Transarterial radioembolization (TARE) is one of the few treatment options available for infiltrative hepatocellular carcinoma with tumor in vein. This is backed by the published data showing marginally favorable toxicity profile compared with other locoregional and systemic therapies. Although lung shunt fraction studies are performed to prevent radiation injury to the lungs, TARE-induced embolization/metastasis to the lungs has not been reported before. We report an intriguing case of new lung metastases within 1 month after TARE for infiltrative hepatocellular carcinoma with a tumor in the vein, with only a slightly elevated but acceptable lung shunt fraction. This report brings to light the possibility of such a complication and argues for improved preprocedural assessment of a tumor in vein burden and embolization potential

Kapoor, Harit

Owen, Joseph W.

Raissi, Driss

Sanampudi, Sreeja

English

University of Kentucky

UKnowledge University of Kentucky UKnowledge Radiology Faculty Publications Radiology 2-2020 Lung Metastasis Postradioembolization of Hepatocellular Carcinoma With Tumor in Vein Harit Kapoor University of Kentucky, haritkapoor@uky.edu Sreeja Sanampudi University of Kentucky, sreeja.sanampudi@uky.edu Joseph W. Owen University of Kentucky, joseph.owen@uky.edu Driss Raissi University of Kentucky, driss.raissi@uky.edu Follow this and additional works at: https://uknowledge.uky.edu/radiology_facpub  Part of the Oncology Commons, and the Radiology Commons Right click to open a feedback form in a new tab to let us know how this document benefits you. Repository Citation Kapoor, Harit; Sanampudi, Sreeja; Owen, Joseph W.; and Raissi, Driss, "Lung Metastasis Postradioembolization of Hepatocellular Carcinoma With Tumor in Vein" (2020). Radiology Faculty Publications. 25. https://uknowledge.uky.edu/radiology_facpub/25 This Article is brought to you for free and open access by the Radiology at UKnowledge. It has been accepted for inclusion in Radiology Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact UKnowledge@lsv.uky.edu. Lung Metastasis Postradioembolization of Hepatocellular Carcinoma With Tumor in Vein Notes/Citation Information Published in ACG Case Reports Journal, v. 7, issue 2, e00322, p. 1-4. © 2020 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Digital Object Identifier (DOI) https://doi.org/10.14309/crj.0000000000000322 This article is available at UKnowledge: https://uknowledge.uky.edu/radiology_facpub/25 Downloadedfromhttps://journals.lww.com/acgcrbyBhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3JIQl/9XFzqQ7+xNkhvNwTbefDiZ/kCm2SVTbm/kmW4pt5QBKoMfjOQ==on06/22/2020Downloadedfromhttps://journals.lww.com/acgcrbyBhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3JIQl/9XFzqQ7+xNkhvNwTbefDiZ/kCm2SVTbm/kmW4pt5QBKoMfjOQ==on06/22/2020ACG CASE REPORTS JOURNALCASE REPORT | LIVERLung Metastasis Postradioembolization ofHepatocellular Carcinoma With Tumor in VeinHarit Kapoor, MBBS1, Sreeja Sanampudi, MD1, Joseph Owen, MD1, and Driss Raissi, MD11Department of Radiology, University of Kentucky Chandler Medical Center, Lexington, KYABSTRACTTransarterial radioembolization (TARE) is one of the few treatment options available for infiltrative hepatocellular carcinoma withtumor in vein. This is backed by the published data showing marginally favorable toxicity profile compared with other locoregionaland systemic therapies. Although lung shunt fraction studies are performed to prevent radiation injury to the lungs, TARE-inducedembolization/metastasis to the lungs has not been reported before. We report an intriguing case of new lung metastases within 1month after TARE for infiltrative hepatocellular carcinomawith a tumor in the vein, with only a slightly elevated but acceptable lungshunt fraction. This report brings to light the possibility of such a complication and argues for improved preprocedural assessment ofa tumor in vein burden and embolization potential.INTRODUCTIONInfiltrative hepatocellular carcinoma (IHCC) is a subtype of advanced HCC that carries a very poor prognosis, especially whenassociated with tumor in vein (TIV). In these patients, treatment options are limited.1 Locoregional therapies such as transarterialradioembolization (TARE) with or without chemotherapy are performed in the liver-limited disease to downstage. TARE delivershepatic-selective brachytherapy, relying on the preferential arterial perfusion of the tumor. TARE has been shown to offer somesurvival benefit but more importantly a milder toxicity profile compared with other therapies for IHCC-TIV.2,3 We present anintriguing case of new lung metastases within 1 month after radioembolization of an IHCC-TIV.CASE REPORTA 56-year-old man with hepatitis C-related cirrhosis presented with new right upper abdominal pain. Other comorbidities includedhypertension, coronary artery disease status post bypass grafting, and epilepsy. He denied gastroenterology follow-up after thediagnosis of cirrhosis 5 years ago. History of present illness revealed unintentional weight loss of 50 pounds and dark colored urineworsening over the past year. Mild icterus and right upper quadrant tenderness were elicited on physical examination. Laboratoryworkup revealed an hemoglobin of 13.5 g/dL, platelets of 205 k/uL, creatinine of 0.6 mg/dL, aspartate aminotransferase of 198 U/L,alanine aminotransferase of 41 U/L, alkaline phosphatase level of 119 IU/L, international normalized ratio of 1.2, serum sodium of127 mmol/L, bilirubin of 2.1 mg/dL, and alpha-feto-protein (AFP) level of 354,260 ng/mL. Specific disease scores were calculated tobe Child-Pugh Class B and Model for End-Stage Liver Disease—Sodium of 21. Imaging showed an infiltrative necrotic 123 10-cmmass within posterior segments of the right liver (VI and VIII) along with the thrombosis of the right posterior portal vein, reportedas Liver Imaging Reporting and Data System—TIV (Figure 1). A complete diagnosis of unresectable Stage IV-B (T3bN1M0)hepatocellular carcinoma was made after tumor board review. Interventional radiology was consulted for TARE. Review of pre-procedural imaging revealed unremarkable arterial anatomy. Three weeks later, the patient underwent arterial mapping withTechnetium-99m macroaggregated albumin (Tc-99m MAA; 4.15 mCi) via standard right femoral artery access and right hepaticsuperselection. Postmapping liver imaging with single-photon emission computed tomography (SPECT-CT) revealed the expectedtracer distribution and an acceptable but borderline high-lung shunt fraction (LSF) of 11% (Figure 2). After another 5-week interval,133.5mCi dose of Y-90 TheraSphere (MDS Nordion, Ottawa, ON, Canada) was administered to targeted segments.ACG Case Rep J 2020;7:e00322. doi:10.14309/crj.0000000000000322. Published online: March 10, 2020Correspondence: Harit Kapoor, MBBS (haritkapoor@uky.edu).ACG Case Reports Journal / Volume 7 acgcasereports.com 1Tracer localization was limited to tumor-containing hepaticsegments on postprocedure bremsstrahlung SPECT-CT. Un-fortunately, the patient presented back to the emergency de-partment 3 weeks post-TARE with severe abdominal pain.Abdominal, thoracic, and pelvic contrast-enhanced CT dem-onstrated necrosis within the index tumor (Figure 3) but withnew findings of multiple lung metastases which were notpresent on the thoracic CT performed 53 days before Y-90embolization (Figure 4). Laboratory test results revealed onlya modest drop in AFP. Prominent arterioportal shunting wasevident on a retrospective review of intraprocedural images(Figure 5). The patient did not tolerate sorafenib therapy andultimately opted for home hospice.DISCUSSIONWe present a case of metastatic disease to the lungs within onemonth after radioembolization of an infiltrative HCC withbranch portal vein thrombus. A significant limitation to thisreport is the possibility of metastatic progression in the near 2-month gap period between preoperative imaging and emboli-zation, especially considering the aggressive tumor profile.However, it would be irrational to dismiss the alternative pos-sibility of iatrogenic metastatic facilitation.Embolization with beta-emitter Y-90 is indicated in unre-sectable HCC when (i) HCC is liver limited, (ii) expectedsurvival of at least 12 weeks with the Eastern CooperativeOncology Group (ECOG) performance status of, 2, and (iii)acceptable hepatic functional status (lack of ascites, total bil-irubin ,2 mg/dL, and albumin .3 mg/dL).4 Absolute con-traindications to the procedure include a LSF . 20%or a predicted single session lung dose estimation of. 30 Gyon postmapping SPECT.4 Complications include procedure-related vascular injury, postembolization syndrome, andmost importantly complications arising from nontargetembolization.Radiation pneumonitis can be a serious complication withhepatopulmonary shunting being quite common in patientswith cirrhosis. In fact, patients who develop HCC and espe-cially those with IHCC-TIV are more strongly associated withsuch shunting.5 This very disease attributemakes itmandatoryto performpreproceduremapping to estimate LSF. In additionto being a good predictor for complications such as radiationpneumonitis, LSF has also been shown to be an independentpredictor of metastatic risk in HCC, with 2 times higher LSFsin those with extrahepatic metastases.6 LSF is currentlyFigure 1. Axial contrast-enhanced computed tomography imagesbefore transarterial radioembolization showing a necrotic mass(white star) and tumor in the veinwithin the right posterior portal veinbranch (white arrow).Figure 2. Single-photon emission computed tomography imagingafter initial arterial mapping procedure.Figure 3.Retrospective review of intraprocedural digital subtractionangiographic acquisition showing prominent arterioportal shunting.ACG Case Reports Journal / Volume 7 acgcasereports.com 2Kapoor et al Lung Metastasis Postradioembolization of HCCperformed by injecting Tc-99m MAA intra-arterially into theliver as a test run before actual Y-90 administration. In mostcenters, images are then obtained using a planar gammacamera. The fraction of total counts reaching the lung (LSF)are derived by calculating the geometric mean of countsdetected in themanually drawn region of interest over the lungon both anterior and posterior planar views. LSF values areknown to become less reliable with time, especially beyond 4hours because of biologic disintegration of MAA.7 LSF wascalculated with planar imaging at 45 minutes postinjection inour case. Although SPECT-CT is performed at many centers,for visual assessment of extrahepatic deposition, it is notroutinely used for LSF calculation. Given its poor anatomicresolution and the inability of performing attenuation cor-rection, planar imaging is prone to overestimation of shuntfractionwhen comparedwith SPECT-CT.8 Ideally, LSF shouldbe less than 10%. Although dose adjustments can be per-formed in patients with LSF ranging between 10% and 20%,those with LSF exceeding 20% are excluded from treatment.9Although our patient only had a borderline high LSF of 11%,multiple other risk factors for metastatic progression werepresent including a large tumor burden with macrovascularinvasion and very high AFP levels. To this point, Fleming et alproposed a judicious way of pre-TARE patient selection byinversely customizing the LSF cutoff based on anatomic tumorbulk and aggressive features.5An abscopal effect of radiation-induced augmentation of anti-tumor immune response has been described in the literature.10On the contrary, this case exhibits a “reverse” abscopal effect.Figure 4. Representative lung window computed tomography images at comparable axial and sagittal planes, (A) before and (B) aftertransarterial radioembolization showing the development of new multifocal rounded pulmonary metastasis (yellow circles).ACG Case Reports Journal / Volume 7 acgcasereports.com 3Kapoor et al Lung Metastasis Postradioembolization of HCCOur literature search for similar cases incidentally revealeda growing body of evidence showing a trend for regional(but not metastatic) tumor potentiation after other locore-gional therapies including ablation and transarterialchemoembolization.11–13 Tumor size, proximity to a sizeableportal vein, infiltrative morphology, and lower age have beenlinked to higher risk of such an occurrence.11 Multiple potentialmechanisms have been proposed: (i) iatrogenic arterioportalshunt creation, (ii) induction of immune activation (high re-gional hepatocyte growth factor which in turn can activatedownstream c-Met pathway leading to a greater vascular endo-thelial growth factor synthesis) and, (iii) increased intratumorpressure from associated edema causing rupture of the indexlesion and dissemination of viable tumor cells.11,12,14 In conclu-sion, this report brings to light the possibility of metastatic po-tentiation after TARE in patients with IHCC-TIV and argues forimproved preprocedural assessment of TIV burden andthoughtful consideration of adjunctive biochemical markers,especially when deciding for TARE candidacy in patients withborderline elevated LSF values.DISCLOSURESAuthor contributions: H. Kapoor and S. Sanampudi wrotethe manuscript. J. Owen and D. Raissi revised the manuscript.H. Kapoor is the article guarantor.Financial disclosure: None to report.Informed consent was obtained for this case report.Received July 7, 2019; Accepted December 19, 2019REFERENCES1. Heimbach JK, Kulik LM, FinnRS, et al. AASLDguidelines for the treatmentof hepatocellular carcinoma. Hepatology. 2018;67(1):358–80.2. Riaz A, Lewandowski R, Salem R. Radioembolization in advanced hepa-tocellular carcinoma. J Clin Oncol. 2018;36(19):1898–901.3. Abouchaleh N, Gabr A, Ali R, et al. Y radioembolization for locally ad-vanced hepatocellular carcinoma with portal vein thrombosis: Long-termoutcomes in a 185-patient cohort. J Nucl Med. 2018;59(7):1042–8.4. Coldwell D, Sangro B, Wasan H, Salem R, Kennedy A. General selectioncriteria for patients for radioembolization of liver tumors: An internationalworking group report. Am J Clin Oncol. 2011;34:337–41.5. Fleming CJ, Andrews JC, Wiseman GA, Gansen DN, Roberts LR. Hepaticvein tumor thrombus as a risk factor for excessive pulmonary deposition ofmicrospheres during TheraSphere therapy for unresectable hepatocellularcarcinoma. J Vasc Interv Radiol. 2009;20(11):1460–3.6. Sandow T, Devun D, Gulotta P, Bohorquez H, KirschD. Elevated lung shuntfraction as a prognostic indicator for disease progression and metastasis inhepatocellular carcinoma. J Vasc Interv Radiol. 2016;27(6):804–11.7. De gersem R, Maleux G, Vanbilloen H, et al. Influence of time delay on theestimated lung shunt fraction on 99mTc-labeledMAA scintigraphy for 90Ymicrosphere treatment planning. Clin Nucl Med. 2013;38(12):940–2.8. Dittmann H, Kopp D, Kupferschlaeger J, et al. A prospective study ofquantitative SPECT/CT for evaluation of lung shunt fraction before SIRT ofliver tumors. J Nucl Med. 2018;59(9):1366–72.9. Kallini JR, Gabr A, Salem R, Lewandowski RJ. Transarterial radio-embolization with yttrium-90 for the treatment of hepatocellular carci-noma. Adv Ther. 2016;33:699–714.10. Waxweiler TV, Raben D. “Chapter 5—Biologics and their interactions withradiation.” In: Gunderson LL, Tepper JE. Clinical Radiation Oncology, 4thedn. Elsevier: Philadelphia, PA, 2016, pp 80–92.e4.11. KangTW,LimHK,ChaDI.Aggressive tumor recurrence after radiofrequencyablation for hepatocellular carcinoma. Clin Mol Hepatol. 2017;23(1):95–101.12. Ahmed M, Kumar G, Moussa M, et al. Hepatic radiofrequency ablation–induced stimulation of distant tumor growth is suppressed by c-Met in-hibition. Radiology. 2016;279(1):103–17.13. Song KD, Lee MW, Rhim H, et al. Aggressive intrasegmental recurrence ofhepatocellular carcinoma after combined transarterial chemoembolizationand radiofrequency ablation. Am J Roentgenol. 2016;207(5):1122–7.14. Kotoh K, Nakamuta M, Morizono S, et al. A multi-step, incremental ex-pansion method for radio frequency ablation: Optimization of the pro-cedure to prevent increases in intra-tumor pressure and to reduce theablation time. Liver Int. 2005;25:542–7.Copyright:ª 2020 The Author(s). Published byWolters Kluwer Health, Inc. on behalf ofThe American College of Gastroenterology. This is an open-access article distributedunder the terms of the Creative Commons Attribution-Non Commercial-No DerivativesLicense 4.0 (CCBY-NC-ND), where it is permissible to download and share the workprovided it is properly cited. The work cannot be changed in any way or used com-mercially without permission from the journal.Figure 5. Axial contrast-enhanced computed tomography imagestaken 53 days after transarterial radioembolization showing thenecrosis of the index tumor (black star).ACG Case Reports Journal / Volume 7 acgcasereports.com 4Kapoor et al Lung Metastasis Postradioembolization of HCC

Lung Metastasis Postradioembolization of Hepatocellular Carcinoma With Tumor in Vein

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Lung Metastasis Postradioembolization of Hepatocellular Carcinoma With Tumor in Vein

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