Management and Outcomes of Advanced Hemangioendothelioma at a Medical Oncology Clinic in an Indian Tertiary Care Center

Figures & data

Figure 1. Histopathological findings of hemangioendothelioma.

(A) H&E image in 100x magnification showing representative photomicrograph of the case of Kaposiform hemangioendothelioma with cannonball pattern of arrangement and slit like vascular spaces lined by mildly pleomorphic endothelial cells. There is no significant atypia and no mitotic figures. (B) Immunostain for FLI-1 showing nuclear positivity in the endothelial cells. (C) H&E image in 200x magnification showing representative photomicrograph from a case of epithelioid hemangioendothelioma with cells with epithelioid morphology showing mild to moderate pleomorphism with abundant eosinophilic cytoplasm. Many cells show presence of intracytoplasmic lumina characteristic of endothelial cells. (D) Immunostain for CD31 antigen showing membrano-cytoplasmic positivity in endothelial cells.

Table 1. Clinico-epidemiological profile of cases under study.

	All subtypes of hemangioendothelioma	EHE only
Median age, years (range)	34.5 (4–60)	32.5 (8–69)
Primary (n, %)	Liver (4, 30.7%) Vertebra (4, 30.7%) Spleen (2, 15.3%) Tibia (1, 7.6%) Chest wall (1, 7.6%) Paravertebral (1, 7.6%)	Liver (4, 40%) Vertebrae (4, 40%) Paravertebral (1, 10%) Spleen (1, 10%)
Pattern of metastasis (%)	Lymph node (6, 46.1%) Bone (6, 46.1%) Lung (3, 23.2%) Liver (2, 15.3%) Others (30.7%)	Lymph node (6, 60%) Bone (5, 50%) Lung (3, 10%) Pancreas (1, 20%) Pleural fluid (1, 10%) Pleura (1, 10%) Liver (1, 10%) Orbit (1, 10%)
Sex distribution (n, %)	Male (9, 69%) Female (4, 31%)	Male (6, 60%) Female (4, 40%)
Symptoms (n, %)	Pain (10, 76.9%) ^† Swelling (1, 7.6%) Paraparesis (1, 7.6%) Asymptomatic (1, 7.6%)	Pain (8, 80%) Paraparesis (1, 10%) Asymptomatic (1, 10%)
Other events		Acute liver failure (1, 10%)

† Splenic rupture with hemoperitoneum in one patient requiring splenectomy.

EHE: Epithelioid hemangioendothelioma.

Table 2. Details of patients in the study including clinical presentation, histologic subtype, treatment given with response and outcomes.

S. no.	Age (years)/sex	Primary site	Histology	Clinical presentation/stage	Metastatic sites	First-line therapy	Best response/duration of therapy (months)	Second-line therapy	Best response/duration of therapy (months)	Current status
1	22/female	Liver	EHE	Postpartum abdominal pain/M	Lung, lymph node	Refused therapy				Deceased
2	45/male	Vertebra	EHE	Back pain/M	Lung, lymph node, bone	Paclitaxel + Bevacizumab	PD/4			Deceased
3	34/male	Liver	EHE	Abdominal pain/M	Bone, lymph node	Sorafenib 400 mg twice daily ^†	SD/36			Alive
4	27/male	Liver	EHE	Abdominal pain/M	Bone, lymph node, pancreas	Pazopanib 800 mg once daily ^†	SD/15			Alive
5	15/male	Spleen	EHE	Detected in mediastinal GCT survivor/M	Liver, lung	Pazopanib 800 mg once daily ^†	PD/4	Paclitaxel ^†	SD/27	Alive
6	60/male	Soft tissue (paravertebral)	EHE	Back pain/M	Pleural fluid, pleural deposit, lymph node	Gemcitabine + paclitaxel	PD/1	Pazopanib 800 mg once daily ^†	PR/27	Alive
7	8/male	Vertebrae	EHE	Paraparesis/M	Bone, orbit	Vinblastine ^†	PD/1	Sorafenib 100 mg once daily ^†	PR/23	Alive
8	69/female	Vertebrae	EHE	Back pain/M	Bone	Pazopanib 400 mg once daily ^†	PD/5			Deceased
9	31/female	Soft tissue (abdomen)	EHE	Abdominal pain/NM		Pazopanib 400 mg once daily ^†	TBA/1			Alive
10	49/female	Liver	EHE	Abdominal pain/M	Lymph node	Thalidomide 100 mg once daily ^‡	PD/3	Pazopanib 800 mg once daily ^† reduced to 400 mg once daily	CR/62	Alive
11	4/male	Tibia	KHE	Leg swelling and pain/LA		Prednisone in slow tapering doses over 20 months ^†	CR/44 [only propranolol for 24 months]			Alive
12	35/male	Chest wall	PMHE	Chest pain/LA		Pazopanib 400 mg once daily ^†	PD/1 month	Doxorubicin	PD/2	Deceased
13	52/male	Spleen	RHE	Acute pain abdomen due to splenic rupture and hemoperitoneum/M	Liver, bone	Gemcitabine + paclitaxel ^†	PD/2 months	Pazopanib 600 mg once daily ^†	PD/less than 1	Deceased

† Propranolol given along with the drug regimen at median dose 80 mg daily.

‡ Celecoxib given along with the drug regimen at dose of 200 mg twice daily.

CR: Complete response; EHE: Epithelioid hemangioendothelioma; GCT: Germ cell tumor; KHE: Kaposiform hemangioendothelioma LA: Locally advanced unresectable; M: Metastatic; NM: Non metastatic; PD: Progressive disease; PR: Partial response; PMHE: Pseudomyogenic hemangioendothelioma; RHE: Retiform hemangioendothelioma; SD: Stable disease; TBA: To be assessed.

Table 3. Details of therapy received, toxicity and survival outcomes.

	First line	Second Line
Medical treatment regimens across lines (n)	TKI Pazopanib + propranolol (5) Sorafenib + propranolol (1)	Pazopanib + propranolol (3) Sorafenib + propranolol (1)
	Others Prednisone + propanolol (1) Thalidomide + celecoxib (1)
	Chemotherapy Gemcitabine + paclitaxel ^† (2) Paclitaxel + Bevacizumab (1) Vinblastine + Propranolol (1)	Doxorubicin (1) Paclitaxel + propranolol (1)
Response at first assessment (%)	CR – 8.3% PR – 0% SD – 16.6% PD – 66.6%	CR – 16% PR – 33% SD – 16% PD – 33%
Toxicity (n, %)	Febrile neutropenia with vinblastine (1, 7.7%) Neuropathy with paclitaxel (1, 7.7%)	Grade III hand foot reaction (1; 10%)

† Combined with propranolol in one patient.

CR: Complete response; PD: Progressive disease; PR: Partial response; SD: Stable disease; TKI: Tyrosine kinase inhibitor.

Figure 2. Fluorodeoxyglucose-positron emission tomography images of a 49-year-old female patient of metastatic hepatic epithelioid hemangioendothelioma.

This scan represents the radiological findings prior to initiation of pazopanib-based therapy for this patient. (A) MIP image FDG PET-CT showing increased tracer uptake in the hepatic region. (B & D) Axial CT abdomen showing confluent hypodense lesions in both the lobes of liver. (C & E) There is increased tracer uptake noted at the liver lesions in the fused PET-CT images.

MIP: Maximum intensity projection.

Figure 3. Post-treatment positron emission tomography-computed tomography scan of the 49-year-old female patient described in Figure 2 after 12 months of pazopanib-based therapy.

(A) Maximum intensity projection image FDG PET-CT showing physiologic tracer uptake in brain, myocardium and urinary bladder and no abnormal tracer uptake in the hepatic region. (B & D) Axial CT abdomen showing confluent hypodense lesions in both the lobes of liver. (C & E) There is no significant abnormal tracer uptake in fused PET-CT images suggestive of complete metabolic response.

Figure 4. Kaplan–Meier curve showing progression free survival with first line of treatment.

Figure 5. Kaplan–Meier curve showing progression free survival with tyrosine kinase inhibitors.

Figure 6. Kaplan–Meier curve showing overall survival among the epithelioid hemangioendothelioma (blue line) and non epithelioid hemangioendothelioma (red line) subsets.

EHE: Epithelioid hemangioendothelioma.

Table 4. Comparison of previous studies of epithelioid hemangioendothelioma with this study regarding use of tyrosine kinase inhibitors for therapy.

Authors	Study type	Patients (n)	TKI used	Response	Median PFS (months)	Ref.
Cioffi A et al.	Retrospective	34	Sorafenib (n = 6; 17.6%)	ORR = 0% SD = 50%	4.8	[35]
			Imatinib (n = 2; 5.8% )	ORR = 0% SD = 0%
Chevreau C et al.	Prospective, phase II	15	Sorafenib (n = 15)	ORR = 13% SD = 60%	6	[32]
Yousaf N et al.	Retrospective	19	Imatinib (n = 1; 3%)	ORR = 0% SD = 100%	NA	[36]
			Axitinib (n = 2; 6%)	ORR = 0% SD = 100%
			Sunitinib (n = 1; 3%)	ORR = 0% SD = 0%
			Pazopanib (n = 1; 3%)	ORR = 0% SD = 0%
Kollar A et al.	Retrospective analysis of prospective trials	10	Pazopanib	ORR = 20% SD = 40%	26	[33]
Shiba S et al.	Retrospective	10	Pazopanib (n = 2;, 20%)	ORR = 0% SD = 100%	NA	[37]
Sparber-Sauer M et al.	Retrospective analysis of prospective trials	6	Pazopanib	ORR = 0%	NA	[38]
Frezza AM et al.	Retrospective	73	Pazopanib (n = 12; 16.4%)	ORR = 0% SD = 75%	2.9 (with pazopanib)	[39]
Current study	Retrospective	13	Sorafenib (n = 2; 15.3%)	ORR = 50% (1/2) SD = 50% (n = 1)	4
			Pazopanib (8; 61.5%)	ORR = 25% (2/8) SD = 12.5% (n = 1)

CR: Complete response; ORR: Overall response rate; PD: Progressive disease; PR: Partial response; PFS: Progression-free survival; SD: Stable disease; TKI: Tyrosine Kinase Inhibitors.

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