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The co-expression of cytokeratin and p63 in epithelioid angiosarcoma of the parotid gland: a diagnostic pitfall
Diagnostic Pathology volume 7, Article number: 118 (2012)
Epithelioid angiosarcoma of the parotid gland is rare, and may pose a great diagnostic challenge. We report a case of primary epithelioid angiosarcoma in a 64-year-old male without history of radiation. The histopathological findings demonstrated a high grade epithelioid neoplasm. Immunostaining showed that the tumor was positive for the pan-cytokeratin, p63, cytokeratin18, Vimentin and vascular markers CD31, and was negative for CD34, cytokeratin5/6, cytokeratin7, cytokeratin20, CD68, CD30, S-100, HMB45, desmin, α–SMA and CD45. The tumor was diagnosed as an epithelioid angiosarcoma. To our knowledge, this is the first reported case of angiosarcoma which showed common positivity for cytokeratin and p63. In addition to cytokeratin, p63 is considered a useful marker for carcinoma. The co-expression of cytokeratin and p63 in epithelioid angiosarcoma represents a diagnostic pitfall. Thus, using a panel of antibodies is essential for distinguishing this tumor from poorly differentiated carcinoma.
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Angiosarcoma predominantly arises in the skin or superficial soft tissue. The majority of neoplasms of the parotid gland are epithelial, while angiosarcoma, especially epithelioid angiosarcoma is extremely rare [1, 2]. Because of its rarity, epitheloid angiosarcoma may be misdiagnosed as an epithelial tumor . Angiosarcoma is a highly aggressive tumor. Local recurrences develop in about one fifth of patients and one half may be expected to die within the first year after diagnosis with metastatic disease in the lung followed by lymph node, bone, and soft tissue . So, it is necessary to distinguish epithelioid angiosarcoma from poorly differentiated squamous cell carcinoma or other epithelioid lesions. Here, we report a case of primary epithelioid angiosarcoma of the parotid gland in a 64-year-old Chinese male without history of radiation to the head and neck.
A 64-year-old male without a previous history of malignancy or radiation in the head and neck area presented with a painful swelling of the right parotid gland. The patient reported the parotid gland increased rapidly in size. A parotidectomy was then performed in our hospital. Three months later, the tumor recurred in the same site, and then the tumor was excised again.
The resected specimens were fixed with 10% neutral-buffered formalin and embedded in paraffin blocks. Tissue blocks were cut into 4-μm slides, deparaffinized in xylene, rehydrated with graded alcohols, and immunostained with the following antibodies: pan-cytokeratin (pan-CK), cytokeratin 5/6 (CK 5/6), cytokeratin18 (CK18), p63, vimentin, CD31, CD34, cytokeratin7 (CK7), cytokeratin20 (CK20), S100, desmin, α–smooth muscle actin(α–SMA), CD45, CD30, CD68, HMB45 and Ki67. Sections were stained with a streptavidin-peroxidase system (KIT-9720, Ultrasensitive TM S-P, MaiXin, China). The chromogen used was diaminobenzidine tetrahydrochloride substrate (DAB kit, MaiXin, China), slightly counterstained with hematoxylin, dehydrated and mounted.
Grossly, the resected parotid gland tissue measured 3.2 × 2.8 × 1.6 cm with irregular shape, and was not well circumscribed, the cut surface showed grey-red or grey –white in colour with focal hemorrhage. Histologically, the tumor was made up of large round or polygonal epithelioid cells which were predominantly arranged in solid sheets or nests. The area of necrosis and hemorrhage could also be seen easily. There was no area of spindle cells in the whole section. The cells had pale to basophilic copious cytoplasm and vesicular nuclei, prominent nucleoli with significant anaplastic features. Focally, the tumor cells were arranged into gaping vessel-like spaces or sinusoid-like spaces (Figure 1).
Immunohistochemistry showed the tumor cells were diffuse (over 50% of tumor cells) positive for pan-CK, p63 and Vimentin, CD31 was also strongly expressed in tumor cells. In addition, a focal and weak immunostaining was seen for CK18. The tumor cells were negative for CD34, CK 5/6, CK7, CK20, S100, desmin, α–SMA, CD45, CD30, CD68 and HMB45. Ki67 was expressed approximately in 50% of all tumor cells (Figure 2). According to the morphological and immunohistochemical findings, the tumor was diagnosed as an epithelioid angiosarcoma.
Angiosarcoma predominantly arises in the skin or superficial soft tissue. Less frequently, it can occur in various organs and has been reported in ovary , oral cavity , small intestine , thyroid , pleura , lung , testis [10, 11] and parotid [2, 3], even in fibroadenoma  and phyllodes tumour . Occasionally, it also may be part of dedifferentiated liposarcoma  or mixed malignant tumors [15, 16]. Epithelioid angiosarcoma most commonly involves deep soft tissue. Histologically, epithelioid angiosarcoma predominantly consists of sheets of highly atypical round cells with prominent nuclei, resembling poorly differentiated carcinoma, so, it may cause a great diagnostic confusion . The diagnosis hint of angiosarcoma may be the existence of sinusoid-like spaces or the remarkable necrosis or hemorrhage. Unfortunately, there is a variant in squamous cell carcinoma, namely, pseudoangiosarcomatous cell carcinoma which also shows anastomosing vascular and gland-like spaces mimicking angiosarcoma . So, in addition to histological findings, immunostaining must be used for distinguishing the two entities.
The endothelial cells show reactivity for several markers, including CD31, CD34 and von Willebrand factor (factor VIII). Among them, CD31 is considered the most sensitive and most specific endothelial cell marker. Epithelioid angiosarcoma is positive for CD31, but it is classically negative for CD34. In our case, there was strong and diffuse expression for CD31 in almost all tumor cells, and CD34 expression was absent. So we made the diagnosis of epithelioid angiosarcoma.
Some papers have documented that angiosarcoma or epithelioid angiosarcoma can express cytokeratin . Miettinen M et al. found that epithelioid angiosarcomas were often positive for CK8 and CK18 (approximately 50%) . Therefore, CK may be not helpful in distinguishing epithelioid angiosarcoma from squamous cell carcinoma. In our case, although CK showed a diffuse expression, but contrary to the diffuse and strong cytokeratin immunoreactivity in most of the carcinoma, the staining seemed to be relatively weak. This may represent an important clue to the possibility of non-epithelial lesions.
P63 is a p53 homolog that is expressed in various normal epithelial tissues and epithelial malignancies [19, 20]. Many pathologists believed that immunohistochemical staining for p63 protein was a useful marker for distinguishing spindle cell carcinoma from sarcoma [21, 22]. Jo VY et al. also demonstrated that p63 immunohistochemical staining is limited in soft tissue tumors, and failed to find expression of P63 in 20 cases of angiosarcomas . On the contrary, in our case we found diffuse p63 expression in the tumor cells. So far, there is only one literature that described the positive expression of p63 in angiosarcoma, that is, Kallen ME et al. reported nuclear p63 expression might been seen in 20%–30% of malignant vascular tumors, including angiosarcoma, epithelioid angiosarcoma and epithelioid hemangioendothelioma . Senoo M et al. found that p63 can affect expression of vascular endothelial growth factor via interactions with hypoxia inducible factor-1α . Consequently, it is reasonable that p63 can express in vascular tumors, and p63 may not be as specific for the epithelial differentiation as the literatures reported [21–23]. Moreover, in contrast to described by Kallen ME et al. that only a minority of tumor cell nuclei were immunoreactive in most p63-positive vascular tumors , in our case over 75% of the tumor cells was positive. The p63 expression in angiosarcoma represents another diagnostic pitfall.
Because of the rarity and closely mimicking carcinoma, epithelioid angiosarcoma is misdiagnosed easily, especially when one unfamiliar with this entity. CK and p63 are usually considered as the markers for carcinoma, but our result indicates the co-expression of them can be seen in angiosarcoma, this may be a further diagnostic pitfall. To avoid the misdiagnosis, using a panel of antibodies including endothelial cell markers is quite essential.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this Journal.
del Rio MJ P, Garcia-Garcia J, Diaz-Iglesias JM, Frasno MF: Radiation-associated angiosarcoma involving the parotid gland. Histopathology. 1998, 33: 586-587. 10.1046/j.1365-2559.1998.0525e.x.
Fanburg-Smith JC, Furlong MA, Childers EL: Oral and salivary gland angiosarcoma: a clinicopathological study of 29 cases. Mod Pathol. 2003, 16: 263-271. 10.1097/01.MP.0000056986.08999.FD.
Terada T: Angiosarcoma of the oral cavity. Head Neck Pathol. 2011, 5 (1): 67-70. 10.1007/s12105-010-0211-5.
Fletcher CDM, Unni KK, Mertens F: World Health Organization classification of tumours: pathology and genetics of tumours of soft tissue and bone. 2002, Lyon: IARC Press
Bösmüller H, Gruber C, Haitchi-Petnehazy S, Wagner D, Webersinke G, Hauptmann S: Primary angiosarcoma of the ovary with prominent fibrosis of the ovarian stroma. case report of an 81-year old patient. Diagn Pathol. 2011, 6: 65-10.1186/1746-1596-6-65.
Delvaux V, Sciot R, Neuville B, Moerman P, Peeters M, Filez L, Van Beckevoort D, Ectors N, Geboes K: Multifocal epithelioid angiosarcoma of the small intestine. Virchows Arch. 2000, 437 (1): 90-94. 10.1007/s004280000183.
Maiorana A, Collina G, Cesinaro AM, Fano RA, Eusebi V: Epithelioid angiosarcoma of the thyroid. clinicopathological analysis of seven cases from non-Alpine areas. Virchows Arch. 1996, 429 (2–3): 131-137.
Kao YC, Chow JM, Wang KM, Fang CL, Chu JS, Chen CL: Primary pleural angiosarcoma as a mimicker of mesothelioma: a case report. Diagn Pathol. 2011, 6: 130-10.1186/1746-1596-6-130.
Pandit SA, Fiedler PN, Westcott JL: Primary angiosarcoma of the lung. Ann Diagn Pathol. 2005, 9: 302-304. 10.1016/j.anndiagpath.2005.04.001.
Masera A, Ovcak Z, Mikuz G: Angiosarcoma of the testis. Virchows Arch. 1999, 434 (4): 351-353. 10.1007/s004280050351.
Armah HB, Rao UN, Parwani AV: Primary angiosarcoma of the testis: report of a rare entity and review of the literature. Diagn Pathol. 2007, 2: 23-10.1186/1746-1596-2-23.
Babarović E, Zamolo G, Mustać E, Strčić M: High grade angiosarcoma arising in fibroadenoma. Diagn Pathol. 2011, 6: 125-10.1186/1746-1596-6-125.
Mamoon N, Mushtaq S, Hassan U, Rashid R, Khadim MT, Sarfraz T, Waqar MA: Angiosarcoma arising in recurrent phyllodes tumour. Histopathology. 2009, 54: 913-916. 10.1111/j.1365-2559.2009.03314.x.
da Cunha IW, Kowalski LP, Soares FA: Dedifferentiated liposarcoma of the oral cavity with angiosarcomatous dedifferentiation. Virchows Arch. 2005, 446 (4): 456-459. 10.1007/s00428-005-1207-5.
Ryan JF, Kealy WF: Concomitant angiosarcoma and carcinoma of the breast: a case report. Histopathology. 1985, 9: 893-899. 10.1111/j.1365-2559.1985.tb02874.x.
Li YF, Yu CP, Wu ST, Dai MS, Lee HS: Malignant mesenchymal tumor with leiomyosarcoma, rhabdomyosarcoma, chondrosarcoma, and osteosarcoma differentiation: case report and literature review. Diagn Pathol. 2011, 6: 35-10.1186/1746-1596-6-35.
Terada T: Papillary squamous cell carcinoma of the oral cavity with acantholytic and pseudovascular features. Int J Clin Exp Pathol. 2011, 4 (8): 794-796.
Miettinen M, Fetsch JF: Distribution of keratins in normal endothelial cells and a spectrum of vascular tumors: implications in tumor diagnosis. Hum Pathol. 2000, 31: 1062-1067. 10.1053/hupa.2000.9843.
Laurikkala J, Mikkola ML, James M, Tummers M, Mills AA, Thesleff I: p63 regulates multiple signalling pathways required for ectodermal organogenesis and differentiation. Development. 2006, 133 (8): 1553-1563. 10.1242/dev.02325.
Nekulova M, Holcakova J, Coates P, Vojtesek B: The role of P63 in cancer, stem cells and cancer stem cells. Cell Mol Biol Lett. 2011, 16 (2): 296-327. 10.2478/s11658-011-0009-9.
Dotto JE, Glusac EJ: P63 is a useful marker for cutaneous spindle cell squamous cell carcinoma. J Cutan Pathol. 2006, 33 (6): 413-417. 10.1111/j.0303-6987.2006.00477.x.
Kurian KM, Al-Nafussi A: Sarcomatoid/metaplastic carcinoma of the breast: a clinicopathological study of 12 cases. Histopathology. 2002, 40 (1): 58-64. 10.1046/j.1365-2559.2002.01319.x.
Jo VY, Fletcher CDM: P63 immunohistochemical staining is limited in soft tissue tumors. Mod Pathol. 2011, 24 (1S): 15A-
Kallen ME, Nunes Rosado FG, Gonzalez AL, Sanders ME, Cates JM: Occasional staining for p63 in malignant vascular tumors: a potential diagnostic pitfall. Pathol Oncol Res. 2012, 18: 97-100. 10.1007/s12253-011-9426-3.
Senoo M, Matsumura Y, Habu S: Ap63γ (p51A) and dNp63α (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression. Oncogene. 2002, 21 (16): 2455-2465. 10.1038/sj.onc.1205330.
The authors declare that they have no competing interests.
L XY participated in the histopathological evaluation, performed the literature review, acquired photomicrographs and drafted the manuscript. LY carried out the immunohistochemical stains evaluation. ZY and YJH conceived and designed the study. WEH gave the final histopathological diagnosis and revised the manuscript. All the authors read and approved the final manuscript.
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Lin, X., Liu, Y., Zhang, Y. et al. The co-expression of cytokeratin and p63 in epithelioid angiosarcoma of the parotid gland: a diagnostic pitfall. Diagn Pathol 7, 118 (2012). https://doi.org/10.1186/1746-1596-7-118