and was transferred to hospice care. Her clinical condition RI PT deteriorated, and she died under hospice care 3 weeks after the surgery. Discussion SC Brain metastasis, which occurs in 10% to 35% of adult patients with cancer,5,6 is frequently diagnosed in M AN U patients with lung cancer (48%), breast cancer (15%), testicular cancer (10%), and malignant melanoma (6%–10%); however, brain metastasis rarely arises from gastrointestinal tract cancers (<4%).2 Brain metastasis from pancreatic adenocarcinoma is extremely rare (0.33%),3 and its clinical features remain elusive. To the best of our knowledge, only 22 cases of brain metastasis from pancreatic adenocarcinoma, TE D including the present case, have been reported (Table 1).3,7-17 Most of the patients (86.4%, 19/22) showed other remote metastases in the liver, lungs, lymph nodes, or bone.16 The median time from diagnosis of EP pancreatic adenocarcinoma to brain metastasis was 17.8 months (range, 0–65 months). The brain AC C metastasis occurred late in the clinical course, but it was the first clinical manifestation in 22.7% (5/22) of the patients. More than half of the patients showed a single lesion rather than multiple lesions (59.1%, 13/22). Seven of the 22 patients showed cystic brain metastases, and 10 patients showed solid metastases. Only one patient in addition to the herein-described patient developed intratumoral hemorrhage of brain metastasis from pancreatic adenocarcinoma.8 However, intratumoral hemorrhage is common in brain metastasis from melanoma, breast, thyroid, and renal cell carcinoma.6 Kamar et al.8 reported a case Matsuo ACCEPTED MANUSCRIPT 7 of multiple brain metastases from pancreatic adenocarcinoma accompanied by small frontoparietal hemorrhage, and repeated MRI showed tumor enlargement with intratumoral hemorrhage in a short time. RI PT The authors did not conclude that the cause of the intratumoral hemorrhage was thrombocytopenia. In our case, the patient’s blood pressure was stable during the hospital stay, and no coagulation disorders were evident. The exact cause remains elusive; however, some systemic factors may result in simultaneous SC intratumoral hemorrhage. Aside from the etiology of the multiple tumor enlargement observed in the can enlarge suddenly and simultaneously. M AN U present case, we should be aware that multiple brain metastatic lesions from pancreatic adenocarcinoma Until recently, pancreatic adenocarcinoma has been an aggressive malignancy with an extremely TE D poor prognosis, and surgical resection of brain metastasis has had a very limited role. However, advancements in imaging techniques for early diagnosis and therapeutic agents have improved the prognosis of pancreatic adenocarcinoma over the past few decades.4 Among 13 patients with a single EP metastatic lesion, 9 (69.2%) patients underwent surgical resection and 6 (46.2%) survived for >12 months AC C after surgery (Table 1). Unless a single metastasis is located in a high-risk area or the patient has a poor performance status, surgical resection appears to have a significant benefit for single metastatic lesions. In patients with multiple metastases (n = 9), the prognosis is extremely poor, and only two patients underwent surgical resection (Table 1). Kumar et al.15 described a patient who underwent three craniotomies followed by whole-brain irradiation during the disease course. However, the postoperative course was not described. In the present case, the patient died 3 weeks after the craniotomy because of worsening of the primary Matsuo ACCEPTED MANUSCRIPT 8 lesion, and resection of the tumors might not have improved the prognosis. However, her disturbance of consciousness improved immediately after the surgery, and she was able to spend the remainder of her life RI PT meaningfully. In this regard, surgical resection might be of benefit to selected patients, even those with multiple brain metastases. SC Conclusion M AN U Brain metastases from pancreatic adenocarcinoma can enlarge suddenly and simultaneously by intratumoral hemorrhage even without coagulation disorders and cause neurological deterioration within a short time. Surgical resection of brain metastases from pancreatic adenocarcinoma has an extremely AC C EP TE D limited role, but it can improve the neurological symptoms even in patients with multiple brain metastases. Matsuo ACCEPTED MANUSCRIPT 9 Acknowledgement We would like to thank Angela Morben, DVM, ELS, from Edanz Group (www.edanzediting.com/ac), for RI PT editing a draft of this manuscript. Funding SC This research did not receive any specific grant from funding agencies in the public, commercial, or AC C EP TE D M AN U not-for-profit sectors. Matsuo ACCEPTED MANUSCRIPT 10 Figure legends Figure 1. Head CT and MRI on admission. (a, b) Axial CT and (c, d) fluid-attenuated inversion recovery RI PT MRI showed multiple mass lesions scattered throughout the parenchyma, including a 3-cm cerebellar lesion. SC Figure 2. Head CT and MRI on Day 3. (a–c) Axial CT images showed an increase in the size of the lesions M AN U with intratumoral hemorrhage. (b) Mild enlargement of the ventricle was apparent. Figure 3. Postoperative head CT images. (a) Axial CT showed complete removal of the tumors in the TE D cerebellum. (b) Enlargement of the ventricle improved after the operation. Figure 4. Histological examination of the resected brain tumor. At ×200, the tumor displayed cribriform, AC C EP acinar, and papillary architectural patterns infiltrating the brain parenchyma. Matsuo ACCEPTED MANUSCRIPT 11 References Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605-1617. 2. Go PH, Klaassen Z, Meadows MC, Chamberlain RS. Gastrointestinal cancer and brain RI PT 1. metastasis: a rare and ominous sign. Cancer. 2011;117:3630-3640. 3. Park KS, Kim M, Park SH, Lee KW. Nervous system involvement by pancreatic cancer. J Sun H, Ma H, Hong G, Sun H, Wang J. Survival improvement in patients with pancreatic cancer M AN U 4. SC Neurooncol. 2003;63:313-316. by decade: a period analysis of the SEER database, 1981-2010. Sci Rep. 2014;4:6747. doi: 10.1038/srep06747. Lin X, DeAngelis LM. Treatment of Brain Metastases. J Clin Oncol. 2015;33(30):3475-3484. 6. Barajas RF Jr, Cha S. Metastasis in Adult Brain Tumors. Neuroimaging Clin N Am. 2016;26:601-620. Kuratsu J, Murakami M, Uemura S, Ushio Y. Brain and skull metastases of hepatic or pancreatic EP 7. TE D 5. 8. AC C cancer--report of six cases. Neurol Med Chir (Tokyo). 1990;30:476-482. El Kamar FG, Jindal K, Grossbard ML, Mizrachi HH, Kozuch PS. Pancreatic carcinoma with brain metastases: case report and literature review. Dig Liver Dis. 2004;36:355-360. 9. Caricato M, Borzomati D, Ausania F, Garberini A, Rabitti C, Tonini G, Coppola R. Cerebellar metastasis from pancreatic adenocarcinoma. A case report. Pancreatology. 2006;6:306-308. 10. Marepaily R, Micheals D, Sloan A, Hatfield J, Adsay V, Joyrich R, Ullah N, Tobi M. Octreotide Matsuo ACCEPTED MANUSCRIPT 12 uptake in intracranial metastasis of pancreatic ductal adenocarcinoma origin in a patient with a prolonged clinical course. Dig Dis Sci. 2009;54:188-190. Lemke J, Barth TF, Juchems M, Kapapa T, Henne-Bruns D, Kornmann M. Long-term survival following resection of brain metastases 2011;31:4599-4603. pancreatic cancer. Anticancer Res. Chiang KC, Yu CC, Chen JR, Huang YT, Huang CC, Yeh CN, Tsai CS, Chen LW, Chen HC, Hsu SC 12. from RI PT 11. M AN U JT, Wang CH, Chen HY. Oncocytic-type intraductal papillary mucinous neoplasm (IPMN)-derived invasive oncocytic pancreatic carcinoma with brain metastasis - a case report. World J Surg Oncol. 2012;10:138. doi: 10.1186/1477-7819-10-138. Rao R, Sadashiv SK, Goday S, Monga D. An extremely rare case of pancreatic cancer presenting TE D 13. with leptomeningeal carcinomatosis and synchronous intraparenchymal brain metastasis. Gastrointest Cancer Res. 2013;6:90-92. Rajappa P, Margetis K, Wernicke G, Ginter P, Cope W, Sherr DL, Lavi E, Fine RL, Schwartz TH, EP 14. AC C Bruckner H, Pannullo SC. Stereotactic radiosurgery plays a critical role in enhancing long-term survival in a patient with pancreatic cancer metastatic to the brain. Anticancer Res. 2013;33:3899-3903. 15. Kumar A, Dagar M, Herman J, Iacobuzio-Donahue C, Laheru D. CNS involvement in pancreatic adenocarcinoma: a report of eight cases from the Johns Hopkins Hospital and review of literature. Matsuo ACCEPTED MANUSCRIPT 13 J Gastrointest Cancer. 2015;46:5-8. Matsumoto H, Yoshida Y. Brain metastasis from pancreatic cancer: A case report and literature EP TE D M AN U SC RI PT review. Asian J Neurosurg. 2015;10:35-39. AC C 16. ACCEPTED MANUSCRIPT Table 1. Summary of reported cases of brain metastasis from pancreatic adenocarcinoma Authors Age (y)/sex Cyst or solid Intratumoral Therapy for brain metastasis Single metastatic lesion Kuratsu et al.7 56/M Cyst - Interval* Survival after (mo) BM diagnosis LN 15 9 mo RI PT hemorrhage Other metastatic lesions Biopsy, Ommaya reservoir placement, radiation Marepaily et al. 11 Lemke et al. Liver 5 2w 51/M Cyst - BSC Lung, liver, bone 0 2.9 ± 1.0 mo 52/M Solid - Radiation Liver 5 2.9 ± 1.0 mo 67/M Solid - Resection LN 24 12 mo 36/F NA - Resection Liver 11 BSC, NA 48/F NA - Resection, radiation Liver 65 139 mo - Resection, radiation LN 12 72 mo - Resection, radiation - 0 20 mo - Resection, radiation Liver 48 36 mo - Resection - 13 108 mo - Radiation Lung 43 NA - Resection LN 0 3 mo Solid - Radiation Lung 4 2.9 ± 1.0 mo Cyst - BSC Lung 0 2.9 ± 1.0 mo Solid + Biopsy Liver, LN 6 4d Solid 54/M Cyst 14 Rajappa et al. 67/M Cyst Kumar et al.15 61.5 (49–70)/NA Solid 61.5 (49–70)/NA Solid 68/M Cyst Chiang et al. Matsumoto and Yoshida16 Multiple metastatic lesions Park et al.3 48/M 62/M 8 AC C 66/M 12 SC Resection M AN U 10 - TE D Caricato et al.9 Solid EP Park et al.3 58/M Kamar et al. 56/M 13 Rao et al. 57/M Solid - Radiation Lung, liver, bone, 0 BSC, NA Kumar et al.15 61.5 (49–70)/NA NA - Resection, radiation - 22 NA ACCEPTED MANUSCRIPT NA - Radiation Liver, bone 2 NA 61.5 (49–70)/NA NA - NA Liver, bone 2 NA 61.5 (49–70)/NA Cyst - NA LN, lung 57 NA 61/F Solid + Resection, BSC Lung, liver, peritoneal 16 3w RI PT Present case 61.5 (49–70)/NA dissemination SC *Interval between diagnosis of pancreatic adenocarcinoma and diagnosis of the metastatic brain tumor. BM, brain metastasis; BSC, best supportive care; d, days; F, female; AC C EP TE D M AN U LN, lymph node; M, male; mo, months; NA, not available; w, weeks AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT