Cutaneous composite hemangioendothelioma: case report and review of published reports.

Composite hemangioendothelioma (CHE) is a rare, locally aggressive, vascular tumor of intermediate-/ low-grade malignancy, and is characterized by varying combinations of benign, low-grade malignant, and malignant vascular components. In cutaneous localization, only 22 cases have been reported so far. A new case of CHE of the gluteal region in a 58-year-old man is described. Microscopically, vascular neoplasm, situated mainly within the deep dermis and the subcutaneous fat tissue, was composed of sinusoidal hemangioma, arteriovenous hemangioma, retiform hemangioendothelioma (RHE), and angiosarcoma. An average number of mitoses within the angiosarcomatous component was 10 per 10 high-power fields. Immunohistochemically, the tumor cells were positive for factor VIII-related antigen, CD34, and CD31 and negative for D2-40 and GLUT-1. Ki-67 labeling index was 21%, 1.2%, and 0% in the areas of angiosarcoma, RHE, and sinusoidal hemangioma, respectively. No recurrent disease was noted 3 months after the surgery. The present case displayed the following features previously undescribed in CHE: a novel component of sinusoidal hemangioma and localization at the gluteal region. We also provide review of clinical, histopathological, and immunohistochemical characteristics of cutaneous CHE from the published cases.

Composite hemangioendothelioma (CHE) is the most recently described vascular neoplasm of low-malignant potential, showing varying combinations of benign angiomatous lesions, and different subtypes of hemangioendothelioma and angiosarcoma. 1 CHE mainly presents as dermal uni- or multinodular lesion on distal extremities of young to middle-aged adults, with a slow evolution, relatively high local recurrence rate, and low metastatic potential.1,2 On the whole, only 22 cases of CHE have been reported so far in cutaneous and/or subcutaneous localization.1,3–13 We report a new case of cutaneous CHE, situated in previously undescribed localization of the gluteal region, with a detailed review of the published reports.

CASE

A 58-year-old man presented with a slowly enlarging palpable cutaneous mass in the right gluteal region, first noticed several years before. The lesion was a subcutaneous nodule measuring approximately 30 mm in greatest diameter. A complete surgical excision was performed. Grossly, the excised specimen measured 58×31×22 mm and contained a subcutaneous bluish-purple circumscribed nodule, 27 mm in diameter.

Histological examination revealed a vascular neoplasm situated mainly within the deep dermis and the subcutaneous fat tissue (Figure 1).

Figure 1

Panoramic view of the large part of cutaneous composite hemangioendothelioma (Hematoxylin eosin, original magnification ×12.5).

The tumor consisted of several angiomatous components that merged with each other. The predominant vascular lesion corresponded to retiform hemangioendothelioma (RHE), occupying approximately 45% of the tumor. Other histological patterns included the areas consistent with sinusoidal hemangioma (25%), arteriovenous hemangioma (10%), and angiosarcoma (20%). Areas resembling RHE were composed of long arborizing thin-walled blood vessels, extending between collagen bundles in a retiform pattern. (Figure 2). A component showing histological features of sinusoidal hemangioma was characterized by closely packed, thin-walled, interconnecting vascular channels lined with bland endothelium without mitotic activity (Figure 3). Tumor areas consistent with the arteriovenous hemangioma displayed collections of large, thick-walled vessels running from the upper dermis to the subcutaneous fat (Figure 4). Angiosarcomatous component showed irregular vascular channels with a complex dissecting and anastomosing growth pattern and frequent intraluminal thrombosis. Several foci of necrosis were present. Endothelial cells exhibited mild-to-moderate nuclear atypia and mitoses: mean 10 per 10 high-power fields (HPFs) with up to 5 mitoses/HPF in the most mitotically active areas (Figure 5).

Figure 2

Retiform hemangioendothelioma composed of long arborizing blood vessels with a hobnail appearance of the lining cells (Hematoxylin eosin, original magnification ×200).

Figure 3

Sinusoidal hemangioma characterized by closely packed, thin-walled interconnecting vascular channels forming a sinusoidal pattern (Hematoxylin eosin, original magnification ×100).

Figure 4

Arteriovenous hemangioma featuring collections of large, thick-walled vessels (right) set near the sinusoidal hemangioma (left) (Hematoxylin eosin, original magnification ×40).

Figure 5

Angiosarcomatous component exhibiting irregular vascular channels with mitotic figures (arrowheads) (Hematoxylin eosin, original magnification ×400)

Endothelial cells within all components of the tumor were immunohistochemically positive for factor VIII-related antigen (Clone F8/86, Dilution 1:25, Dako, Glostrup, Denmark), CD34 (Clone QBEnd10, 1:25, Dako), and CD31 (Clone JC/70A, 1:20, Dako) and negative for D2-40 (Clone D2-40, 1:200, Dako) and GLUT-1 (Polyclonal, 1:200, Lab Vision, Fremont, CA). Ki-67 (MIB-1, 1:25, Dako) labeling index was 21% in the angiosarcomatous component, 1.2% in the retiform HE, and 0% in the sinusoidal hemangioma.

Histological and immunohistochemical findings were consistent with a diagnosis of CHE. No recurrent disease was noted 3 months after the surgery. The patient was then lost for follow-up.

DISCUSSION

CHE is the most recently described vascular neoplasm in the realm of the hemangioendothelioma,1 included in the 2002 WHO classification of tumors of soft tissue and bone.2 CHE is defined as a locally aggressive, rarely metastasizing neoplasm with vascular differentiation, containing an admixture of histologically benign, intermediate, and malignant components that merge with each other and vary in their relative proportions.2

After the first report of Nayler et al. that included 7 cutaneous CHE cases and 1 in the extracutaneous localization,1 only 15 additional tumors occuring in the skin/subcutis have been reported so far.3–13 The clinical and histopathological features of these cases in addition to our example are shown in Table 1.

Table 1

Clinical, histopathological, and immunohistochemical characteristics of cutaneous composite hemangioendothelioma from published cases.

Authors	Case	Sex/Age, y	Location	Pre-operative duration	Size, mm	Histological components	Mitoses	Necrosis	Immunohistochemistry	Treatment and follow-up
Nayler et al 20001	1	M/42	Foot	12 y	60×45×40	SCH, EHE, AS	SCH: 0AS: few	-	Generally: cases 1–7: greater positivity for CD31 and FVIII than for CD34	NSR after 1 y
	2	F/27	Foot	Since childhood	7–20	SCH, EHE, RHE, AS	SCH: 0RHE: 0AS: few	-		Recurrences for 4 y; excision and reexcision followed by a below-knee amputation: NSR after 6 y
	3	M/21	Finger	Several months	2 nodules of unstated size	SCH, AVM, RHE	SCH: 0RHE: 0	-		NSR after 13 y
	4	M/44	Finger	Several years	10	EHE, RHE, AS	RHE: 0AS: few	-		NSR after 2 y
	5	F/31	Foot	2 y	10	SCH, EHE, RHE, AS	SCH: 0RHE: 0AS: few	-		NA
	6	F/71	Foot	6 y	30–40	L, EHE, RHE, AS	RHE: 0AS: few	-		NA
	7	M/35	Hand	Several years	30	EHE, RHE, AS	RHE: 0AS: 7/10HPF	-		Recurrence within 4 y
Reis-Filho et al, 20023	8	F/23	Forearm, hand	Since infancy	130×130 ×70	SCH, CAH, EHE, RHE, ASL	EHE: 6/mm2RHE: 3/mm2ASL: 9/mm2	NA	SCH, CAH, RHE, EHE: positivity for FVIII, CD31, CD34	Below-elbow amputation: NSR after 7 y
Biagioli et al, 20054	9	F/46	Toe	3 y	20×15	SCH, EHE, RHE	NA	N NA	SCH, EHE, RHE: positivity for CD31; EHE, RHE: negativity for CD34	CO2 laser therapy: first recurrence after 2 y; surgical excision: local recurrence after 18 mo; resection of toes: NSR after 1 y
Tronnier et al, 20065	10	F/73	I: Third toeII: Between first and second toeIII: FootIV: Achilles tendon	1.5 y10 yFew monthsFew months	28×31×1020×19×14NANA	Tumor I: EHETumor III: biopsy not performedTumor III: EHETumor IV: SCH	NA	NA	Tumor I and III: positive for CD31, FVIII; negative for actinTumor IV: positive for CD31	Excision: local recurrence after 20 mo
Chu et al, 20066	11	F/18	Axilla	2 mo	60×45×40	SCH, CAH, CH, AVM, EHE, RHE, KHE, AS	AS: 3/10HPFRHE: mitotically inactive	+	Greater positivity for CD31 than for FVIII and CD34; VEGF in ASL; negativity for: CK, EMA; Ki-67: 8%–42% in AS, 1%–6% in HE, <1% in HVM	Lymph node metastases (RHE) at diagnosis, bone metastases after 4 mo; chemotherapy and radiotherapy: lung, bones, and liver metastases after 2 y; AWRD
Fukunaga et al, 20077	12	F/39	Ankle, foot	Since birth	300	SCH, L, EHE, RHE, AS	NA	NA	Cases: 12,13,14,15 positive at least focally for 2 of the following: CD31, CD34, or FVIII; negative for D2-40	Partial excision: AWRD
	13	F/75	Thigh	10 y	35	EHE, RHE	NA	NA		Excision: recurrence after 27 mo
	14	F/37	Upper arm	Since birth	40	CAH, L, AVM, A, EHE, RHE, AS	NA	NA		AWRD since birth
	15	F/22	Foot	3 y	50	EHE, RHE	NA	NA		Partial excision; follow-up NA
Requena et al, 20088	16	M/60	Leg, foot	Since childhood	NA	SCH, EHE, RHE	NA	NA	Positivity for: CD31, CD34, FVIII; EHE: positive for Prox-1; Ki-67: 50% in EHE	Excision: local recurrence and lymph node metastases (EHE) after few months; lymphadenectomy and chemotherapy: AWRD after 1 y
Utas et al, 20089	17	F/62	Forearm, hand	4 mo	50×90	SCH, CAH, EHE, RHE, ASL	ASL: brisk mitotic activity	NA	Positivity for: CD31, CD34 and FVIII	Therapy with interferon; follow-up NA
Tejera-Vaquerizo et al, 200810	18	F/23	Back	2 y	30	SCH, EHE, RHE, AS	AS: 10/10 HPF	NA	Positivity for: CD31; Negativity for CD34, CK7 and S100	Excision: NSR after 30 mo
Aydingöz et al, 200911	19	F/48	Thigh	2 y	10–15	CH, SCH, EH, RHE, KS	None	NA	Positivity for: CD34; Negativity for: S100, desmin and keratin	Multiple local recurrences; multiple excisions; lymph node metastases at 2 y; lymphadenectomy, broad en bloc excision with 100-mm margins, chemotherapy and radiotherapy: NSR after 2 y
Tsai et al, 201112	20	F/23	Foot	NA	40	EHE, RHE	NA	NA	Positivity for: CD31, CD34, FLI-1, D2-40Negativity for:HHV8	Excision: NSR at 7 mo
	21	M/8	Elbow	18 mo	16	SCH, RHE	NA	NA	Positivity for: CD31, CD34, FLI-1, D2-40 Negativity for: HHV8	Excision: NSR at 48 mo
Tateishi et al, 201213	22	F/34	Nose	7 mo	8×8	EHE, RHE	NA	NA	Positivity for: CD31, CD34, FVIII, D2-40, VEGFNegativity for CAM5.2	Treatment with electron beam: NSR at 9 mo
Present case	23	M/58	Gluteal region	Several years	27	SH, AVH, RHE, AS	AS: 10/10HPFRHE: 0/HPFSH: 0/HPF	+	Positivity for: CD31, CD34, FVIIINegativity for: D2-40, GLUT-1 Ki-67: 21% in AS, 1.2% in RHE, 0% in SH	Excision: NSR at 3 mo

A: Angiomatosis, AS: angiosarcoma, ASL: angiosarcoma-like, AVH: arteriovenous hemangioma, AVM: arteriovenous malformation, AWD: alive without disease, AWRD, alive with residual disease, CAH: cavernous hemangioma, CH: capillary hemangioma, EH: epithelioid hemangioma; EHE, epithelioid hemangioendothelioma; HE, hemangioendothelioma; HPF, high power field; HVM, hemangioma/vascular malformation, KHE: Kaposiform hemangioendothelioma, KS: Kaposi sarcoma, L: lymphangioma, NA: not available, NSR: no sign of recurrence, RHE: retiform hemangioendothelioma, SCH: spindle cell hemangioma, SH: sinusoidal hemangioma.

The ratio of females to males affected was 2.7:1. The age at presentation ranged from 8 to 75 years (mean, 39 years). In 3 patients, CHEs were present from birth.3,7

Previously reported CHEs presented as poorly circumscribed single or multinodular (multicentric) lesions on distal extremities, mostly on hands and feet. Two tumors were situated on the thigh and 1 on the back and in axilla, each. CHE in our patient was localized in the skin of the, previously unreported, gluteal region. In the majority of patients, the preoperative duration of CHEs was long (mean, 16 years; range, 1.5–60 years), and in only 5 patients CHEs developed more rapidly within several months.1,5,6,9,13 Individual tumors measured 8 mm to 300 mm in size (mean, 50.6 mm and median 31 mm).

Within the histological components of CHEs, the most frequent were retiform HE and epithelioid HE, occurring in 91%, (20/22)1,3,4,6–13 and 86% (19/22)1,3–10,12,13 of patients, respectively. The present case was also characterized by the dominant component of retiform HE, occupying approximately 45% of the tumor. Areas similar to angiosarcoma were identified in 54.5% (12/22) of all cases,1,3,6,7,9,10 occupying from less than 1% to 5% when stated.3,6,9 The angiosarcomatous component was more widespread in the CHE reported by Tejera-Vaquerizo et al10 and in our case, forming 20% of the tumor; nevertheless no recurrent tumor was noted after 30 months and 3 months, respectively.

Tumor necrosis was not present in the cases of Nayler et al,1 and its existence was not mentioned in other CHEs at all except in the gross description of the case of Chu et al.6

Data regarding the mitotic activity in cutaneous CHE are scarce. Mitoses were noted mainly in the angiosarcoma areas, ranging from few mitoses1 to 3 to 10 mitoses/10 HPF,1,6,10 similarly to the present case that exhibited 10 mitoses/10 HPF. In the retiform HE component of our case, no mitoses were seen as in the other cases.1,6,11 Exceptionally, Reis-Filho et al recorded 3 mitoses/mm2 in the retiform HE, in addition to 6 mitoses/mm2 within the epithelioid HE-component.3

Most frequent benign vascular component was the spindle cell hemangioma, found in 14/21 (67%) cases,1,3–12 followed by cavernous hemangioma in 4/21 (19%) cases,3,6,7,9 and arteriovenous malformation and lymphangioma in 3/21 (14%) each.1,6,7 We describe the sinusoidal hemangioma as a benign vascular component of CHE for the first time. Sinusoidal hemangioma is considered to be a variant of cavernous hemangioma, 14,15 or an uncommon benign vascular tumor with some similarities to a venous malformation (“cavernous hemangioma”).16

Immunohistochemically, all of the previous cutaneous CHEs expressed 1 or more endothelial markers. 1,3–13 Our case was also positive for CD31, CD34, and factor VIII–related antigen but negative for lymphatic endothelial marker D2-40, like the cases of Fukunaga et al7 Variable immunopositivity for D2-40, observed in retiform HE component,12,13 and positive immunoreactivity for Prox-1 antibody, seen in epithelioid HE component,8 supported a lymphatic line of differentiation in these cases.8,12 HE component8 supported a lymphatic line of differentiation in these cases. 8,12 Ki-67 proliferation index has been cited in only 2 reports of CHEs6,8 with up to 42% in angiosarcomatous component6 and 50% in the areas of epithelioid hemangioendothelioma.8 In our case, angiosarcoma component exhibited Ki-67 positivity in 21% of cells, while in the areas of retiform HE and sinusoidal hemangioma, Ki-67 index was 1.2% and 0%, respectively, reflecting the differences in proliferative activity of various CHE components.

Regarding the biological behavior of CHE, follow-up data were available in 18 of 22 cases of cutaneous tumors reported previously. Eight patients (44%) were free of the disease,1,3,10,12,13 7 patients (39%) exhibited 1 or more recurrences or residual disease,1,4,5,7,8,11 and 3 patients (17%) developed metastatic lesions in lymph nodes, including 1 patient with additional liver, lung, and bone metastases.6,8,11 Therefore, 55.5% (10/18) of patients with cutaneous CHE had a recurrent and/or metastatic disease. After excisional therapy, local recurrences developed after several months to 4 years.1,4,5,7,8,11 Lymph node metastases were present either at diagnosis, 6 or they developed after a few months8 or 2 years.11 Out of 3 CHEs that metastasized, only 1 primary tumor contained a component of angiosarcoma; nevertheless, the lymph node metastases in this case were composed only of RHE.6 Lymph node metastases of the other 2 cases of metastatic CHEs displayed epithelioid hemangioendothelioma8 and small-vessel proliferation with many eosinophils.11 These findings confirmed the initial view of Nayler et al that the common presence of an apparently angiosarcomatous component was not associated with a worse prognosis as expected in conventional angiosarcoma.1 CHE should be considered in the differential diagnosis of cutaneous vascular tumors to avoid inappropriately aggressive therapy.