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Epithelioid haemangioendothelioma of the breast
The Breast (1999) 8, 295–297 © 1999 Harcourt Publishers Ltd
CASE REPORT
Epithelioid haemangioendothelioma of the breast L. Insabato, D. Di Vizio, L. M. Terracciano and G. Pettinato Department of Anatomic Pathology, University of Naples ‘Federico II’, Naples, Italy S U M M A R Y. This article describes histopathologica, immunohistologic, and morphometric features of an epithelioid haemangioendothelioma that presented in the breast of a 30-year-old woman. Histologically the tumour was composed of large round, polygonal, slightly spindle shaped endothelial cells lying in a myxoid matrix. The lesion exhibited primitive vasoformation characterized by the presence of cytoplasmic vacuoles. The tumour cells reacted positively to F-VIII related antigen, whereas mammary ducts entrapped by the tumour cells reacted positively with keratin. Although the breast is an unusual location for this type of lesion, epithelioid haemangioendothelioma should be considered a rare differential diagnosis of a breast mass. © 1999 Harcourt Publishers Ltd.
examination revealed a slightly painful, mobile, tender nodule, 2 cm in diameter, in the upper outer quadrant of the left breast. No axillary lymph nodes were palpated. A mammographic examination showed a radioopaque nodule with not well-defined margins. An excisional biopsy was carried out. The postoperative course was uneventful, and the patient remained asymtomatic and free of disease 22 months after surgery.
INTRODUCTION Epithelioid haemangioendothelioma (EH) is a rare vascular neoplasm occurring almost exclusively in adults. This tumour is composed of epithelioid endothelial cells with cosinophilic cytoplasm, and cytoplasmic vacuolization Rosai et al., employing an umbrella term of ‘histiocytoid haemangioma’,1 unified several previously described entities of skin, soft tissue, large vessels, bone, and heart, separating histiocytoid haemangioma from Kimura’s disease, a cutaneous lesion which had been erroneously equated with EH. The latter commonly occurs in soft tissue,2 however, other organs may be involved.3 A case of epithelioid angiosarcoma of the breast has been recently reported,4 but to our knowledge EH has not been previously described in the breast. We report the histologic, immunohistochemical, and morphometric findings in a case of EH of the breast.
HISTOPATHOLOGIC FINDINGS The surgical specimen consisted of a 5 3 4 3 3.5 cm breast tissue. On cut sections it showed a poorly defined firm white–grey nodule of 2 cm in diameter. Haemorrhage and necrosis were not observed. Formalin-fixed, paraffin embedded sections were stained with haematoxylin and eosin, and periodic acid-schiff (PAS) with and without diastase digestion. The mass had an ill-defined growth pattern with infiltrative margins. It was composed of large round, polygonal and slightly spindle shaped endothelial cells with a relatively abundant eosinophilic cytoplasm lying in a myxoid matrix. The nuclei were round, oval, and regular, but they did show folds or grooves and contained one or two small nucleoli. The lesion frequently exhibited primitive vasoformation characterized by the presence of cytoplasmic vacuoles. These vacuoles did not contain mucin, but occasional contained red blood cells. Because of this vacuolization, tumour cells frequently show a signetoid appearance, and there was in parts a tendency towards a targetoid pattern around mammary ducts (Fig. 1). Mammary ducts embedded
CASE REPORT A 30-year-old woman presented with a left breast nodule of approximately six months duration. There was no history of oral contraceptive use or recent pregnancy. The patient was a non-smoker with only social alcohol usage. Physical
Address correspondence to: Dr Luigi Insabato, Dipartimento di Anatomia Patologica, Università di Napoli ‘Federico II’ via S. Pansini 5, 80131 Naples, Italy. Tel.: 81 7463433; Fax: 81 7463475; E-mail: [email protected]
295
296
The Breast DISCUSSION
Fig. 1 Epithelioid tumour cells showing ample cytoplasm. An intranuclear vacuole is noted (Arrow). (H/E stain, original magnification 3 400).
within the tumour were observed. Immunohistochemical marker studies were performed on paraffin-embedded sections. Tumour cells showed strong cytoplasmic and membranous positivity for F-VIII related antigen with staining around the circumference of the cytoplasmic vacuoles (Fig. 2b). Cytoplasmic keratin was not identified. Mammary ducts entrapped within the tumour reacted positively with keratin (Fig. 2). Adjacent breast parenchyma showed sclerosing adenosis, and foci of pregnancy-like changes in some lobules were observed. DNA ploidy was evaluated by image analysis. Dissociated nuclei were analysed with a FACS scan flow cytometer (Becton–Dickinson Immunocytometry System, San Jose, CA). Only one G0–G1 peak was present given a DNA index of 1.00, and the G2M peak was less than 15%.
A
B Fig. 2 (A) Mammary ducts entrapped within the tumour reacting positively with keratin (Original magnificant 3106). (B) epithelioid tumour cells strongly reacting with F-VIII related antigen (Original magnification 3400).
Epithelioid haemangioendothelioma (EH) is an endothelial tumour of intermediate malignancy, that belongs to the spectrum of the histiocytoid haemangioma.1 It is composed of distinctive epithelioid changes of endothelial cells, which have polygonal or fusiform shapes, central round or oval nuclei, and deeply eosinophilic cytoplasm. Although EH commonly occurs in soft tissue,3 other organs and tissues may be affected. The rarity of this tumour is probably the main cause of the controversy surrounding classification and the name attached to this lesion. It has been termed ‘intravascular bronchioloalveolar tumour’ in the lung,5 ‘sclerosing pericholangitic tumour’ in the liver,6 and ‘haemangioendothelioma’ in bone.7,8 To our knowledge this is the first well-documented case of EH of breast in an adult. Indeed, we were able to find in the literature only one citation of EH of the breast in a comprehensive report of epithelioid haemangioendothelioma and related lesions.3 Although Macias-Martinez and co-workers stated that epithelioid haemangioendothelioma has not been described in the breast,4 one of us (GP) described a case of EH in the breast of a child within a series of breast lesions in children.9 Our case showed typical features of EH, it was composed of short strands of solid nests of rounded to slightly spindled endothelial cells embedded in a myxoid matrix. These cells strongly reacted positively with F-VIII related antigen, unlike mammary ducts entrapped within the tumour which were positive for keratin. A remarkable feature was the presence of sharply demarcated intracytoplasmic lumina; although these vacuolated cells may resemble the signet-ring cells of an adenocarcinoma, the vacuoles do not contain mucin, but may contain red blood cells. In addition intranuclear cytoplasmic vacuoles were observed. These latter two findings, in addition to the epithelioid appearance of the cells, can be considered hallmarks of EH as described in the cytologic literature.10,11 Rosai et al. affirmed that lesions composed of these large eosinophilic cells were a peculiar form of endothelial cell having histiocyte-like properties.1 They gave the name of ‘histiocytoid haemangioma’ to these lesions. Subsequent to this report the name ‘histiocytoid’ was abandoned by some authors3 in favour of the diagnostic term ‘epithelioid haemangioma’. Differential diagnosis is from an epithelial metastasis or an epithelioid sarcoma, both of which are strongly keratin and EMA positive; although positive staining for keratin in vascular tumours has been described,12 EH also shows consistent positivity for endothelial markers, particularly CD31 and FVIII protein. Because of the tendency of tumour cells to encircle mammary ducts in a targetoid fashion, a diagnosis of lobular carcinoma of the breast must be excluded. It can be difficult to differentiate EH from epithelioid
Epithelioid haemangioendothelioma of the breast 297 haemangioma, because in the latter vascular differentiation procedes the formation of multicellular canalized vascular channels, whereas vascular differentiation in epithelioid haemangioendothelioma is primitive and is expressed primarily at the cellular level. A close relative of the EH is the epithelioid angiosarcoma, a rare morphologic variant of a malignant vascular neoplasm recently described in the breast.14 It shows a high mitotic activity, and necrosis, and has features of distinct vascular channels which are rarely seen in the EH except at the periphery of the tumour. EH has to be considered a rare differential diagnosis of tumour masses, in the breast and immunohistochemistry is a useful tool in differentiating these vascular tumours from other neoplasms.
References 1. Rosai J, Gold J, Landy R. The histiocytoid hemangioma: a unifying concept embracing several previously described entities of skin, soft tissue, large vessels, bone, and heart. Hum Pathol 1979; 10: 707–730. 2. Weiss S W, Ishak K G, Dail DH et al. Epithelioid hemangioendothelioma and related lesions. Sem Diagn Pathol 1986; 3: 259–287. 3. Weiss S W, Enzinger F M. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 1983; 50: 970–981.
4. Martinez V M, Tiburcio L M, Cardenas H M et al. Epithelioid angiosarcoma of the breast. Clinicopathologic, immunohistochemical, and ultrastructural study of a case. Am J Surg Pathol 1997; 21: 599–604. 5. Dail D H, Liebow A A, Gmelich J T et al. Intravascular bronchial and alveolar tumor of the lung (IVBAT): an analysis of twenty cases of a peculiar sclerosing endothelial tumor. Cancer 1983; 51: 452–464. 6. Ishak K G, Sesterhenn I A, Godman Z D et al. Epithelioid hemangioendothelioma of the liver: A clinico-pathologic and followup study of 32 cases. Hum Pathol 1984; 150: 839–852. 7. Kleer C G, Unni K, Mc Leod R A. Epithelioid hemangioendothelioma of bone. Am J Surg Pathol 1996; 20: 1301–1311. 8. Tsuneyoshi M, Dorfman H D, Bauer T W. Epithelioid hemangioendothelioma of bone: A clinicopathologic, ultrastructural and immunohistochemical study. Am J Surg Pathol 1986; 10: 754–764. 9. Pettinato G, Manivel J C, Kelly D R et al. Lesions of the breast in children exclusive of typical fibroadenoma and gynecomastia: a clinicopathologic study of 113 cases. Pathol Ann 1989; 24: 295–328. 10. Pettinato G, Insabato L, De Chiara A et al. Intranuclear cytoplasmic inclusions in epithelioid hemangioendothelioma. Acta Cytol 1988; 32: 604–605. 11. Pettinato G, Insabato L, De Chiara A et al. Epithelioid hemangioendothelioma of soft tissue. Fine needle aspiration cytology, histology, electron microscopy and immunohistochemistry of a case. Acta Cytol 1986; 30: 194–200. 12. Gray M H, Rosemberg A E, Dickersin G R et al. Cytokeratin expression in epithelioid vascular neoplasms. Hum Pathol 1990; 21: 212–217.
298
The Breast
CASE REPORT
Epithelioid haemangioendothelioma of the breast L. Insabato, D. Di Vizio, L. M. Terracciano and G. Pettinato Department of Anatomic Pathology, University of Naples ‘Federico II’, Naples, Italy S U M M A R Y. This article describes histopathologica, immunohistologic, and morphometric features of an epithelioid haemangioendothelioma that presented in the breast of a 30-year-old woman. Histologically the tumour was composed of large round, polygonal, slightly spindle shaped endothelial cells lying in a myxoid matrix. The lesion exhibited primitive vasoformation characterized by the presence of cytoplasmic vacuoles. The tumour cells reacted positively to F-VIII related antigen, whereas mammary ducts entrapped by the tumour cells reacted positively with keratin. Although the breast is an unusual location for this type of lesion, epithelioid haemangioendothelioma should be considered a rare differential diagnosis of a breast mass. © 1999 Harcourt Publishers Ltd.
examination revealed a slightly painful, mobile, tender nodule, 2 cm in diameter, in the upper outer quadrant of the left breast. No axillary lymph nodes were palpated. A mammographic examination showed a radioopaque nodule with not well-defined margins. An excisional biopsy was carried out. The postoperative course was uneventful, and the patient remained asymtomatic and free of disease 22 months after surgery.
INTRODUCTION Epithelioid haemangioendothelioma (EH) is a rare vascular neoplasm occurring almost exclusively in adults. This tumour is composed of epithelioid endothelial cells with cosinophilic cytoplasm, and cytoplasmic vacuolization Rosai et al., employing an umbrella term of ‘histiocytoid haemangioma’,1 unified several previously described entities of skin, soft tissue, large vessels, bone, and heart, separating histiocytoid haemangioma from Kimura’s disease, a cutaneous lesion which had been erroneously equated with EH. The latter commonly occurs in soft tissue,2 however, other organs may be involved.3 A case of epithelioid angiosarcoma of the breast has been recently reported,4 but to our knowledge EH has not been previously described in the breast. We report the histologic, immunohistochemical, and morphometric findings in a case of EH of the breast.
HISTOPATHOLOGIC FINDINGS The surgical specimen consisted of a 5 3 4 3 3.5 cm breast tissue. On cut sections it showed a poorly defined firm white–grey nodule of 2 cm in diameter. Haemorrhage and necrosis were not observed. Formalin-fixed, paraffin embedded sections were stained with haematoxylin and eosin, and periodic acid-schiff (PAS) with and without diastase digestion. The mass had an ill-defined growth pattern with infiltrative margins. It was composed of large round, polygonal and slightly spindle shaped endothelial cells with a relatively abundant eosinophilic cytoplasm lying in a myxoid matrix. The nuclei were round, oval, and regular, but they did show folds or grooves and contained one or two small nucleoli. The lesion frequently exhibited primitive vasoformation characterized by the presence of cytoplasmic vacuoles. These vacuoles did not contain mucin, but occasional contained red blood cells. Because of this vacuolization, tumour cells frequently show a signetoid appearance, and there was in parts a tendency towards a targetoid pattern around mammary ducts (Fig. 1). Mammary ducts embedded
CASE REPORT A 30-year-old woman presented with a left breast nodule of approximately six months duration. There was no history of oral contraceptive use or recent pregnancy. The patient was a non-smoker with only social alcohol usage. Physical
Address correspondence to: Dr Luigi Insabato, Dipartimento di Anatomia Patologica, Università di Napoli ‘Federico II’ via S. Pansini 5, 80131 Naples, Italy. Tel.: 81 7463433; Fax: 81 7463475; E-mail: [email protected]
295
296
The Breast DISCUSSION
Fig. 1 Epithelioid tumour cells showing ample cytoplasm. An intranuclear vacuole is noted (Arrow). (H/E stain, original magnification 3 400).
within the tumour were observed. Immunohistochemical marker studies were performed on paraffin-embedded sections. Tumour cells showed strong cytoplasmic and membranous positivity for F-VIII related antigen with staining around the circumference of the cytoplasmic vacuoles (Fig. 2b). Cytoplasmic keratin was not identified. Mammary ducts entrapped within the tumour reacted positively with keratin (Fig. 2). Adjacent breast parenchyma showed sclerosing adenosis, and foci of pregnancy-like changes in some lobules were observed. DNA ploidy was evaluated by image analysis. Dissociated nuclei were analysed with a FACS scan flow cytometer (Becton–Dickinson Immunocytometry System, San Jose, CA). Only one G0–G1 peak was present given a DNA index of 1.00, and the G2M peak was less than 15%.
A
B Fig. 2 (A) Mammary ducts entrapped within the tumour reacting positively with keratin (Original magnificant 3106). (B) epithelioid tumour cells strongly reacting with F-VIII related antigen (Original magnification 3400).
Epithelioid haemangioendothelioma (EH) is an endothelial tumour of intermediate malignancy, that belongs to the spectrum of the histiocytoid haemangioma.1 It is composed of distinctive epithelioid changes of endothelial cells, which have polygonal or fusiform shapes, central round or oval nuclei, and deeply eosinophilic cytoplasm. Although EH commonly occurs in soft tissue,3 other organs and tissues may be affected. The rarity of this tumour is probably the main cause of the controversy surrounding classification and the name attached to this lesion. It has been termed ‘intravascular bronchioloalveolar tumour’ in the lung,5 ‘sclerosing pericholangitic tumour’ in the liver,6 and ‘haemangioendothelioma’ in bone.7,8 To our knowledge this is the first well-documented case of EH of breast in an adult. Indeed, we were able to find in the literature only one citation of EH of the breast in a comprehensive report of epithelioid haemangioendothelioma and related lesions.3 Although Macias-Martinez and co-workers stated that epithelioid haemangioendothelioma has not been described in the breast,4 one of us (GP) described a case of EH in the breast of a child within a series of breast lesions in children.9 Our case showed typical features of EH, it was composed of short strands of solid nests of rounded to slightly spindled endothelial cells embedded in a myxoid matrix. These cells strongly reacted positively with F-VIII related antigen, unlike mammary ducts entrapped within the tumour which were positive for keratin. A remarkable feature was the presence of sharply demarcated intracytoplasmic lumina; although these vacuolated cells may resemble the signet-ring cells of an adenocarcinoma, the vacuoles do not contain mucin, but may contain red blood cells. In addition intranuclear cytoplasmic vacuoles were observed. These latter two findings, in addition to the epithelioid appearance of the cells, can be considered hallmarks of EH as described in the cytologic literature.10,11 Rosai et al. affirmed that lesions composed of these large eosinophilic cells were a peculiar form of endothelial cell having histiocyte-like properties.1 They gave the name of ‘histiocytoid haemangioma’ to these lesions. Subsequent to this report the name ‘histiocytoid’ was abandoned by some authors3 in favour of the diagnostic term ‘epithelioid haemangioma’. Differential diagnosis is from an epithelial metastasis or an epithelioid sarcoma, both of which are strongly keratin and EMA positive; although positive staining for keratin in vascular tumours has been described,12 EH also shows consistent positivity for endothelial markers, particularly CD31 and FVIII protein. Because of the tendency of tumour cells to encircle mammary ducts in a targetoid fashion, a diagnosis of lobular carcinoma of the breast must be excluded. It can be difficult to differentiate EH from epithelioid
Epithelioid haemangioendothelioma of the breast 297 haemangioma, because in the latter vascular differentiation procedes the formation of multicellular canalized vascular channels, whereas vascular differentiation in epithelioid haemangioendothelioma is primitive and is expressed primarily at the cellular level. A close relative of the EH is the epithelioid angiosarcoma, a rare morphologic variant of a malignant vascular neoplasm recently described in the breast.14 It shows a high mitotic activity, and necrosis, and has features of distinct vascular channels which are rarely seen in the EH except at the periphery of the tumour. EH has to be considered a rare differential diagnosis of tumour masses, in the breast and immunohistochemistry is a useful tool in differentiating these vascular tumours from other neoplasms.
References 1. Rosai J, Gold J, Landy R. The histiocytoid hemangioma: a unifying concept embracing several previously described entities of skin, soft tissue, large vessels, bone, and heart. Hum Pathol 1979; 10: 707–730. 2. Weiss S W, Ishak K G, Dail DH et al. Epithelioid hemangioendothelioma and related lesions. Sem Diagn Pathol 1986; 3: 259–287. 3. Weiss S W, Enzinger F M. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 1983; 50: 970–981.
4. Martinez V M, Tiburcio L M, Cardenas H M et al. Epithelioid angiosarcoma of the breast. Clinicopathologic, immunohistochemical, and ultrastructural study of a case. Am J Surg Pathol 1997; 21: 599–604. 5. Dail D H, Liebow A A, Gmelich J T et al. Intravascular bronchial and alveolar tumor of the lung (IVBAT): an analysis of twenty cases of a peculiar sclerosing endothelial tumor. Cancer 1983; 51: 452–464. 6. Ishak K G, Sesterhenn I A, Godman Z D et al. Epithelioid hemangioendothelioma of the liver: A clinico-pathologic and followup study of 32 cases. Hum Pathol 1984; 150: 839–852. 7. Kleer C G, Unni K, Mc Leod R A. Epithelioid hemangioendothelioma of bone. Am J Surg Pathol 1996; 20: 1301–1311. 8. Tsuneyoshi M, Dorfman H D, Bauer T W. Epithelioid hemangioendothelioma of bone: A clinicopathologic, ultrastructural and immunohistochemical study. Am J Surg Pathol 1986; 10: 754–764. 9. Pettinato G, Manivel J C, Kelly D R et al. Lesions of the breast in children exclusive of typical fibroadenoma and gynecomastia: a clinicopathologic study of 113 cases. Pathol Ann 1989; 24: 295–328. 10. Pettinato G, Insabato L, De Chiara A et al. Intranuclear cytoplasmic inclusions in epithelioid hemangioendothelioma. Acta Cytol 1988; 32: 604–605. 11. Pettinato G, Insabato L, De Chiara A et al. Epithelioid hemangioendothelioma of soft tissue. Fine needle aspiration cytology, histology, electron microscopy and immunohistochemistry of a case. Acta Cytol 1986; 30: 194–200. 12. Gray M H, Rosemberg A E, Dickersin G R et al. Cytokeratin expression in epithelioid vascular neoplasms. Hum Pathol 1990; 21: 212–217.
298
The Breast