Case 6 -

Angiomyofibroblastoma–like Tumor of Scrotum Hema Samaratunga MD, FRCPA Sullivan Nicolaides Pathology, Brisbane, Queensland, Australia

Clinical History: A 63-year-old male presented with a painless left scrotal mass, which was first noted a few weeks previously. There were no associated symptoms. The mass was found to be external to the testis. A radical orchidectomy was performed in continuity with the mass. Case 6 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathological Findings: An ovoid soft lobulated mass was attached to the surface of the tunica measured 4 cm in maximum dimension. On sectioning, the cut surface was nodular brownish and reddish tan spongy tissue interspersed with yellowish tissue resembling fat. The lesion appeared circumscribed with an apparent capsule. Sections revealed a circumscribed mass surrounded by a pseudocapsule. The lesion was composed of a spindle cell proliferation interspersed with numerous blood vessels within finely collagenous and focally oedematous appearing stroma. Adipose tissue was noted throughout the lesion with adipocytes present singly and in small clusters. The cellularity of the lesion was variable with hypercellular and hypocellular zones. Focally, compact short fascicles were present with nuclear palisading resembling a neurilemmomatous growth pattern. The spindle cells were wavy and had bland ovoid to elongated nuclei and scanty eosinophilic cytoplasm. Nuclei had fine chromatin and nucleoli were inconspicuous. Mitotic figures were not seen. Large numbers of mast cells and lymphocytes were noted throughout the lesion. The vascular component consisted of small to medium-sized rounded thick walled blood vessels, curvilinear thin-walled vessels and collections of capillaries. Blood vessel walls displayed fibrinoid change and focally, fibrinoid necrosis. Perivascular hyaline fibrosis was also noted. Throughout the lesion, the stroma contained thin collagen fibres, which were loosely textured in some areas. Colloidal iron staining revealed moderately strong reactivity confirming presence of stromal acidic mucin. Immunohistochemical staining revealed that the lesional cells were diffusely and strongly positive for CD 34 and moderately strongly positive in most cells for oestrogen receptors. Spindle cells were negative for desmin, smooth muscle actin, S-100 protein, cytokeratin, EMA and progesterone receptors. Muscle specific actin was found in sparse numbers of spindle cells around blood vessels. Diagnosis: Angiomyofibroblastoma-like tumor of scrotum (cellular angiofibroma) Discussion: The term angiomyofibroblastoma (AMF) was first coined in 1992 by Fletcher et al [1]to describe a distinctive benign soft tissue tumour of predominantly the vulva, rarely the scrotum, mimicking and often misdiagnosed as a cellular variant of aggressive angiomyxoma. It was noted that unlike aggressive angiomyxoma, these tumours were well circumscribed and had no recurrence after excision. These lesions were composed of alternating hypercellular and hypocellular oedematous areas composed of bland ovoid to fusiform cells and epithelioid cells that had a tendency to concentrate around blood vessels, sometimes forming solid compact foci. Abundant blood vessels, varying amounts of adipose tissue, background delicate or thick wavy collagen fibrils and an infiltrate of mast cells and lymphocytes were characteristically found in this lesion. Lesional cell were often positive for desmin, but less commonly for muscle specific actin or alpha-smooth muscle actin. [2, 3] The designation AMF was given due to its prominent vascular component with a stromal cell component displaying histological, ultrastructural and immunohistochemical features of myofibroblasts. [1] Since then there have been other reports of a similar tumour occurring in the male genital system with cases reported in the scrotum, spermatic cord and the inguinal region. [4, 5, 6] In the first large series of this entity in the male genital system of 11 cases, Laskin et al [5] noted that while these tumours had features of vulvo-vaginal AMF, these also had similarities to spindle cell lipoma. They also noted that these tumours had several significant differences from the female AMF. The mean and median age at presentation was higher for male patients than for female patients. There were several histological differences with lesional cells primarily spindled rather than epithelioid. Spindle cells were seen haphazardly or in loose fascicles without exhibiting perivascular growth or forming nests or cords, typical of female AMF. More acid mucin was found in male tumours in contrast to the oedematous, loosely textured stroma found in female tumours. Ectatic and hemangiopericytomatous blood vessels were commonly found in males whereas they were only focally found in females. The immunoprofile was also slightly different from that of female AMF with less desmin expression (only 40% in contrast to female cases with> 90%) [1, 5, 7] and more cases reacting with anti-actin (50% compared with 15% with muscle specific or alpha smooth muscle actin) [1, 5, 7]. The mean oestrogen and progesterone receptor staining was also substantially higher in female AMF. [3, 5] For these reasons, the male tumours were labelled AMF-like tumours. Recently it has been noted that AMF-like tumours have morphological features more in common with cellular angiofibroma [8] with component cells displaying more prominent fibroblastic than myofibroblastic differentiation. While it is recognised that AMF does occur in the male genital system, [1, 4] most cases reported in the literature are AMF-like tumours (cellular angiofibroma). [5, 9] In the recent WHO classification of soft tissue tumours, these are labelled cellular angiofibroma, while it is noted that they are related to and share morphological features with AMF. [10]These are benign mesenchymal tumours usually arising in the superficial soft tissues of the vulva [8] and the inguino-scrotal region of males. [5] Extra genital locations of this tumour include the retroperitoneum and chest. [11, 12] These occur most commonly in the fifth through seventh decades of life. Reported cases are rare [5, 8, 13] with < 40 cases reported in the male genital system. [5, 9, 13] These tumours usually present as a painless mass. Rarely, there can be intermittent genital bleeding and pain. [13] There can be an associated hydrocoele or hernia [5]. As seen in our case, these tumours are usually small, although they can be quite large (2.5-25cm) in males, lobulated, well circumscribed nodules. Cut surface is solid with a brownish to pink colour. Occasional cases have had foci of hemorrhage and necrosis and rarely there can be infiltration into surrounding tissues. [13] Most tumours have features similar to that seen in our case with bland, spindle-shaped cells, short bundles of wispy collagen, numerous small- to medium-sized thick-walled vessels and intralesional fat. Tumour cells are haphazardly arrayed or form vague fascicles. Perivascular hyaline fibrosis is seen in most cases. Rarely there can be epithelioid appearing cells present focally, mild cytological atypia or frequent mitoses. [5, 13] Female cases are more likely to have frequent mitoses. [8] Significant nuclear atypia and abnormal mitoses are not found. Myxoid stroma, cystic change, vascular thrombosis and fibrinoid necrosis may be seen. [10] With immunohistochemistry, most cases express CD34. There is variable expression of muscles specific actin, smooth muscle actin and desmin. Some cases are positive for oestrogen receptors and progesterone receptors. These lesions are negative for S-100 protein. [10] Differential diagnostic considerations of AMF-like tumour include aggressive angiomyxoma (AA), superficial angiomyxoma, neural tumours, myxoid smooth muscle tumours, spindle cell lipoma and solitary fibrous tumor. Differentiation from AA can be somewhat problematic in small biopsies. Distinction is crucial as surgical treatment of the two lesions is very different with AMF-like tumour necessitating only local excision, while AA needs wide resection. AA occurs most often in the pelvic soft tissues and perineum in relatively young females, and rarely occurs in males. In contrast to AMF-like tumour, aggressive angiomyxoma is an often poorly demarcated infiltrating poorly cellular tumour with less vascularity, more stromal mucin and red cell extravasation. Foci of increased cellularity have been reported in these cases. Immunohistochemical staining is not useful in the distinction between these tumours as both display myofibroblastic differentiation and myofibroblastic markers. [15] Superficial angiomyxoma is another lesion occurring in this location which may recur. The usually dermal location and absence of thick walled blood vessels are helpful in this distinction. A focal fascicular pattern with wavy spindle cells suggests the possibility of a neural tumour. AMF- like tumour lacks the typical lamellar or whorled pattern of a perineurioma and is EMA negative. Myxoid neurofibroma and neurilemmoma display S-100 protein staining. The prominent vascular component seen in angiomyofibroblastoma is also not seen in neural tumours. Solitary fibrous tumour can be distinguished from AMF- like tumour by its "patternless " architecture, marked variation in cellularity, keloidal hyalinisation and a frequent hemangiopericytomatous vascular pattern. CD 34 is not useful to distinguish between these lesions as solitary fibrous tumour is invariably positive, and most cases of AMF-like tumour are positive. Spindle cell lipoma is another differential diagnostic consideration due to the presence of mature adipocytes and bland spindle cells. Presence of numerous blood vessels with hyalinized walls and wispy delicate collagen are not typical of spindle cell lipoma, which tends to have more eosinophilic ropy refractile collagen bundles. Unlike AMF-like tumour, most spindle cell lipomas occur in the head and neck region. Smooth muscle tumours are rare in genitalia. In contrast to AMF-like tumours, these are composed of intersecting fascicles of cells with abundant eosinophilic cytoplasm and cigar shaped nuclei. Histogenesis of these tumours is uncertain. Lesional cells display fibroblastic and sometimes myofibroblastic differentiation. Given the immunohistochemical expression of oestrogen and progesterone receptors in some cases, hormones may have influence in the pathogenesis of these tumours. AMF- like tumour is a benign neoplasm, with no evidence of metastatic disease and only one case reported to recur [5, 13] A complete local excision with clear margins appears to be adequate treatment of these lesions. References: Fletcher CD et al. Angiomyofibroblastoma of the vulva. A benign neoplasm distinct from aggressive angiomyxoma. Am J Surg Pathol 1992; 16(4):373-82. Nielsen GP et al Angiomyofibroblastoma of the vulva and vagina Mod Pathol 1996; 9(3): 284-291 Laskin WB et al. Angiomyofibroblastoma of the female genital tract Hum Pathol 1997; 28:1046-1055 Ockner DM et al. Genital angiomyofibroblastoma. Comparison with aggressive angiomyxoma and other myxoid neoplasms of skin and soft tissue. Am J Clin Pathol 1997;107(1):36-44. Laskin WB et al. Angiomyofibroblastomalike tumor of the male genital tract: analysis of 11 cases with comparison to female angiomyofibroblastoma and spindle cell lipoma. Am J Surg Pathol 1998; 22(1):6-16. Siddiqui M et al. Angiomyofibroblastoma of the spermatic cord. Br J Urol 1997; 79(3):475-6. Fukunaga M, et al. Vulval angiomyofibroblastoma. Clinicopathologic analysis of six cases. Am J Clin Pathol 1997; 1007:45-51 Nucci M et al. Cellular angiofibroma: a benign neoplasm distinct from angiomyofibroblastoma and spindle cell lipoma.Am J Surg Pathol 1997 ;21(6):636-44. Hara N et al. Angiomyxoid Tumour with an intermediate feature between cellular angiofibroma and angiomyofibroblastoma in the male inguinal region. Int J Urol 2005; 12: 768-772. Laskin WB et al. Cellular angiofibroma. Pathology and genetics of tumours of soft tissue and bone. World Health Organisation Classification of Tumours. IARC press. Ed. Fletcher CDM et al. Lyon 2002. Nucci MR et al. Vuvo- vaginal soft tissue tumours update and review Histopathology 2000; 36:97-108. Garijo MF et al. Extra vulvar subcutaneous cellular angiofibroma.J Cutaneous Pathol 1990; 25:327-332. Iwasa Y, Fletcher CD Cellular angiofibroma: clinicopathologic and immunohistochemical analysis of 51 cases. Am J Surg Pathol 2004 ;28(11):1426-35 Granter SR et al. Aggressive angiomyxoma: reappraisal of its relationship to angiomyofibroblastoma in a series of 16 cases. Histopathol 1997: 30:3-10.