Recurrence of Epithelioid Hemangioendothelioma during ... · Recurrence of Epithelioid Hemangioendothelioma during

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

REVIEW ARTICLE

Recurrence of Epithelioid Hemangioendothelioma during Pregnancy: Case Report and Systematic ReviewMichael 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

ABSTRACTIntroduction: Epithelioid hemangioendothelioma (EHE) is a family of blood vessel

tumors originating in blood vessels, bone, brain, kidney, liver, and lung. EHE is more com-mon in women, and chemotherapy, radiation, and surgery have brought few successes.

Case presentation: We present a case of a 28-year-old woman whose EHE recurred during pregnancy, suggesting hormonal involvement. We conducted a systematic re-view to provide analysis and interpretation of the potential significance of her disease recurring, with fatal outcome, during pregnancy.

Discussion: Very little research has explored the use of individual hormonal markers. Strongly positive expression of placenta growth factor (PlGF) and 17-beta estradiol receptors have been reported. Expression of PlGF is noteworthy in our case, in that our patient’s disease quickly and dramatically flared in the 25th week of pregnancy, near the peak in maternal PlGF production. PlGF binds to vascular endothelial growth factor-1 (VEGF-1), and PlGF may accelerate VEGF-induced angiogenesis. Taken together, these factors may explain our patient’s EHE recurrence and rapid flare-up during pregnancy. Treatment of EHE with VEGF inhibition, potentially in combination with other antian-giogenic and tumor-inhibiting therapies such as lenalidomide, thalidomide, sorafenib, and sunitinib, may also hold promise.

INTRODUCTIONEpithelioid hemangioendothelioma

(EHE) is a family of vascular tumors, originating in the endothelium and sharing clinical characteristics with both angiosarcoma and benign hemangioma. EHE was first identified in 19821 and is extremely rare, with an incidence rate of 0.1 per 100,000, and fewer than 200 cases ever reported in the medical literature.2 Because there is limited re-search on prognosis, a layperson registry has been established. The International Hemangioendothioma, Epithelioid Hemangioendothelioma, and Related Vascular Disorders Support Group has tracked more than 260 patients.3

The clinical presentation of EHE is quite varied; it can originate in bone, brain, kidney, liver, lung, and vascu-lar and other soft tissues. Diagnosis is sometimes delayed owing to uncertainty about correct pathologic classification,

which can significantly worsen progno-sis.4 Little is known about prognostic factors for patients with EHE, although recent work has identified genetic altera-tions involving activation of the ROS1 receptor tyrosine kinase, which for other cancers has led to effective therapies working through ROS1 inhibition.5

Two case series have described the prognosis of patients with hepatic EHE. In a series from China (N = 33), survival was longer in patients younger than age 47 years (hazard ratio, 7.0; p = 0.035), in those without symptoms (hazard ra-tio, 86.5; p = 0.001), and in those with serum cancer antigen 19-9 below 37 units/mL (hazard ratio, 5.0; p = 0.018).6 In a series from the United Kingdom (N = 50), patients with bilateral hepatic disease had shorter 5-year survival (51%) compared with those with unilateral dis-ease (81%), although the study size was too small to show a significant difference

(p = 0.1). There was additionally nonsig-nificant lower 5-year survival in meta-static (69%) compared with localized (78.3%) disease (p = 0.7). Treatment with any chemotherapy decreased 5-year sur-vival, compared with no chemotherapy (43.6% vs 82.9%; p = 0.02).7

Diagnostic approaches to EHE include computed tomography (CT),8 magnetic resonance imaging,9,10 CT and magnetic resonance imaging,9 and serial bone scintigraphy.11 (18)F-fluorodeoxyglucose-positron emission tomography with strong (18)F-fluorodeoxyglucose uptake has been used12 but is limited by lack of correlation between lesion size and maxi-mum standardized uptake value.13

Little is known about efficacy of ther-apy because the low incidence of EHE precludes conduct of human clinical trials. Options currently include che-motherapy, radiation, hormone therapy, thermo-ablation, and surgery, although most do not change the usually poor prognosis of a diagnosis with EHE. In patients with primary hepatic EHE, overall survival is no different following liver resection or transcatheter arterial chemoembolization (p = 0.50).6 Al-though patients with hepatic EHE have longer median survival compared with those with other hepatic vascular tumors, in these patients surgical resection does not improve survival.14

Development and testing of newer therapies based on vascular endothe-lial growth factor (VEGF) inhibition is supported by recent studies showing positive expression of VEGF receptor in biopsied lesions.15,16 Additional case reports of success with lenalidomide,17 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 Oncology 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].

85The Permanente Journal/Perm J 2016 Summer;20(3):15-152

REVIEW ARTICLERecurrence 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

CASE PRESENTATIONWe report a case of a 28-year-old

woman originally diagnosed with EHE in 2002, at age 18 years. CT-guided biopsy of 1 of her liver lesions revealed EHE based on hematoxylin/eosin and im-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 interferon, which was not tolerated. The patient was then followed up with serial 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 chest radiograph revealed multiple pulmonary nodules bi-laterally, confirmed as “innumerable” by chest CT, along with bulky mediastinal adenopathy and multiple liver lesions con-sistent with metastatic disease (Figure 7).

In mid-2012, the patient presented with diffuse joint pain 6 months into her first pregnancy, and went into labor at 25 weeks. The baby was delivered and died 8 days later. The patient’s pain then continued to escalate and she developed severe cough. Repeat CT scan of her chest, abdomen, and pelvis revealed significant progression of disease, especially in the lungs and mediastinum. Biopsy of medi-astinal adenopathy confirmed recurrent EHE, and the diffuse nature of disease precluded surgery.

The patient’s diffuse joint and bone pain continued to worsen, resulting in hospitalization for pain control. Bone

scan was consistent with hypertrophic osteoarthropathy. During this time her respiratory status continued to worsen: chest CT revealed compression of the right upper lobe bronchus and right pleu-ral effusion. A right-sided chest tube was inserted with drainage of a large amount of pleural fluid and palliative radiation to the mediastinal adenopathy was started. Unfortunately the patient’s respiratory status continued to decline from progres-sive disease as well as pneumonia. She was intubated; her condition continued to decline; she was placed on comfort measures, and she subsequently died. Figure 4. Immunohistochemical stain positive for

vascular marker CD34 (magnification ×600).

Figure 3. Immunohistochemical stain positive for vascular marker CD31 (magnification ×600).

Figure 2. Hematoxylin/eosin stain showing epithe-lioid cells with cytoplasmic vacuoles (magnification ×600).

Figure 1. Hematoxylin/eosin stain showing epithe-lioid cells with cytoplasmic vacuoles (magnification ×400).

Figure 5. Computed tomography angiography of the chest, showing stable disease in 2008.

Figure 6. Computed tomography angiography of the chest, showing stable disease in 2011.



A timeline showing progression of the case is provided in Figure 8.

DISCUSSION Despite numerous publications, EHE

remains a little-understood disease of poor prognosis. In the case of localized disease, prompt surgical resection appears to con-fer a survival advantage. Improvements in early clinical identification of suspected lesions may be accelerated by further re-search on the integration of tumor marker and/or hormonal testing.

In Table 1 we present results of a sys-tematic search of treatment outcomes published since January 2011. Tumor marker expression in EHE has been re-ported for endothelial markers (CD31, CD34, and factor VIII-related antigen),21 VEGF and VEGF receptor 2,15 and strong expression of CD31 and vimentin.12 Errani et al22,23 reported that WWTR1-CAMTA1 fusion is a genetic hallmark of EHE, regardless of site of origin; they also used reverse transcription-polymerase chain reaction and gene sequencing to

Figure 7. Computed tomography angiography of the chest, following disease recurrence in 2012.

Table 1. Epithelioid hemangioendothelioma primary tumor sites, first-line therapy, and maximum reported survival with therapy Author, year

Primary tumor site

Extent of disease

First-line therapy

Patient(s)

Survival

Case seriesAngelini et al,1 2014 Bone Unifocal (49%);

multifocal (13%)Wide excision or intralesional surgery

N = 62; men, n = 39; women, n = 23; mean age = 39 years

Survival at 10 years: unifocal, 97%; multifocal, 74%

Zheng et al,2 2012 Brain Intracranial, with localized extension to bone and muscle

Surgery 25-year-old man; 44-year-old woman

9 years

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 extrahepatic

Liver resection, transcatheter arterial chemoembolization (TACE), resection and TACE, or liver transplantation

N = 33 Up to 3 years of follow-up

Theodosopoulos et al,5 2013

Intracranial Metastatic Surgery N = 38; men, n = 23; women, n = 15

2 months-11 years

Case reportsGherman and Fodor,6 2011

Bone Localized Wide surgical excision 24-year-old man No local recurrence or metastasis at 2 years

Sumrall et al,7 2010 Brain Intracranial, localized extension to skull, connective tissue

Lenalidomide 31-year-old woman 6 years, stable disease

Osawa et al,8 2012 Carotid artery Localized Surgery 59-year-old man; 14 years after embolization for carotid aneurysm

Rapid death

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

chemoembolization83-year-old man Metastatic recurrence

after 3 months Grenader et al,11 2011 Liver Localized Pegylated liposomal

doxorubicin32-year-old man 2 years, stable disease

with maintenance therapy at time of publication

Sangro et al,12 2012 Liver Metastatic to lungs Sorafenib 22-year-old man 2 yearsSalech et al,13 2011 Liver Metastatic to lungs Thalidomide 40-year-old woman 9 years, stable diseaseMizota et al,14 2011 Lung Localized Bevacizumab 59-year-old woman 3 monthsIimuro et al,15 2012 Retroperitoneum Localized, then distant

lymph metastasis months later

Surgical removal of both occurrences

48-year-old woman No recurrence at 13 months after resection of metastasis

Kerry et al,16 2012 Spinal region Multifocal Endovascular embolization, radiochemotherapy

25-year-old man 8 weeks

De Palma et al,17 2012 Vascular Localized Surgical removal of entire azygos vein

47-year-old man No recurrence at 1 year

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ascertain that in multifocal EHE, those multiple sites are monoclonal in nature, and therefore metastatic implants of the same tumor and not simultaneous oc-currence of multiple neoplastic clones. Additionally, both CD31 and VEGF are overexpressed in non-small cell lung cancer,24 breast cancer,25 prostate can-cer,26 renal cell carcinoma,27 mantle cell lymphoma,28 meningioma,29 pituitary adenomas,30 and uveal melanoma.31

EHE is more common in women, and there are 3 prior case reports of its diagnosis during pregnancy,17 with ours being the fourth. A case report has also been published of successful management of multifocal hepatic infantile heman-gioendothelioma with tamoxifen-based therapy.32 Tamoxifen (20 mg daily) was part of the management strategy used for our patient over a 9-day course during her acute disease recurrence.

Very little research has explored the clinical utility of individual hormonal markers in EHE. There was strongly posi-tive expression of placenta growth factor (PlGF) in 1 case,33 positive expression of 17-beta estradiol receptors in only 1 of a series of 5 EHE patients,34 and no estro-gen or progesterone receptors in another case.35 Expression of PlGF is noteworthy in our case, in that our patient’s disease quickly and dramatically flared in the

Author, year

Primary tumor site

Extent of disease

First-line 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

publicationDemir et al,19 2013 Liver Parenchymal lesion

with metastases to lungCarboplatin, pharmorubucin 24-year-old woman

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, pharmorubucin

49-year-old woman Stable disease 1 year after diagnosis

Yu et al,22 2013 Lung Lung (localized to myocardium)

Carboplatin/etoposide, followed by surgical excision

39-year-old woman Alive 14 months after 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 hemangioendotheliomas. 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 vascular tumor: 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.

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25th week of pregnancy, near the peak in maternal PlGF production. Although in our patient’s case PlGF was not tested, we did note an abnormally low human chorionic gonadotropin level during the second trimester of pregnancy of 23 IU/mL.

A translocation involving PlGF has also been discovered in a case of EHE.15 Furthermore, it is known that there is binding of PlGF to VEGF receptor-1, and that PlGF may influence VEGF-induced angiogenesis,36 which may ex-plain our patient’s rapid disease flare-up.

Although the scarcity of cases im-pedes rapid progress in histochemical characterization of EHE, a composite picture has begun to emerge that may aid researchers in its early identifica-tion, perhaps leading to earlier diagnosis and more definitive treatment. VEGF expression15 and hormonal receptor expression have been reported in EHE. Furthermore, there are multiple reports of successful management of this vascu-lar cancer with antiangiogenic therapy (lenalidomide,17,18 thalidomide,2,37-39 and sorafenib18). We therefore suggest it is possible that combination therapy of EHE with sequenced or concurrent

anti-angiogenic, hormonal, and anti-VEGF agents has value as an avenue of future clinical investigation. v

Disclosure StatementThe author(s) have no conflicts of interest to

disclose.

AcknowledgmentMary Corrado, ELS, provided editorial assistance.

How to Cite this ArticleMcCulloch M, Russin M, Nachat A. Recurrence of epithelioid hemangioendothelioma during pregnancy: Case report and systematic review. Perm J 2016 Summer;20(3):15-152. DOI: http://dx.doi.org/10.7812/TPP/15-152

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Figure 8. Timeline of the patient’s case.CT = computed tomography scan.



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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

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Recurrence of Epithelioid Hemangioendothelioma during ... · Recurrence of Epithelioid Hemangioendothelioma during