Endocr Pathol (2014) 25:404–409 DOI 10.1007/s12022-014-9330-y
A Mimic of Sarcomatoid Adrenal Cortical Carcinoma: Epithelioid Angiosarcoma Occurring in Adrenal Cortical Adenoma Toshitetsu Hayashi & Hasan Gucer & Ozgur Mete
Published online: 23 September 2014 # Springer Science+Business Media New York 2014
Abstract The adrenal gland is a site of various neoplasms; however, it is rarely involved by sarcomas. We present herein an unusual adrenal neoplasm consisting of epithelioid angiosarcoma and adrenal cortical adenoma. In this report, the authors highlight the diagnostic challenges associated with an epithelioid angiosarcoma occurring in an adrenal cortical neoplasm by providing a comprehensive discussion on the spectrum of vascular proliferations seen in the adrenal gland along with a roadmap for practicing pathologists. The presence of angiosarcoma within an adrenal cortical adenoma may represent a collision tumor; however, one can speculate that the rich vasculature of endocrine lesions can also create a favorable milieu for the occurrence of this phenomenon. While the latter needs to be further clarified, the presented case should be added to the unusual clinical presentations of vascular lesions of the adrenal gland mimicking a sarcomatoid adrenal cortical carcinoma. Keywords Epithelioid angiosarcoma . Adrenal cortical adenoma . Adrenal cortical carcinoma . Sarcomatoid carcinoma . SF-1
skin and soft tissue, visceral forms have also been described in many organs [1]. Malignant vascular endothelial neoplasms in which epithelioid cells predominate are classified as epithelioid angiosarcomas. Epithelioid angiosarcomas can easily be mistaken for carcinomas because of their morphologic and immunohistochemical similarities [1, 2]. While most adrenal angiosarcomas represent metastases from another primary tumor site, primary angiosarcoma of the adrenal gland is uncommon and usually of epithelioid type, with only 29 reported cases in the literature [3–22] (Table 1). We present herein an unusual adrenal neoplasm consisting of composite epithelioid angiosarcoma and adrenal cortical adenoma that mimics a sarcomatoid adrenal cortical carcinoma. In this report, the authors aimed to discuss the diagnostic challenges associated with an epithelioid angiosarcoma occurring in an adrenal cortical neoplasm by providing a comprehensive discussion on the spectrum of vascular proliferations seen in the adrenal gland along with a road map for practicing pathologists.
Case Report Introduction Angiosarcomas are malignant neoplasms recapitulating both morphological and functional features of endothelium to a variable degree. While these neoplasms are often seen in the T. Hayashi : H. Gucer : O. Mete (*) Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON M5G2C4, Canada e-mail: [email protected] O. Mete Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
A 63-year-old man with a previous history of smoking-related chronic obstructive pulmonary disease was admitted to hospital due to progressive dyspnea and progressive marked weight loss along with abdominal discomfort of 6-month duration. Both abdominal ultrasound and computed tomography scan identified a large right adrenal mass measuring up to 7.8 cm. In addition, enlarged mediastinal lymph nodes with a predominant right hilar 3-cm nodule were detected. While the imaging studies were highly suspicious for tumor metastasis, no endobronchial lesion was identified on bronchoscopy. Bronchial biopsy and bronchoalveolar lavage smears were negative for malignancy or granulomatous inflammation. Multiple dynamic and functional tests (ACTH stimulation
Endocr Pathol (2014) 25:404–409
405
Table 1 Characteristics of previously reported cases of adrenal angiosarcomas Histological subtype
Number of cases
Age (gender)
Cytokeratin CD31 CD34 Factor VIII
Ki67
Concomitant adrenal lesion
Reference
1. Epithelioid 2. NOS 3. Epithelioid 4. Epithelioid
1 1 1 1
68 (M) 55 (M) 62 (F) 42 (M)
Focal + NA NA +
+ NA + +
− NA + −
+ NA NA −
NA NA 90 % 60 %
− − Cystic lesion Vascular cyst
[3] [4] [5] [6]
5. Epithelioid 6. Epithelioid 7. Epithelioid 8. Epithelioid 9. Epithelioid 10. Epithelioid 11. Epithelioid 12. Epithelioid 13. Epithelioid 14. Epithelioid 15. Epithelioid
1 1 1 1 1 1 1 1 1 1 9
NA + + NA NA NA + − + − + (6 cases)
NA + + NA NA NA + NA NA + NA
16. Epithelioid 17. Epithelioid
1 1
61 (M) 35 (M) 69 (F) 49 (F) 69 (M) 71 (M) 70 (M) 63 (M) 41 (M) 50 (M) 45−85 (5 M/4 F) 70 (F) 54 (M)
NA + + NA NA NA + + NA NA +
NA + NA NA NA NA + Focal + + + +
NA NA NA NA NA NA NA NA NA NA NA
− Adrenal cortical adenoma − − − − − − − − −
[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
NA NA
+ NA
NA NA
NA NA
NA NA
− −
[18] [19]
18. Epithelioid 19. Epithelioid and NOS 20. Epithelioid 21. Epithelioid
1 2
60 (M) 67 (M), 60 (F)
+ NA
+ NA
+ NA
NA +
NA NA
− −
[20] [21]
1 1
59 (M) 63 (M)
(x) +
(x) +
(x) −
(x) NA
(x) − [22] 90 % Adrenal cortical adenoma Current case
NA not available, M male, F female; (x) data not available for the authors
test, dexamethasone suppression test, aldosterone and plasma renin activity, and plasma catecholamines) were within normal limits. A core biopsy from the right adrenal mass performed at an outside institution was reported as “adrenal cortical neoplasm.” Given the large size (>4.0 cm) of the adrenal neoplasm and concomitant mediastinal masses radiologically suspicious for metastatic disease, a preoperative clinical diagnosis of adrenal cortical carcinoma was questioned. Subsequently, the patient underwent right adrenalectomy at the same outside institution. Gross examination confirmed an 8.5×7.5×6.5-cm mass confined to the adrenal gland weighing 146 g. The lesion consisted of an orange to yellow nodule intermingling with regions of tan-firm areas and hemorrhage and necrosis. The specimen was sent for consultation to our endocrine site group with a preliminary diagnosis of sarcomatoid adrenal cortical carcinoma. On histologic examination, the adrenal mass was composed of a clear cell adrenal cortical adenoma intermingled with areas of necrosis surrounded by anastomosing vascular channels lined by plump endothelial cells with focal papillary configuration and sheet-like growth, consistent with angiosarcoma (Fig. 1a–d). The endothelial cells exhibited enlarged pleomorphic nuclei, prominent nucleoli, and increased mitotic activity
(up to 12 per 10 high-power fields) (Fig. 1). Immunohistochemically, the angiosarcoma component was positive for vimentin, CK7, AE1/AE3, CAM5.2, CD31, p53 (approximately 90 %), and galectin-3, but was negative for S100 protein, TTF-1, chromogranin-A, synaptophysin, high molecular weight cytokeratin (34betaE12), CK20, CD34, podoplanin (D2-40), HHV-8 (Human Herpesvirus 8), WT-1, calretinin, Melan-A (clone A-103), HMB45, alpha-inhibin, and SF-1 (Fig. 2). On the other hand, the adrenal cortical adenoma stained for SF-1 (Fig. 2), calretinin, Melan-A, and alpha-inhibin. Both p53 and MIB-1 labeling indices were around 90 % in the angiosarcoma component and were less than 1 % in the adenoma component (Fig. 2). IGF-2 immunohistochemistry was negative in the adrenal cortical adenoma. The morphological and immunohistochemical findings were diagnostic of an epithelioid angiosarcoma arising in adrenal cortical adenoma.
Discussion The adrenal gland is a site of various neoplasms; however, it is rarely involved by sarcomas [23]. While composite/mixed
406
Endocr Pathol (2014) 25:404–409
Fig. 1 The adrenal mass was composed of a clear cell adrenal cortical adenoma (a) intermingled with areas of anastomosing vascular channels lined by plump epithelioid endothelial cells (b– d). The endothelial cells exhibited enlarged pleomorphic nuclei, prominent nucleoli, and increased mitotic activity (b–d)
adrenal neoplasms are extremely rare, they often consist of rare corticomedullary tumors or pheochromocytomas admixed with neuroblastoma, ganglioneuroblastoma, ganglioneuroma, or malignant peripheral nerve sheath tumors [24, 25]. To our knowledge, only one single case report of mixed primary adrenal angiosarcoma and a functional adrenocortical adenoma was reported in the English literature [8]. The presented case is another example of this phenomenon posing diagnostic challenges for practicing pathologists. While no well-defined predisposing factors have been identified so far, exposure to arsenicals has been speculated in one case [22]. The light microscopic diagnosis of epithelioid angiosarcoma of the adrenal gland can be challenging for several reasons, including its broad spectrum of clinical presentation, its remarkable epithelioid appearance to mimic sarcomatoid adrenal cortical carcinoma or metastatic carcinoma with sarcomatoid change, and the possibility of sampling error due to coexistence of benign and malignant lesions [6, 8]. In this setting, one should remember the spectrum of vascular lesions in the adrenal gland which include reactive vascular proliferations seen at sites of degeneration especially in adrenal cortical adenomas, endothelial cysts (also known as “vascular cysts”), hemangiomas (capillary or cavernous), lymphangiomas, angiosarcomas, and Kaposi sarcomas. From a morphological perspective, one should be aware that both Kaposi sarcoma and angiosarcoma can display a sinusoidal growth extending between residual adrenal cortical cells creating a diagnostic challenge. On the other hand, the extent of necrosis and degenerative changes can sometimes make the identification of angiosarcoma difficult in the background of an adrenal cortical neoplasm. Other common entities such as
reactive papillary endothelial hyperplasia in a degenerated adenoma, or vascular cyst or pseudocyst showing necrotic material and/or thrombus formation may also generate challenges in this distinction. Angiosarcoma with extensive cystic degeneration or reorganized hemorrhage can sometimes be indistinguishable from a vascular cyst. Thus, this distinction often requires a thorough sampling of the vascular lesion or cystic wall. The identification of plump epithelioid endothelial cells with vesicular chromatin, prominent nucleoli, nuclear pleomorphism, and increased mitotic figures is useful in establishing a diagnosis of epithelioid angiosarcoma [1, 2]. Epithelioid angiosarcoma can also mimic metastatic carcinomas and adrenal cortical carcinomas with sarcomatous change. Sarcomatous change within adrenal cortical carcinoma (referred to variably as adrenal carcinosarcoma or sarcomatoid adrenal cortical carcinoma) is exceptionally rare and typically combines features of adrenal cortical carcinoma with areas of sarcomas including osteogenic, chondroid, and myoid [26–28]. Most adrenal angiosarcomas are of the epithelioid type with a solid epithelioid pattern rather than a vasoformative pattern. The latter can mimic an adrenal cortical carcinoma that often shows a diffuse solid architecture. It is well known that positivity for cytokeratin in epithelioid angiosarcoma may be mistaken as an evidence of carcinoma. Therefore, negativity for steroidogenic factor-1 (SF-1) and/or other adrenal cortical differentiation markers (Melan-A, alpha-inhibin, calretinin, and synaptophysin) and positivity for vascular differentiation markers (CD31, CD34, D2-40, Factor VIII) and/or the ultrastructural evidence of Weibel-Palade bodies can be served as ancillary tools in the distinction from an adrenal cortical neoplasm [1, 2, 29]. Adenomatoid tumor of the adrenal gland can also mimic epithelioid angiosarcoma.
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407
Fig. 2 SF-1 was negative in the angiosarcoma component and stained adenoma component along with nontumorous adrenal cortical cells (a). The nontumorous endocrine vasculature (b) and angiosarcoma component were positive for CD31 (c–d). The angiosarcoma component was positive for AE1/AE3 (e) and galectin-3 (f). Both p53 and MIB1 labeling indices were around 90 % in the angiosarcoma component and were less than 1 % in the adenoma component (g and h, respectively)
Moreover, adenomatoid tumor frequently exhibits an infiltrative growth pattern intermixed with adrenal cortical cells. At this point, one has to be aware that both keratins and D2-40 can be expressed in adenomatoid tumors and angiosarcomas. Therefore, the use of other mesothelial markers such as calretinin or WT-1 can solve the quandary [30]. Friend leukemia virus integration 1 (Fli-1) has also been reported as the first nuclear marker of endothelial differentiation [31]. The sensitivity of the Fli-1 polyclonal antibody was about 90 % in angiosarcomas and in all other endothelial derived neoplasms. Rossi et al. concluded that Fli-1 can serve as a very reliable nuclear marker of endothelial differentiation [31]. However, Fli-1 immunoreactivity has been reported also in other neoplasms [32]. Metastatic carcinomas with sarcomatoid change
or direct invasion from the carcinosarcoma of the liver to the adrenal gland can be potential pitfalls in the diagnosis of epithelioid angiosarcoma. However, the lack of expression for vascular markers and a detailed systemic examination would reliably exclude the possibility of metastatic lesion [33]. Endocrine organs are typically irrigated by a network of fenestrated capillaries that allow transendothelial transit of small- to medium-sized molecules [34]. Several lines of evidence indicate that endocrine neoplasms have also a rich vascular network, likely due to angiogenic factors secreted by tumor cells and/or stroma reflecting tumor cell-extracellular matrix interactions [35]. While the etiology is unknown, endothelial proliferation after recurrent
408
intralesional hemorrhage or posttraumatic hemorrhage in a long-standing lesion could potentially be considered to initiate a possible neoplastic transformation in many endocrine organs [35]. It has been shown that angiosarcoma can occur in the background of inflammation, cysts, or neoplasms in endocrine organs like the thyroid and ovary [2, 22, 36–39]. An interesting feature of the presented case is the identification of angiosarcoma within an adrenal cortical adenoma. Lepoutre-Lussey et al. reported an adrenocortical adenoma presenting with hypokalemic hypertension in a young man associating with a primary adrenal angiosarcoma [8]. While this phenomenon may represent a possible collision tumor phenomenon [8], one can speculate that the rich vasculature of endocrine lesions creates a favorable milieu for neoplastic transformation. However, the latter still remains unproven. In summary, the presented case should be added to the unusual clinical presentations of vascular lesions of the adrenal gland mimicking a sarcomatoid adrenal cortical carcinoma.
References 1. Fletcher CDM, Bridge J, Hogendoom PCW, Mertens F (Eds): WHO classification of Tumours of Soft Tissue and Bone. IARC: Lyon, 2013. 2. Kefeli M, Mete O. An unusual malignant thyroid nodule: coexistence of epithelioid angiosarcoma and follicular variant papillary thyroid carcinoma. Endocr Pathol 2013 Apr 23. 3. Criscuolo M, Valerio J, Gianicolo ME, Gianicolo EA, Portaluri M. A vinyl chloride-exposed worker with an adrenal gland angiosarcoma: a case report. Ind Health 52:66–70, 2014. 4. Kędzierski L, Hawrot-Kawecka A, Holecki M, Duława J. Angiosarcoma of the adrenal gland. Pol Arch Med Wewn. 123: 502–503, 2013. 5. Sebastiano C, Zhao X, Deng FM, Das K. Cystic lesions of the adrenal gland: our experience over the last 20 years. Hum Pathol. 44:1797– 803, 2013. 6. Sung JY, Ahn S, Kim SJ, Park YS, Choi YL. Angiosarcoma arising within a long-standing cystic lesion of the adrenal gland: a case report. J Clin Oncol 31:e132-6, 2013. 7. Derlin T, Clauditz TS, Habermann CR. Adrenal epithelioid angiosarcoma metastatic to the epicardium: diagnosis by 18F-FDG PET/CT. Clin Nucl Med 37:914–915, 2012. 8. Lepoutre-Lussey C, Rousseau A, Al Ghuzlan A, Amar L, Hignette C, Cioffi A, Zinzindohoué F, Leboulleux S, Plouin PF. Primary adrenal angiosarcoma and functioning adrenocortical adenoma: an exceptional combined tumor. Eur J Endocrinol 166: 131–135, 2012. 9. Schreiner AM, Hoda RS. Primary adrenal epithelioid angiosarcoma showing rhabdoid morphology on air-dried smears. Diagn Cytopathol 40 Suppl 2:E162-4, 2012. 10. Gambino G, Mannone T, Rizzo A, Scio A, Branca M, Airò Farulla M, Guccione M,Spallitta IS, Nicoli N. Adrenal epithelioid angiosarcoma: a case report. Chir Ital 60:463–467, 2008. 11. Galmiche L, Morel HP, Moreau A, Labrosse PA, Coindre JM, Heymann MF. Primary adrenal angiosarcoma. Ann Pathol 24:371– 373, 2004.
Endocr Pathol (2014) 25:404–409 12. Tousi-Sadr HR, Lam GW. Angiosarcoma of the adrenal gland. Ugeskr Laeger 164:911–912, 2002. 13. Krüger S, Kujath P, Johannisson R, Feller AC. Primary epithelioid angiosarcoma of the adrenal gland case report and review of the literature. Tumori 87:262–265, 2001. 14. Croitoru AG, Klausner AP, McWilliams G, Unger PD. Primary epithelioid angiosarcoma of the adrenal gland. Ann Diagn Pathol 5: 300–303, 2001. 15. Ben-Izhak O, Auslander L, Rabinson S, Lichtig C, Sternberg A. Epithelioid angiosarcoma of the adrenal gland with cytokeratin expression. Report of a case with accompanying mesenteric fibromatosis. Cancer 69:1808–1812, 1992. 16. Al-Meshan MK, Katchy KC. An unusual angiosarcoma. A case report. Med Princ Pract 13:295–297, 2004. 17. Wenig BM, Abbondanzo SL, Heffess CS. Epithelioid angiosarcoma of the adrenal glands. A clinicopathologic study of nine cases with a discussion of the implications of finding “epithelial-specific” markers. Am J Surg Pathol 18:62–73, 1994. 18. Pasqual E, Bertolissi F, Grimaldi F, Beltrami CA, Scott CA, Bacchetti S, Waclaw BU, Cagol PP. Adrenal angiosarcoma: report of a case. Surg Today 32:563–565, 2002. 19. Kareti LR, Katlein S, Siew S, Blauvelt A. Angiosarcoma of the adrenal gland. Arch Pathol Lab Med 112:1163–1165, 1988. 20. Sidoni A, Magro G, Cavaliere A, Scheibel M, Bellezza G. Primary adrenal angiosarcoma. Pathologica 95:60–63, 2003. 21. Ferrozzi F, Tognini G, Bova D, Zuccoli G, Pavone P. Hemangiosarcoma of the adrenal glands: CT findings in two cases. Abdom Imaging 26:336–339, 2001. 22. Livaditou A, Alexiou G, Floros D, Filippidis T, Dosios T, Bays D. Epithelioid angiosarcoma of the adrenal gland associated with chronic arsenical intoxication? Pathol Res Pract187(2–3):284–9, 1991. 23. Dekou A, N’dah JK, Kouame B, Kohou L, Abroulaye F, Gowe E, Kassanyou S, ManzanK. Primary leiomyosarcoma of adrenal gland, in black African woman: diagnosis and therapeutically aspects. Prog Urol 23:421–4, 2013. 24. Kimura N, Watanabe T, Fukase M, Wakita A, Noshiro T, Kimura I. Neurofibromin and NF1 gene analysis in composite pheochromocytoma and tumors associated with von Recklinghausen’s disease. Mod Pathol 15:183–8, 2002. 25. Mete O, Tischler AS, de Krijger R, McNicol AM, Eisenhofer G, Pacak K, Ezzat S, Asa SL. Protocol for the examination of specimens from patients with pheochromocytomas and extra-adrenal paragangliomas. Arch Pathol Lab Med138:182–8, 2014. 26. Thway K, Olmos D, Shah C, Flora R, Shipley J, Fisher C. Oncocytic adrenal cortical carcinosarcoma with pleomorphic rhabdomyosarcomatous metastases. Am J Surg Pathol 36:470–6, 2012. 27. de Krijger RR, Papathomas TG. Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants. Virchows Arch 460:9–18, 2012. 28. Kao CS, Grignon DJ, Ulbright TM, Idrees MT. A case report of adrenocortical carcinosarcoma with oncocytic and primitive neuroectodermal-like features. Hum Pathol44:1947–55, 2013. 29. Carstens HB, Ghadially FN, Henderson DW, Stirling JW. Case for the panel. Weibel-Palade body-like lamellar structure in angiosarcoma. Ultrastruct Pathol 19:137–43, 1995. 30. Białas M, Szczepański W, Szpor J, Okoń K, Kostecka-Matyja M, Hubalewska-Dydejczyk A, Tomaszewska R. Adenomatoid tumour of the adrenal gland: a case report and literature review. Pol J Pathol 61:97–102, 2010. 31. Rossi S, Orvieto E, Furlanetto A, Laurino L, Ninfo V, Dei Tos AP. Utility of the immunohistochemical detection of FLI-1 expression in round cell and vascular neoplasm using a monoclonal antibody. Mod Pathol 17:547–52, 2004. 32. Cuda J, Mirzamani N, Kantipudi R, Robbins J, Welsch MJ, Sundram UN. Diagnostic utility of Fli-1 and D2-40 in distinguishing atypical
Endocr Pathol (2014) 25:404–409
33. 34.
35. 36.
fibroxanthoma from angiosarcoma. Am J Dermatopathol 35:316–18, 2013. Naka N, Ohsawa M, Tomita Y, Kanno H, Uchida A, Aozasa K. Angiosarcoma in Japan. A review of 99 cases. Cancer 75:989–96, 1995. Schaeffer M, Hodson DJ, Lafont C, Mollard P. Endocrine cells and blood vessels work in tandem to generate hormone pulses. J Mol Endocrinol 47:59–66, 2011. Turner HE, Harris AL, Melmed S, Wass JA. Angiogenesis in endocrine tumors. Endocr Rev 24:600–32, 2003. Aozasa K, Naka N, Tomita Y, Ohsawa M, Kanno H, Uchida A, Ono K. Angiosarcoma developing from chronic pyothorax. Mod Pathol 7: 906–11, 1994.
409 37. Schneider T, Renney J, Hayman J. Angiosarcoma occurring with chronic osteomyelitis and residual foreign material: case report of a late World War II wound complication. Aust N Z J Surg 67:576–8, 1997. 38. Schmitz BA, Singh C, Gulbahce HE, Manivel JC, Pambuccian SE. Florid capsular and pericapsular papillary endothelial proliferation associated with poorly differentiated thyroid carcinoma. Int J Surg Pathol 19:110–2, 2011. 39. Petronella P, Scorzelli M, Luise R, Iannaci G, Sapere P, Ferretti M, Costanzo RM, Freda F, Canonico S, Rossiello R. Primary thyroid angiosarcoma: an unusual localization. World J Surg Oncol 3;10:73, 2012.
A Mimic of Sarcomatoid Adrenal Cortical Carcinoma: Epithelioid Angiosarcoma Occurring in Adrenal Cortical Adenoma Toshitetsu Hayashi & Hasan Gucer & Ozgur Mete
Published online: 23 September 2014 # Springer Science+Business Media New York 2014
Abstract The adrenal gland is a site of various neoplasms; however, it is rarely involved by sarcomas. We present herein an unusual adrenal neoplasm consisting of epithelioid angiosarcoma and adrenal cortical adenoma. In this report, the authors highlight the diagnostic challenges associated with an epithelioid angiosarcoma occurring in an adrenal cortical neoplasm by providing a comprehensive discussion on the spectrum of vascular proliferations seen in the adrenal gland along with a roadmap for practicing pathologists. The presence of angiosarcoma within an adrenal cortical adenoma may represent a collision tumor; however, one can speculate that the rich vasculature of endocrine lesions can also create a favorable milieu for the occurrence of this phenomenon. While the latter needs to be further clarified, the presented case should be added to the unusual clinical presentations of vascular lesions of the adrenal gland mimicking a sarcomatoid adrenal cortical carcinoma. Keywords Epithelioid angiosarcoma . Adrenal cortical adenoma . Adrenal cortical carcinoma . Sarcomatoid carcinoma . SF-1
skin and soft tissue, visceral forms have also been described in many organs [1]. Malignant vascular endothelial neoplasms in which epithelioid cells predominate are classified as epithelioid angiosarcomas. Epithelioid angiosarcomas can easily be mistaken for carcinomas because of their morphologic and immunohistochemical similarities [1, 2]. While most adrenal angiosarcomas represent metastases from another primary tumor site, primary angiosarcoma of the adrenal gland is uncommon and usually of epithelioid type, with only 29 reported cases in the literature [3–22] (Table 1). We present herein an unusual adrenal neoplasm consisting of composite epithelioid angiosarcoma and adrenal cortical adenoma that mimics a sarcomatoid adrenal cortical carcinoma. In this report, the authors aimed to discuss the diagnostic challenges associated with an epithelioid angiosarcoma occurring in an adrenal cortical neoplasm by providing a comprehensive discussion on the spectrum of vascular proliferations seen in the adrenal gland along with a road map for practicing pathologists.
Case Report Introduction Angiosarcomas are malignant neoplasms recapitulating both morphological and functional features of endothelium to a variable degree. While these neoplasms are often seen in the T. Hayashi : H. Gucer : O. Mete (*) Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON M5G2C4, Canada e-mail: [email protected] O. Mete Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
A 63-year-old man with a previous history of smoking-related chronic obstructive pulmonary disease was admitted to hospital due to progressive dyspnea and progressive marked weight loss along with abdominal discomfort of 6-month duration. Both abdominal ultrasound and computed tomography scan identified a large right adrenal mass measuring up to 7.8 cm. In addition, enlarged mediastinal lymph nodes with a predominant right hilar 3-cm nodule were detected. While the imaging studies were highly suspicious for tumor metastasis, no endobronchial lesion was identified on bronchoscopy. Bronchial biopsy and bronchoalveolar lavage smears were negative for malignancy or granulomatous inflammation. Multiple dynamic and functional tests (ACTH stimulation
Endocr Pathol (2014) 25:404–409
405
Table 1 Characteristics of previously reported cases of adrenal angiosarcomas Histological subtype
Number of cases
Age (gender)
Cytokeratin CD31 CD34 Factor VIII
Ki67
Concomitant adrenal lesion
Reference
1. Epithelioid 2. NOS 3. Epithelioid 4. Epithelioid
1 1 1 1
68 (M) 55 (M) 62 (F) 42 (M)
Focal + NA NA +
+ NA + +
− NA + −
+ NA NA −
NA NA 90 % 60 %
− − Cystic lesion Vascular cyst
[3] [4] [5] [6]
5. Epithelioid 6. Epithelioid 7. Epithelioid 8. Epithelioid 9. Epithelioid 10. Epithelioid 11. Epithelioid 12. Epithelioid 13. Epithelioid 14. Epithelioid 15. Epithelioid
1 1 1 1 1 1 1 1 1 1 9
NA + + NA NA NA + − + − + (6 cases)
NA + + NA NA NA + NA NA + NA
16. Epithelioid 17. Epithelioid
1 1
61 (M) 35 (M) 69 (F) 49 (F) 69 (M) 71 (M) 70 (M) 63 (M) 41 (M) 50 (M) 45−85 (5 M/4 F) 70 (F) 54 (M)
NA + + NA NA NA + + NA NA +
NA + NA NA NA NA + Focal + + + +
NA NA NA NA NA NA NA NA NA NA NA
− Adrenal cortical adenoma − − − − − − − − −
[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
NA NA
+ NA
NA NA
NA NA
NA NA
− −
[18] [19]
18. Epithelioid 19. Epithelioid and NOS 20. Epithelioid 21. Epithelioid
1 2
60 (M) 67 (M), 60 (F)
+ NA
+ NA
+ NA
NA +
NA NA
− −
[20] [21]
1 1
59 (M) 63 (M)
(x) +
(x) +
(x) −
(x) NA
(x) − [22] 90 % Adrenal cortical adenoma Current case
NA not available, M male, F female; (x) data not available for the authors
test, dexamethasone suppression test, aldosterone and plasma renin activity, and plasma catecholamines) were within normal limits. A core biopsy from the right adrenal mass performed at an outside institution was reported as “adrenal cortical neoplasm.” Given the large size (>4.0 cm) of the adrenal neoplasm and concomitant mediastinal masses radiologically suspicious for metastatic disease, a preoperative clinical diagnosis of adrenal cortical carcinoma was questioned. Subsequently, the patient underwent right adrenalectomy at the same outside institution. Gross examination confirmed an 8.5×7.5×6.5-cm mass confined to the adrenal gland weighing 146 g. The lesion consisted of an orange to yellow nodule intermingling with regions of tan-firm areas and hemorrhage and necrosis. The specimen was sent for consultation to our endocrine site group with a preliminary diagnosis of sarcomatoid adrenal cortical carcinoma. On histologic examination, the adrenal mass was composed of a clear cell adrenal cortical adenoma intermingled with areas of necrosis surrounded by anastomosing vascular channels lined by plump endothelial cells with focal papillary configuration and sheet-like growth, consistent with angiosarcoma (Fig. 1a–d). The endothelial cells exhibited enlarged pleomorphic nuclei, prominent nucleoli, and increased mitotic activity
(up to 12 per 10 high-power fields) (Fig. 1). Immunohistochemically, the angiosarcoma component was positive for vimentin, CK7, AE1/AE3, CAM5.2, CD31, p53 (approximately 90 %), and galectin-3, but was negative for S100 protein, TTF-1, chromogranin-A, synaptophysin, high molecular weight cytokeratin (34betaE12), CK20, CD34, podoplanin (D2-40), HHV-8 (Human Herpesvirus 8), WT-1, calretinin, Melan-A (clone A-103), HMB45, alpha-inhibin, and SF-1 (Fig. 2). On the other hand, the adrenal cortical adenoma stained for SF-1 (Fig. 2), calretinin, Melan-A, and alpha-inhibin. Both p53 and MIB-1 labeling indices were around 90 % in the angiosarcoma component and were less than 1 % in the adenoma component (Fig. 2). IGF-2 immunohistochemistry was negative in the adrenal cortical adenoma. The morphological and immunohistochemical findings were diagnostic of an epithelioid angiosarcoma arising in adrenal cortical adenoma.
Discussion The adrenal gland is a site of various neoplasms; however, it is rarely involved by sarcomas [23]. While composite/mixed
406
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Fig. 1 The adrenal mass was composed of a clear cell adrenal cortical adenoma (a) intermingled with areas of anastomosing vascular channels lined by plump epithelioid endothelial cells (b– d). The endothelial cells exhibited enlarged pleomorphic nuclei, prominent nucleoli, and increased mitotic activity (b–d)
adrenal neoplasms are extremely rare, they often consist of rare corticomedullary tumors or pheochromocytomas admixed with neuroblastoma, ganglioneuroblastoma, ganglioneuroma, or malignant peripheral nerve sheath tumors [24, 25]. To our knowledge, only one single case report of mixed primary adrenal angiosarcoma and a functional adrenocortical adenoma was reported in the English literature [8]. The presented case is another example of this phenomenon posing diagnostic challenges for practicing pathologists. While no well-defined predisposing factors have been identified so far, exposure to arsenicals has been speculated in one case [22]. The light microscopic diagnosis of epithelioid angiosarcoma of the adrenal gland can be challenging for several reasons, including its broad spectrum of clinical presentation, its remarkable epithelioid appearance to mimic sarcomatoid adrenal cortical carcinoma or metastatic carcinoma with sarcomatoid change, and the possibility of sampling error due to coexistence of benign and malignant lesions [6, 8]. In this setting, one should remember the spectrum of vascular lesions in the adrenal gland which include reactive vascular proliferations seen at sites of degeneration especially in adrenal cortical adenomas, endothelial cysts (also known as “vascular cysts”), hemangiomas (capillary or cavernous), lymphangiomas, angiosarcomas, and Kaposi sarcomas. From a morphological perspective, one should be aware that both Kaposi sarcoma and angiosarcoma can display a sinusoidal growth extending between residual adrenal cortical cells creating a diagnostic challenge. On the other hand, the extent of necrosis and degenerative changes can sometimes make the identification of angiosarcoma difficult in the background of an adrenal cortical neoplasm. Other common entities such as
reactive papillary endothelial hyperplasia in a degenerated adenoma, or vascular cyst or pseudocyst showing necrotic material and/or thrombus formation may also generate challenges in this distinction. Angiosarcoma with extensive cystic degeneration or reorganized hemorrhage can sometimes be indistinguishable from a vascular cyst. Thus, this distinction often requires a thorough sampling of the vascular lesion or cystic wall. The identification of plump epithelioid endothelial cells with vesicular chromatin, prominent nucleoli, nuclear pleomorphism, and increased mitotic figures is useful in establishing a diagnosis of epithelioid angiosarcoma [1, 2]. Epithelioid angiosarcoma can also mimic metastatic carcinomas and adrenal cortical carcinomas with sarcomatous change. Sarcomatous change within adrenal cortical carcinoma (referred to variably as adrenal carcinosarcoma or sarcomatoid adrenal cortical carcinoma) is exceptionally rare and typically combines features of adrenal cortical carcinoma with areas of sarcomas including osteogenic, chondroid, and myoid [26–28]. Most adrenal angiosarcomas are of the epithelioid type with a solid epithelioid pattern rather than a vasoformative pattern. The latter can mimic an adrenal cortical carcinoma that often shows a diffuse solid architecture. It is well known that positivity for cytokeratin in epithelioid angiosarcoma may be mistaken as an evidence of carcinoma. Therefore, negativity for steroidogenic factor-1 (SF-1) and/or other adrenal cortical differentiation markers (Melan-A, alpha-inhibin, calretinin, and synaptophysin) and positivity for vascular differentiation markers (CD31, CD34, D2-40, Factor VIII) and/or the ultrastructural evidence of Weibel-Palade bodies can be served as ancillary tools in the distinction from an adrenal cortical neoplasm [1, 2, 29]. Adenomatoid tumor of the adrenal gland can also mimic epithelioid angiosarcoma.
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Fig. 2 SF-1 was negative in the angiosarcoma component and stained adenoma component along with nontumorous adrenal cortical cells (a). The nontumorous endocrine vasculature (b) and angiosarcoma component were positive for CD31 (c–d). The angiosarcoma component was positive for AE1/AE3 (e) and galectin-3 (f). Both p53 and MIB1 labeling indices were around 90 % in the angiosarcoma component and were less than 1 % in the adenoma component (g and h, respectively)
Moreover, adenomatoid tumor frequently exhibits an infiltrative growth pattern intermixed with adrenal cortical cells. At this point, one has to be aware that both keratins and D2-40 can be expressed in adenomatoid tumors and angiosarcomas. Therefore, the use of other mesothelial markers such as calretinin or WT-1 can solve the quandary [30]. Friend leukemia virus integration 1 (Fli-1) has also been reported as the first nuclear marker of endothelial differentiation [31]. The sensitivity of the Fli-1 polyclonal antibody was about 90 % in angiosarcomas and in all other endothelial derived neoplasms. Rossi et al. concluded that Fli-1 can serve as a very reliable nuclear marker of endothelial differentiation [31]. However, Fli-1 immunoreactivity has been reported also in other neoplasms [32]. Metastatic carcinomas with sarcomatoid change
or direct invasion from the carcinosarcoma of the liver to the adrenal gland can be potential pitfalls in the diagnosis of epithelioid angiosarcoma. However, the lack of expression for vascular markers and a detailed systemic examination would reliably exclude the possibility of metastatic lesion [33]. Endocrine organs are typically irrigated by a network of fenestrated capillaries that allow transendothelial transit of small- to medium-sized molecules [34]. Several lines of evidence indicate that endocrine neoplasms have also a rich vascular network, likely due to angiogenic factors secreted by tumor cells and/or stroma reflecting tumor cell-extracellular matrix interactions [35]. While the etiology is unknown, endothelial proliferation after recurrent
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intralesional hemorrhage or posttraumatic hemorrhage in a long-standing lesion could potentially be considered to initiate a possible neoplastic transformation in many endocrine organs [35]. It has been shown that angiosarcoma can occur in the background of inflammation, cysts, or neoplasms in endocrine organs like the thyroid and ovary [2, 22, 36–39]. An interesting feature of the presented case is the identification of angiosarcoma within an adrenal cortical adenoma. Lepoutre-Lussey et al. reported an adrenocortical adenoma presenting with hypokalemic hypertension in a young man associating with a primary adrenal angiosarcoma [8]. While this phenomenon may represent a possible collision tumor phenomenon [8], one can speculate that the rich vasculature of endocrine lesions creates a favorable milieu for neoplastic transformation. However, the latter still remains unproven. In summary, the presented case should be added to the unusual clinical presentations of vascular lesions of the adrenal gland mimicking a sarcomatoid adrenal cortical carcinoma.
References 1. Fletcher CDM, Bridge J, Hogendoom PCW, Mertens F (Eds): WHO classification of Tumours of Soft Tissue and Bone. IARC: Lyon, 2013. 2. Kefeli M, Mete O. An unusual malignant thyroid nodule: coexistence of epithelioid angiosarcoma and follicular variant papillary thyroid carcinoma. Endocr Pathol 2013 Apr 23. 3. Criscuolo M, Valerio J, Gianicolo ME, Gianicolo EA, Portaluri M. A vinyl chloride-exposed worker with an adrenal gland angiosarcoma: a case report. Ind Health 52:66–70, 2014. 4. Kędzierski L, Hawrot-Kawecka A, Holecki M, Duława J. Angiosarcoma of the adrenal gland. Pol Arch Med Wewn. 123: 502–503, 2013. 5. Sebastiano C, Zhao X, Deng FM, Das K. Cystic lesions of the adrenal gland: our experience over the last 20 years. Hum Pathol. 44:1797– 803, 2013. 6. Sung JY, Ahn S, Kim SJ, Park YS, Choi YL. Angiosarcoma arising within a long-standing cystic lesion of the adrenal gland: a case report. J Clin Oncol 31:e132-6, 2013. 7. Derlin T, Clauditz TS, Habermann CR. Adrenal epithelioid angiosarcoma metastatic to the epicardium: diagnosis by 18F-FDG PET/CT. Clin Nucl Med 37:914–915, 2012. 8. Lepoutre-Lussey C, Rousseau A, Al Ghuzlan A, Amar L, Hignette C, Cioffi A, Zinzindohoué F, Leboulleux S, Plouin PF. Primary adrenal angiosarcoma and functioning adrenocortical adenoma: an exceptional combined tumor. Eur J Endocrinol 166: 131–135, 2012. 9. Schreiner AM, Hoda RS. Primary adrenal epithelioid angiosarcoma showing rhabdoid morphology on air-dried smears. Diagn Cytopathol 40 Suppl 2:E162-4, 2012. 10. Gambino G, Mannone T, Rizzo A, Scio A, Branca M, Airò Farulla M, Guccione M,Spallitta IS, Nicoli N. Adrenal epithelioid angiosarcoma: a case report. Chir Ital 60:463–467, 2008. 11. Galmiche L, Morel HP, Moreau A, Labrosse PA, Coindre JM, Heymann MF. Primary adrenal angiosarcoma. Ann Pathol 24:371– 373, 2004.
Endocr Pathol (2014) 25:404–409 12. Tousi-Sadr HR, Lam GW. Angiosarcoma of the adrenal gland. Ugeskr Laeger 164:911–912, 2002. 13. Krüger S, Kujath P, Johannisson R, Feller AC. Primary epithelioid angiosarcoma of the adrenal gland case report and review of the literature. Tumori 87:262–265, 2001. 14. Croitoru AG, Klausner AP, McWilliams G, Unger PD. Primary epithelioid angiosarcoma of the adrenal gland. Ann Diagn Pathol 5: 300–303, 2001. 15. Ben-Izhak O, Auslander L, Rabinson S, Lichtig C, Sternberg A. Epithelioid angiosarcoma of the adrenal gland with cytokeratin expression. Report of a case with accompanying mesenteric fibromatosis. Cancer 69:1808–1812, 1992. 16. Al-Meshan MK, Katchy KC. An unusual angiosarcoma. A case report. Med Princ Pract 13:295–297, 2004. 17. Wenig BM, Abbondanzo SL, Heffess CS. Epithelioid angiosarcoma of the adrenal glands. A clinicopathologic study of nine cases with a discussion of the implications of finding “epithelial-specific” markers. Am J Surg Pathol 18:62–73, 1994. 18. Pasqual E, Bertolissi F, Grimaldi F, Beltrami CA, Scott CA, Bacchetti S, Waclaw BU, Cagol PP. Adrenal angiosarcoma: report of a case. Surg Today 32:563–565, 2002. 19. Kareti LR, Katlein S, Siew S, Blauvelt A. Angiosarcoma of the adrenal gland. Arch Pathol Lab Med 112:1163–1165, 1988. 20. Sidoni A, Magro G, Cavaliere A, Scheibel M, Bellezza G. Primary adrenal angiosarcoma. Pathologica 95:60–63, 2003. 21. Ferrozzi F, Tognini G, Bova D, Zuccoli G, Pavone P. Hemangiosarcoma of the adrenal glands: CT findings in two cases. Abdom Imaging 26:336–339, 2001. 22. Livaditou A, Alexiou G, Floros D, Filippidis T, Dosios T, Bays D. Epithelioid angiosarcoma of the adrenal gland associated with chronic arsenical intoxication? Pathol Res Pract187(2–3):284–9, 1991. 23. Dekou A, N’dah JK, Kouame B, Kohou L, Abroulaye F, Gowe E, Kassanyou S, ManzanK. Primary leiomyosarcoma of adrenal gland, in black African woman: diagnosis and therapeutically aspects. Prog Urol 23:421–4, 2013. 24. Kimura N, Watanabe T, Fukase M, Wakita A, Noshiro T, Kimura I. Neurofibromin and NF1 gene analysis in composite pheochromocytoma and tumors associated with von Recklinghausen’s disease. Mod Pathol 15:183–8, 2002. 25. Mete O, Tischler AS, de Krijger R, McNicol AM, Eisenhofer G, Pacak K, Ezzat S, Asa SL. Protocol for the examination of specimens from patients with pheochromocytomas and extra-adrenal paragangliomas. Arch Pathol Lab Med138:182–8, 2014. 26. Thway K, Olmos D, Shah C, Flora R, Shipley J, Fisher C. Oncocytic adrenal cortical carcinosarcoma with pleomorphic rhabdomyosarcomatous metastases. Am J Surg Pathol 36:470–6, 2012. 27. de Krijger RR, Papathomas TG. Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants. Virchows Arch 460:9–18, 2012. 28. Kao CS, Grignon DJ, Ulbright TM, Idrees MT. A case report of adrenocortical carcinosarcoma with oncocytic and primitive neuroectodermal-like features. Hum Pathol44:1947–55, 2013. 29. Carstens HB, Ghadially FN, Henderson DW, Stirling JW. Case for the panel. Weibel-Palade body-like lamellar structure in angiosarcoma. Ultrastruct Pathol 19:137–43, 1995. 30. Białas M, Szczepański W, Szpor J, Okoń K, Kostecka-Matyja M, Hubalewska-Dydejczyk A, Tomaszewska R. Adenomatoid tumour of the adrenal gland: a case report and literature review. Pol J Pathol 61:97–102, 2010. 31. Rossi S, Orvieto E, Furlanetto A, Laurino L, Ninfo V, Dei Tos AP. Utility of the immunohistochemical detection of FLI-1 expression in round cell and vascular neoplasm using a monoclonal antibody. Mod Pathol 17:547–52, 2004. 32. Cuda J, Mirzamani N, Kantipudi R, Robbins J, Welsch MJ, Sundram UN. Diagnostic utility of Fli-1 and D2-40 in distinguishing atypical
Endocr Pathol (2014) 25:404–409
33. 34.
35. 36.
fibroxanthoma from angiosarcoma. Am J Dermatopathol 35:316–18, 2013. Naka N, Ohsawa M, Tomita Y, Kanno H, Uchida A, Aozasa K. Angiosarcoma in Japan. A review of 99 cases. Cancer 75:989–96, 1995. Schaeffer M, Hodson DJ, Lafont C, Mollard P. Endocrine cells and blood vessels work in tandem to generate hormone pulses. J Mol Endocrinol 47:59–66, 2011. Turner HE, Harris AL, Melmed S, Wass JA. Angiogenesis in endocrine tumors. Endocr Rev 24:600–32, 2003. Aozasa K, Naka N, Tomita Y, Ohsawa M, Kanno H, Uchida A, Ono K. Angiosarcoma developing from chronic pyothorax. Mod Pathol 7: 906–11, 1994.
409 37. Schneider T, Renney J, Hayman J. Angiosarcoma occurring with chronic osteomyelitis and residual foreign material: case report of a late World War II wound complication. Aust N Z J Surg 67:576–8, 1997. 38. Schmitz BA, Singh C, Gulbahce HE, Manivel JC, Pambuccian SE. Florid capsular and pericapsular papillary endothelial proliferation associated with poorly differentiated thyroid carcinoma. Int J Surg Pathol 19:110–2, 2011. 39. Petronella P, Scorzelli M, Luise R, Iannaci G, Sapere P, Ferretti M, Costanzo RM, Freda F, Canonico S, Rossiello R. Primary thyroid angiosarcoma: an unusual localization. World J Surg Oncol 3;10:73, 2012.
