CASE REPORTS Pediatric Dermatology Vol. 32 No. 3 e64–e69, 2015
Cutaneous Epithelioid Hemangioendothelioma on the Sole of a Child Carmen Carranza-Romero, M.D.,* Ana Maria Molina-Ruiz, M.D.,* Cristian Perna Monroy, M.D.,† Jes us Cuevas Santos, M.D.,† and Luis Requena, M.D.* *Department of Dermatology, Fundaci on Jim enez Diaz, Universidad Aut onoma de Madrid, Madrid, Spain, †Department of Pathology, Hospital Universitario de Guadalajara, Universidad de Alcal a de Henares, Madrid, Spain
Abstract: Epithelioid hemangioendothelioma (EHE) has been considered to be a low-grade malignant vascular neoplasm, although follow-up of recent series has demonstrated that EHE involving the skin and soft tissues should be better regarded as a fully malignant vascular tumor since it has more metastatic potential than previously thought. We report a case of an EHE involving the left sole of 6-year-old boy, the youngest patient with cutaneous EHE described to date. Immunohistochemical studies demonstrated a lymphatic endothelial line of differentiation for neoplastic cells. Cutaneous EHE is rare in childhood, with only five previously described cases.
Epithelioid hemangioendothelioma (EHE) is a low-grade, malignant, vascular neoplasm first described in 1982 by Weiss and Enzinger (1). It mostly presents as a solitary, slightly painful softtissue tumor, although it has also been identified in the skin (2–31). EHEs occur without sex preference and at any age, although most described cases developed in adults (ages 30–50 yrs), and they are extremely uncommon during childhood, with only five infantile cases reported to date (12,24–27). We report the case of an EHE that developed on the left sole of a 6-year-old boy. CASE REPORT A 6-year-old boy presented with an approximately 6month history of a nodular lesion of the sole of the left
foot that had grown quickly over the last 4 months. The lesion had become painful in the last month. Physical examination revealed a firm nodular mass measuring 2.5 cm in diameter located on the anterior part of the sole of the left foot (Fig. 1). There were no palpable lymph nodes. Histopathologic study from a biopsy demonstrated that the lesion was composed of several poorly circumscribed dermal nodules covered by hyperplastic acral epidermis. Neoplastic aggregates involved mostly deep reticular dermis and in some areas extended to the subcutis, whereas the upper half of the dermis was spared (Fig. 2A). The neoplasm was composed of cords and clusters of epithelioid cells embedded in a sclerotic stroma (Fig. 2B). In some areas the stroma showed a more fibromyxoid appearance. Many of these neoplastic cells contained
Address correspondence to Luis Requena, M.D., Department of Dermatology, Fundaci on Jimenez Dıaz, Avda. Reyes Cat olicos 2, 28040-Madrid, Spain, or e-mail: [email protected]. DOI: 10.1111/pde.12539
e64
© 2015 Wiley Periodicals, Inc.
Carranza-Romero et al: Infantile Cutaneous Epithelioid Hemangioendothelioma
e65
pan-cytokeratin AE1/AE3 was negative. Immunostaining for alpha smooth muscle actin demonstrated a preserved ring of pericytes around only a few of the neoformed neoplastic vessels, whereas most vascular structures lacked that ring. Surgery was performed, with complete removal of the lesion, and histopathologic study of the excised specimen demonstrated that the deepest margin of the neoplasm extended into the superficial subcutis, but all margins of excision were free of neoplasm. No adjuvant treatment was required. After 9 months of follow-up, the patient has remained well, with no evidence of recurrence or metastatic spread.
Figure 1. Erythematous nodule on the left sole.
vacuoles within their cytoplasm as a sign of primitive vascular differentiation (Fig. 2C), sometimes with a single intravacuolar erythrocyte. Those cells showed vesicular nuclei with prominent nucleoli and large eosinophilic cytoplasm (Fig. 2D). Slight nuclear pleomorphism and occasional mitotic figures were also found. No necrosis of single cells or necrosis en masse was found. Immunohistochemically, neoplastic cells expressed immunoreactivity for factor VIII, CD31 (Fig. 3A, B), CD34, and podoplanin/D2-40 (Fig. 3C, D). Ki-67 marked approximately 20% of the nuclei of neoplastic cells. Immunostaining for cytokeratins 7 and 18 and
DISCUSSION In 1982, Weiss and Enzinger (1) coined the term EHE to refer a biologically borderline neoplasm between a hemangioma and a conventional angiosarcoma. Since then, EHE has been considered to be a low-grade malignant vascular neoplasm with low metastatic potential but high a tendency to recur, although in a recent series of 30 cases of EHE of the skin and superficial soft tissues, follow-up of 24 cases showed local recurrence in 3 cases and systemic metastases in 5 cases, and 4 patients died of the tumor, suggesting that EHE of the skin and soft tissues should be
A
B
C
D
Figure 2. Histopathologic features. (A) Scanning power view shows a poorly circumscribed lesion composed of several nodules involving superficial and deep dermis (original magnification 109). (B) The nodules were composed of cords of cells with hyperchromatic basophilic nuclei (original magnification 409). (C) Some of the neoplastic cells showed cytoplasmic vacuolization as expression of primitive vascular differentiation (original magnification 2009). (D) Higher magnification of neoplastic cells demonstrates their vesicular and pleomorphic nuclei (original magnification 4009).
e66 Pediatric Dermatology Vol. 32 No. 3 May/June 2015
A
B
C
D
Figure 3. Immunohistochemical characteristics of the lesion. (A) Scanning power view of CD31 immunostaining (original magnification 109). (B) Higher magnification demonstrates the CD31 positivity of neoplastic cells (original magnification 4009). (C) Scanning power view of podoplanin/D2-40 immunostaining (original magnification 109). (D) Higher magnification demonstrates the podoplanin/D2-40 immunoexpression in neoplastic cells (original magnification 4009).
regarded as a fully malignant rather than borderline vascular neoplasm, albeit with a better prognosis than with a conventional angiosarcoma (29). The incidence of EHE is the same in men and women, although liver and lung lesions are more common in women (4). It generally affects middleaged patients and is extremely rare in childhood, with only five previously described cutaneous cases (12,24– 27). The etiology of EHE remains unknown, although Dean et al (32) suggested that the greater incidence of EHE of the liver in women might be related to oral contraceptive use, and Davies et al (33) have also reported a possible relationship between chronic vinyl chloride exposure and EHE. In the skin, it seems that this neoplasm usually arises from a medium-sized or large vein, mainly in the superficial or deep soft tissue, and only approximately 10% of the cases arise from superficial dermal vessels of the skin or mucous membranes (1,6–28). Although the clinical presentation of EHE may be variable, the neoplasm in the skin usually presents as a solitary, rarely multiple, erythematous papule, nodule, plaque, or hyperkeratotic or nonhealing ulcer (10–17) that may subsequently extend to the underlying tissues, including the bone. In most cases the signs and symptoms of EHE are nonspecific and consist of a painful or tender mass or a slowly growing tumor. It can arise at any body site, but the most common
location is the lower extremities. In some cases occlusion of the affected vessel causes more profound symptoms, such as edema or thrombophlebitis of the involved limb. The usual clinical differential diagnoses include hemangioma, pyogenic granuloma, arteriovenous malformation, and hamartoma. Definitive diagnosis of EHE relies on its histopathologic and immunohistochemical features. Histopathologically, EHE consist of a poorly circumscribed neoplasm with infiltrative growth pattern composed of cords or solid aggregates of ovoid, cuboidal, or short spindle cells with an abundant eosinophilic cytoplasm, rounded vesicular nuclei, conspicuous nucleoli, and prominent cytoplasmic vacuolization. Cytoplasmic vacuolization represents primitive lumen formation by a single cell, and it is a characteristic, although not totally pathognomonic feature of EHE. Some of these cytoplasmic vacuoles may contain a single erythrocyte. From an immunohistochemical point of view, neoplastic cells of EHE are immunoreactive for factor VIII, Ulex europaeus, CD31, CD34, and ERG (12,30,34). Often, neoplastic cells of epithelioid hemangioendothelioma also express the endothelial lymphatic markers podoplanin/D2-40, Lyve-1, and Prox-1, supporting a lymphatic immunophenotype for this neoplasm (35,36). Immunohistochemical analyses of EHE must be interpreted with caution.
Carranza-Romero et al: Infantile Cutaneous Epithelioid Hemangioendothelioma
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TABLE 1. Examples of Cutaneous Epithelioid Hemangioendothelioma Described in Children Case
Author
Age, years
Sex
Location
Clinical features
Immunohistochemistry
Follow-up
1
Forschner et al (12) Zhang et al (24) Madura et al (25)
11
Female
Right foot
Painful ulcer
FVIII, CD31, CD34
12 9
Male Male
Right armpit Left iliac
Painful ulcer Asymptomatic
CD31, CD34, CK, vimentin CD31
Erythematous plaque Erythematous plaque
FVIII, CD31, CD34, smooth muscle actin CD31, CD34, vimentin
Asymptomatic
FVIII, CD31, CD34, D2-40
Lymph node metastasis 2 wks after excision Lymph node metastases No local recurrence or region nodule metastasis after 10 mos No local recurrence or metastasis after 20 mos Lymph node metastasis; no local recurrence or metastasis after 18 mos No local recurrence or nodule metastasis after 12 mos
2 3 4
Roh et al (26)
8
Female
Frontal scalp
5
Egberts et al (41)
9
Male
Nose
6
This report
6
Male
Left sole
Because of the presence of large numbers of intermediate filaments in the cytoplasm of the neoplastic cells of EHE, these cells may also express various cytokeratins, including cytokeratins 7 and 18 (29,37), as well as alpha smooth muscle actin (11,29). This immunophenotype may cause considerable diagnostic confusion since it is remarkable that the large epithelioid endothelial neoplastic cells of EHE strongly express cytokeratins; in particular cytokeratin 7, which almost always stains endothelial cells of all vessel types, should never be used in an antibody panel intended for differential diagnosis of epithelioid tumors. In these cases, ERG could be a useful marker. Ultrastructural studies have revealed the endothelial nature of the tumor cells surrounded by basal lamina, dotted with surface pinocytotic vesicles, intracytoplasmic lumina, and occasionally containing Weibel–Palade bodies (38), but they are no longer used for diagnosis. The t(1;3)(p36;q23–25) translocation is specific for EHE (16). This translocation fuses the WWTR1 gene in 3q23–24 with the CAMTA1 gene in 1p36, creating the WWTR1-CAMTA fusion gene. The t(1;3)(p36.3;q23–25) translocation is found in all cases of EHE, regardless of its location, and has not been detected in any of the other epithelioid cell vascular neoplasms, including epithelioid hemangioma and angiolymphoid hyperplasia with eosinophilia, epithelioid angiosarcoma, or pseudomyogenic hemangioendothelioma (also known as epithelioid sarcoma-like hemangioendothelioma) (39). Cytogenetic studies using appropriate fluorescence in situ hybridization probes for t(1;3)(p36;q23–25) are helpful for differential diagnosis and may show that multicentric EHE is a metastatic vascular tumor originating from a single neoplasm. The differential diagnosis of EHE includes metastatic carcinoma and other cutaneous and soft-tissue
tumors with epithelioid appearance of their neoplastic cells. In general, metastatic carcinomas to skin are not angiocentric, display more nuclear atypia and higher mitotic index, and usually express a wider spectrum of cytokeratins. Epithelioid hemangioma is better circumscribed than epithelioid hemangioendothelioma, neoplastic cells exhibit less atypia, and the stroma characteristically show an abundant number of eosinophils and lymphoid aggregates. Endothelial cells of pyogenic granuloma may focally exhibit epithelioid appearance, but the lesion characteristically shows the pattern of lobular capillary hemangioma. Epithelioid angiosarcomas are usually composed of solid sheets of pleomorphic neoplastic cells with high atypia and mitotic activity, and areas of necrosis en masse are frequently found. Epithelioid sarcoma should also be considered. Neoplastic cells of epithelioid sarcoma are rounded and eosinophilic and surround areas of degenerated collagen. Characteristically, neoplastic cells of epithelioid sarcoma express low and high molecular weight cytokeratins, as well as EMA and CD34, whereas there is loss of nuclear expression of SMARCB1 (INI1) (40). This tumor is capable of producing regional and distant metastases, with the lung and lymph nodes being the two most common metastatic sites. Treatment of EHE requires surgical excision with negative margins. Radiotherapy and chemotherapy regimens have not led to greater survival in patients with EHE. A risk stratification system has been proposed to identify EHE lesions at high risk of tumor progression that will require more aggressive therapy, and tumors larger than 3 cm in diameter with more than three mitoses/50 high-power fields are high risk and require more aggressive surgery (19). In conclusion, this report describes the case of EHE arising on the left sole of a 6-year-old boy. Immunohistochemical studies supported a lymphatic line of
e68 Pediatric Dermatology Vol. 32 No. 3 May/June 2015
differentiation for neoplastic cells. Although recent reports of EHE involving the skin and superficial soft tissues have demonstrated that this neoplasm behaves more aggressively than previously thought (41), our patient has remained well with no evidence of recurrence or metastatic spread after 12 months of followup. Table 1 summarizes cases of cutaneous EHE that have been described in children. REFERENCES 1. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma. A vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970–981. 2. Mentzel T, Kutzner H. Hemangioendotheliomas: heterogeneous vascular neoplasms. Dermatopathol Pract Concept 1999;5:102–109. 3. Requena L, Ackerman AB. Hemangioendothelioma? Dermatopathol Pract Concept 1999;5:110–112. 4. Weiss SW, Ishak KG, Dial DH et al. Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol 1986;3:259–287. 5. Ellis GL, Kratochvill FJ. Epithelioid hemangioendothelioma of the head and neck: a clinicopathologic report of twelve cases. Oral Surg Oral Med Oral Pathol 1986;61:61–68. 6. Tyring S, Guest P, Lee P et al. Epithelioid hemangioendothelioma of the skin and femur. J Am Acad Dermatol 1989;20:362–366. 7. Resnik KS, Kantor GR, Spielvogel RL et al. Cutaneous epithelioid hemangioendothelioma without systemic involvement. Am J Dermatopathol 1993;15:272–276. 8. Malane SL, Sau P, Benson PM. Epithelioid hemangioendothelioma associated with reflex sympathetic dystrophy. J Am Acad Dermatol 1992;26:325–328. 9. McKenzie ML. Epithelioid hemangioendothelioma of the wrist. Plast Reconstr Surg 1985;76:781–783. 10. Polk P, Webb JM. Isolated cutaneous epithelioid hemangioendothelioma. J Am Acad Dermatol 1997;36: 1026–1028. 11. Quante M, Patel NK, Hill S et al. Epithelioid hemangioendothelioma presenting in the skin. A clinicopathologic study of eight cases. Am J Dermatopathol 1998; 20:541–546. 12. Forschner A, Harms D, Metzler G et al. Ulcerated epithelioid hemangioendothelioma of the foot in childhood. J Am Acad Dermatol 2003;49:113–116. 13. Clarke LE, Lee R, Militello G et al. Cutaneous epithelioid hemangioendothelioma. J Cutan Pathol 2008; 35:236–240. 14. Kikuchi K, Watanabe M, Terui T et al. Nail-destroying epithelioid haemangioendothelioma showing an erythematous scar-like appearance on the finger. Br J Dermatol 2003;148:834–836. 15. Egberts F, Mentzel T, Leuschner I et al. Metastasizing epithelioid hemangioendothelioma of the nose in childhood. J Cutan Pathol 2008;35(Suppl 1):80–82. 16. Mendlick MR, Nelson M, Pickering D et al. Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma. Am J Surg Pathol 2001;25:684–687.
17. Sanchez Carpintero I, Martınez MI, Mihm MC Jr. Clinical and histopathologic observations of the action of imiquimod in an epithelioid hemangioendothelioma and Paget’s mammary disease. J Am Acad Dermatol 2006;55:75–79. 18. Tronnier M, Vogelbruch M, Kutzner H. Spindle cell hemangioma and epithelioid hemangioendothelioma arising in an area of lymphedema. Am J Dermatopathol 2006;28:223–227. 19. Deyrup AT, Tighiouart M, Montag AG et al. Epithelioid hemangioendothelioma of soft tissue. A proposal for risk stratification based on 49 cases. Am J Surg Pathol 2008;32:924–927. 20. De Araujo VC, Marcucci G, Sesso A et al. Epithelioid hemangioendothelioma of the gingiva: case report and ultrastructural study. Oral Surg Oral Med Oral Pathol 1987;63:472–477. 21. Marrogi AJ, Boyd D, el-Mofty S et al. Epithelioid hemangioendothelioma of the oral cavity: report of two cases and review of literature. J Oral Maxillofac Surg 1991;49:633–638. 22. Orsini G, Fioroni M, Rubini C et al. Epithelioid hemangioendothelioma of the oral cavity: report of case. J Oral Maxillofac Surg 2001;59:334–337. 23. Grezard P, Balme B, Ceruse P et al. Ulcerated cutaneous epithelioid hemangioendothelioma. Eur J Dermatol 1999;9:487–490. 24. Zhang W, He J, Wang J et al. Ulcerated epithelioid hemangioendothelioma of the right armpit in childhood. J Pediatr Hematol Oncol 2009;31:595–598. 25. Madura C, Sacchidanand S, Barde NG et al. Epithelioid hemangioendothelioma in a child. J Cutan Aesthet Surg 2013;6:232–235. 26. Roh HS, Kim YS, Suhr KB et al. A case of childhood epithelioid hemangioendothelioma. J Am Acad Dermatol 2000;42:897–899. 27. Lakshmi SV, Prabhavathy D, Jayakumar S et al. Epithelioid hemangioendothelioma: a rare vascular tumor. Indian J Dermatol 2012;57:53–54. 28. Bettencourt MS, Burton CS, Prieto VG et al. Recurrent papules on the left extremity of a 50-year-old man. Arch Dermatol 2001;137:365–367. 29. Mentzel T, Beham A, Calonje E et al. Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and inmunohistochemical study of 30 cases. Am J Surg Pathol 1997;21:363–374. 30. Kanib AB, Hall JD, Bhawan J. Eruptive epithelioid hemangioendothelioma with spindle cells. Am J Dermatopathol 1995;17:612–617. 31. Vignon-Pennamen MD, Rybojad M, Verola A et al. Hemangioendotheliome epithelioide: evolution dans 3 cas. Ann Dermatol Venereol 1997;124:165–166. 32. Dean PJ, Haggit RC, O’Hara CJ. Malignant epithelioid hemangioendothelioma of the liver in young women: relationship to oral contraceptive use. Am J Surg Pathol 1985;9:695–704. 33. Davies MF, Curtis M, Howat JM. Cutaneous haemangioendothelioma: a possible link with chronic exposure to vinyl chloride. Br J Ind Med 1990;47:65–67. 34. Miettinen M, Wang ZF, Paetau A et al. ERG transcription factor as an immunohistochemical marker for vascular endothelial tumors and prostatic carcinoma. Am J Surg Pathol 2011;35:432–441.
Carranza-Romero et al: Infantile Cutaneous Epithelioid Hemangioendothelioma
35. Naqvi J, Ordonez NG, Luna MA et al. Epithelioid hemangioendothelioma of the head and neck: role of podoplanin in the differential diagnosis. Head Neck Pathol 2008;2:25–30. 36. Miettinen M, Wang ZF. Prox1 transcription factor as a marker for vascular tumors-evaluation of 314 vascular endothelial and 1086 nonvascular tumors. Am J Surg Pathol 2012;36:351–359. 37. Gray MH, Rosenberg AE, Dicersin GR et al. Cytokeratin expression in epithelioid vascular neoplasms. Hum Pathol 1990;21:212–217. 38. Vasquez M, Ordo~ nez NG, English GW et al. Epithelioid hemangioendothelioma of soft tissue: report of a
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case with ultrastructural observations. Ultrastruct Pathol 1998;22:73–78. 39. Errani C, Zhang L, Sung YS et al. A novel WWTR1CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosom Cancer 2011;50:644–653. 40. Hornick JL, Dal Cin P, Fletcher CD. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol 2009;33:542–550. 41. Egberts F, Mentzel T, Leuschner I et al. Metastasizing epithelioid hemangioendothelioma of the nose in childhood. J Cutan Pathol 2008;35:80–82.
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Cutaneous Epithelioid Hemangioendothelioma on the Sole of a Child Carmen Carranza-Romero, M.D.,* Ana Maria Molina-Ruiz, M.D.,* Cristian Perna Monroy, M.D.,† Jes us Cuevas Santos, M.D.,† and Luis Requena, M.D.* *Department of Dermatology, Fundaci on Jim enez Diaz, Universidad Aut onoma de Madrid, Madrid, Spain, †Department of Pathology, Hospital Universitario de Guadalajara, Universidad de Alcal a de Henares, Madrid, Spain
Abstract: Epithelioid hemangioendothelioma (EHE) has been considered to be a low-grade malignant vascular neoplasm, although follow-up of recent series has demonstrated that EHE involving the skin and soft tissues should be better regarded as a fully malignant vascular tumor since it has more metastatic potential than previously thought. We report a case of an EHE involving the left sole of 6-year-old boy, the youngest patient with cutaneous EHE described to date. Immunohistochemical studies demonstrated a lymphatic endothelial line of differentiation for neoplastic cells. Cutaneous EHE is rare in childhood, with only five previously described cases.
Epithelioid hemangioendothelioma (EHE) is a low-grade, malignant, vascular neoplasm first described in 1982 by Weiss and Enzinger (1). It mostly presents as a solitary, slightly painful softtissue tumor, although it has also been identified in the skin (2–31). EHEs occur without sex preference and at any age, although most described cases developed in adults (ages 30–50 yrs), and they are extremely uncommon during childhood, with only five infantile cases reported to date (12,24–27). We report the case of an EHE that developed on the left sole of a 6-year-old boy. CASE REPORT A 6-year-old boy presented with an approximately 6month history of a nodular lesion of the sole of the left
foot that had grown quickly over the last 4 months. The lesion had become painful in the last month. Physical examination revealed a firm nodular mass measuring 2.5 cm in diameter located on the anterior part of the sole of the left foot (Fig. 1). There were no palpable lymph nodes. Histopathologic study from a biopsy demonstrated that the lesion was composed of several poorly circumscribed dermal nodules covered by hyperplastic acral epidermis. Neoplastic aggregates involved mostly deep reticular dermis and in some areas extended to the subcutis, whereas the upper half of the dermis was spared (Fig. 2A). The neoplasm was composed of cords and clusters of epithelioid cells embedded in a sclerotic stroma (Fig. 2B). In some areas the stroma showed a more fibromyxoid appearance. Many of these neoplastic cells contained
Address correspondence to Luis Requena, M.D., Department of Dermatology, Fundaci on Jimenez Dıaz, Avda. Reyes Cat olicos 2, 28040-Madrid, Spain, or e-mail: [email protected]. DOI: 10.1111/pde.12539
e64
© 2015 Wiley Periodicals, Inc.
Carranza-Romero et al: Infantile Cutaneous Epithelioid Hemangioendothelioma
e65
pan-cytokeratin AE1/AE3 was negative. Immunostaining for alpha smooth muscle actin demonstrated a preserved ring of pericytes around only a few of the neoformed neoplastic vessels, whereas most vascular structures lacked that ring. Surgery was performed, with complete removal of the lesion, and histopathologic study of the excised specimen demonstrated that the deepest margin of the neoplasm extended into the superficial subcutis, but all margins of excision were free of neoplasm. No adjuvant treatment was required. After 9 months of follow-up, the patient has remained well, with no evidence of recurrence or metastatic spread.
Figure 1. Erythematous nodule on the left sole.
vacuoles within their cytoplasm as a sign of primitive vascular differentiation (Fig. 2C), sometimes with a single intravacuolar erythrocyte. Those cells showed vesicular nuclei with prominent nucleoli and large eosinophilic cytoplasm (Fig. 2D). Slight nuclear pleomorphism and occasional mitotic figures were also found. No necrosis of single cells or necrosis en masse was found. Immunohistochemically, neoplastic cells expressed immunoreactivity for factor VIII, CD31 (Fig. 3A, B), CD34, and podoplanin/D2-40 (Fig. 3C, D). Ki-67 marked approximately 20% of the nuclei of neoplastic cells. Immunostaining for cytokeratins 7 and 18 and
DISCUSSION In 1982, Weiss and Enzinger (1) coined the term EHE to refer a biologically borderline neoplasm between a hemangioma and a conventional angiosarcoma. Since then, EHE has been considered to be a low-grade malignant vascular neoplasm with low metastatic potential but high a tendency to recur, although in a recent series of 30 cases of EHE of the skin and superficial soft tissues, follow-up of 24 cases showed local recurrence in 3 cases and systemic metastases in 5 cases, and 4 patients died of the tumor, suggesting that EHE of the skin and soft tissues should be
A
B
C
D
Figure 2. Histopathologic features. (A) Scanning power view shows a poorly circumscribed lesion composed of several nodules involving superficial and deep dermis (original magnification 109). (B) The nodules were composed of cords of cells with hyperchromatic basophilic nuclei (original magnification 409). (C) Some of the neoplastic cells showed cytoplasmic vacuolization as expression of primitive vascular differentiation (original magnification 2009). (D) Higher magnification of neoplastic cells demonstrates their vesicular and pleomorphic nuclei (original magnification 4009).
e66 Pediatric Dermatology Vol. 32 No. 3 May/June 2015
A
B
C
D
Figure 3. Immunohistochemical characteristics of the lesion. (A) Scanning power view of CD31 immunostaining (original magnification 109). (B) Higher magnification demonstrates the CD31 positivity of neoplastic cells (original magnification 4009). (C) Scanning power view of podoplanin/D2-40 immunostaining (original magnification 109). (D) Higher magnification demonstrates the podoplanin/D2-40 immunoexpression in neoplastic cells (original magnification 4009).
regarded as a fully malignant rather than borderline vascular neoplasm, albeit with a better prognosis than with a conventional angiosarcoma (29). The incidence of EHE is the same in men and women, although liver and lung lesions are more common in women (4). It generally affects middleaged patients and is extremely rare in childhood, with only five previously described cutaneous cases (12,24– 27). The etiology of EHE remains unknown, although Dean et al (32) suggested that the greater incidence of EHE of the liver in women might be related to oral contraceptive use, and Davies et al (33) have also reported a possible relationship between chronic vinyl chloride exposure and EHE. In the skin, it seems that this neoplasm usually arises from a medium-sized or large vein, mainly in the superficial or deep soft tissue, and only approximately 10% of the cases arise from superficial dermal vessels of the skin or mucous membranes (1,6–28). Although the clinical presentation of EHE may be variable, the neoplasm in the skin usually presents as a solitary, rarely multiple, erythematous papule, nodule, plaque, or hyperkeratotic or nonhealing ulcer (10–17) that may subsequently extend to the underlying tissues, including the bone. In most cases the signs and symptoms of EHE are nonspecific and consist of a painful or tender mass or a slowly growing tumor. It can arise at any body site, but the most common
location is the lower extremities. In some cases occlusion of the affected vessel causes more profound symptoms, such as edema or thrombophlebitis of the involved limb. The usual clinical differential diagnoses include hemangioma, pyogenic granuloma, arteriovenous malformation, and hamartoma. Definitive diagnosis of EHE relies on its histopathologic and immunohistochemical features. Histopathologically, EHE consist of a poorly circumscribed neoplasm with infiltrative growth pattern composed of cords or solid aggregates of ovoid, cuboidal, or short spindle cells with an abundant eosinophilic cytoplasm, rounded vesicular nuclei, conspicuous nucleoli, and prominent cytoplasmic vacuolization. Cytoplasmic vacuolization represents primitive lumen formation by a single cell, and it is a characteristic, although not totally pathognomonic feature of EHE. Some of these cytoplasmic vacuoles may contain a single erythrocyte. From an immunohistochemical point of view, neoplastic cells of EHE are immunoreactive for factor VIII, Ulex europaeus, CD31, CD34, and ERG (12,30,34). Often, neoplastic cells of epithelioid hemangioendothelioma also express the endothelial lymphatic markers podoplanin/D2-40, Lyve-1, and Prox-1, supporting a lymphatic immunophenotype for this neoplasm (35,36). Immunohistochemical analyses of EHE must be interpreted with caution.
Carranza-Romero et al: Infantile Cutaneous Epithelioid Hemangioendothelioma
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TABLE 1. Examples of Cutaneous Epithelioid Hemangioendothelioma Described in Children Case
Author
Age, years
Sex
Location
Clinical features
Immunohistochemistry
Follow-up
1
Forschner et al (12) Zhang et al (24) Madura et al (25)
11
Female
Right foot
Painful ulcer
FVIII, CD31, CD34
12 9
Male Male
Right armpit Left iliac
Painful ulcer Asymptomatic
CD31, CD34, CK, vimentin CD31
Erythematous plaque Erythematous plaque
FVIII, CD31, CD34, smooth muscle actin CD31, CD34, vimentin
Asymptomatic
FVIII, CD31, CD34, D2-40
Lymph node metastasis 2 wks after excision Lymph node metastases No local recurrence or region nodule metastasis after 10 mos No local recurrence or metastasis after 20 mos Lymph node metastasis; no local recurrence or metastasis after 18 mos No local recurrence or nodule metastasis after 12 mos
2 3 4
Roh et al (26)
8
Female
Frontal scalp
5
Egberts et al (41)
9
Male
Nose
6
This report
6
Male
Left sole
Because of the presence of large numbers of intermediate filaments in the cytoplasm of the neoplastic cells of EHE, these cells may also express various cytokeratins, including cytokeratins 7 and 18 (29,37), as well as alpha smooth muscle actin (11,29). This immunophenotype may cause considerable diagnostic confusion since it is remarkable that the large epithelioid endothelial neoplastic cells of EHE strongly express cytokeratins; in particular cytokeratin 7, which almost always stains endothelial cells of all vessel types, should never be used in an antibody panel intended for differential diagnosis of epithelioid tumors. In these cases, ERG could be a useful marker. Ultrastructural studies have revealed the endothelial nature of the tumor cells surrounded by basal lamina, dotted with surface pinocytotic vesicles, intracytoplasmic lumina, and occasionally containing Weibel–Palade bodies (38), but they are no longer used for diagnosis. The t(1;3)(p36;q23–25) translocation is specific for EHE (16). This translocation fuses the WWTR1 gene in 3q23–24 with the CAMTA1 gene in 1p36, creating the WWTR1-CAMTA fusion gene. The t(1;3)(p36.3;q23–25) translocation is found in all cases of EHE, regardless of its location, and has not been detected in any of the other epithelioid cell vascular neoplasms, including epithelioid hemangioma and angiolymphoid hyperplasia with eosinophilia, epithelioid angiosarcoma, or pseudomyogenic hemangioendothelioma (also known as epithelioid sarcoma-like hemangioendothelioma) (39). Cytogenetic studies using appropriate fluorescence in situ hybridization probes for t(1;3)(p36;q23–25) are helpful for differential diagnosis and may show that multicentric EHE is a metastatic vascular tumor originating from a single neoplasm. The differential diagnosis of EHE includes metastatic carcinoma and other cutaneous and soft-tissue
tumors with epithelioid appearance of their neoplastic cells. In general, metastatic carcinomas to skin are not angiocentric, display more nuclear atypia and higher mitotic index, and usually express a wider spectrum of cytokeratins. Epithelioid hemangioma is better circumscribed than epithelioid hemangioendothelioma, neoplastic cells exhibit less atypia, and the stroma characteristically show an abundant number of eosinophils and lymphoid aggregates. Endothelial cells of pyogenic granuloma may focally exhibit epithelioid appearance, but the lesion characteristically shows the pattern of lobular capillary hemangioma. Epithelioid angiosarcomas are usually composed of solid sheets of pleomorphic neoplastic cells with high atypia and mitotic activity, and areas of necrosis en masse are frequently found. Epithelioid sarcoma should also be considered. Neoplastic cells of epithelioid sarcoma are rounded and eosinophilic and surround areas of degenerated collagen. Characteristically, neoplastic cells of epithelioid sarcoma express low and high molecular weight cytokeratins, as well as EMA and CD34, whereas there is loss of nuclear expression of SMARCB1 (INI1) (40). This tumor is capable of producing regional and distant metastases, with the lung and lymph nodes being the two most common metastatic sites. Treatment of EHE requires surgical excision with negative margins. Radiotherapy and chemotherapy regimens have not led to greater survival in patients with EHE. A risk stratification system has been proposed to identify EHE lesions at high risk of tumor progression that will require more aggressive therapy, and tumors larger than 3 cm in diameter with more than three mitoses/50 high-power fields are high risk and require more aggressive surgery (19). In conclusion, this report describes the case of EHE arising on the left sole of a 6-year-old boy. Immunohistochemical studies supported a lymphatic line of
e68 Pediatric Dermatology Vol. 32 No. 3 May/June 2015
differentiation for neoplastic cells. Although recent reports of EHE involving the skin and superficial soft tissues have demonstrated that this neoplasm behaves more aggressively than previously thought (41), our patient has remained well with no evidence of recurrence or metastatic spread after 12 months of followup. Table 1 summarizes cases of cutaneous EHE that have been described in children. REFERENCES 1. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma. A vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970–981. 2. Mentzel T, Kutzner H. Hemangioendotheliomas: heterogeneous vascular neoplasms. Dermatopathol Pract Concept 1999;5:102–109. 3. Requena L, Ackerman AB. Hemangioendothelioma? Dermatopathol Pract Concept 1999;5:110–112. 4. Weiss SW, Ishak KG, Dial DH et al. Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol 1986;3:259–287. 5. Ellis GL, Kratochvill FJ. Epithelioid hemangioendothelioma of the head and neck: a clinicopathologic report of twelve cases. Oral Surg Oral Med Oral Pathol 1986;61:61–68. 6. Tyring S, Guest P, Lee P et al. Epithelioid hemangioendothelioma of the skin and femur. J Am Acad Dermatol 1989;20:362–366. 7. Resnik KS, Kantor GR, Spielvogel RL et al. Cutaneous epithelioid hemangioendothelioma without systemic involvement. Am J Dermatopathol 1993;15:272–276. 8. Malane SL, Sau P, Benson PM. Epithelioid hemangioendothelioma associated with reflex sympathetic dystrophy. J Am Acad Dermatol 1992;26:325–328. 9. McKenzie ML. Epithelioid hemangioendothelioma of the wrist. Plast Reconstr Surg 1985;76:781–783. 10. Polk P, Webb JM. Isolated cutaneous epithelioid hemangioendothelioma. J Am Acad Dermatol 1997;36: 1026–1028. 11. Quante M, Patel NK, Hill S et al. Epithelioid hemangioendothelioma presenting in the skin. A clinicopathologic study of eight cases. Am J Dermatopathol 1998; 20:541–546. 12. Forschner A, Harms D, Metzler G et al. Ulcerated epithelioid hemangioendothelioma of the foot in childhood. J Am Acad Dermatol 2003;49:113–116. 13. Clarke LE, Lee R, Militello G et al. Cutaneous epithelioid hemangioendothelioma. J Cutan Pathol 2008; 35:236–240. 14. Kikuchi K, Watanabe M, Terui T et al. Nail-destroying epithelioid haemangioendothelioma showing an erythematous scar-like appearance on the finger. Br J Dermatol 2003;148:834–836. 15. Egberts F, Mentzel T, Leuschner I et al. Metastasizing epithelioid hemangioendothelioma of the nose in childhood. J Cutan Pathol 2008;35(Suppl 1):80–82. 16. Mendlick MR, Nelson M, Pickering D et al. Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma. Am J Surg Pathol 2001;25:684–687.
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