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Angiomyolipoma of the anterior mediastinum
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Annals of Diagnostic Pathology 12 (2008) 293 – 295
Angiomyolipoma of the anterior mediastinum Carrie S. Knight, MDa, Robert J. Cerfolio, MDb, Thomas S. Winokur, MDa,4 a
Department of Pathology, University of Alabama School of Medicine, Birmingham, AL, USA b Department of Surgery, University of Alabama School of Medicine, Birmingham, AL, USA
Abstract
Angiomyolipoma is a benign tumor composed of varying proportions of smooth muscle cells, blood vessels, and adipose tissue that most commonly occurs in the kidney. Sporadic lesions and lesions arising in the setting of the tuberous sclerosis complex have been reported in extrarenal sites. We present the case of an incidentally discovered angiomyolipoma in the anterior mediastinum. Thymoma was suspected clinically, and the lesion was composed mainly of spindled-to-epithelioid cells arranged in a histologic pattern reminiscent of hemangiopericytoma, a pattern that has been described in thymoma. Immunohistochemical stains revealed positivity for smooth muscle actin and HMB-45, revealing the expression of smooth muscle and melanocytic markers characteristic of angiomyolipoma and other lesions in the PEComa family. D 2008 Elsevier Inc. All rights reserved.
Keywords:
Angiomyolipoma; PEComa; Perivascular epithelioid cell; Mediastinum
1. Introduction Angiomyolipoma is a benign tumor that most often occurs in the kidney but has been reported in a variety of extrarenal sites. We report on the case of an angiomyolipoma arising in the anterior mediastinum, representing only the third reported incidence in this location. In the present case, the tumor mimicked a spindle cell thymoma with a hemangiopericytic pattern because of its location and its appearance on routine histologic sections.
levels were within normal limits, and the patient underwent sternotomy for resection of the mass. Intraoperatively, a mass was appreciated within the left side of the thymus, and the entire thymus was removed. Gross examination revealed a firm-to-rubbery, well-circumscribed tan mass measuring 3.0 2.4 1.8 cm (Fig. 1). Frozen section demonstrated a lesion composed mostly of spindled and epithelioid cells with prominent vascular
2. Case report The patient was a 57-year-old woman with a strong family history of breast cancer who underwent bilateral breast magnetic resonance imaging that revealed an anterior mediastinal mass as an incidental finding. On computed tomographic scan of the chest, the mass showed heterogeneous enhancement and was estimated to measure 4.4 2.5 cm. a-Fetoprotein and b-human chorionic gonadotropin
4 Corresponding author. Department of Pathology, NP3541, University of Alabama at Birmingham, Birmingham, AL 35249, USA. Tel.: +1 205 975 8880; fax: +1 205 975 5242. E-mail address: [email protected] (T.S. Winokur). 1092-9134/$ – see front matter D 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2006.12.007
Fig. 1. Gross appearance of the cut surface of the tumor.
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C.S. Knight et al. / Annals of Diagnostic Pathology 12 (2008) 293 – 295
Fig. 2. Histologic appearance of the lesion on frozen section with spindledto-epithelioid cells arranged in a hemangiopericytoma-like pattern.
Fig. 4. Immunohistochemical staining for HMB-45 showing positivity in PECs.
spaces (Fig. 2), and the diagnosis of a thymic epithelial neoplasm was considered. Permanent hematoxylin-eosin–stained histologic sections confirmed the spindled-to-epithelioid appearance of the tumor cells with prominent vascular spaces suggesting a hemangiopericytoma-like pattern. Mature adipose tissue and thick-walled vessels were also noted within the lesion (Fig. 3). The surrounding thymic tissue was composed of mature fibroadipose tissue with scattered foci of residual atrophic thymic parenchyma with Hassall’s corpuscles. Immunohistochemical staining of the tumor was negative for keratin and epithelial membrane antigen. The immunohistochemical staining pattern also included HMB-45– positive perivascular cells (Fig. 4), smooth muscle actin positivity in the epithelioid-to-spindled cells, and CD34positive endothelial cells lining the vascular spaces. With the identification of vascular, smooth muscle, and adipose
components and the characteristic immunophenotype, the diagnosis of angiomyolipoma in this unusual site was made.
Fig. 3. Low-power view of the permanent section showing scattered areas of adipose tissue and prominent vessels.
3. Discussion To our knowledge, this is only the third reported case of an angiomyolipoma arising in the anterior mediastinum and the eighth reported case in any mediastinal location [1]. Including the present case, reported cases of mediastinal angiomyolipoma have involved 2 men and 6 women (mean age = 46 years). Whereas our patient presented with a small lesion as an incidental finding, others presented with complaints of cough and dyspnea on exertion [1]. One patient developed dysrhythmias and palpitations caused by the mediastinal component of an angiomyolipoma, although the tumor was believed to have risen in the retroperitoneum [2]. Angiomyolipoma is a tumor composed of varying proportions of smooth muscle cells, blood vessels, and adipose tissue that most commonly occurs in the kidney. A wide variety of extrarenal sites have also been described, with the most common being the liver. This tumor is associated with the tuberous sclerosis complex, an autosomal dominant disorder caused by mutations in either TSC1 (tuberous sclerosis complex 1) on chromosome 9q34, which encodes the protein hamartin, or TSC2 (tuberous sclerosis complex 2) on chromosome 16p13, which encodes the protein tuberin [3]. Loss of heterozygosity of chromosome 16p13 has also been demonstrated in sporadic angiomyolipomas [4]. Although angiomyolipoma was originally regarded as a hamartomatous lesion, there is evidence of clonality in sporadic lesions [5] and in lesions associated with tuberous sclerosis [6]. Angiomyolipoma is characteristically immunoreactive for the melanosome-associated protein HMB-45 and smooth muscle–associated antigens [7]. Although other melanocytic
C.S. Knight et al. / Annals of Diagnostic Pathology 12 (2008) 293 – 295
markers may be expressed, HMB-45 appears to be the most sensitive, followed by Melan-A. Microphthalmia transcription factor and tyrosinase are expressed much less consistently in angiomyolipomas [8]. Ultrastructural features of smooth muscle cells and premelanosome-like structures have been reported in the spindled and epithelioid cells of angiomyolipomas [7]. A variant composed predominantly of epithelioid cells has been described and presents difficulties in diagnosis because it may be confused with renal cell carcinoma [9]. Although angiomyolipomas most often have a benign clinical course, rare incidences of malignant behavior have been reported [10]; no long-term follow-up information is available for the rare mediastinal presentation. Bonetti et al [11] first suggested the term perivascular epithelioid cell (PEC) for a cell type seen in angiomyolipoma, clear cell or bsugarQ tumor of the lung, and lymphangiomyomatosis. This cell type has an epithelioid appearance, with clear-to-acidophilic cytoplasm, and a perivascular distribution. The authors suggested HMB-45 as a useful immunohistochemical marker for the PEC [11] and demonstrated the morphological and immunophenotypic similarities between angiomyolipoma and clear cell tumor of the lung [12]. These tumors are now considered to be part of a family of soft tissue tumors known as PEComas, which have in common the presence of these PECs. The PEComas have been reported in a variety of soft tissue and visceral sites, some with malignant behavior, including locally invasive growth and distant metastases. They are characterized by a female predominance and by immunoreactivity for smooth muscle and melanocytic markers [13]. The histogenesis of this family of lesions remains unclear. Angiomyolipomas composed predominantly of smooth muscle cells are known to pose problems in diagnosis on routine histologic sections [14]. This is especially true for those in extrarenal locations, as in the present case. The differential diagnosis of an anterior mediastinal mass includes lymphoma, thymoma, germ cell tumor, and a lesion of intrathoracic thyroid or parathyroid tissue. Spindle cell thymoma may be arranged in a hemangiopericytic pattern [15,16] and is an important diagnostic consideration in this case because of the location of the lesion and its appearance on routine sections. However, there is no immunohistochemical staining for keratin or epithelial membrane antigen in the lesional cells, as would be expected in a neoplasm of thymic epithelial origin. The pattern of staining for smooth muscle actin and HMB-45 seen in our case is characteristic of angiomyolipoma and has not been reported in thymoma. Recognition of the
295
thick-walled vessels and adipose tissue components of the lesion, along with these immunohistochemical staining properties, reveals the diagnosis of angiomyolipoma. This case demonstrates the value of thorough sampling and appropriate use of immunohistochemical stains in evaluating a spindle cell lesion in the mediastinum.
References [1] Amir AM, Zeebregts CJ, Mulder HJ. Anterior mediastinal presentation of a giant angiomyolipoma. Ann Thorac Surg 2004;78:2161 - 3. [2] Torigian DA, Kaiser LR, Soma LA, et al. Symptomatic dysrhythmia caused by a posterior mediastinal angiomyolipoma. Am J Roentgenol 2002;178:93 - 6. [3] Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006;355:1345 - 56. [4] Henske EP, Neumann HP, Scheithauer BW, et al. Loss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band l6p13 occurs in sporadic as well as TSC-associated renal angiomyolipomas. Genes Chromosomes Cancer 1995;13:295 - 8. [5] Saxena A, Alport EC, Custead S, Skinnider LF. Molecular analysis of clonality of sporadic angiomyolipoma. J Pathol 1999;189:79 - 84. [6] Green AJ, Sepp T, Yates JR. Clonality of tuberous sclerosis hamartomas shown by non-random X-chromosome inactivation. Hum Genet 1996;97:240 - 3. [7] Stone CH, Lee MW, Amin MB, et al. Renal angiomyolipoma: further immunophenotypic characterization of an expanding morphologic spectrum. Arch Pathol Lab Med 2001;125:751 - 8. [8] Makhlouf HR, Ishak KG, Shekar R, et al. Melanoma markers in angiomyolipoma of the liver and kidney: a comparative study. Arch Pathol Lab Med 2002;126:49 - 55. [9] Eble JN, Amin MB, Young RH. Epithelioid angiomyolipoma of the kidney: a report of five cases with a predominant and diagnostically confusing epithelioid smooth muscle component. Am J Surg Pathol 1997;21:1123 - 30. [10] Cibas ES, Goss GA, Kulke MH, et al. Malignant epithelioid angiomyolipoma (dsarcoma ex angiomyolipomaT) of the kidney: a case report and review of the literature. Am J Surg Pathol 2001;25:121 - 6. [11] Bonetti F, Pea M, Martignoni G, Zamboni G. PEC and sugar. Am J Surg Pathol 1992;16:307 - 8. [12] Bonetti F, Pea M, Martignoni G, et al. Clear cell (bsugarQ) tumor of the lung is a lesion strictly related to angiomyolipoma—the concept of a family of lesions characterized by the presence of the perivascular epithelioid cells (PEC). Pathology 1994;26:230 - 6. [13] Hornick JL, Fletcher CD. PEComa: what do we know so far? Histopathology 2006;48:75 - 82. [14] Nonomura A, Minato H, Kurumaya H. Angiomyolipoma predominantly composed of smooth muscle cells: problems in histological diagnosis. Histopathology 1998;33:20 - 7. [15] Rosai J, editor. Rosai and Ackerman’s surgical pathology. 9th ed. St. Louis (Mo)7 Mosby; 2004. p. 2291 - 2. [16] Pan C, Chen WY, Chiang H. Spindle cell and mixed spindle/ lymphocytic thymomas: an integrated clinicopathologic and immunohistochemical study of 81 cases. Am J Surg Pathol 2001;25: 111 - 20.
Annals of Diagnostic Pathology 12 (2008) 293 – 295
Angiomyolipoma of the anterior mediastinum Carrie S. Knight, MDa, Robert J. Cerfolio, MDb, Thomas S. Winokur, MDa,4 a
Department of Pathology, University of Alabama School of Medicine, Birmingham, AL, USA b Department of Surgery, University of Alabama School of Medicine, Birmingham, AL, USA
Abstract
Angiomyolipoma is a benign tumor composed of varying proportions of smooth muscle cells, blood vessels, and adipose tissue that most commonly occurs in the kidney. Sporadic lesions and lesions arising in the setting of the tuberous sclerosis complex have been reported in extrarenal sites. We present the case of an incidentally discovered angiomyolipoma in the anterior mediastinum. Thymoma was suspected clinically, and the lesion was composed mainly of spindled-to-epithelioid cells arranged in a histologic pattern reminiscent of hemangiopericytoma, a pattern that has been described in thymoma. Immunohistochemical stains revealed positivity for smooth muscle actin and HMB-45, revealing the expression of smooth muscle and melanocytic markers characteristic of angiomyolipoma and other lesions in the PEComa family. D 2008 Elsevier Inc. All rights reserved.
Keywords:
Angiomyolipoma; PEComa; Perivascular epithelioid cell; Mediastinum
1. Introduction Angiomyolipoma is a benign tumor that most often occurs in the kidney but has been reported in a variety of extrarenal sites. We report on the case of an angiomyolipoma arising in the anterior mediastinum, representing only the third reported incidence in this location. In the present case, the tumor mimicked a spindle cell thymoma with a hemangiopericytic pattern because of its location and its appearance on routine histologic sections.
levels were within normal limits, and the patient underwent sternotomy for resection of the mass. Intraoperatively, a mass was appreciated within the left side of the thymus, and the entire thymus was removed. Gross examination revealed a firm-to-rubbery, well-circumscribed tan mass measuring 3.0 2.4 1.8 cm (Fig. 1). Frozen section demonstrated a lesion composed mostly of spindled and epithelioid cells with prominent vascular
2. Case report The patient was a 57-year-old woman with a strong family history of breast cancer who underwent bilateral breast magnetic resonance imaging that revealed an anterior mediastinal mass as an incidental finding. On computed tomographic scan of the chest, the mass showed heterogeneous enhancement and was estimated to measure 4.4 2.5 cm. a-Fetoprotein and b-human chorionic gonadotropin
4 Corresponding author. Department of Pathology, NP3541, University of Alabama at Birmingham, Birmingham, AL 35249, USA. Tel.: +1 205 975 8880; fax: +1 205 975 5242. E-mail address: [email protected] (T.S. Winokur). 1092-9134/$ – see front matter D 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2006.12.007
Fig. 1. Gross appearance of the cut surface of the tumor.
294
C.S. Knight et al. / Annals of Diagnostic Pathology 12 (2008) 293 – 295
Fig. 2. Histologic appearance of the lesion on frozen section with spindledto-epithelioid cells arranged in a hemangiopericytoma-like pattern.
Fig. 4. Immunohistochemical staining for HMB-45 showing positivity in PECs.
spaces (Fig. 2), and the diagnosis of a thymic epithelial neoplasm was considered. Permanent hematoxylin-eosin–stained histologic sections confirmed the spindled-to-epithelioid appearance of the tumor cells with prominent vascular spaces suggesting a hemangiopericytoma-like pattern. Mature adipose tissue and thick-walled vessels were also noted within the lesion (Fig. 3). The surrounding thymic tissue was composed of mature fibroadipose tissue with scattered foci of residual atrophic thymic parenchyma with Hassall’s corpuscles. Immunohistochemical staining of the tumor was negative for keratin and epithelial membrane antigen. The immunohistochemical staining pattern also included HMB-45– positive perivascular cells (Fig. 4), smooth muscle actin positivity in the epithelioid-to-spindled cells, and CD34positive endothelial cells lining the vascular spaces. With the identification of vascular, smooth muscle, and adipose
components and the characteristic immunophenotype, the diagnosis of angiomyolipoma in this unusual site was made.
Fig. 3. Low-power view of the permanent section showing scattered areas of adipose tissue and prominent vessels.
3. Discussion To our knowledge, this is only the third reported case of an angiomyolipoma arising in the anterior mediastinum and the eighth reported case in any mediastinal location [1]. Including the present case, reported cases of mediastinal angiomyolipoma have involved 2 men and 6 women (mean age = 46 years). Whereas our patient presented with a small lesion as an incidental finding, others presented with complaints of cough and dyspnea on exertion [1]. One patient developed dysrhythmias and palpitations caused by the mediastinal component of an angiomyolipoma, although the tumor was believed to have risen in the retroperitoneum [2]. Angiomyolipoma is a tumor composed of varying proportions of smooth muscle cells, blood vessels, and adipose tissue that most commonly occurs in the kidney. A wide variety of extrarenal sites have also been described, with the most common being the liver. This tumor is associated with the tuberous sclerosis complex, an autosomal dominant disorder caused by mutations in either TSC1 (tuberous sclerosis complex 1) on chromosome 9q34, which encodes the protein hamartin, or TSC2 (tuberous sclerosis complex 2) on chromosome 16p13, which encodes the protein tuberin [3]. Loss of heterozygosity of chromosome 16p13 has also been demonstrated in sporadic angiomyolipomas [4]. Although angiomyolipoma was originally regarded as a hamartomatous lesion, there is evidence of clonality in sporadic lesions [5] and in lesions associated with tuberous sclerosis [6]. Angiomyolipoma is characteristically immunoreactive for the melanosome-associated protein HMB-45 and smooth muscle–associated antigens [7]. Although other melanocytic
C.S. Knight et al. / Annals of Diagnostic Pathology 12 (2008) 293 – 295
markers may be expressed, HMB-45 appears to be the most sensitive, followed by Melan-A. Microphthalmia transcription factor and tyrosinase are expressed much less consistently in angiomyolipomas [8]. Ultrastructural features of smooth muscle cells and premelanosome-like structures have been reported in the spindled and epithelioid cells of angiomyolipomas [7]. A variant composed predominantly of epithelioid cells has been described and presents difficulties in diagnosis because it may be confused with renal cell carcinoma [9]. Although angiomyolipomas most often have a benign clinical course, rare incidences of malignant behavior have been reported [10]; no long-term follow-up information is available for the rare mediastinal presentation. Bonetti et al [11] first suggested the term perivascular epithelioid cell (PEC) for a cell type seen in angiomyolipoma, clear cell or bsugarQ tumor of the lung, and lymphangiomyomatosis. This cell type has an epithelioid appearance, with clear-to-acidophilic cytoplasm, and a perivascular distribution. The authors suggested HMB-45 as a useful immunohistochemical marker for the PEC [11] and demonstrated the morphological and immunophenotypic similarities between angiomyolipoma and clear cell tumor of the lung [12]. These tumors are now considered to be part of a family of soft tissue tumors known as PEComas, which have in common the presence of these PECs. The PEComas have been reported in a variety of soft tissue and visceral sites, some with malignant behavior, including locally invasive growth and distant metastases. They are characterized by a female predominance and by immunoreactivity for smooth muscle and melanocytic markers [13]. The histogenesis of this family of lesions remains unclear. Angiomyolipomas composed predominantly of smooth muscle cells are known to pose problems in diagnosis on routine histologic sections [14]. This is especially true for those in extrarenal locations, as in the present case. The differential diagnosis of an anterior mediastinal mass includes lymphoma, thymoma, germ cell tumor, and a lesion of intrathoracic thyroid or parathyroid tissue. Spindle cell thymoma may be arranged in a hemangiopericytic pattern [15,16] and is an important diagnostic consideration in this case because of the location of the lesion and its appearance on routine sections. However, there is no immunohistochemical staining for keratin or epithelial membrane antigen in the lesional cells, as would be expected in a neoplasm of thymic epithelial origin. The pattern of staining for smooth muscle actin and HMB-45 seen in our case is characteristic of angiomyolipoma and has not been reported in thymoma. Recognition of the
295
thick-walled vessels and adipose tissue components of the lesion, along with these immunohistochemical staining properties, reveals the diagnosis of angiomyolipoma. This case demonstrates the value of thorough sampling and appropriate use of immunohistochemical stains in evaluating a spindle cell lesion in the mediastinum.
References [1] Amir AM, Zeebregts CJ, Mulder HJ. Anterior mediastinal presentation of a giant angiomyolipoma. Ann Thorac Surg 2004;78:2161 - 3. [2] Torigian DA, Kaiser LR, Soma LA, et al. Symptomatic dysrhythmia caused by a posterior mediastinal angiomyolipoma. Am J Roentgenol 2002;178:93 - 6. [3] Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006;355:1345 - 56. [4] Henske EP, Neumann HP, Scheithauer BW, et al. Loss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band l6p13 occurs in sporadic as well as TSC-associated renal angiomyolipomas. Genes Chromosomes Cancer 1995;13:295 - 8. [5] Saxena A, Alport EC, Custead S, Skinnider LF. Molecular analysis of clonality of sporadic angiomyolipoma. J Pathol 1999;189:79 - 84. [6] Green AJ, Sepp T, Yates JR. Clonality of tuberous sclerosis hamartomas shown by non-random X-chromosome inactivation. Hum Genet 1996;97:240 - 3. [7] Stone CH, Lee MW, Amin MB, et al. Renal angiomyolipoma: further immunophenotypic characterization of an expanding morphologic spectrum. Arch Pathol Lab Med 2001;125:751 - 8. [8] Makhlouf HR, Ishak KG, Shekar R, et al. Melanoma markers in angiomyolipoma of the liver and kidney: a comparative study. Arch Pathol Lab Med 2002;126:49 - 55. [9] Eble JN, Amin MB, Young RH. Epithelioid angiomyolipoma of the kidney: a report of five cases with a predominant and diagnostically confusing epithelioid smooth muscle component. Am J Surg Pathol 1997;21:1123 - 30. [10] Cibas ES, Goss GA, Kulke MH, et al. Malignant epithelioid angiomyolipoma (dsarcoma ex angiomyolipomaT) of the kidney: a case report and review of the literature. Am J Surg Pathol 2001;25:121 - 6. [11] Bonetti F, Pea M, Martignoni G, Zamboni G. PEC and sugar. Am J Surg Pathol 1992;16:307 - 8. [12] Bonetti F, Pea M, Martignoni G, et al. Clear cell (bsugarQ) tumor of the lung is a lesion strictly related to angiomyolipoma—the concept of a family of lesions characterized by the presence of the perivascular epithelioid cells (PEC). Pathology 1994;26:230 - 6. [13] Hornick JL, Fletcher CD. PEComa: what do we know so far? Histopathology 2006;48:75 - 82. [14] Nonomura A, Minato H, Kurumaya H. Angiomyolipoma predominantly composed of smooth muscle cells: problems in histological diagnosis. Histopathology 1998;33:20 - 7. [15] Rosai J, editor. Rosai and Ackerman’s surgical pathology. 9th ed. St. Louis (Mo)7 Mosby; 2004. p. 2291 - 2. [16] Pan C, Chen WY, Chiang H. Spindle cell and mixed spindle/ lymphocytic thymomas: an integrated clinicopathologic and immunohistochemical study of 81 cases. Am J Surg Pathol 2001;25: 111 - 20.