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

Abstract

Introduction:

Epithelioid hemangioendothelioma (EHE) is a family of blood vessel tumors originating in blood vessels, bone, brain, kidney, liver, and lung. EHE is more common 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 review 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 antiangiogenic and tumor-inhibiting therapies such as lenalidomide, thalidomide, sorafenib, and sunitinib, may also hold promise.

INTRODUCTION

Epithelioid 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 research 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 vascular and other soft tissues. Diagnosis is sometimes delayed owing to uncertainty about correct pathologic classification, which can significantly worsen prognosis.⁴ Little is known about prognostic factors for patients with EHE, although recent work has identified genetic alterations 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 ratio, 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 disease (81%), although the study size was too small to show a significant difference (p = 0.1). There was additionally nonsignificant lower 5-year survival in meta-static (69%) compared with localized (78.3%) disease (p = 0.7). Treatment with any chemotherapy decreased 5-year survival, 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 maximum standardized uptake value.¹³

Little is known about efficacy of therapy because the low incidence of EHE precludes conduct of human clinical trials. Options currently include chemotherapy, 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 Although 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 endothelial 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 antiangiogenic and antiproliferative activity),¹⁸ and sunitinib¹⁹ suggest other targeted molecular therapies may also hold promise.

The current case report documents diagnosis of recurrent EHE in a pregnant woman and discusses the case in the context of a systematic review of the current literature. This report was prepared in accordance with the CARE (CAse REport) guidelines.²⁰

CASE PRESENTATION

We 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 immunohistochemical 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, significant 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).

Figure 1.

Hematoxylin/eosin stain showing epithelioid cells with cytoplasmic vacuoles (magnification ×400).

Figure 2.

Hematoxylin/eosin stain showing epithelioid cells with cytoplasmic vacuoles (magnification ×600).

Figure 3.

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

Figure 4.

Immunohistochemical stain positive for vascular marker CD34 (magnification ×600).

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.

In 2012, the patient presented to the Emergency Department with chest pain and in acute respiratory distress. A posterior-anterior/lateral chest radiograph revealed multiple pulmonary nodules bilaterally, confirmed as “innumerable” by chest CT, along with bulky mediastinal adenopathy and multiple liver lesions consistent with metastatic disease (Figure 7).

Figure 7.

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

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 mediastinal 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 pleural 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 progressive disease as well as pneumonia. She was intubated; her condition continued to decline; she was placed on comfort measures, and she subsequently died. A timeline showing progression of the case is provided in Figure 8.

Figure 8.

Timeline of the patient’s case.

CT = computed tomography scan.

DISCUSSION

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

In Table 1 we present results of a systematic search of treatment outcomes published since January 2011. Tumor marker expression in EHE has been reported 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 al^22,23 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 ascertain that in multifocal EHE, those multiple sites are monoclonal in nature, and therefore metastatic implants of the same tumor and not simultaneous occurrence of multiple neoplastic clones. Additionally, both CD31 and VEGF are overexpressed in non-small cell lung cancer,²⁴ breast cancer,²⁵ prostate cancer,²⁶ renal cell carcinoma,²⁷ mantle cell lymphoma,²⁸ meningioma,²⁹ pituitary adenomas,³⁰ and uveal melanoma.³¹

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 series
Angelini 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 reports
Gherman 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 chemoembolization	83-year-old man	Metastatic recurrence after 3 months
Grenader et al,11 2011	Liver	Localized	Pegylated liposomal doxorubicin	32-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 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 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
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 with metastases to lung	Carboplatin, 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

¹Angelini 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.

²Zheng 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.

³Agulnik 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.

⁴Wang 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.

⁵Theodosopoulos 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.

⁶Gherman 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.

⁷Sumrall 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.

⁸Osawa 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.

⁹Tolkach 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.

¹⁰Harada 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.

¹¹Grenader 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.

¹²Sangro 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.

¹³Salech 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.

¹⁴Mizota 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.

¹⁵Iimuro 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.

¹⁶Kerry 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.

¹⁷De 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.

¹⁸Wu 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.

¹⁹Demir 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.

²⁰Kiratli 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.

²¹Pálföldi 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.

²²Yu 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.

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 hemangioendothelioma 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 positive 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 estrogen 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 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 explain our patient’s rapid disease flare-up.

Although the scarcity of cases impedes rapid progress in histochemical characterization of EHE, a composite picture has begun to emerge that may aid researchers in its early identification, 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 vascular 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.

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