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Pathology International 2014; 64: 289–291
doi:10.1111/pin.12161
Letter to the Editor
Angiofibroma of soft tissue: A recently described entity To the Editor: Angiofibroma of soft tissue was first described by MarinoEnrıquez1 in 2012, as having the characteristics of a well circumscribed fibro-/fibroblastic tumor with unique vascular features. It is clinically and pathologically distinct from cellular angiofibroma and nasopharyngeal angiofibroma. Before this description was made, these entities had been mistaken as a vascular neoplasms, low-grade sarcomas, myxofibrosarcoma, or myxoid liposarcoma, depending on the clinical context.1 We recently experienced a case and reviewed the English literature for this newly described disease. A 51-year-old, previously healthy woman presented with a slow growing, painless mass in her thigh. She didn’t report a history of trauma. Ultrasonography revealed a 2.5 cm lobulated hypervascular mass in the rectus femoris muscle, suggesting a soft tissue tumor with cystic changes or combined with an infection. Magnetic resonance imaging showed a homogenously and strongly enhanced 2.5 cm mass with an infiltrative margin (Fig. 1a), suggesting a malignant soft tissue tumor. A needle biopsy showed a low grade fibrovascular lesion, which could not be subclassified; a complete excision was performed. To date, there has not been any clinical evidence of local recurrence or distant metastasis. Grossly, the tumor was an ovoid, solid mass, measuring 2.2 × 2.0 × 1.3 cm. The cut surface of the tumor was
pinkish gray, smooth, rubbery with focal hemorrhage and an infiltrative margin. Microscopically, the tumor was vaguely lobulated, but uncapsulated, with alteranting myxoid and collagenous areas, and having regional variations in cellularity (Fig. 1b). Variable sized branching blood vessels with notably thick walls, were evenly distributed throughout the lesion (Fig. 1c). Among the capillary network, short spindle cells with a pale cytoplasm were present; they also had short, ovoid or tapering nuclei, with fine chromatin. Mitotic activity was absent. Multinucleated hyperchromatic cells were occasionally scattered throughout both the cellular and myxoid areas and some cells in the myxoid areas looked like pseudolipoblasts (Fig. 1d, inset), similar to those seen in myxoid liposarcoma. Mast cells and small lymphocytes were admixed with the spindle cells. Immunohistochemically, the spindle cells were partly positive for epithelial membrane antigen (EMA,1:100, Dako, Glostrup, Denmark, Figure S1a) and negative for smooth muscle actin (SMA, 1:50, Santa Cruz Biotechnology, Santa Cruz, CA, USA), desmin (1:25, DAKO), S-100 protein (1:500, ZYMED, San Francisco, CA, USA), CD34(1:500, Immunotech, Marseille, France), MDM2 (1:100, ZETA corporation, Arcadia, CA, USA), MUC-4 (1:100, Invitrogen, Carlsbad, CA, USA, Figure S1b) and CDK4 (1:50, INVITROGEN). The vascular pattern was highlighted by CD 34 staining of the endothelial cells and SMA. The Ki-67 (1:200, ZYMED) labeling index was less than 1%.
Figure 1 (a) A well-defined, lobulated mass present in the distal portion of the right vastus lateralis muscle, showing strong enhancement by T1 weighted magnetic resonance imaging. (b) Alternating myxoid and collagenous areas with gradual transitions are characteristic. The myxoid area is relatively hypocellular, but the collagenous stroma is more cellular. (c) The tumor cells are haphazardly arranged with very prominent branching blood vessels. Mast cells and small lymphocytes are present in the collagenous area. The nucleus of the spindle cells are ovoid or tapering with inconspicuous cytoplasm. Occasionally, hyperchromatic multinucleated cells are identified (inset). (d) A Myxoid hypocellular area shows fibrillary stroma with multinucleated cells mimicking pseudolipoblasts (inset). © 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
290
Table 1
Letter to the Editor
Review of reported cases of angiofibroma of soft tissue (cases from 3 previous publications and the current case)
Study
Sex
Age (years)
Size (cm)
Location
Treatment
Outcome
Marino-Enriquez et al.1
F(x25) and M(x12)
6–86 (median 47)
1.2–7.2 (mean 4.3)
Arbajian et al.8 Edgar et al.2
F F(x1) and M(x1) F
41 62 and 68
NA 7 and NA
Lower extremity† (x23) Upper extremity‡ (x5) Back (x3) Others§ (x6) Thigh Iliac crest and chest wall
51
2.2
Thigh (R)
SE (x29) WE(x6) Amputation (x1) NA NA Radical excision and NA SE
NED (x23,6–122 m) Recurrence (x4, 9, 12, 36 and 120 m) NA(x9) NA NED(x1, 9mon) and NA (x1) NED
Song et al. (current case)
†Lower extremity includes foot, ankle, popliteal fossa, knee, thigh, lower leg. ‡Upper extremity includes the wrist, arm and forearm. §Others includes the shoulder, pelvic cavity, breast, inguinal area, pectoralis muscle and abdominal wall. F, female; m, months; M, male; NA, not available; NED, no evidence of disease; SE, simple excision; WE, wide excision.
Angiofibroma of soft tissue is a rare and recently described tumor with only 40 cases, from three publications reported in the English literature (Table 1). In brief, this tumor is more common in females (male to female ration of 1:2.1), and has been diagnosed in individuals over a wide range of ages (6–86, median 47 years). The mass is located in the soft tissue of the lower extremity, often adjacent to a joint, but unusual anatomic locations have been reported, including the back, abdominal wall, pelvic cavity, and breast. Four patients developed local recurrence at 9, 13, 36 and 120 months after the primary tumor diagnosis, but none developed metastasis. Mario-Enriquez et al.1 described immunohistochemical features of soft tissue angiofibroma in their study, and they showed that about half of the cases (44%) were positive for EMA. Our case also showed partial immunopositivity for EMA consistent with their results (Figure S1a). The differential diagnosis includes a wide range of benign and low-grade malignant soft tissue tumors. The hypervascularity, with bland stromal spindle cells, cellular angiofibroma, and solitary fibrous tumor (SFT) should be differentiating. Angiofibroma of soft tissue mainly occurs in the upper and lower extremities and typically display branching blood vessels, whereas cellular angiofibroma occurs nearly exclusively in the pelvic and perineal regions and contains more round blood vessels, rather than branching ones. Moreover, the spindle cells of cellular angiofibroma are more uniformly cellular compared with those of angiofibroma of soft tissue. Although some cases of angiofibroma of soft tissue present with stag horn vascular features,1,2 SFT are not accompanied by the abundant smaller capillary vessels typical of angiofibroma of soft tissue.3 Low-grade myxoid tumors, with hypervascularity, should also be differentiated including low-grade fibromyxoid sarcoma (LGFMS), low-grade myxofibrosarcoma, and myxoid liposarcoma. LGFMS shows alternating collagenous and myxoid areas, usually a whorled growth pattern. They
also have arcades of thin-walled vessels, but vascularity is not prominent,4 compared with angiofibroma of soft tissue. MUC4 immunopositivity is helpful for confirming a LGFMS diagnosis.5 We performed immunohistochemistry for MUC-4 to exclude LGFMS and the result was negative, while the positive control tissue diagnosed as low grade fibromyxoid sarcoma was positive for MUC-4 (Fig. S1b). Myxofibrosarcoma6 shows obvious cytologic features of malignancy, including hyperchromatic, atypical or pleomorphic nuclei with numerous mitotic activities and no resemblance to the abundant vascular network of angiofibroma of soft tissue except the myxoid stroma. Myxoid liposarcoma contains prominent plexiform, arborizing networks of thin walled capillaries with univacuolated or mutivacuolated lipoblasts. Although our case showed multinucleated pseudolipoblasts in the myxoid area, less abundant myxoid stroma and thicker vessel walls of even the smallest vessels, compared with the vessels of myxoid liposarcoma, allowed the angiofibroma of soft tissue to be distinguished from myxoid liposarcoma. Recently, Jin et al.7 reported t(5;8)(p15;q12), resulting in an AHRR-NCOA2 fusion gene in 7 of 14 angiofibromas of soft tissue. Arbajian et al.,8 also demonstrated a GTF2I-NCOA2 fusion in a soft tissue angiofibroma, emphasizing the role of NCOA2. With the limited data available, to date, NCOA2 rearrangement may be helpful for diagnosis. In conclusion, we reported a case of angiofibroma of soft tissue and provided brief review of literature with an emphasis on the recognition of this disease entity to avoid a malignancy diagnosis that may result in overtreatment. Joon Seon Song,1 Soonchan Park,2 Jong-Seok Lee, Gyungyup Gong1 and Kyung-Ja Cho1 3
Departments of 1Pathology and 3Orthopedic Surgery, University of Ulsan College of Medicine, Asan Medical Center and 2Department of Radiology, Kyung Hee University Hospital at Gang-dong, Seoul, Republic of Korea
© 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Letter to the Editor
REFERENCES 1 Marino-Enriquez A, Fletcher CD. Angiofibroma of soft tissue: Clinicopathologic characterization of a distinctive benign fibrovascular neoplasm in a series of 37 cases. Am J Surg Pathol 2012; 36: 500–8. 2 Edgar MA, Lauer SR, Bridge JA, Rizzo M. Soft tissue angiofibroma: Report of 2 cases of a recently described tumor. Hum Pathol 2013; 44: 438–41. 3 Hasegawa T, Hirose T, Seki K, Yang P, Sano T. Solitary fibrous tumor of the soft tissue. An immunohistochemical and ultrastructural study. Am J Clin Pathol 1996; 106: 325–31. 4 Evans HL. Low-grade fibromyxoid sarcoma. A report of two metastasizing neoplasms having a deceptively benign appearance. Am J Clin Pathol 1987; 88: 615–19. 5 Doyle LA, Moller E, Dal Cin P, Fletcher CD, Mertens F, Hornick JL. MUC4 is a highly sensitive and specific marker for lowgrade fibromyxoid sarcoma. Am J Surg Pathol 2011; 35: 733– 41. 6 Mentzel T, Calonje E, Wadden C et al. Myxofibrosarcoma. Clinicopathologic analysis of 75 cases with emphasis on the low-grade variant. Am J Surg Pathol 1996; 20: 391–405.
291
7 Jin Y, Moller E, Nord KH et al. Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes. Genes Chromosomes Cancer 2012; 51: 510–20. 8 Arbajian E, Magnusson L, Mertens F, Domanski HA, Vult von Steyern F, Nord KH. A novel GTF2I/NCOA2 fusion gene emphasizes the role of NCOA2 in soft tissue angiofibroma development. Genes Chromosomes Cancer 2013; 52: 330–1.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Figure S1 a. The tumor cells are partly positive for EMA by immunohistochemistry (×400). b. The tumor cells are negative for MUC-4 (×400), while the positive control tissue diagnosed as low grade fibromyxoid sarcoma is positive for MUC-4 (×400, inset) by immunohistochemistry.
© 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Pathology International 2014; 64: 289–291
doi:10.1111/pin.12161
Letter to the Editor
Angiofibroma of soft tissue: A recently described entity To the Editor: Angiofibroma of soft tissue was first described by MarinoEnrıquez1 in 2012, as having the characteristics of a well circumscribed fibro-/fibroblastic tumor with unique vascular features. It is clinically and pathologically distinct from cellular angiofibroma and nasopharyngeal angiofibroma. Before this description was made, these entities had been mistaken as a vascular neoplasms, low-grade sarcomas, myxofibrosarcoma, or myxoid liposarcoma, depending on the clinical context.1 We recently experienced a case and reviewed the English literature for this newly described disease. A 51-year-old, previously healthy woman presented with a slow growing, painless mass in her thigh. She didn’t report a history of trauma. Ultrasonography revealed a 2.5 cm lobulated hypervascular mass in the rectus femoris muscle, suggesting a soft tissue tumor with cystic changes or combined with an infection. Magnetic resonance imaging showed a homogenously and strongly enhanced 2.5 cm mass with an infiltrative margin (Fig. 1a), suggesting a malignant soft tissue tumor. A needle biopsy showed a low grade fibrovascular lesion, which could not be subclassified; a complete excision was performed. To date, there has not been any clinical evidence of local recurrence or distant metastasis. Grossly, the tumor was an ovoid, solid mass, measuring 2.2 × 2.0 × 1.3 cm. The cut surface of the tumor was
pinkish gray, smooth, rubbery with focal hemorrhage and an infiltrative margin. Microscopically, the tumor was vaguely lobulated, but uncapsulated, with alteranting myxoid and collagenous areas, and having regional variations in cellularity (Fig. 1b). Variable sized branching blood vessels with notably thick walls, were evenly distributed throughout the lesion (Fig. 1c). Among the capillary network, short spindle cells with a pale cytoplasm were present; they also had short, ovoid or tapering nuclei, with fine chromatin. Mitotic activity was absent. Multinucleated hyperchromatic cells were occasionally scattered throughout both the cellular and myxoid areas and some cells in the myxoid areas looked like pseudolipoblasts (Fig. 1d, inset), similar to those seen in myxoid liposarcoma. Mast cells and small lymphocytes were admixed with the spindle cells. Immunohistochemically, the spindle cells were partly positive for epithelial membrane antigen (EMA,1:100, Dako, Glostrup, Denmark, Figure S1a) and negative for smooth muscle actin (SMA, 1:50, Santa Cruz Biotechnology, Santa Cruz, CA, USA), desmin (1:25, DAKO), S-100 protein (1:500, ZYMED, San Francisco, CA, USA), CD34(1:500, Immunotech, Marseille, France), MDM2 (1:100, ZETA corporation, Arcadia, CA, USA), MUC-4 (1:100, Invitrogen, Carlsbad, CA, USA, Figure S1b) and CDK4 (1:50, INVITROGEN). The vascular pattern was highlighted by CD 34 staining of the endothelial cells and SMA. The Ki-67 (1:200, ZYMED) labeling index was less than 1%.
Figure 1 (a) A well-defined, lobulated mass present in the distal portion of the right vastus lateralis muscle, showing strong enhancement by T1 weighted magnetic resonance imaging. (b) Alternating myxoid and collagenous areas with gradual transitions are characteristic. The myxoid area is relatively hypocellular, but the collagenous stroma is more cellular. (c) The tumor cells are haphazardly arranged with very prominent branching blood vessels. Mast cells and small lymphocytes are present in the collagenous area. The nucleus of the spindle cells are ovoid or tapering with inconspicuous cytoplasm. Occasionally, hyperchromatic multinucleated cells are identified (inset). (d) A Myxoid hypocellular area shows fibrillary stroma with multinucleated cells mimicking pseudolipoblasts (inset). © 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
290
Table 1
Letter to the Editor
Review of reported cases of angiofibroma of soft tissue (cases from 3 previous publications and the current case)
Study
Sex
Age (years)
Size (cm)
Location
Treatment
Outcome
Marino-Enriquez et al.1
F(x25) and M(x12)
6–86 (median 47)
1.2–7.2 (mean 4.3)
Arbajian et al.8 Edgar et al.2
F F(x1) and M(x1) F
41 62 and 68
NA 7 and NA
Lower extremity† (x23) Upper extremity‡ (x5) Back (x3) Others§ (x6) Thigh Iliac crest and chest wall
51
2.2
Thigh (R)
SE (x29) WE(x6) Amputation (x1) NA NA Radical excision and NA SE
NED (x23,6–122 m) Recurrence (x4, 9, 12, 36 and 120 m) NA(x9) NA NED(x1, 9mon) and NA (x1) NED
Song et al. (current case)
†Lower extremity includes foot, ankle, popliteal fossa, knee, thigh, lower leg. ‡Upper extremity includes the wrist, arm and forearm. §Others includes the shoulder, pelvic cavity, breast, inguinal area, pectoralis muscle and abdominal wall. F, female; m, months; M, male; NA, not available; NED, no evidence of disease; SE, simple excision; WE, wide excision.
Angiofibroma of soft tissue is a rare and recently described tumor with only 40 cases, from three publications reported in the English literature (Table 1). In brief, this tumor is more common in females (male to female ration of 1:2.1), and has been diagnosed in individuals over a wide range of ages (6–86, median 47 years). The mass is located in the soft tissue of the lower extremity, often adjacent to a joint, but unusual anatomic locations have been reported, including the back, abdominal wall, pelvic cavity, and breast. Four patients developed local recurrence at 9, 13, 36 and 120 months after the primary tumor diagnosis, but none developed metastasis. Mario-Enriquez et al.1 described immunohistochemical features of soft tissue angiofibroma in their study, and they showed that about half of the cases (44%) were positive for EMA. Our case also showed partial immunopositivity for EMA consistent with their results (Figure S1a). The differential diagnosis includes a wide range of benign and low-grade malignant soft tissue tumors. The hypervascularity, with bland stromal spindle cells, cellular angiofibroma, and solitary fibrous tumor (SFT) should be differentiating. Angiofibroma of soft tissue mainly occurs in the upper and lower extremities and typically display branching blood vessels, whereas cellular angiofibroma occurs nearly exclusively in the pelvic and perineal regions and contains more round blood vessels, rather than branching ones. Moreover, the spindle cells of cellular angiofibroma are more uniformly cellular compared with those of angiofibroma of soft tissue. Although some cases of angiofibroma of soft tissue present with stag horn vascular features,1,2 SFT are not accompanied by the abundant smaller capillary vessels typical of angiofibroma of soft tissue.3 Low-grade myxoid tumors, with hypervascularity, should also be differentiated including low-grade fibromyxoid sarcoma (LGFMS), low-grade myxofibrosarcoma, and myxoid liposarcoma. LGFMS shows alternating collagenous and myxoid areas, usually a whorled growth pattern. They
also have arcades of thin-walled vessels, but vascularity is not prominent,4 compared with angiofibroma of soft tissue. MUC4 immunopositivity is helpful for confirming a LGFMS diagnosis.5 We performed immunohistochemistry for MUC-4 to exclude LGFMS and the result was negative, while the positive control tissue diagnosed as low grade fibromyxoid sarcoma was positive for MUC-4 (Fig. S1b). Myxofibrosarcoma6 shows obvious cytologic features of malignancy, including hyperchromatic, atypical or pleomorphic nuclei with numerous mitotic activities and no resemblance to the abundant vascular network of angiofibroma of soft tissue except the myxoid stroma. Myxoid liposarcoma contains prominent plexiform, arborizing networks of thin walled capillaries with univacuolated or mutivacuolated lipoblasts. Although our case showed multinucleated pseudolipoblasts in the myxoid area, less abundant myxoid stroma and thicker vessel walls of even the smallest vessels, compared with the vessels of myxoid liposarcoma, allowed the angiofibroma of soft tissue to be distinguished from myxoid liposarcoma. Recently, Jin et al.7 reported t(5;8)(p15;q12), resulting in an AHRR-NCOA2 fusion gene in 7 of 14 angiofibromas of soft tissue. Arbajian et al.,8 also demonstrated a GTF2I-NCOA2 fusion in a soft tissue angiofibroma, emphasizing the role of NCOA2. With the limited data available, to date, NCOA2 rearrangement may be helpful for diagnosis. In conclusion, we reported a case of angiofibroma of soft tissue and provided brief review of literature with an emphasis on the recognition of this disease entity to avoid a malignancy diagnosis that may result in overtreatment. Joon Seon Song,1 Soonchan Park,2 Jong-Seok Lee, Gyungyup Gong1 and Kyung-Ja Cho1 3
Departments of 1Pathology and 3Orthopedic Surgery, University of Ulsan College of Medicine, Asan Medical Center and 2Department of Radiology, Kyung Hee University Hospital at Gang-dong, Seoul, Republic of Korea
© 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Letter to the Editor
REFERENCES 1 Marino-Enriquez A, Fletcher CD. Angiofibroma of soft tissue: Clinicopathologic characterization of a distinctive benign fibrovascular neoplasm in a series of 37 cases. Am J Surg Pathol 2012; 36: 500–8. 2 Edgar MA, Lauer SR, Bridge JA, Rizzo M. Soft tissue angiofibroma: Report of 2 cases of a recently described tumor. Hum Pathol 2013; 44: 438–41. 3 Hasegawa T, Hirose T, Seki K, Yang P, Sano T. Solitary fibrous tumor of the soft tissue. An immunohistochemical and ultrastructural study. Am J Clin Pathol 1996; 106: 325–31. 4 Evans HL. Low-grade fibromyxoid sarcoma. A report of two metastasizing neoplasms having a deceptively benign appearance. Am J Clin Pathol 1987; 88: 615–19. 5 Doyle LA, Moller E, Dal Cin P, Fletcher CD, Mertens F, Hornick JL. MUC4 is a highly sensitive and specific marker for lowgrade fibromyxoid sarcoma. Am J Surg Pathol 2011; 35: 733– 41. 6 Mentzel T, Calonje E, Wadden C et al. Myxofibrosarcoma. Clinicopathologic analysis of 75 cases with emphasis on the low-grade variant. Am J Surg Pathol 1996; 20: 391–405.
291
7 Jin Y, Moller E, Nord KH et al. Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes. Genes Chromosomes Cancer 2012; 51: 510–20. 8 Arbajian E, Magnusson L, Mertens F, Domanski HA, Vult von Steyern F, Nord KH. A novel GTF2I/NCOA2 fusion gene emphasizes the role of NCOA2 in soft tissue angiofibroma development. Genes Chromosomes Cancer 2013; 52: 330–1.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Figure S1 a. The tumor cells are partly positive for EMA by immunohistochemistry (×400). b. The tumor cells are negative for MUC-4 (×400), while the positive control tissue diagnosed as low grade fibromyxoid sarcoma is positive for MUC-4 (×400, inset) by immunohistochemistry.
© 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
