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Primary angiosarcoma of the parotid gland arising from benign congenital hemangioma
Primary angiosarcoma of the parotid gland arising from benign congenital hemangioma Stefania Damiani, MD,a Barbara Corti, MD,b Fabrizio Neri, MD,c Guido Collina, MD,d and Franco Bertoni, MD,e Bologna, Italy UNIVERSITY OF BOLOGNA AND BELLARIA HOSPITAL A case of malignant transformation of a benign congenital hemangioma of the parotid gland is presented. The malignant tumor occurred in a woman with a history of congenital hemangioma surgically removed 8 years previously. No radiotherapy had been administered at the time of primary excision. The recurrent tumor consisted of a large lesion occupying nearly all the parotid gland and infiltrating the surrounding soft tissues and overlying skin. Its histopathologic features were typical of epithelioid angiosarcoma. The vast majority of vascular lesions of major salivary glands are benign. However, pathologists should be aware of the remote possibility of malignant transformation in these lesions. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;96:66-9)
Benign hemangioma is the most common tumor of the parotid gland in childhood.1 This tumor is more frequent in females and includes both the capillary and cavernous types. Capillary hemangioma occurs in early childhood and is often present at birth. Usually, it presents as a solitary lesion, with most cases undergoing spontaneous regression. Mitotic activity is often present but is not by itself predictive of malignant behavior. More rarely, capillary hemangioma presents as multiple lesions and may be associated with Kasabach-Merritt syndrome. Cavernous hemangiomas are less common and occur in late childhood. They are characterized by dilated venous vessels separated by delicate fibrous strands. No cases with spontaneous regression have been documented to date. Neither capillary nor cavernous hemangiomas have exhibited a *Section Editor’s note: At the time that this article was written, there were no published reports of angiosarcoma arising in a nonirradiated hemangioma. Since the writing of this article for publication in Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics, an article detailing this malignant transformation has appeared in another journal. Please see: Rossi S, Fletcher CD. Angiosarcoma arising in hemangioma/vascular malformation: report of four cases and review of the literature. Am J Surg Pathol 2002; 26(10):1319-29. a Assistant Professor, Department of Oncology, Section of Anatomic Pathology, University of Bologna. b Consultant, Department of Oncology, Section of Anatomic Pathology, University of Bologna. c Consultant, Division of Maxillo-Facial Surgery, Bellaria Hospital. d Consultant, Department of Oncology, Section of Anatomic Pathology, University of Bologna. e Professor, Section of Anatomic Pathology, Rizzoli Institute, University of Bologna. Received for publication Jul 29, 2002; returned for revision Sep 19, 2002; accepted for publication Jan 14, 2003. © 2003, Mosby, Inc. All rights reserved. 1079-2104/2003/$30.00 ⫹ 0 doi:10.1016/S1079-2104(02)91704-X
66
propensity for spontaneous malignant transformation.1 Nevertheless, a risk of malignant transformation has been reported after radiation therapy.2 Here we report a case of angiosarcoma of the parotid gland arising within a benign congenital hemangioma. The occurrence of malignant vascular tumors in salivary glands is exceptionally rare. To the best of our knowledge, this is the first reported case spontaneously arising in a benign hemangioma.* CASE REPORT The female patient presented with bilateral blindness and painless swelling of the right parotid region, with both conditions present since birth. In 1992, at 14 years of age, the patient noticed an increase in the dimensions of the parotid lesion. At that time, magnetic resonance imaging of the right parotid gland revealed a nodule measuring 5 cm on its major axis, located in the parotid parenchyma. The nodule was ovoid and had well-defined borders. A nodulectomy was performed, and a histopathologic diagnosis of benign hemangioma was given. The patient was well and without any evidence of disease until 1998, when a 0.3-cm bluish nodule appeared close to the scar from the previous surgery. A biopsy specimen was taken from the recurrent nodule, and the diagnosis was again benign hemangioma. However, 2 years later, the patient, aged 22, presented again with a nodular swelling at the same site. The magnetic resonance image revealed a 5.0 ⫻ 4.2 ⫻ 3.0-cm nodule with borders ranging from sharply defined to infiltrative. The lesion was rapidly enlarging, so the patient underwent surgery. The right parotid gland and overlying skin were resected because the skin appeared involved by a tumor. Grossly, the resected specimen was a large, spongy mass that was bluish in color with a soft consistency. The cut surface was grossly microcystic with large areas of necrosis and hemorrhage. Total-body computerized tomography revealed no additional evidence of a tumor. Adjuvant radiotherapy was administered after surgery, and the patient was followed up with magnetic resonance imaging every 4 months. Two years
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 96, Number 1
Fig 1. Congenital hemangioma: The lesion has well-defined borders and is primarily composed of large vessels lined by flattened endothelial cells (hematoxylin-eosin, ⫻100). Inset, Solid focal areas composed of spindle and epithelioid cells with irregular nuclei were also observed (hematoxylin-eosin, ⫻200).
after surgery, she is alive and well with no evidence of residual disease.
MATERIAL AND METHODS Tissue samples were fixed in 10% buffered formalin, embedded in paraffin, and routinely stained with hematoxylin-eosin. Tissue sections for the immunohistochemical studies were incubated with antibodies against CD31 (1:20; Dako, Milan, Italy), CD34 (clone QB-END10, 1:30; YLEM Novocastra, Newcastle, United Kingdom), vimentin (1:50; Dako), wide-spectrum keratin (clone MNF116, 1:10; Dako), CAM 5.2 low–molecular weight keratin (1:100; Becton Dickinson, Missisauga, Ontario, Canada), S-100 protein (1: 1500; Dako), and smooth muscle actin (clone 1A4, 1:100; Dako). Sections for keratin stains were predigested with a 0.05% pepsin solution, and those for CD31, CD34, and vimentin were treated by using a pressure-cooking antigen-retrieval technique with Microstain MS–Unmasker buffer (Diapath, Brescia, Italy) (pH 8.0) for 6 minutes. Primary antibody binding was revealed through the use of the avidin-biotinperoxidase complex method. Appropriate positive controls were used for each primary antibody. PATHOLOGIC FINDINGS The first lesion, removed in 1992, consisted of a well-circumscribed nodule measuring 5 cm on its major axis. It was bluish and soft in consistency. Microscopically, large, thin-walled vessels constituted most of the nodule (Fig 1). These vessels were situated in a delicate
Damiani et al 67
Fig 2. Angiosarcoma: The parotid gland appears diffusely infiltrated by proliferating vessels (hematoxylin-eosin, ⫻125).
fibrous stroma and lined by flattened benign-looking endothelial cells. However, a minor part of the lesion had a solid growth pattern and was composed of spindle and epithelioid cells with only focal lumen formation (Fig 1, inset). In this part, which represented no more than 5% of the lesion, the cells had ovoid nuclei with sometimes irregular outlines. Nucleoli were absent or small. Mitotic figures were present but not atypical. An area of necrosis was also evident. The lesion had welldefined borders and easily shelled out. However, no normal tissue was present around the nodule, and the tumor involved the surgical margins. The 1998 biopsy specimen from the recurrent nodule had only large, thin-walled vessels arranged around a medium venous vessel. Epithelioid cells were not evident in the specimen. The histopathologic features of the tumor removed 2 years later were typical of a malignant neoplasm. Almost all the parotid gland was involved by a tumor (Fig 2), with extension beyond the parotid capsule and diffuse infiltration of the surrounding soft tissues and overlying skin (Fig 3). The tumor was composed of freely anastomosing irregular-shaped vascular spaces, at times demonstrating small papillary luminal structures (Fig 4). Focal, poorly differentiated areas with a solid growth pattern were also evident (Figs 3 and 5). The appearance of the neoplastic cells was the same in both solid areas and in those regions with anastomosing channels. These cells were large and epithelioid, and had abundant pink cytoplasm, vesicular nuclei, and prominent eosinophilic nucleoli (Fig 5). Mitoses were numerous and sometimes atypical; furthermore, spotty areas of necrosis were also observed. A small superficial area of the tumor retained the histopathologic fea-
68 Damiani et al
Fig 3. Angiosarcoma: The neoplasm extends beyond the parotid gland and invades the nerve bundles (A, hematoxylineosin, ⫻350) and overlying skin (B, hematoxylin-eosin, ⫻200).
Fig 4. Angiosarcoma: The tumor is composed of freely anastomosing vascular spaces, sometimes with small papillary projections in their lumina. The extravascular location, nuclear pleomorphism, and high mitotic rate of angiosarcoma help distinguish it from intravascular papillary endothelial hyperplasia, which has similar architectural features (hematoxylin-eosin, ⫻200).
tures of a cavernous hemangioma. In this part of the tumor, the vessels were apparently well formed, nonanastomosing, thin walled, and lined by flattened cells with bland nuclei. Immunohistochemically, the neoplastic cells were diffusely positive for CD31 (Fig 6), CD34, and vimentin antibodies and negative for wide-spectrum cytokeratin, CAM 5.2 low–molecular weight cytokeratin, S-100 protein, and smooth muscle actin.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY July 2003
Fig 5. Angiosarcoma: Poorly differentiated areas with a solid pattern of growth are evident throughout the tumor. Neoplastic cells have abundant eosinophilic cytoplasm and large vesicular nuclei with prominent nucleoli and numerous mitoses (hematoxylin-eosin, ⫻400).
Fig 6. Angiosarcoma: The neoplastic cells stain positive for CD31 antibody (avidin-biotin-peroxidase complex method, ⫻350).
DISCUSSION Our case exhibits clinicopathologic features consistent with epithelioid angiosarcoma spontaneously arising in congenital hemangioma of the parotid gland. Hemangiopericytoma, a tumor of the pericytes, is one of the most common sarcomas of the major salivary glands.3 True malignant vascular tumors, such as angiosarcoma and hemangioendothelioma, are exceptionally rare in the salivary glands. In 1979, Tomec et al4 reported a primary tumor of the submaxillary gland that they termed epithelioid hemangioendothelioma. This was a poorly differentiated angiosarcoma mimicking a
Damiani et al 69
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 96, Number 1
carcinoma, and the diagnosis was made on the basis of Weibel-Palade bodies found during an ultrastructural examination. Seifert and Oehne,5 in their review of 167 mesenchymal salivary gland tumors, found only 1 case of malignant hemangioendothelioma. Three other cases of malignant vascular tumors have been reported in the parotid gland. Mullick et al6 described a case of parotid angiosarcoma that was initially misinterpreted as adenocarcinoma. In 1998, Perez del Rio et al7 reported high-grade angiosarcoma arising 12 years after radiotherapy for squamous cell carcinoma of the larynx. In addition, a low-grade hemangioendothelioma was recently described by Pigadas et al.8 Our case appears to be unique because the malignant tumor occurred spontaneously in a benign congenital hemangioma. Malignant transformation in a benign vascular lesion usually represents a sequela of radiotherapy.2 To our knowledge, the occurrence of spontaneous malignant transformation in a benign hemangioma has not been previously reported. In the present case, a small portion of the tumor excised in 1992 exhibited a zone of solid growth composed of spindle and epithelioid cells with brisk mitotic activity. However, these cells were cytologically distinct from the malignant epithelioid cells seen in the recurrence, in that the former had nuclei with fine chromatin and no prominent nucleoli whereas the latter were highly atypical with abundant cytoplasm, vesicular nuclei, and prominent nucleoli. Moreover, the malignant tumor occurred 8 years after the original diagnosis of benign hemangioma, and the lesion had been clinically evident since birth. Therefore, the possibility of a malignant tumor ab initio appears unlikely. The pathologist should be aware of the possibility of a primary salivary gland angiosarcoma to prevent a misdiagnosis. A well-differentiated tumor, or a tumor with well-differentiated areas, may be misdiagnosed as benign hemangioma, particularly if only a small—and not fully representative— biopsy specimen is submitted for histopathologic examination. In these cases, an accurate evaluation of the cytologic features, together with correct information regarding the tumor dimensions and clinical features, can be very helpful. Poorly differentiated angiosarcoma can be difficult to distinguish from other poorly differentiated neoplasms such as malignant myoepithelioma, melanoma, sarcomas, and metastatic and primary carcinomas. Metastatic melanoma can be easily excluded if the specimen is negative for S-100 protein, HMB45, and MART1 antibodies. Many cases of epithelioid angiosarcoma are cytokeratin-positive.9 In these instances, the immunohistochemical demonstration of positivity with endo-
thelial markers CD31, CD34, and factor VIII is usually helpful. In addition, an ultrastructural examination revealing Weibel-Palade bodies can be useful in identifying poorly differentiated angiosarcoma characterized by a loss of vascular antigens.1 Salivary gland angiosarcomas are very rare, with only a few cases previously described. Thus, few published data are available to guide one in the choice of effective therapy. In general, primary angiosarcoma requires a wide margin of excision. Some studies have indicated that patients may benefit from combined surgery and radiotherapy.10,11 Our patient received adjuvant radiotherapy and is alive and disease-free after 2 years. REFERENCES 1. Weiss SW, Goldblum JR. Benign tumors and tumor-like lesions of blood vessels. In: Weiss SW, Goldblum JR, editors. Enzinger and Weiss’s soft tissue tumors. 4th ed. St Louis: Mosby; 2001. 837-90. 2. Cancellieri A, Eusebi V, Mambelli V, Ricotti G, Gardini G, Pasquinelli G. Well-differentiated angiosarcoma of the skin following radiotherapy. Pathol Res Pract 1991;187:301-6. 3. Auclair PL, Langloss JM, Weiss SW, Corio RL. Sarcomas and sarcomatoid neoplasms of the major salivary gland regions. A clinicopathologic and immunohistochemical study of 67 cases and review of the literature. Cancer 1986;58:1305-15. 4. Tomec R, Ahmed I, Fu YS, Jaffe S. Malignant hemangioendothelioma (angiosarcoma) of the salivary gland: an ultrastructural study. Cancer 1979;43:1664-71. 5. Seifert G, Oehne H. Mesenchymal (non-epithelial) salivary gland tumors. Analysis of 167 tumor cases of the salivary gland register. Laryngol Rhinol Otol (Stuttg) 1986;65:485-91. 6. Mullick SS, Mody DR, Schwartz MR. Angiosarcoma at unusual sites. A report of two cases with aspiration cytology and diagnostic pitfalls. Acta Cytol 1997;41:839-44. 7. Perez del Rio MJ, Garcia-Garcia J, Diaz-Iglesias JM, Fresno MF. Radiation-associated angiosarcoma involving the parotid gland [letter]. Histopathology 1998;33:586-7. 8. Pigadas N, Mohamid W, McDermott P. Epithelioid hemangioendothelioma of the parotid salivary gland. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:730-8. 9. Eusebi V, Carcangiu ML, Dina R, Rosai J. Keratin-positive epithelioid angiosarcoma of the thyroid: a report of four cases. Am J Surg Pathol 1990;14:737-47. 10. Aust MR, Olsen KD, Lewis JE, Nascimento AG, Meland NB, Foote RL, et al. Angiosarcoma of the head and neck: clinical and pathologic characteristics. Ann Otol Rhinol Laryngol 1997;106: 943-51. 11. Bullen R, Larson PO, Landeck AE, Nychay S, Snow SN, Hazen P, et al. Angiosarcoma of the head and neck managed by a combination of multiple biopsies to determine tumor margin and radiation therapy. Report of three cases and review of the literature. Dermatol Surg 1998;24:1105-10. Reprint requests: Stefania Damiani, MD Anatomia Patologica Ospedale Bellaria Via Altura 3, 40139 Bologna Italy [email protected]
Benign hemangioma is the most common tumor of the parotid gland in childhood.1 This tumor is more frequent in females and includes both the capillary and cavernous types. Capillary hemangioma occurs in early childhood and is often present at birth. Usually, it presents as a solitary lesion, with most cases undergoing spontaneous regression. Mitotic activity is often present but is not by itself predictive of malignant behavior. More rarely, capillary hemangioma presents as multiple lesions and may be associated with Kasabach-Merritt syndrome. Cavernous hemangiomas are less common and occur in late childhood. They are characterized by dilated venous vessels separated by delicate fibrous strands. No cases with spontaneous regression have been documented to date. Neither capillary nor cavernous hemangiomas have exhibited a *Section Editor’s note: At the time that this article was written, there were no published reports of angiosarcoma arising in a nonirradiated hemangioma. Since the writing of this article for publication in Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics, an article detailing this malignant transformation has appeared in another journal. Please see: Rossi S, Fletcher CD. Angiosarcoma arising in hemangioma/vascular malformation: report of four cases and review of the literature. Am J Surg Pathol 2002; 26(10):1319-29. a Assistant Professor, Department of Oncology, Section of Anatomic Pathology, University of Bologna. b Consultant, Department of Oncology, Section of Anatomic Pathology, University of Bologna. c Consultant, Division of Maxillo-Facial Surgery, Bellaria Hospital. d Consultant, Department of Oncology, Section of Anatomic Pathology, University of Bologna. e Professor, Section of Anatomic Pathology, Rizzoli Institute, University of Bologna. Received for publication Jul 29, 2002; returned for revision Sep 19, 2002; accepted for publication Jan 14, 2003. © 2003, Mosby, Inc. All rights reserved. 1079-2104/2003/$30.00 ⫹ 0 doi:10.1016/S1079-2104(02)91704-X
66
propensity for spontaneous malignant transformation.1 Nevertheless, a risk of malignant transformation has been reported after radiation therapy.2 Here we report a case of angiosarcoma of the parotid gland arising within a benign congenital hemangioma. The occurrence of malignant vascular tumors in salivary glands is exceptionally rare. To the best of our knowledge, this is the first reported case spontaneously arising in a benign hemangioma.* CASE REPORT The female patient presented with bilateral blindness and painless swelling of the right parotid region, with both conditions present since birth. In 1992, at 14 years of age, the patient noticed an increase in the dimensions of the parotid lesion. At that time, magnetic resonance imaging of the right parotid gland revealed a nodule measuring 5 cm on its major axis, located in the parotid parenchyma. The nodule was ovoid and had well-defined borders. A nodulectomy was performed, and a histopathologic diagnosis of benign hemangioma was given. The patient was well and without any evidence of disease until 1998, when a 0.3-cm bluish nodule appeared close to the scar from the previous surgery. A biopsy specimen was taken from the recurrent nodule, and the diagnosis was again benign hemangioma. However, 2 years later, the patient, aged 22, presented again with a nodular swelling at the same site. The magnetic resonance image revealed a 5.0 ⫻ 4.2 ⫻ 3.0-cm nodule with borders ranging from sharply defined to infiltrative. The lesion was rapidly enlarging, so the patient underwent surgery. The right parotid gland and overlying skin were resected because the skin appeared involved by a tumor. Grossly, the resected specimen was a large, spongy mass that was bluish in color with a soft consistency. The cut surface was grossly microcystic with large areas of necrosis and hemorrhage. Total-body computerized tomography revealed no additional evidence of a tumor. Adjuvant radiotherapy was administered after surgery, and the patient was followed up with magnetic resonance imaging every 4 months. Two years
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 96, Number 1
Fig 1. Congenital hemangioma: The lesion has well-defined borders and is primarily composed of large vessels lined by flattened endothelial cells (hematoxylin-eosin, ⫻100). Inset, Solid focal areas composed of spindle and epithelioid cells with irregular nuclei were also observed (hematoxylin-eosin, ⫻200).
after surgery, she is alive and well with no evidence of residual disease.
MATERIAL AND METHODS Tissue samples were fixed in 10% buffered formalin, embedded in paraffin, and routinely stained with hematoxylin-eosin. Tissue sections for the immunohistochemical studies were incubated with antibodies against CD31 (1:20; Dako, Milan, Italy), CD34 (clone QB-END10, 1:30; YLEM Novocastra, Newcastle, United Kingdom), vimentin (1:50; Dako), wide-spectrum keratin (clone MNF116, 1:10; Dako), CAM 5.2 low–molecular weight keratin (1:100; Becton Dickinson, Missisauga, Ontario, Canada), S-100 protein (1: 1500; Dako), and smooth muscle actin (clone 1A4, 1:100; Dako). Sections for keratin stains were predigested with a 0.05% pepsin solution, and those for CD31, CD34, and vimentin were treated by using a pressure-cooking antigen-retrieval technique with Microstain MS–Unmasker buffer (Diapath, Brescia, Italy) (pH 8.0) for 6 minutes. Primary antibody binding was revealed through the use of the avidin-biotinperoxidase complex method. Appropriate positive controls were used for each primary antibody. PATHOLOGIC FINDINGS The first lesion, removed in 1992, consisted of a well-circumscribed nodule measuring 5 cm on its major axis. It was bluish and soft in consistency. Microscopically, large, thin-walled vessels constituted most of the nodule (Fig 1). These vessels were situated in a delicate
Damiani et al 67
Fig 2. Angiosarcoma: The parotid gland appears diffusely infiltrated by proliferating vessels (hematoxylin-eosin, ⫻125).
fibrous stroma and lined by flattened benign-looking endothelial cells. However, a minor part of the lesion had a solid growth pattern and was composed of spindle and epithelioid cells with only focal lumen formation (Fig 1, inset). In this part, which represented no more than 5% of the lesion, the cells had ovoid nuclei with sometimes irregular outlines. Nucleoli were absent or small. Mitotic figures were present but not atypical. An area of necrosis was also evident. The lesion had welldefined borders and easily shelled out. However, no normal tissue was present around the nodule, and the tumor involved the surgical margins. The 1998 biopsy specimen from the recurrent nodule had only large, thin-walled vessels arranged around a medium venous vessel. Epithelioid cells were not evident in the specimen. The histopathologic features of the tumor removed 2 years later were typical of a malignant neoplasm. Almost all the parotid gland was involved by a tumor (Fig 2), with extension beyond the parotid capsule and diffuse infiltration of the surrounding soft tissues and overlying skin (Fig 3). The tumor was composed of freely anastomosing irregular-shaped vascular spaces, at times demonstrating small papillary luminal structures (Fig 4). Focal, poorly differentiated areas with a solid growth pattern were also evident (Figs 3 and 5). The appearance of the neoplastic cells was the same in both solid areas and in those regions with anastomosing channels. These cells were large and epithelioid, and had abundant pink cytoplasm, vesicular nuclei, and prominent eosinophilic nucleoli (Fig 5). Mitoses were numerous and sometimes atypical; furthermore, spotty areas of necrosis were also observed. A small superficial area of the tumor retained the histopathologic fea-
68 Damiani et al
Fig 3. Angiosarcoma: The neoplasm extends beyond the parotid gland and invades the nerve bundles (A, hematoxylineosin, ⫻350) and overlying skin (B, hematoxylin-eosin, ⫻200).
Fig 4. Angiosarcoma: The tumor is composed of freely anastomosing vascular spaces, sometimes with small papillary projections in their lumina. The extravascular location, nuclear pleomorphism, and high mitotic rate of angiosarcoma help distinguish it from intravascular papillary endothelial hyperplasia, which has similar architectural features (hematoxylin-eosin, ⫻200).
tures of a cavernous hemangioma. In this part of the tumor, the vessels were apparently well formed, nonanastomosing, thin walled, and lined by flattened cells with bland nuclei. Immunohistochemically, the neoplastic cells were diffusely positive for CD31 (Fig 6), CD34, and vimentin antibodies and negative for wide-spectrum cytokeratin, CAM 5.2 low–molecular weight cytokeratin, S-100 protein, and smooth muscle actin.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY July 2003
Fig 5. Angiosarcoma: Poorly differentiated areas with a solid pattern of growth are evident throughout the tumor. Neoplastic cells have abundant eosinophilic cytoplasm and large vesicular nuclei with prominent nucleoli and numerous mitoses (hematoxylin-eosin, ⫻400).
Fig 6. Angiosarcoma: The neoplastic cells stain positive for CD31 antibody (avidin-biotin-peroxidase complex method, ⫻350).
DISCUSSION Our case exhibits clinicopathologic features consistent with epithelioid angiosarcoma spontaneously arising in congenital hemangioma of the parotid gland. Hemangiopericytoma, a tumor of the pericytes, is one of the most common sarcomas of the major salivary glands.3 True malignant vascular tumors, such as angiosarcoma and hemangioendothelioma, are exceptionally rare in the salivary glands. In 1979, Tomec et al4 reported a primary tumor of the submaxillary gland that they termed epithelioid hemangioendothelioma. This was a poorly differentiated angiosarcoma mimicking a
Damiani et al 69
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 96, Number 1
carcinoma, and the diagnosis was made on the basis of Weibel-Palade bodies found during an ultrastructural examination. Seifert and Oehne,5 in their review of 167 mesenchymal salivary gland tumors, found only 1 case of malignant hemangioendothelioma. Three other cases of malignant vascular tumors have been reported in the parotid gland. Mullick et al6 described a case of parotid angiosarcoma that was initially misinterpreted as adenocarcinoma. In 1998, Perez del Rio et al7 reported high-grade angiosarcoma arising 12 years after radiotherapy for squamous cell carcinoma of the larynx. In addition, a low-grade hemangioendothelioma was recently described by Pigadas et al.8 Our case appears to be unique because the malignant tumor occurred spontaneously in a benign congenital hemangioma. Malignant transformation in a benign vascular lesion usually represents a sequela of radiotherapy.2 To our knowledge, the occurrence of spontaneous malignant transformation in a benign hemangioma has not been previously reported. In the present case, a small portion of the tumor excised in 1992 exhibited a zone of solid growth composed of spindle and epithelioid cells with brisk mitotic activity. However, these cells were cytologically distinct from the malignant epithelioid cells seen in the recurrence, in that the former had nuclei with fine chromatin and no prominent nucleoli whereas the latter were highly atypical with abundant cytoplasm, vesicular nuclei, and prominent nucleoli. Moreover, the malignant tumor occurred 8 years after the original diagnosis of benign hemangioma, and the lesion had been clinically evident since birth. Therefore, the possibility of a malignant tumor ab initio appears unlikely. The pathologist should be aware of the possibility of a primary salivary gland angiosarcoma to prevent a misdiagnosis. A well-differentiated tumor, or a tumor with well-differentiated areas, may be misdiagnosed as benign hemangioma, particularly if only a small—and not fully representative— biopsy specimen is submitted for histopathologic examination. In these cases, an accurate evaluation of the cytologic features, together with correct information regarding the tumor dimensions and clinical features, can be very helpful. Poorly differentiated angiosarcoma can be difficult to distinguish from other poorly differentiated neoplasms such as malignant myoepithelioma, melanoma, sarcomas, and metastatic and primary carcinomas. Metastatic melanoma can be easily excluded if the specimen is negative for S-100 protein, HMB45, and MART1 antibodies. Many cases of epithelioid angiosarcoma are cytokeratin-positive.9 In these instances, the immunohistochemical demonstration of positivity with endo-
thelial markers CD31, CD34, and factor VIII is usually helpful. In addition, an ultrastructural examination revealing Weibel-Palade bodies can be useful in identifying poorly differentiated angiosarcoma characterized by a loss of vascular antigens.1 Salivary gland angiosarcomas are very rare, with only a few cases previously described. Thus, few published data are available to guide one in the choice of effective therapy. In general, primary angiosarcoma requires a wide margin of excision. Some studies have indicated that patients may benefit from combined surgery and radiotherapy.10,11 Our patient received adjuvant radiotherapy and is alive and disease-free after 2 years. REFERENCES 1. Weiss SW, Goldblum JR. Benign tumors and tumor-like lesions of blood vessels. In: Weiss SW, Goldblum JR, editors. Enzinger and Weiss’s soft tissue tumors. 4th ed. St Louis: Mosby; 2001. 837-90. 2. Cancellieri A, Eusebi V, Mambelli V, Ricotti G, Gardini G, Pasquinelli G. Well-differentiated angiosarcoma of the skin following radiotherapy. Pathol Res Pract 1991;187:301-6. 3. Auclair PL, Langloss JM, Weiss SW, Corio RL. Sarcomas and sarcomatoid neoplasms of the major salivary gland regions. A clinicopathologic and immunohistochemical study of 67 cases and review of the literature. Cancer 1986;58:1305-15. 4. Tomec R, Ahmed I, Fu YS, Jaffe S. Malignant hemangioendothelioma (angiosarcoma) of the salivary gland: an ultrastructural study. Cancer 1979;43:1664-71. 5. Seifert G, Oehne H. Mesenchymal (non-epithelial) salivary gland tumors. Analysis of 167 tumor cases of the salivary gland register. Laryngol Rhinol Otol (Stuttg) 1986;65:485-91. 6. Mullick SS, Mody DR, Schwartz MR. Angiosarcoma at unusual sites. A report of two cases with aspiration cytology and diagnostic pitfalls. Acta Cytol 1997;41:839-44. 7. Perez del Rio MJ, Garcia-Garcia J, Diaz-Iglesias JM, Fresno MF. Radiation-associated angiosarcoma involving the parotid gland [letter]. Histopathology 1998;33:586-7. 8. Pigadas N, Mohamid W, McDermott P. Epithelioid hemangioendothelioma of the parotid salivary gland. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:730-8. 9. Eusebi V, Carcangiu ML, Dina R, Rosai J. Keratin-positive epithelioid angiosarcoma of the thyroid: a report of four cases. Am J Surg Pathol 1990;14:737-47. 10. Aust MR, Olsen KD, Lewis JE, Nascimento AG, Meland NB, Foote RL, et al. Angiosarcoma of the head and neck: clinical and pathologic characteristics. Ann Otol Rhinol Laryngol 1997;106: 943-51. 11. Bullen R, Larson PO, Landeck AE, Nychay S, Snow SN, Hazen P, et al. Angiosarcoma of the head and neck managed by a combination of multiple biopsies to determine tumor margin and radiation therapy. Report of three cases and review of the literature. Dermatol Surg 1998;24:1105-10. Reprint requests: Stefania Damiani, MD Anatomia Patologica Ospedale Bellaria Via Altura 3, 40139 Bologna Italy [email protected]