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REVIEW ARTICLE Recurrence of Epithelioid during Pregnancy: Case Report and Systematic Review

Michael McCulloch, LAc, MPH, PhD; Michael Russin, MD; Arian Nachat, MD Perm J 2016 Summer;20(3):15-152 E-pub: 07/25/2016 http://dx.doi.org/10.7812/TPP/15-152

ABSTRACT (p = 0.1). There was additionally nonsig- Introduction: Epithelioid hemangioendothelioma (EHE) is a family of nificant lower 5-year survival in meta- tumors originating in blood vessels, , brain, , , and . EHE is more com- static (69%) compared with localized mon in women, and , radiation, and surgery have brought few successes. (78.3%) disease (p = 0.7). Treatment with Case presentation: We present a case of a 28-year-old woman whose EHE recurred any chemotherapy decreased 5-year sur- during pregnancy, suggesting hormonal involvement. We conducted a systematic re- vival, compared with no chemotherapy view to provide analysis and interpretation of the potential significance of her disease (43.6% vs 82.9%; p = 0.02).7 recurring, with fatal outcome, during pregnancy. Diagnostic approaches to EHE include Discussion: Very little research has explored the use of individual hormonal markers. computed tomography (CT),8 magnetic Strongly positive expression of placenta growth factor (PlGF) and 17-beta estradiol resonance imaging,9,10 CT and magnetic receptors have been reported. Expression of PlGF is noteworthy in our case, in that our resonance imaging,9 and serial bone patient’s disease quickly and dramatically flared in the 25th week of pregnancy, near the scintigraphy.11 (18)F-fluorodeoxyglucose- peak in maternal PlGF production. PlGF binds to vascular endothelial growth factor-1 positron emission tomography with (VEGF-1), and PlGF may accelerate VEGF-induced angiogenesis. Taken together, these strong (18)F-fluorodeoxyglucose uptake factors may explain our patient’s EHE recurrence and rapid flare-up during pregnancy. has been used12 but is limited by lack of Treatment of EHE with VEGF inhibition, potentially in combination with other antian- correlation between lesion size and maxi- giogenic and tumor-inhibiting therapies such as lenalidomide, thalidomide, sorafenib, mum standardized uptake value.13 and sunitinib, may also hold promise. Little is known about efficacy of ther- apy because the low incidence of EHE INTRODUCTION which can significantly worsen progno- precludes conduct of human clinical Epithelioid hemangioendothelioma sis.4 Little is known about prognostic trials. Options currently include che- (EHE) is a family of vascular tumors, factors for patients with EHE, although motherapy, radiation, hormone therapy, originating in the and recent work has identified genetic altera- thermo-ablation, and surgery, although sharing clinical characteristics with both tions involving activation of the ROS1 most do not change the usually poor and benign . receptor tyrosine kinase, which for other prognosis of a diagnosis with EHE. In EHE was first identified in 19821 and is cancers has led to effective therapies patients with primary hepatic EHE, extremely rare, with an incidence rate working through ROS1 inhibition.5 overall survival is no different following of 0.1 per 100,000, and fewer than Two case series have described the liver resection or transcatheter arterial 200 cases ever reported in the medical prognosis of patients with hepatic EHE. chemoembolization (p = 0.50).6 Al- literature.2 Because there is limited re- In a series from China (N = 33), survival though patients with hepatic EHE have search on prognosis, a layperson registry was longer in patients younger than age longer median survival compared with has been established. The International 47 years (hazard ratio, 7.0; p = 0.035), those with other hepatic vascular tumors, Hemangioendothioma, Epithelioid in those without symptoms (hazard ra- in these patients surgical resection does Hemangioendothelioma, and Related tio, 86.5; p = 0.001), and in those with not improve survival.14 Vascular Disorders Support Group has serum cancer antigen 19-9 below 37 Development and testing of newer tracked more than 260 patients.3 units/mL (hazard ratio, 5.0; p = 0.018).6 therapies based on vascular endothe- The clinical presentation of EHE is In a series from the United Kingdom lial growth factor (VEGF) inhibition quite varied; it can originate in bone, (N = 50), patients with bilateral hepatic is supported by recent studies showing brain, kidney, liver, lung, and vascu- disease had shorter 5-year survival (51%) positive expression of VEGF receptor lar and other soft tissues. Diagnosis is compared with those with unilateral dis- in biopsied lesions.15,16 Additional case sometimes delayed owing to uncertainty ease (81%), although the study size was reports of success with lenalidomide,17 about correct pathologic classification, too small to show a significant difference thalidomide,2 sorafenib (possessing both

Michael McCulloch, LAc, MPH, PhD, is the Research Lead for Integrative Medicine at the Walnut Creek Hospital in CA and a Research Chief at the Pine Street Foundation in San Anselmo, CA. E-mail: [email protected]. Michael Russin, MD, is the Chief at the Walnut Creek Hospital in CA. E-mail: [email protected]. Arian Nachat, MD, is the Director of Integrative Medicine at the Walnut Creek Hospital in CA. E-mail: [email protected].

84 The Permanente Journal/Perm J 2016 Summer;20(3):15-152 REVIEW ARTICLE Recurrence of Epithelioid Hemangioendothelioma during Pregnancy: Case Report and Systematic Review

antiangiogenic and antiproliferative ac- tivity),18 and sunitinib19 suggest other targeted molecular therapies may also hold promise. The current case report documents di- agnosis of recurrent EHE in a pregnant woman and discusses the case in the con- text of a systematic review of the current literature. This report was prepared in ac- cordance with the CARE (CAse REport) guidelines.20 Figure 1. Hematoxylin/eosin stain showing epithe- lioid cells with cytoplasmic vacuoles (magnification CASE PRESENTATION ×400). We report a case of a 28-year-old woman originally diagnosed with EHE in 2002, at age 18 years. CT-guided of 1 of her liver lesions revealed EHE based on hematoxylin/eosin and im- Figure 5. Computed tomography angiography of the chest, showing stable disease in 2008. munohistochemical stains (Figures 1-4). Repeated CT of her chest, abdomen, and pelvis 3 months later showed progression of disease. At that time she underwent 6 cycles of carboplatin and etoposide with stabilization of disease; however, signifi- cant chest pain remained, requiring high doses of opiates. She received 1 dose of Figure 2. Hematoxylin/eosin stain showing epithe- interferon, which was not tolerated. The lioid cells with cytoplasmic vacuoles (magnification patient was then followed up with serial ×600). CT scan showing stable disease through 2011 (Figures 5 and 6). In 2012, the patient presented to the Emergency Department with chest pain and in acute respiratory distress. A pos- terior-anterior/lateral revealed multiple pulmonary nodules bi- laterally, confirmed as “innumerable” by chest CT, along with bulky mediastinal Figure 6. Computed tomography angiography of the adenopathy and multiple liver lesions con- chest, showing stable disease in 2011. sistent with metastatic disease (Figure 7). In mid-2012, the patient presented with diffuse joint pain 6 months into Figure 3. Immunohistochemical stain positive for scan was consistent with hypertrophic vascular marker CD31 (magnification ×600). her first pregnancy, and went into labor osteoarthropathy. During this time her at 25 weeks. The baby was delivered and respiratory status continued to worsen: died 8 days later. The patient’s pain then chest CT revealed compression of the continued to escalate and she developed right upper lobe bronchus and right pleu- severe cough. Repeat CT scan of her chest, ral effusion. A right-sided chest tube was abdomen, and pelvis revealed significant inserted with drainage of a large amount progression of disease, especially in the of pleural fluid and palliative radiation to and mediastinum. Biopsy of medi- the mediastinal adenopathy was started. astinal adenopathy confirmed recurrent Unfortunately the patient’s respiratory EHE, and the diffuse nature of disease status continued to decline from progres- precluded surgery. sive disease as well as pneumonia. She The patient’s diffuse joint and bone was intubated; her condition continued pain continued to worsen, resulting in to decline; she was placed on comfort Figure 4. Immunohistochemical stain positive for hospitalization for pain control. Bone measures, and she subsequently died. vascular marker CD34 (magnification ×600).

The Permanente Journal/Perm J 2016 Summer;20(3):15-152 85 REVIEW ARTICLE Recurrence of Epithelioid Hemangioendothelioma during Pregnancy: Case Report and Systematic Review

A timeline showing progression of the In Table 1 we present results of a sys- case is provided in Figure 8. tematic search of treatment outcomes published since January 2011. Tumor DISCUSSION marker expression in EHE has been re- Despite numerous publications, EHE ported for endothelial markers (CD31, remains a little-understood disease of poor CD34, and factor VIII-related antigen),21 prognosis. In the case of localized disease, VEGF and VEGF receptor 2,15 and strong prompt surgical resection appears to con- expression of CD31 and .12 fer a survival advantage. Improvements in Errani et al22,23 reported that WWTR1- early clinical identification of suspected CAMTA1 fusion is a genetic hallmark lesions may be accelerated by further re- of EHE, regardless of site of origin; they Figure 7. Computed tomography angiography of the chest, following disease recurrence in 2012. search on the integration of tumor marker also used reverse transcription-polymerase and/or hormonal testing. chain reaction and gene sequencing to

Table 1. Epithelioid hemangioendothelioma primary tumor sites, first-line therapy, and maximum reported survival with therapy Primary Extent First-line Author, year tumor site of disease therapy Patient(s) Survival Case series Angelini et al,1 2014 Bone Unifocal (49%); Wide excision or intralesional N = 62; men, n = 39; Survival at 10 years: multifocal (13%) surgery women, n = 23; mean unifocal, 97%; multifocal, age = 39 years 74% Zheng et al,2 2012 Brain Intracranial, with Surgery 25-year-old man; 9 years localized extension to 44-year-old woman bone and muscle Agulnik et al,3 2013 Multifocal Metastatic Bevacizumab N = 7 Partial response, n = 2; stable disease, n = 4; progressive disease, n = 1 Wang et al,4 2012 Liver Localized and Liver resection, transcatheter N = 33 Up to 3 years of follow-up extrahepatic arterial chemoembolization (TACE), resection and TACE, or liver transplantation Theodosopoulos et al,5 Intracranial Metastatic Surgery N = 38; men, n = 23; 2 months-11 years 2013 women, n = 15 Case reports Gherman and Fodor,6 Bone Localized Wide surgical excision 24-year-old man No local recurrence or 2011 at 2 years Sumrall et al,7 2010 Brain Intracranial, localized Lenalidomide 31-year-old woman 6 years, stable disease extension to skull, connective tissue Osawa et al,8 2012 Carotid artery Localized Surgery 59-year-old man; 14 Rapid death years after embolization for carotid aneurysm Tolkach et al,9 2012 Kidney Metastatic Sunitinib 53-year-old man 3 years, stable disease Harada et al,10 2011 Liver Localized Transcatheter arterial 83-year-old man Metastatic recurrence chemoembolization after 3 months Grenader et al,11 2011 Liver Localized Pegylated liposomal 32-year-old man 2 years, stable disease doxorubicin with maintenance therapy at time of publication Sangro et al,12 2012 Liver Metastatic to lungs Sorafenib 22-year-old man 2 years Salech et al,13 2011 Liver Metastatic to lungs Thalidomide 40-year-old woman 9 years, stable disease Mizota et al,14 2011 Lung Localized Bevacizumab 59-year-old woman 3 months Iimuro et al,15 2012 Retroperitoneum Localized, then distant Surgical removal of both 48-year-old woman No recurrence at 13 lymph metastasis occurrences months after resection of months later metastasis Kerry et al,16 2012 Spinal region Multifocal Endovascular embolization, 25-year-old man 8 weeks radiochemotherapy De Palma et al,17 2012 Vascular Localized Surgical removal of entire 47-year-old man No recurrence at 1 year azygos vein (Continued on next page)

86 The Permanente Journal/Perm J 2016 Summer;20(3):15-152 REVIEW ARTICLE Recurrence of Epithelioid Hemangioendothelioma during Pregnancy: Case Report and Systematic Review

ascertain that in multifocal EHE, those EHE is more common in women, Very little research has explored the multiple sites are monoclonal in nature, and there are 3 prior case reports of its clinical utility of individual hormonal and therefore metastatic implants of the diagnosis during pregnancy,17 with ours markers in EHE. There was strongly posi- same tumor and not simultaneous oc- being the fourth. A case report has also tive expression of placenta growth factor currence of multiple neoplastic clones. been published of successful management (PlGF) in 1 case,33 positive expression of Additionally, both CD31 and VEGF of multifocal hepatic infantile heman- 17-beta estradiol receptors in only 1 of a are overexpressed in non-small cell lung gioendothelioma with -based series of 5 EHE patients,34 and no estro- cancer,24 breast cancer,25 prostate can- therapy.32 Tamoxifen (20 mg daily) was gen or receptors in another cer,26 renal cell carcinoma,27 mantle cell part of the management strategy used for case.35 Expression of PlGF is noteworthy lymphoma,28 ,29 pituitary our patient over a 9-day course during her in our case, in that our patient’s disease adenomas,30 and uveal melanoma.31 acute disease recurrence. quickly and dramatically flared in the

(Continued from previous page) Primary Extent First-line Author, year tumor site of disease therapy Patient(s) Survival Case reports (continued) Wu et al,18 2014 Vascular Localized Surgery 58-year-old woman 2 years, stable at time of publication Demir et al,19 2013 Liver Parenchymal lesion Carboplatin, pharmorubucin 24-year-old woman with metastases to lung Kiratli et al,20 2013 Eyelid Localized Excisional biopsy 22-year-old woman No recurrence at 44 months Pálföldi et al,21 2013 Lung Metastatic to bone Carboplatin, docetaxel, 49-year-old woman Stable disease 1 year pharmorubucin after diagnosis Yu et al,22 2013 Lung Lung (localized to Carboplatin/etoposide, 39-year-old woman Alive 14 months after myocardium) followed by surgical excision surgery 1 Angelini A, Mavrogenis AF, Gambarotti M, Merlino B, Picci P, Ruggieri P. Surgical treatment and results of 62 patients with epithelioid hemangioendothelioma of bone. J Surg Oncol 2014 Jun;109(8):791-7. DOI: http://dx.doi.org/10.1002/jso.23587. 2 Zheng J, Liu L, Wang J, Wang S, Cao Y, Zhao J. Primary intracranial epithelioid hemangioendothelioma: a low-proliferation tumor exhibiting clinically malignant behavior. J Neurooncol 2012 Oct;110(1):119-27. DOI: http://dx.doi.org/10.1007/s11060-012-0945-x. 3 Agulnik M, Yarber JL, Okuno SH, et al. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid . Ann Oncol 2013 Jan;24(1):257-63. DOI: http://dx.doi.org/10.1093/annonc/mds237. 4 Wang LR, Zhou JM, Zhao YM, et al. Clinical experience with primary hepatic epithelioid hemangioendothelioma: retrospective study of 33 patients. World J Surg 2012 Nov;36(11):2677-83. DOI: http://dx.doi.org/10.1007/s00268-012-1714-x. 5 Theodosopoulos T, Dellaportas D, Tsangkas A, et al. Clinicopathological features and management of hepatic vascular tumors. A 20-year experience in a Greek University Hospital. J BUON 2013 Oct-Dec;18(4):1026-31. 6 Gherman CD, Fodor D. Epithelioid hemangioendothelioma of the forearm with radius involvement. Case report. Diagn Pathol 2011 Dec 6;6:120. DOI: http://dx.doi.org/10.1186/1746-1596-6-120. 7 Sumrall A, Fredericks R, Berthold A, Shumaker G. Lenalidomide stops progression of multifocal epithelioid hemangioendothelioma including intracranial disease. J Neurooncol 2010 Apr;97(2):275-7. DOI: http://dx.doi.org/10.1007/s11060-009-0017-z. 8 Osawa S, Saito A, Shimizu H, Ogawa T, Watanabe M, Tominaga T. A case of intravascular epithelioid hemangioendothelioma occurring 14 years after coil embolization for an extracranial internal carotid artery aneurysm. J Vasc Surg 2012 Jan;55(1):230-3. DOI: http://dx.doi.org/10.1016/j.jvs.2011.06.108. 9 Tolkach Y, Petrov S, Lerut E, Van Poppel H. Epithelioid hemangioendothelioma of the kidney treated with sunitinib. Onkologie 2012;35(6):376-8. DOI: http://dx.doi.org/10.1159/000338944. 10 Harada J, Yoshida H, Ueda J, et al. Malignant hepatic epithelioid hemangioendothelioma with abdominal pain due to rapid progression. J Nippon Med Sch 2011;78(4):246-51. DOI: http:// dx.doi.org/10.1272/jnms.78.246. 11 Grenader T, Vernea F, Reinus C, Gabizon A. Malignant epithelioid hemangioendothelioma of the liver successfully treated with pegylated liposomal doxorubicin. J Clin Oncol 2011 Sep 1;29(25):e722-4. DOI: http://dx.doi.org/10.1200/jco.2011.35.5891. 12 Sangro B, Iñarrairaegui M, Fernández-Ros N. Malignant epithelioid hemangioendothelioma of the liver successfully treated with Sorafenib. Rare Tumors 2012 Apr 12;4(2):e34. DOI: http:// dx.doi.org/10.4081/rt.2012.e34. 13 Salech F, Valderrama S, Nervi B, et al. Thalidomide for the treatment of metastatic hepatic epithelioid hemangioendothelioma: a case report with a long term follow-up. Ann Hepatol 2011 Jan-Mar;10(1):99-102. 14 Mizota A, Shitara K, Fukui T. Bevacizumab chemotherapy for pulmonary epithelioid hemangioendothelioma with severe dyspnea. J Thorac Oncol 2011 Mar;6(3):651-2. DOI: http://dx.doi. org/10.1097/jto.0b013e31820b9e23. 15 Iimuro Y, Nakai N, Asano Y, et al. Primary epithelioid hemangioendothelioma of the retroperitoneum: report of a case. Surg Today 2012 Oct;42(10):1026-31. DOI: http://dx.doi.org/10.1007/ s00595-012-0173-1. 16 Kerry G, Marx O, Kraus D, et al. Multifocal epithelioid hemangioendothelioma derived from the spine region: case report and literature review. Case Rep Oncol 2012 Jan;5(1):91-8. DOI: http://dx.doi.org/10.1159/000336947. 17 De Palma A, Pagliarulo V, Ardò N, Loizzi D. Surgical treatment of a rare case of epithelioid hemangioendothelioma of the azygos vein. Interact Cardiovasc Thorac Surg 2012 Jan;14(1):91- 3. DOI: http://dx.doi.org/10.1093/icvts/ivr064. 18 Wu XN, Chen MJ, Li DQ, Hu JG, Yu FL. Pulmonary artery pseudoaneurysm caused by a rare : epithelioid hemangioendothelioma. Thorac Cardiovasc Surg 2014 Feb;62(1):92-4. DOI: http://dx.doi.org/10.1055/s-0031-1299588. 19 Demir L, Can A, Oztop R, et al. Malignant epithelioid hemangioendothelioma progressing after chemotherapy and Interferon treatment: a case presentation and a brief review of the literature. J Cancer Res Ther 2013 Jan-Mar;9(1):125-7. DOI: http://dx.doi.org/10.4103/0973-1482.110386. 20 Kiratli H, Tarlan B, Ruacan S. Epitheloid hemangioendothelioma of the palpebral lobe of the lacrimal gland. Orbit 2013 Apr;32(2):120-3. DOI: http://dx.doi.org/10.3109/01676830.2013.764443. 21 Pálföldi R, Radács M, Csada E, et al. Pulmonary epithelioid haemangioendothelioma studies in vitro and in vivo: new diagnostic and treatment methods. In Vivo 2013 Mar-Apr;27(2):221-5. 22 Yu L, Gu T, Xiu Z, Shi E, Zhao X. Primary pleural epithelioid hemangioendothelioma compressing the myocardium. J Card Surg 2013 May;28(3):266-8. DOI: http://dx.doi.org/10.1111/jocs.12094.

The Permanente Journal/Perm J 2016 Summer;20(3):15-152 87 REVIEW ARTICLE Recurrence of Epithelioid Hemangioendothelioma during Pregnancy: Case Report and Systematic Review

4. Osawa S, Saito A, Shimizu H, Ogawa T, Watanabe M, Tominaga T. A case of intravascular epithelioid hemangioendothelioma occurring 14 years after coil embolization for an extracranial internal carotid artery aneurysm. J Vasc Surg 2012 Jan;55(1):230-3. DOI: http://dx.doi.org/10.1016/j. jvs.2011.06.108. 5. Davies KD, Doebele RC. Molecular pathways: ROS1 fusion in cancer. Clin Cancer Res 2013 Aug 1;19(15):4040-5. DOI: http://dx.doi.org/10.1158/1078- 0432.ccr-12-2851. 6. Wang LR, Zhou JM, Zhao YM, et al. Clinical experience with primary hepatic epithelioid hemangioendothelioma: retrospective study of 33 patients. World J Surg 2012 Nov;36(11):2677-83. DOI: http://dx.doi.org/10.1007/s00268-012-1714-x. 7. Thomas RM, Aloia TA, Truty MJ, et al. Treatment sequencing strategy for hepatic epithelioid haemangioendothelioma. HPB (Oxford) 2014 Jul;16(7):677-85. DOI: http://dx.doi.org/10.1111/ hpb.12202. 8. Marchiori E, Hochhegger B, Zanetti G. Optimizing the utility of computed tomography in diagnosing pulmonary epithelioid hemangioendothelioma. Isr Med Assoc J 2012 Jun;14(6):403. 9. Lin J, Ji Y. CT and MRI diagnosis of hepatic epithelioid hemangioendothelioma. Hepatobiliary Pancreat Dis Int 2010 Apr;9(2):154-8. 10. Rocha Oliveira PC, Alcantara FP, de Souza- Vianna PE, Brito AP. Cerebral epithelioid Figure 8. Timeline of the patient’s case. hemangioendothelioma with thoracic simultaneous CT = computed tomography scan. involvement: advanced MRI features. Arq Neuropsiquiatr 2012 Aug;70(8):637-8. DOI: http:// dx.doi.org/10.1590/s0004-282x2012000800015. 11. Swainson I, Chan WL, Abbati D. Serial bone 25th week of pregnancy, near the peak anti-angiogenic, hormonal, and anti- scintigraphy in a case of malignant epithelioid in maternal PlGF production. Although VEGF agents has value as an avenue of hemangioendothelioma. Clin Nucl Med 2012 Apr;37(4):396-9. DOI: http://dx.doi.org/10.1097/ in our patient’s case PlGF was not tested, future clinical investigation. v rlu.0b013e31823eaac4. we did note an abnormally low human 12. Iimuro Y, Nakai N, Asano Y, et al. Primary epithelioid chorionic gonadotropin level during Disclosure Statement hemangioendothelioma of the retroperitoneum: report of a case. Surg Today 2012 Oct;42(10):1026-31. the second trimester of pregnancy of The author(s) have no conflicts of interest to DOI: http://dx.doi.org/10.1007/s00595-012-0173-1. 23 IU/mL. disclose. 13. Dong A, Dong H, Wang Y, Gong J, Lu J, Zuo C. MRI A translocation involving PlGF has and FDG PET/CT findings of hepatic epithelioid hemangioendothelioma. Clin Nucl Med 2013 15 Acknowledgment also been discovered in a case of EHE. Feb;38(2):e66-73. DOI: http://dx.doi.org/10.1097/ Furthermore, it is known that there is Mary Corrado, ELS, provided editorial assistance. rlu.0b013e318266ceca. binding of PlGF to VEGF receptor-1, 14. Groeschl RT, Miura JT, Oshima K, Gamblin TC, How to Cite this Article Turaga KK. Does histology predict outcome for and that PlGF may influence VEGF- malignant vascular tumors of the liver? J Surg McCulloch M, Russin M, Nachat A. Recurrence induced angiogenesis,36 which may ex- Oncol 2014 Apr;109(5):483-6. DOI: http://dx.doi. of epithelioid hemangioendothelioma during plain our patient’s rapid disease flare-up. org/10.1002/jso.23517. pregnancy: Case report and systematic review. 15. Matsuzawa S, Kanazawa T, Yamaguchi T, Nishino H, Although the scarcity of cases im- Perm J 2016 Summer;20(3):15-152. Kawada K, Ichimura K. Case of high-risk epithelioid pedes rapid progress in histochemical DOI: http://dx.doi.org/10.7812/TPP/15-152 hemangioendothelioma of the . Head Neck 2013 Oct;35(10):E317-20. DOI: http://dx.doi.org/10.1002/ characterization of EHE, a composite hed.23160. picture has begun to emerge that may References 16. Park MS, Ravi V, Araujo DM. Inhibiting the VEGF- aid researchers in its early identifica- 1. Weiss SW, Enzinger FM. Epithelioid VEGFR pathway in angiosarcoma, epithelioid hemangioendothelioma: a vascular tumor hemangioendothelioma, and / tion, perhaps leading to earlier diagnosis often mistaken for a carcinoma. Cancer solitary fibrous tumor. Curr Opin Oncol 2010 and more definitive treatment. VEGF 1982 Sep 1;50(5):970-81. DOI: http://dx.doi. Jul;22(4):351-5. DOI: http://dx.doi.org/10.1097/ expression15 and hormonal receptor org/10.1002/1097-0142(19820901)50:5<970::aid- cco.0b013e32833aaad4. cncr2820500527>3.0.co;2-z. 17. Sumrall A, Fredericks R, Berthold A, Shumaker G. expression have been reported in EHE. 2. Salech F, Valderrama S, Nervi B, et al. Thalidomide Lenalidomide stops progression of multifocal Furthermore, there are multiple reports for the treatment of metastatic hepatic epithelioid epithelioid hemangioendothelioma including of successful management of this vascu- hemangioendothelioma: a case report with a intracranial disease. J Neurooncol 2010 long term follow-up. Ann Hepatol 2011 Jan- Apr;97(2):275-7. DOI: http://dx.doi.org/10.1007/ lar cancer with antiangiogenic therapy Mar;10(1):99-102. s11060-009-0017-z. 17,18 2,37-39 (lenalidomide, thalidomide, 3. Lau K, Massad M, Pollak C, et al. Clinical patterns 18. Sangro B, Iñarrairaegui M, Fernández-Ros N. and sorafenib18). We therefore suggest and outcome in epithelioid hemangioendothelioma Malignant epithelioid hemangioendothelioma of with or without pulmonary involvement: insights from the liver successfully treated with Sorafenib. Rare it is possible that combination therapy an internet registry in the study of a rare cancer. Tumors 2012 Apr 12;4(2):e34. 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88 The Permanente Journal/Perm J 2016 Summer;20(3):15-152 REVIEW ARTICLE Recurrence of Epithelioid Hemangioendothelioma during Pregnancy: Case Report and Systematic Review

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All Attempts at a Rational Method of Cure

The main part of the science of disease is of a purely descriptive character, a scientific interpretation of facts and a clear insight into the intimate connection subsisting between different phenomena, which may precede all attempts at a rational method of cure, having been attained in a few instances only. … Therapeutic researchers must be regulated in the same manner as pathological. … The more careful tracing of the progress of morbid processes, and the insight into their modes of origin and retrogression, enable us to determine the principles of treatment with greater clearness than formerly.

— Friedrich Theodor von Frerichs, 1819-1885, German pathologist

The Permanente Journal/Perm J 2016 Summer;20(3):15-152 89