Management and outcomes of advanced hemangioendothelioma at a medical oncology clinic in an Indian tertiary care center

Aim Hemangioendotheliomas (HEs) are malignant vascular tumors with sparse descriptions in literature owing to their rarity. Study design Ours is a retrospective study among patients of advanced HEs registered between September 2015 and April 2021. Results There were 13 patients with median age 34.6 (range: 4–69 years), male preponderance (69%) and predominant subtype of epithelioid HE (76.9%). Common primary sites were viscera (46.2%) and bone (30.8%). Tyrosine kinase inhibitors (TKIs) yielded objective responses in 30% patients whereas chemotherapy only produced disease stabilization in 7.7%. Conclusion We recognize an aggressive subset of HEs with manifestations such as acute liver failure and splenic rupture. Currently no biomarkers predict the efficacy of TKIs over chemotherapy; however, TKIs showed promising outcomes in this series.


Results
We analyzed a total of 13 patients with the most prevalent histopathological subtype being EHE (n = 10; 77%). The other subtypes, namely, Kaposiform (Figure 1), retiform and pseudomyogenic HE, were second-most common (n = 1; 7.6% each). Our patient population comprised of nine males (69%) and four females (31%). The median age at presentation overall was 34.6 (age range: 4-60 years). Further details of epidemiologic findings and clinical presentation of EHE and other subtypes are further described in Table 1.
All surgical treatments for HE were performed in five patients (38.4%) at outside hospitals following which the diagnosis of HE was made. Debulking surgery was done for three patients (epithelioid, pseudomyogenic and Kaposiform subtypes) while the other two underwent orthotopic liver transplantation plus metastasectomy of costal metastasis and splenectomy respectively (epithelioid and retiform subtypes respectively).
TKIs were used in six out of 13 (46.1%) patients in first line and four out of six (66%) patients in second line. The two TKIs used among our patients were pazopanib (80%) and sorafenib (20%) in combination with propranolol (median dose 80 mg daily) in 100% cases.
Conventional chemotherapeutic agents were used in large volume or organ threatening disease and comprised of gemcitabine plus paclitaxel (n = 2), bevacizumab plus paclitaxel (n = 1), single-agent paclitaxel (n = 1), vinblastine (n = 1), doxorubicin (n = 1), as summarized in Table 3. The TKIs were started at a lower dose as per our prior published experience of higher toxicities in Indian patients at lower TKI dosages. The patients who continued to receive reduced doses were decided based on physicians' discretion and/or who experienced grade 3 or 4 toxicities with the full doses. Propranolol was added to chemotherapy in 60% and to TKIs in 100% patients, at a median dose of 80 mg daily. Table 2 elucidates the maximum doses of TKIs received by our patients. The clinical scenarios where chemotherapy was administered were rapidly progressive and painful soft tissue mass, vision-threatening orbital metastases, acute onset paraparesis and splenic rupture with impending hepatic rupture. The patient with postpartum EHE refused treatment and passed away due to disease progression. Further details of the various treatment regimens used across all lines of therapy are provided in Table 3.
TKIs produced objective response in 30% patients (three out of ten response assessments) including 20% PR (n = 2) while stable disease was attained in 20% (n = 2). A total of 10% patients (n = 1) attained CR with use of TKIs which has been radiologically depicted in Figures 2 & 3. There were no objective responses noted in patients who received conventional chemotherapy, while stable disease response has been attained in 7.7% (n = 1). The pseudomyogenic subtype was refractory to both TKI and chemotherapy, while the retiform subtype progressed to chemotherapy within 3 months followed by refractoriness to TKI. The median PFS with first-line therapy was 4 months (95% CI: 2.48-5.53) ( Figure 4) while the median PFS with second line of therapy and that with TKI was not reached ( Figure 5). In the overall and the EHE population, median overall survival (OS) at 20 months follow-up was not reached. In the non-EHE subgroup, the median OS was 8 months (95% CI: 1.5-14.4) but this difference between the EHE and non-EHE subgroups was not statistically significant (p = 0.06) ( Figure 6). The 12-month OS was 75% (95% CI: 50-NE), while that at 20 months of median follow-up was 65% (95% CI: 37.6-NE). The 12 month PFS with first line of treatment overall was 36% (95% CI: 9-63%) and with TKIs was 58% (95% CI: 26.6-84.1%). The four deaths in the study comprised of patients of EHE (n = 2) and one patient each of pseudomyogenic and retiform subtypes.
Grade 3 or 4 adverse events noted in our patients consisted of febrile neutropenia with vinblastine, periphery sensory neuropathy with paclitaxel and hand foot skin reaction with pazopanib (n = 1; 10% each).

Discussion
Epithelioid hemangioendothelioma EHE was the commonest subtype of HE in our series. The occurrence of liver as the commonest primary site is consistent with previous studies; however, the median age is younger than previously reported [8,9]. We also observed that the EHE patients in our study were predominantly male, contrary to the female preponderance reported in literature [7]. While bone is the commonest reported metastatic site in studies [10], we found lymph node to be the most frequent metastatic site in EHE. Rarer sites of metastases found in our series were pancreas and orbit. While pancreatic metastases have been scantily reported [7], orbital metastases in EHE have never been previously described in literature. 10 Table 3. Details of therapy received, toxicity and survival outcomes.

First line Second Line
Medical treatment regimens across lines (n)

Kaposiform hemangioendothelioma
Our patient had cutaneous and bony symptoms from infancy, which were misdiagnosed before he presented to us at the age of 3 years. He had locally advanced and infiltrative disease at the lower extremity, which corroborates with findings of previous studies [13]. A more detailed description of this case and discussion on KHE has already been published from our center [24].

Pseudomyogenic hemangioendothelioma
Previous series describe the extremities as the most common (78%) site of disease; however, our patient had a chest wall primary which has been found in 18% patients in published literature [15]. The locally aggressive behavior of the disease with multiple local recurrences was similar to that described in past studies [25], but our patient had a more rapid tempo of disease. Following an incomplete surgical resection, the patient had disease progression within 2 months of pazopanib and doxorubicin each and eventually succumbed to his disease.

Retiform hemangioendothelioma
Contrary to the reported description of retiform HE with primary site being extremities [17], our patient had primary disease at the spleen. Retiform splenic HE has only been rarely reported in literature, with a single case of purely retiform pathology described so far [26]. Besides this, only few reports of composite HE with epithelioid and retiform components have been published [27]. Despite classically having a low risk of metastases [17], our patient had hepatic and vertebral metastases at baseline. Spontaneous splenic rupture as first presentation of HE has been rarely reported among cases of EHE [28] and KHE [29] but no case of retiform HE presenting with splenic rupture has been described till date.
One of the largest studies on EHE was carried out retrospectively at the Royal Marsden Hospital between 1998 and 2013 with 32 patients by Agulnik et al. [30]. Chemotherapy (paclitaxel and anthracyclines) was used in maximum cases and did not yield any objective responses with the best response being stable disease. The use of newer agents in the last decade, such as celecoxib, imatinib, axitinib, thalidomide, pazopanib and sunitinib was also described. Median PFS was 6.7, 3.3, 1.5, 1.4 months in first, second, third and fourth lines of medical treatment, respectively. The absence of objective responses with conventional chemotherapy is similar to the findings we have obtained in our study.
Prior to presentation at our center, five patients had already undergone surgical management which included life-saving splenectomy due to splenic rupture and shock in one patient of Retiform HE. As per our protocols, we gave chemotherapy to patients with HE who presented with high volume and severe symptoms. We also added propranolol with the primary therapeutic regimen after evidence of its role in management of angiosarcoma [31]. Recent times have seen a shift from use of chemotherapy to targeted therapy in vascular sarcomas. The overall response rate to TKIs (pazopanib and sorafenib in all lines) in our study population was 30% with median PFS not reached at 20 months of follow-up. In a phase II study by Chevreau et al. in 15 patients with sorafenib producing median PFS of 6 months with median OS not being reached after 12 months of follow-up in a progressive EHE [32]. A 2016 retrospective review of EORTC Soft Tissue and Bone Sarcoma Group phase II and III clinical trials on pazopanib in advanced vascular sarcomas analyzed 52 patients including ten HE patients, yielding 20% response rates and median PFS of 26.3 months [33]. In a case report, Bally et al. described a sustained PFS of more than 100 months in metastatic hepatic EHE with pazopanib based therapy [34]. Similarly, in a patient in our study, such sustained benefit has been achieved for 63 months with pazopanib in the second line. Table 4 further lists studies that have highlighted the use of TKIs in EHE and their outcomes in comparison to our study.
Stachiotti et al. have recently published a consensus paper on EHE [40] and have recognized it as an ultra-rare cancer which needs collaborative research efforts from the global medical community. Surgery with or without adjuvant radiotherapy has been advised for unifocal EHE with the aim for R0 resection. For metastatic disease, surgical modality should be tailored depending on the other available treatment options. Liver transplant for hepatic EHE without evidence of extrahepatic metastases has been suggested as an option. However, the EHE patient of our study, who underwent orthotopic liver transplantation outside also had distant bone metastases hence required systemic therapy eventually. Active surveillance has been advised by Stachiotti et al. as an acceptable option in advanced disease with low symptom burden, while systemic therapy in form of interferon, VEGF inhibitors, TKIs and chemotherapy should be given in others. The MEK inhibitor, trametinib, is a promising option under evaluation in phase II trials because MEK is overexpressed in these cases owing to CAMTA1 fusion. The limitations of our study are its retrospective nature, small sample size and limited follow-up time. It is difficult to draw definite conclusions on the efficacy of TKIs in comparison with chemotherapy without larger, prospective studies. The phenomenon of pregnancy related EHE merits further exploration, with the background of few reports suggesting the role of hormones such as placental growth factor (PGF) in its pathogenesis [41]. The development of hepatic EHE in a treated patient of mediastinal germ cell tumor does not have a precedent in reported literature and more studies are needed to suggest its possible occurrence as a secondary malignancy. Dedicated research on other subtypes of HE is required, but is limited by the rarity of the disease.

Conclusion
This study offers unique insights from the developing world into the clinical presentation, diagnostic challenges and treatment options for advanced HEs. Chemotherapy has only limited role and literature on newer options such as TKIs is emerging.

Future perspective
In rare cancers such as HEs, the conduct of larger randomized control studies is a challenge. In future, there should be collaborative efforts by various international sarcoma groups to develop patient registries of these cases. Biomarkers must be recognized in the future, to predict which tumors would respond to chemotherapy or TKIs to tailor the patient's treatment. Newer modalities of therapy should also be explored as options, such as trametinib which is under research as of now.

Summary points
• Hemangioendothelioma has multiple subtypes, the most common one being epithelioid hemangioendothelioma.
• Hemangioendothelioma has a spectrum of presentations, ranging from indolent behaviour to aggressive malignant disease. • The most common primary sites are the liver and vertebrae, while the most common metastatic sites are lymph nodes and bone. • Chemotherapy can be used for treatment of rapidly progressive and organ-threatening disease; however, documented responses to chemotherapy have been dismal. • Tyrosine kinase inhibitors (TKIs) have a vital role in therapy and produce overall response rates of 30% (irrespective of line of therapy). • Beta blockers can be used along with the chemotherapy or TKI agent.
• TKIs can also lead to complete remission in rare cases.
• Other anti-angiogenic agents such as bevacizumab and thalidomide can also be used for treatment.

Author contributions
Study concept and design: S Rastogi and G Tansir. Acquisition, analysis and interpretation of data: S Rastogi, G Tansir, S Shrivastava.
Drafting of the manuscript: S Rastogi and G Tansir. Critical revision of the manuscript: all authors. All authors read and approved the final manuscript.