J Cutan Pathol 2015: 42: 441–451 doi: 10.1111/cup.12507 John Wiley & Sons. Printed in Singapore
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Review
Genital soft tissue tumors Mesenchymal neoplasms of the vulvovaginal and inguinoscrotal regions are among the most diagnostically challenging specimens in the pathology laboratory owing largely to their unique intersection between general soft tissue tumors and relatively genital-specific mesenchymal tumors. Genital stromal tumors are a unique subset of soft tissue tumors encountered at this location, and this group includes fibroepithelial stromal polyp, superficial (cervicovaginal) myofibroblastoma, cellular angiofibroma, mammary-type myofibroblastoma, angiomyofibroblastoma and aggressive angiomyxoma. Aside from the striking morphologic and immunophenotypic similarity that is seen with these entities, there is evidence that a subset of genital stromal tumors may be linked genetically. This review will focus on simplifying this group of tumors and provide the pathologist or dermatopathologist with practical management information. Smooth muscle tumors of the external genitalia will also be discussed. Keywords: angiomyofibroblastoma, angiomyxoma, cellular angiofibroma, genital stromal tumors, smooth muscle tumors Schoolmeester JK, Fritchie KJ. Genital soft tissue tumors. J Cutan Pathol 2015; 42: 441–451. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
While a broad variety of soft tissue tumors may occur at vulvovaginal and inguinoscrotal sites, the genital stromal tumors are a rare and unique subset of neoplasms that are virtually exclusive to this region. This group includes fibroepithelial stromal polyp, superficial (cervicovaginal) myofibroblastoma, cellular angiofibroma, mammary-type myofibroblastoma, angiomyofibroblastoma and aggressive angiomyxoma (Table 1). Many of these entities probably originate from a distinct zone of subepithelial stromal cells or subepithelial mesenchyme extending from the endocervix to the vulva resulting in striking morphologic, immunophenotypic and genetic overlap. Consequently, definitive diagnosis is often challenging, even for soft tissue and gynecologic pathologists who see these specimens with some frequency. Work-up can be further complicated by either
John K. Schoolmeester1,2 and Karen J. Fritchie1 1
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA and 2 Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
Karen J. Fritchie, Mayo Clinic, Department of Anatomic Pathology, Hilton 11, 200 First Street, SW, Rochester, MN 55905, USA Tel: +507 284 3768 Fax: +507 284 1599 e-mail: [email protected] Accepted for publication April 4, 2015
limited tissue for evaluation or unknown information about the patient’s clinical presentation. The main focus of this review is to highlight the characteristic clinicopathologic features of the genital stromal tumors while providing practical information for the general surgical pathologist as to how to handle these tumors. Smooth muscle tumors of the male and female external genitalia will also be discussed. Genital stromal tumors Fibroepithelial stromal polyp Fibroepithelial stromal polyp, otherwise known as cellular pseudosarcomatous fibroepithelial stromal polyp,1 pseudosarcoma botryoides2 or mesodermal stromal polyp,3 is a benign polypoid growth (Fig. 1A) of the vagina (most common), vulva or cervix that is strongly tied to hormonal
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Review Table 1. Genital stromal tumors (synonyms listed in bullets) Fibroepithelial stromal polyp • Mesodermal stromal polyp • Cellular pseudosarcomatous fibroepithelial stromal polyp • Pseudosarcoma botryoides Superficial myofibroblastoma • Superficial cervicovaginal myofibroblastoma • Vulvovaginal myofibroblastoma Cellular angiofibroma • Angiomyofibroblastoma-like tumor of the male genital tract Angiomyofibroblastoma Mammary-type myofibroblastoma Aggressive angiomyxoma
stimulation. It occurs most often during pregnancy but may also be found in reproductive age women or postmenopausal women undergoing hormone replacement therapy, and regression in the postpartum period is typical.1 Rare cases have also been reported in infants.4,5 The typical clinical presentation of this entity is the finding of one or more polyps that may be symptomatic by causing bleeding, discharge or discomfort depending on the size of the lesion (usually 1–5 cm but may be as large as 18.5 cm).6 Fibroepithelial stromal polyp is microscopically composed of three components: central fibrovascular core, pedunculated or polypoid proliferation of stroma and overlying squamous epithelium. The stromal cells range from spindle to stellate with some multinucleated forms (Fig. 1B), but overall their nuclear features are bland. The distribution of cells is variable, but characteristic: the stellate and multinucleate forms tend to aggregate along the stromal–epithelial junction as well as around the blood vessels of the central fibrovascular core. The squamous epithelium lying atop the stromal proliferation is normal to hyperplastic. The stromal cells of fibroepithelial stromal polyp are consistently reactive to desmin, estrogen receptor (ER), progesterone receptor (PR) and sometimes smooth muscle actin.7 Pseudosarcomatous change of stromal cells is a known phenomenon in fibroepithelial stromal polyp and may manifest as marked hypercellularity (Fig. 1C), marked nuclear pleomorphism, increased mitotic rate (more than 10 mitotic figures per 10 high power fields) or atypical mitoses.1 Even lesions with three or
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more of these features behave in a benign fashion with low rates of nondestructive recurrence and no evidence of metastasis. It is important, however, to distinguish fibroepithelial stromal polyp from the botryoid variant of embryonal rhabdomyosarcoma. Morphologic review of embryonal rhabdomyosarcoma will show rhabdomyoblasts and a dense layer of tumor cells at the epithelial–stromal interface (cambium layer) (Fig. 1D). While rare cases of myogenin positivity in fibroepithelial stromal polyps have been reported,8 the presence of myogenin and myoD1 staining, especially in a pediatric patient, should raise concern for embryonal rhabdomyosarcoma. Superficial (cervicovaginal) myofibroblastoma Superficial myofibroblastoma, synonymous with superficial cervicovaginal myofibroblastoma,9 is a benign tumor that may arise in the vulva, vagina or cervix. It presents as a nodular or polypoid painless mass in adults most commonly in their 50s, but cases have been reported in patients from 23 to 80 years.9 Gross examination yields a well circumscribed, firm and dense mass from 1 to 6.5 cm in size.3,10 Superficial myofibroblastoma is characterized histopathologically by a moderately cellular, uniform proliferation of bland-appearing spindle or stellate shaped cells growing in a mostly sieve-like pattern just below the epithelium. There is a consistent Grenz zone or uninvolved band-like segment of lamina propria between the overlying squamous epithelium and the lesion (Fig. 2A). The tumor cells have scant wispy cytoplasm, ovoid or wavy nuclei and are deposited in a finely collagenous and myxoid background (Fig. 2B,C). Mitotic activity may be present but is minimal. The vasculature tends to be centralized in the tumor, thin walled and dilated. Desmin is positive in 75–100% of cases, ER and PR are positive in 80–100%, CD34 is positive in 50–85% and smooth muscle actin is positive in 0–45%.3,9,10 Cellular angiofibroma Cellular angiofibroma, also known as angiomyofibroblastoma-like tumor of the male genital tract, is a benign neoplasm found in the vulvovaginal and inguinoscrotal areas of middle-aged patients with a female predominance.11,12 The classic presentation is usually a subcutaneous painless nodule usually not exceeding 7 cm.13 Its gross appearance shows a well circumscribed, solid fibrous mass.
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Fig. 1. A–D) Fibroepithelial stromal polyp forms a polypoid or pedunculated lesion composed of fibrous stroma, a fibrovascular core and overlying hyperplasia squamous epithelium (A, ×20). Characteristic stellate and multinucleate cells are located just underneath the epithelial–stromal junction (B, ×200). Pseudosarcomatous change in a fibroepithelial stromal polyp manifesting as hypercellularity with stromal cells organized in interlacing fascicles (C, ×100). An example of the botryoid variant of rhabdomyosarcoma with cambium layer (D, ×200).
The typical morphology of cellular angiofibroma includes a moderately cellular, monotonous spindle cell neoplasm growing in short, interweaving fascicles with numerous prominent medium-sized vessels that often have hyalinized walls (Fig. 3). The stroma contains wispy collagen. Mast cells and mitotic activity are variably seen. The spindled cells have pale eosinophilic cytoplasm, small round to ovoid nuclei and indistinct cell borders that create a streaming look to the fascicles. These same spindled cells may occasionally show cytologic atypia such as nuclear enlargement, multinucleation or hyperchromasia as scattered cells or rarely clusters.14 Some tumors contain a component of mature adipose tissue.13 The immunoprofile of cellular angiofibroma is inconsistent with variable expression of CD34, desmin, smooth muscle actin, ER and PR.11,13 Angiomyofibroblastoma Angiomyofibroblastoma is a benign mesenchymal neoplasm of the vulva and vagina.15 The expected presentation is an adult woman with a
painless mass which may be interpreted clinically as a Bartholin’s gland cyst.16 Angiomyofibroblastoma may also uncommonly present as a pedunculated lesion. Most angiomyofibroblastomas are a grossly well circumscribed, firm to rubbery and smaller than 5 cm.17,18 The typical morphology of angiomyofibroblastoma is a richly vascularized neoplasm with alternating zones of hyper- and hypocellularity. The stromal cells are small with a distinct plasmacytoid appearance and characteristically cluster around the tumor’s numerous thin-walled small and medium-sized blood vessels (Fig. 4A). The matrix is extensively edematous and often contains mast cells. Varying quantities of mature adipose tissue can be found in some angiomyofibroblastomas and, if a major constituent of the tumor, it is dubbed the lipomatous variant (Fig. 4B).19 Immunohistochemically, this entity usually expresses desmin, ER and PR and less commonly CD34 and smooth muscle actin.19
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Fig. 2. A,B) Superficial myofibroblastoma is so superficially located that it creates a Grenz zone or thin intervening band of uninvolved/nonneoplastic stroma between the tumor and the overlying epithelium (A, ×40). The lesional cells tend to form a sieve-like growth pattern. The vessels range from thin-walled and small to large and tend to be positioned toward the center of the tumor (B, ×100). High power view shows slender uniform spindle cells with no cytologic atypia (C, ×200).
and pelvic regions.20,21 Most cases occur in men. Gross examination reveals a circumscribed but unencapsulated mass, and extra-mammary cases have a median size of 6 cm.20 Microscopic evaluation reveals short fascicles of uniform spindle cells admixed with thick collagen bundles (Fig. 5). Many lesions contain areas of mature adipose tissue. Scattered blood vessels may be seen but they are typically not prominent. The spindle cell population usually shows reactivity for CD34 and desmin with variable positivity for smooth muscle actin.20 Fig. 3. Cellular angiofibroma shows uniform spindle cells surrounding medium-sized blood vessels with hyalinized walls (A, ×100).
Mammary-type myofibroblastoma Although the entity known as myofibroblastoma was initially described in the breast, a subsequent review described several cases in the inguinal
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Aggressive angiomyxoma Aggressive angiomyxoma, or deep angiomyxoma, was first described as a low grade myxomatous neoplasm specific to the deep vulvovaginal, perineal and pelvic tissues of women.22 While there is a strong female predisposition, several dozen cases have been subsequently reported in men, most of which arise in the analogous inguinoscrotal and
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Fig. 4. A,B) Angiomyofibroblastoma is a richly vascularized tumor characterized by plasmacytoid-shaped cells clustered around small blood vessels (A, ×400). Occasionally, this tumor shows a prominent adipocytic component (B, ×40).
Fig. 5. Mammary-type myofibroblastoma is composed of uniform plump spindle cells in short fascicles intermixed with thick bundles of eosinophilic collagen (×100).
perineal regions.23,24 In both men and women, the usual presentation is a patient in the fourth decade of life (but has been recorded in childhood and the elderly) with a painless cystic mass often exceeding 10 cm.25,26 Macroscopically, aggressive angiomyxoma exhibits a gelatinous to fibrogelatinous cut surface that is poorly circumscribed and shows tendril-like extension into surrounding tissues. The microscopic picture of aggressive angiomyxoma is that of a uniformly paucicellular tumor composed large pools or sheets of myxomatous stroma with thin spindle cells without cytologic atypia (Fig. 6A). There is virtually no mitotic activity. The stroma often contains small to medium-sized blood vessels, some of which have thick, muscular walls or are hyalinized. The periphery of the tumor shows an irregular, invasive interface with surrounding nonneoplastic tissue. Aggressive angiomyxoma
is typically positivity for desmin, SMA, ER and PR, including tumors arising in men,23,26 with variable CD34 reactivity.26 It is important to recognize that aggressive angiomyxoma is one of the rarest and perhaps most overdiagnosed entities within the group of genital stromal tumors. Virtually all other genital stromal tumors and even non-neoplastic genital tissue can harbor myxoid foci (Fig. 7A). Smooth muscle tumors in this region also are prone to myxoid change (Fig. 7B). Fortunately, there are generally areas within a smooth muscle tumor that show the expected architecture and cytology of a smooth muscle neoplasm: intersecting fascicles of spindled cells with eosinophilic cytoplasm and elongated or blunt-ended nuclei. Even in their most myxoid form, smooth muscle tumors are more cellular than aggressive angiomyxoma. Again, for accurate diagnosis of aggressive angiomyxoma the lesion must be thoroughly sampled, homogeneously hypocellular and without significant atypia. Caution should be exercised on small biopsy specimens. Other potential mimics of aggressive angiomyxoma include: well differentiated liposarcoma, superficial angiomyxoma and myxoid liposarcoma. Well differentiated liposarcoma is characterized by atypical hyperchromatic stromal cells (Fig. 7C), and the presence of cytologic atypia would exclude the diagnosis of aggressive angiomyxoma. As these diagnostic cells may be focal, ancillary testing for MDM2 amplification by fluorescence in situ hybridization can be helpful, and if positive, would support the diagnosis of well differentiated liposarcoma. Superficial angiomyxoma, as its name implies, presents as a mass in the dermis or subcutis (Fig. 7D). Additionally, superficial
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Fig. 6. A,B) Aggressive angiomyxoma is an paucicellular neoplasm with no overt architecture other than sheets of mucin containing bland stromal cells and vessels, often with hyalinized walls (A, ×100). Aggressive angiomyxoma typically shows infiltration into surrounding soft tissues (B, ×40).
Fig. 7. A–D) Examples of vulvar tissue with reactive changes (A, ×40), smooth muscle tumor with marked myxoid change (B, ×100), well differentiated liposarcoma with atypical hyperchromatic stromal cells (C, ×100) and superficial angiomyxoma (D, ×100) are all potential mimics of aggressive angiomyxoma.
angiomyxoma tends to be small (less than 5 cm) and lobulated, whereas aggressive angiomyxomas are usually larger (exceeding 10 cm) and deep-seated with an infiltrative growth pattern. Myxoid liposarcoma is a malignant adipocytic
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tumor characterized by a distinct and prominent plexiform capillary network. Furthermore, the cells of myxoid liposarcoma are ovoid to round rather than spindled, and this tumor bears a unique t(12;16)(q13;p11) or FUS-DDIT3 fusion
Review Table 2. Clinicopathologic features of genital stromal tumors Key microscopic features Fibroepithelial stromal polyp Superficial myofibroblastoma Cellular angiofibroma
Polypoid growth with stellate stromal cells Superficial location; sieve-like pattern of spindle cells Spindle cells, wispy collagen and prominent medium-sized blood vessels Angiomyofibroblastoma Plasmacytoid cells that are clustered around small to medium-sized blood vessels Mammary-type myofibroblastoma Spindle cells in short fascicles with thick collagen bundles Aggressive angiomyxoma Uniformly paucicellular proliferation of bland spindle cells in myxomatous stroma
in the majority of cases with a minority harboring rearrangement of EWSR1. Genetic findings in genital stromal tumors Given the morphologic and immunophenotypic overlap among genital stromal tumors it is not surprising that a subset of these tumors seem to be linked genetically. Studies have shown that superficial myofibroblastoma, cellular angiofibroma and mammary-type myofibroblastoma share monoallelic loss of RB1/13q1427 – 32 Accordingly, RB1 immunoexpression is also lost in these tumors.33 Interestingly, studies to date have not shown similar findings in aggressive angiomyxoma, angiomyofibroblastoma or fibroepithelial stromal polyp.33,34 A practical approach to differentiating genital stromal tumors Genital stromal tumors are often diagnostically challenging specimens given their significant clinicopathologic overlap (Table 2). From a management prospective, aggressive angiomyxoma is the only genital stromal tumor which exhibits a significant risk for local recurrence. The extent of local infiltration in cases of aggressive angiomyxoma is not always clinically or surgically appreciable resulting in incomplete resection and traditional recurrence rates of 30–40% (Fig. 6B).26,35 Recent studies have shown that the recurrence rate can be reduced to less than 10% with aggressive surgical procedures.36,37 Complete local excision is the treatment of choice in addition to long term follow-up since recurrence may be as late as 7 years following resection.22,24,26 The remaining genital stromal tumors (fibroepithelial stromal polyp, superficial myofibroblastoma, cellular angiofibroma, mammary-type myofibroblastoma and angiomyofibroblastoma) generally do not recur unless incompletely excised, and simple excision is
Loss of RB1/13q14
Behavior
No Yes Yes
Minimal risk of recurrence Minimal risk of recurrence Minimal risk of recurrence
No
Minimal risk of recurrence
Yes No
Minimal risk of recurrence 30–40% recurrence rate
typically curative. Therefore, correct identification of aggressive angiomyxoma is critical. However, once aggressive angiomyxoma has been excluded, the label ‘benign genital stromal tumor’ is appropriate when definitive classification is not possible due to hybrid or indistinct features. While this approach is not always satisfying to the pathologist, it provides clinicians with information on how to treat and manage the patient. Of note, rare examples of sarcomatous transformation of cellular angiofibroma and angiomyofibroblastoma have been reported.14,38 Criteria for malignancy have not been established for genital stromal tumors, but malignant transformation usually manifests as an abrupt transition to a high grade or pleomorphic sarcoma. Therefore, thorough pathologic examination should be performed on all genital stromal tumors to exclude malignancy. Smooth muscle tumors of the external genitalia Smooth muscle tumors of the female (vulva, vagina) and male (scrotum) external genitalia have similar gross and pathologic features to their peripheral soft tissue and uterine counterparts, but criteria for malignancy vary depending on the specific site. General features of smooth muscle tumors of the external genitalia Gross features of smooth muscle tumors of the external genitalia are similar to those arising in the uterus and soft tissue. Leiomyomas of the vulva usually present as well circumscribed, whorled, dense masses whereas leiomyosarcomas may be well circumscribed or infiltrative and have a variegated cut surface with variable hemorrhage and necrosis.39 Grossly, scrotal smooth muscle tumors are typically ill-defined or infiltrative, and many have prominent lymphoid
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Fig. 8. A–D) Leiomyomas are composed of uniform spindle cells with blunt-ended nuclei and brightly eosinophilic cytoplasm (A, ×100). Occasionally, leiomyomas may exhibit an epithelioid morphology (B, ×100) or abundant myxoid change (C, ×100). An example of leiomyosarcoma with marked cytologic atypia and a brisk mitotic rate (D, ×100).
aggregates at the periphery.40 Upon histopathologic examination, leiomyomas are composed of spindled cells with cigar-shaped nuclei and brightly eosinophilic cytoplasm (Fig. 8A). Thick walled blood vessels are present throughout, and some cases may have hyaline plaques of varying thickness. Degenerative changes such as edema, dystrophic calcification or ischemic-type necrosis are sometimes seen.16 Variants include those tumors with predominantly epithelioid morphology (Fig. 8B) or significant myxoid change (Fig. 8C). Leiomyosarcomas show some combination of cytologic atypia, increased mitotic activity, increased size or infiltrative growth (Fig. 8D). Smooth muscle tumors show expression of desmin, smooth muscle actin and h-caldesmon. Smooth muscle tumors of the vulva Leiomyomas are one of the more common vulvar mesenchymal tumors, and generally present in the fourth or fifth decade as a small (less than 3 cm) mass. Patients who present with multiple
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leiomyomas of the vulva may be manifesting one of the signs of Alport syndrome, a hereditary disorder characterized chiefly by glomerulonephritis, ocular abnormalities and hearing loss that is caused by mutations in COL4A3, COL4A4 or COL4A5, genes responsible for collagen synthesis.41 In 1979, Tavassoli and Norris examined a series of vulvar smooth muscle tumors and found that lesions greater than 5 cm with infiltrative margins and five or more mitoses per 10 high power fields should be labeled as leiomyosarcomas.42 Nielsen et al. subsequently expanded these criteria to include moderate to marked cytologic atypia and proposed a risk stratification scheme based on these variables (Table 3).39 In this setting, the sole presence of cytologic atypia has no prognostic significance and should not be misinterpreted as leiomyosarcoma. Smooth muscle tumors of the vagina Although data for evaluation of vaginal smooth muscle tumors is limited, a study by Tavassoli and Norris suggest that tumors with significant
Review Table 3. Criteria to classify smooth muscle tumors of the vulva Features
Proposed classification
Gross size ≥ 5 cm Infiltrative margins Moderate-marked cytologic atypia Mitotic index ≥ 5 per 10 high power field
0 or 1 feature = leiomyoma 2 features = atypical leiomyoma 3 or 4 features = leiomyosarcoma
cytologic atypia and five or more mitotic figures per 10 high power should be considered leiomyosarcomas.43 Smooth muscle tumors of the scrotum Smooth muscle tumors of the scrotum are uncommon, and most are leiomyosarcomas exhibiting overt cytologic atypia, mitotic activity and necrosis. Smooth muscle tumors in this region without atypia or mitotic activity are rare, and only those lesions that have been extensively sampled may be cautiously labeled as leiomyoma with a recommendation of long-term clinical follow-up.44 Any mitotic activity in a scrotal smooth muscle tumor warrants classification as malignant.40 Although there is some limited evidence to suggest that scrotal smooth muscle tumors with only cytologic atypia (so-called symplastic leiomyomas) exist, long-term follow-up is lacking and most would advocate labeling these lesions as ‘atypical’ or ‘of uncertain biologic potential’.44 – 46 Differential diagnosis of smooth muscle tumors of the external genitalia The differential diagnosis of benign and malignant smooth muscle tumors at these sites includes entities such as neurofibroma, solitary fibrous tumor, inflammatory myofibroblastic tumor and sarcomatoid carcinoma. While careful morphologic examination is usually sufficient for distinguishing these entities, immunohistochemical stains may be helpful on biopsy specimens. The lesional cells of neurofibroma are classically S100 protein-positive
‘comma-shaped’ and embedded within a myxoid stroma with thin strands of collagen. Solitary fibrous tumor is a CD34-positive neoplasm composed of ovoid to spindle shaped cells surrounding prominent hemangiopericytic vessels admixed with keloid-type collagen. Recent work has found STAT6 to be a sensitive and specific marker for solitary fibrous tumor.47,48 Inflammatory myofibroblastic tumor is composed of fascicles of myofibroblasts and fibroblasts accompanied by a mixed population of inflammatory cells including plasma cells, lymphocytes and eosinophils. ALK immunohistochemistry is positive in 50–60% of cases and generally correlates with rearrangement of ALK .49 Finally, the differential diagnosis of leiomyosarcoma at these locations should include sarcomatoid carcinoma. Examination of the overlying epithelium for high grade squamous intraepithelial lesion and differentiated-type vulvar intraepithelial neoplasia (dVIN) is critical and would support the diagnosis of sarcomatoid carcinoma. While diffuse cytokeratin expression would favor sarcomatoid carcinoma, caution should be exercised because leiomyosarcomas may also aberrantly express this immunostain.50 Conclusion Genital soft tissue tumors are a rare group of mesenchymal entities, and both genital stromal tumors and smooth muscle tumors of the external genitalia present their own diagnostic challenges. Aggressive angiomyxoma is the only genital stromal tumor with significant risk of local recurrence necessitating accurate diagnosis. Fortunately, it is also one of the most microscopically distinctive tumors in this group. Fibroepithelial stromal polyp, cellular angiofibroma, mammary-type myofibroblastoma, superficial myofibroblastoma and angiomyofibroblastoma typically do not recur following complete excision and may be labeled ‘benign genital stromal tumor’ if definitive classification is not possible. Finally, pathologists should remember to use site-specific criteria for malignancy when evaluating smooth muscle tumors of the external genitalia.
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19. Laskin WB, Fetsch JF, Tavassoli FA. Angiomyofibroblastoma of the female genital tract: analysis of 17 cases including a lipomatous variant. Hum Pathol 1997; 28: 1046. 20. McMenamin ME, Fletcher CD. Mammarytype myofibroblastoma of soft tissue: a tumor closely related to spindle cell lipoma. Am J Surg Pathol 2001; 25: 1022. 21. Wargotz ES, Weiss SW, Norris HJ. Myofibroblastoma of the breast. Sixteen cases of a distinctive benign mesenchymal tumor. Am J Surg Pathol 1987; 11: 493. 22. Steeper TA, Rosai J. Aggressive angiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm. Am J Surg Pathol 1983; 7: 463. 23. Idrees MT, Hoch BL, Wang BY, Unger PD. Aggressive angiomyxoma of male genital region. Report of 4 cases with immunohistochemical evaluation including hormone receptor status. Ann Diagn Pathol 2006; 10: 197. 24. Iezzoni JC, Fechner RE, Wong LS, Rosai J. Aggressive angiomyxoma in males. A report of four cases. Am J Clin Pathol 1995; 104: 391. 25. Kim HS, Park SH, Chi JG. Aggressive angiomyxoma of childhood: two unusual cases developed in the scrotum. Pediatr Dev Pathol 2003; 6: 187. 26. Fetsch JF, Laskin WB, Lefkowitz M, Kindblom LG, Meis-Kindblom JM. Aggressive angiomyxoma: a clinicopathologic study of 29 female patients. Cancer 1996; 78: 79. 27. Flucke U, van Krieken JH, Mentzel T. Cellular angiofibroma: analysis of 25 cases emphasizing its relationship to spindle cell lipoma and mammary-type myofibroblastoma. Mod Pathol 2011; 24: 82. 28. Hameed M, Clarke K, Amer HZ, Mahmet K, Aisner S. Cellular angiofibroma is genetically similar to spindle cell lipoma: a case report. Cancer Genet Cytogenet 2007; 177: 131. 29. Maggiani F, Debiec-Rychter M, Vanbockrijck M, Sciot R. Cellular angiofibroma: another mesenchymal tumour with 13q14 involvement, suggesting a link with spindle cell lipoma and (extra)-mammary myofibroblastoma. Histopathology 2007; 51: 410. 30. Maggiani F, Debiec-Rychter M, Verbeeck G, Sciot R. Extramammary myofibroblastoma is genetically related to spindle cell lipoma. Virchows Arch 2006; 449: 244. 31. Magro G, Righi A, Casorzo L, et al. Mammary and vaginal myofibroblastomas are genetically related lesions: fluorescence in situ hybridization analysis shows deletion of 13q14 region. Hum Pathol 2012; 43: 1887. 32. Pauwels P, Sciot R, Croiset F, Rutten H, Van den Berghe H, Dal Cin P. Myofibroblastoma of the breast: genetic link with spindle cell lipoma. J Pathol 2000; 191: 282.
33. Chen BJ, Marino-Enriquez A, Fletcher CD, Hornick JL. Loss of retinoblastoma protein expression in spindle cell/pleomorphic lipomas and cytogenetically related tumors: an immunohistochemical study with diagnostic implications. Am J Surg Pathol 2012; 36: 1119. 34. Magro G, Righi A, Caltabiano R, Casorzo L, Michal M. Vulvovaginal angiomyofibroblastomas: morphologic, immunohistochemical, and fluorescence in situ hybridization analysis for deletion of 13q14 region. Hum Pathol 2014; 45: 1647. 35. Granter SR, Nucci MR, Fletcher CD. Aggressive angiomyxoma: reappraisal of its relationship to angiomyofibroblastoma in a series of 16 cases. Histopathology 1997; 30: 3. 36. Amezcua CA, Begley SJ, Mata N, Felix JC, Ballard CA. Aggressive angiomyxoma of the female genital tract: a clinicopathologic and immunohistochemical study of 12 cases. Int J Gynecol Cancer 2005; 15: 140. 37. van Roggen JF, van Unnik JA, Briaire-de Bruijn IH, Hogendoorn PC. Aggressive angiomyxoma: a clinicopathological and immunohistochemical study of 11 cases with long-term follow-up. Virchows Arch 2005; 446: 157. 38. Nielsen GP, Young RH, Dickersin GR, Rosenberg AE. Angiomyofibroblastoma of the vulva with sarcomatous transformation ("angiomyofibrosarcoma"). Am J Surg Pathol 1997; 21: 1104. 39. Nielsen GP, Rosenberg AE, Koerner FC, Young RH, Scully RE. Smooth-muscle tumors of the vulva. A clinicopathological study of 25 cases and review of the literature. Am J Surg Pathol 1996; 20: 779. 40. Newman PL, Fletcher CD. Smooth muscle tumours of the external genitalia: clinicopathological analysis of a series. Histopathology 1991; 18: 523. 41. Garcia-Torres R, Cruz D, Orozco L, Heidet L, Gubler MC. Alport syndrome and diffuse leiomyomatosis. Clinical aspects, pathology, molecular biology and extracellular matrix studies. A synthesis. Nephrologie 2000; 21: 9. 42. Tavassoli FA, Norris HJ. Smooth muscle tumors of the vulva. Obstet Gynecol 1979; 53: 213. 43. Tavassoli FA, Norris HJ. Smooth muscle tumors of the vagina. Obstet Gynecol 1979; 53: 689. 44. Miettinen M, Fetsch JF. Evaluation of biological potential of smooth muscle tumours. Histopathology 2006; 48: 97. 45. Matoso A, Chen S, Plaza JA, Osunkoya AO, Epstein JI. Symplastic leiomyomas of the scrotum: a comparative study to usual leiomyomas and leiomyosarcomas. Am J Surg Pathol 2014; 38: 1410. 46. Slone S, O’Connor D. Scrotal leiomyomas with bizarre nuclei: a report of three cases. Mod Pathol 1998; 11: 282.
Review 47. Doyle LA, Vivero M, Fletcher CD, Mertens F, Hornick JL. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol 2014; 27: 390. 48. Mohajeri A, Tayebwa J, Collin A, et al. Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion
gene, nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor. Genes Chromosomes Cancer 2013; 52: 873. 49. Coffin CM, Patel A, Perkins S, Elenitoba-Johnson KS, Perlman E, Griffin CA. ALK1 and p80 expression and
chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol 2001; 14: 569. 50. Iwata J, Fletcher CD. Immunohistochemical detection of cytokeratin and epithelial membrane antigen in leiomyosarcoma: a systematic study of 100 cases. Pathol Int 2000; 50: 7.
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© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Review
Genital soft tissue tumors Mesenchymal neoplasms of the vulvovaginal and inguinoscrotal regions are among the most diagnostically challenging specimens in the pathology laboratory owing largely to their unique intersection between general soft tissue tumors and relatively genital-specific mesenchymal tumors. Genital stromal tumors are a unique subset of soft tissue tumors encountered at this location, and this group includes fibroepithelial stromal polyp, superficial (cervicovaginal) myofibroblastoma, cellular angiofibroma, mammary-type myofibroblastoma, angiomyofibroblastoma and aggressive angiomyxoma. Aside from the striking morphologic and immunophenotypic similarity that is seen with these entities, there is evidence that a subset of genital stromal tumors may be linked genetically. This review will focus on simplifying this group of tumors and provide the pathologist or dermatopathologist with practical management information. Smooth muscle tumors of the external genitalia will also be discussed. Keywords: angiomyofibroblastoma, angiomyxoma, cellular angiofibroma, genital stromal tumors, smooth muscle tumors Schoolmeester JK, Fritchie KJ. Genital soft tissue tumors. J Cutan Pathol 2015; 42: 441–451. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
While a broad variety of soft tissue tumors may occur at vulvovaginal and inguinoscrotal sites, the genital stromal tumors are a rare and unique subset of neoplasms that are virtually exclusive to this region. This group includes fibroepithelial stromal polyp, superficial (cervicovaginal) myofibroblastoma, cellular angiofibroma, mammary-type myofibroblastoma, angiomyofibroblastoma and aggressive angiomyxoma (Table 1). Many of these entities probably originate from a distinct zone of subepithelial stromal cells or subepithelial mesenchyme extending from the endocervix to the vulva resulting in striking morphologic, immunophenotypic and genetic overlap. Consequently, definitive diagnosis is often challenging, even for soft tissue and gynecologic pathologists who see these specimens with some frequency. Work-up can be further complicated by either
John K. Schoolmeester1,2 and Karen J. Fritchie1 1
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA and 2 Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
Karen J. Fritchie, Mayo Clinic, Department of Anatomic Pathology, Hilton 11, 200 First Street, SW, Rochester, MN 55905, USA Tel: +507 284 3768 Fax: +507 284 1599 e-mail: [email protected] Accepted for publication April 4, 2015
limited tissue for evaluation or unknown information about the patient’s clinical presentation. The main focus of this review is to highlight the characteristic clinicopathologic features of the genital stromal tumors while providing practical information for the general surgical pathologist as to how to handle these tumors. Smooth muscle tumors of the male and female external genitalia will also be discussed. Genital stromal tumors Fibroepithelial stromal polyp Fibroepithelial stromal polyp, otherwise known as cellular pseudosarcomatous fibroepithelial stromal polyp,1 pseudosarcoma botryoides2 or mesodermal stromal polyp,3 is a benign polypoid growth (Fig. 1A) of the vagina (most common), vulva or cervix that is strongly tied to hormonal
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Review Table 1. Genital stromal tumors (synonyms listed in bullets) Fibroepithelial stromal polyp • Mesodermal stromal polyp • Cellular pseudosarcomatous fibroepithelial stromal polyp • Pseudosarcoma botryoides Superficial myofibroblastoma • Superficial cervicovaginal myofibroblastoma • Vulvovaginal myofibroblastoma Cellular angiofibroma • Angiomyofibroblastoma-like tumor of the male genital tract Angiomyofibroblastoma Mammary-type myofibroblastoma Aggressive angiomyxoma
stimulation. It occurs most often during pregnancy but may also be found in reproductive age women or postmenopausal women undergoing hormone replacement therapy, and regression in the postpartum period is typical.1 Rare cases have also been reported in infants.4,5 The typical clinical presentation of this entity is the finding of one or more polyps that may be symptomatic by causing bleeding, discharge or discomfort depending on the size of the lesion (usually 1–5 cm but may be as large as 18.5 cm).6 Fibroepithelial stromal polyp is microscopically composed of three components: central fibrovascular core, pedunculated or polypoid proliferation of stroma and overlying squamous epithelium. The stromal cells range from spindle to stellate with some multinucleated forms (Fig. 1B), but overall their nuclear features are bland. The distribution of cells is variable, but characteristic: the stellate and multinucleate forms tend to aggregate along the stromal–epithelial junction as well as around the blood vessels of the central fibrovascular core. The squamous epithelium lying atop the stromal proliferation is normal to hyperplastic. The stromal cells of fibroepithelial stromal polyp are consistently reactive to desmin, estrogen receptor (ER), progesterone receptor (PR) and sometimes smooth muscle actin.7 Pseudosarcomatous change of stromal cells is a known phenomenon in fibroepithelial stromal polyp and may manifest as marked hypercellularity (Fig. 1C), marked nuclear pleomorphism, increased mitotic rate (more than 10 mitotic figures per 10 high power fields) or atypical mitoses.1 Even lesions with three or
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more of these features behave in a benign fashion with low rates of nondestructive recurrence and no evidence of metastasis. It is important, however, to distinguish fibroepithelial stromal polyp from the botryoid variant of embryonal rhabdomyosarcoma. Morphologic review of embryonal rhabdomyosarcoma will show rhabdomyoblasts and a dense layer of tumor cells at the epithelial–stromal interface (cambium layer) (Fig. 1D). While rare cases of myogenin positivity in fibroepithelial stromal polyps have been reported,8 the presence of myogenin and myoD1 staining, especially in a pediatric patient, should raise concern for embryonal rhabdomyosarcoma. Superficial (cervicovaginal) myofibroblastoma Superficial myofibroblastoma, synonymous with superficial cervicovaginal myofibroblastoma,9 is a benign tumor that may arise in the vulva, vagina or cervix. It presents as a nodular or polypoid painless mass in adults most commonly in their 50s, but cases have been reported in patients from 23 to 80 years.9 Gross examination yields a well circumscribed, firm and dense mass from 1 to 6.5 cm in size.3,10 Superficial myofibroblastoma is characterized histopathologically by a moderately cellular, uniform proliferation of bland-appearing spindle or stellate shaped cells growing in a mostly sieve-like pattern just below the epithelium. There is a consistent Grenz zone or uninvolved band-like segment of lamina propria between the overlying squamous epithelium and the lesion (Fig. 2A). The tumor cells have scant wispy cytoplasm, ovoid or wavy nuclei and are deposited in a finely collagenous and myxoid background (Fig. 2B,C). Mitotic activity may be present but is minimal. The vasculature tends to be centralized in the tumor, thin walled and dilated. Desmin is positive in 75–100% of cases, ER and PR are positive in 80–100%, CD34 is positive in 50–85% and smooth muscle actin is positive in 0–45%.3,9,10 Cellular angiofibroma Cellular angiofibroma, also known as angiomyofibroblastoma-like tumor of the male genital tract, is a benign neoplasm found in the vulvovaginal and inguinoscrotal areas of middle-aged patients with a female predominance.11,12 The classic presentation is usually a subcutaneous painless nodule usually not exceeding 7 cm.13 Its gross appearance shows a well circumscribed, solid fibrous mass.
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Fig. 1. A–D) Fibroepithelial stromal polyp forms a polypoid or pedunculated lesion composed of fibrous stroma, a fibrovascular core and overlying hyperplasia squamous epithelium (A, ×20). Characteristic stellate and multinucleate cells are located just underneath the epithelial–stromal junction (B, ×200). Pseudosarcomatous change in a fibroepithelial stromal polyp manifesting as hypercellularity with stromal cells organized in interlacing fascicles (C, ×100). An example of the botryoid variant of rhabdomyosarcoma with cambium layer (D, ×200).
The typical morphology of cellular angiofibroma includes a moderately cellular, monotonous spindle cell neoplasm growing in short, interweaving fascicles with numerous prominent medium-sized vessels that often have hyalinized walls (Fig. 3). The stroma contains wispy collagen. Mast cells and mitotic activity are variably seen. The spindled cells have pale eosinophilic cytoplasm, small round to ovoid nuclei and indistinct cell borders that create a streaming look to the fascicles. These same spindled cells may occasionally show cytologic atypia such as nuclear enlargement, multinucleation or hyperchromasia as scattered cells or rarely clusters.14 Some tumors contain a component of mature adipose tissue.13 The immunoprofile of cellular angiofibroma is inconsistent with variable expression of CD34, desmin, smooth muscle actin, ER and PR.11,13 Angiomyofibroblastoma Angiomyofibroblastoma is a benign mesenchymal neoplasm of the vulva and vagina.15 The expected presentation is an adult woman with a
painless mass which may be interpreted clinically as a Bartholin’s gland cyst.16 Angiomyofibroblastoma may also uncommonly present as a pedunculated lesion. Most angiomyofibroblastomas are a grossly well circumscribed, firm to rubbery and smaller than 5 cm.17,18 The typical morphology of angiomyofibroblastoma is a richly vascularized neoplasm with alternating zones of hyper- and hypocellularity. The stromal cells are small with a distinct plasmacytoid appearance and characteristically cluster around the tumor’s numerous thin-walled small and medium-sized blood vessels (Fig. 4A). The matrix is extensively edematous and often contains mast cells. Varying quantities of mature adipose tissue can be found in some angiomyofibroblastomas and, if a major constituent of the tumor, it is dubbed the lipomatous variant (Fig. 4B).19 Immunohistochemically, this entity usually expresses desmin, ER and PR and less commonly CD34 and smooth muscle actin.19
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Fig. 2. A,B) Superficial myofibroblastoma is so superficially located that it creates a Grenz zone or thin intervening band of uninvolved/nonneoplastic stroma between the tumor and the overlying epithelium (A, ×40). The lesional cells tend to form a sieve-like growth pattern. The vessels range from thin-walled and small to large and tend to be positioned toward the center of the tumor (B, ×100). High power view shows slender uniform spindle cells with no cytologic atypia (C, ×200).
and pelvic regions.20,21 Most cases occur in men. Gross examination reveals a circumscribed but unencapsulated mass, and extra-mammary cases have a median size of 6 cm.20 Microscopic evaluation reveals short fascicles of uniform spindle cells admixed with thick collagen bundles (Fig. 5). Many lesions contain areas of mature adipose tissue. Scattered blood vessels may be seen but they are typically not prominent. The spindle cell population usually shows reactivity for CD34 and desmin with variable positivity for smooth muscle actin.20 Fig. 3. Cellular angiofibroma shows uniform spindle cells surrounding medium-sized blood vessels with hyalinized walls (A, ×100).
Mammary-type myofibroblastoma Although the entity known as myofibroblastoma was initially described in the breast, a subsequent review described several cases in the inguinal
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Aggressive angiomyxoma Aggressive angiomyxoma, or deep angiomyxoma, was first described as a low grade myxomatous neoplasm specific to the deep vulvovaginal, perineal and pelvic tissues of women.22 While there is a strong female predisposition, several dozen cases have been subsequently reported in men, most of which arise in the analogous inguinoscrotal and
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Fig. 4. A,B) Angiomyofibroblastoma is a richly vascularized tumor characterized by plasmacytoid-shaped cells clustered around small blood vessels (A, ×400). Occasionally, this tumor shows a prominent adipocytic component (B, ×40).
Fig. 5. Mammary-type myofibroblastoma is composed of uniform plump spindle cells in short fascicles intermixed with thick bundles of eosinophilic collagen (×100).
perineal regions.23,24 In both men and women, the usual presentation is a patient in the fourth decade of life (but has been recorded in childhood and the elderly) with a painless cystic mass often exceeding 10 cm.25,26 Macroscopically, aggressive angiomyxoma exhibits a gelatinous to fibrogelatinous cut surface that is poorly circumscribed and shows tendril-like extension into surrounding tissues. The microscopic picture of aggressive angiomyxoma is that of a uniformly paucicellular tumor composed large pools or sheets of myxomatous stroma with thin spindle cells without cytologic atypia (Fig. 6A). There is virtually no mitotic activity. The stroma often contains small to medium-sized blood vessels, some of which have thick, muscular walls or are hyalinized. The periphery of the tumor shows an irregular, invasive interface with surrounding nonneoplastic tissue. Aggressive angiomyxoma
is typically positivity for desmin, SMA, ER and PR, including tumors arising in men,23,26 with variable CD34 reactivity.26 It is important to recognize that aggressive angiomyxoma is one of the rarest and perhaps most overdiagnosed entities within the group of genital stromal tumors. Virtually all other genital stromal tumors and even non-neoplastic genital tissue can harbor myxoid foci (Fig. 7A). Smooth muscle tumors in this region also are prone to myxoid change (Fig. 7B). Fortunately, there are generally areas within a smooth muscle tumor that show the expected architecture and cytology of a smooth muscle neoplasm: intersecting fascicles of spindled cells with eosinophilic cytoplasm and elongated or blunt-ended nuclei. Even in their most myxoid form, smooth muscle tumors are more cellular than aggressive angiomyxoma. Again, for accurate diagnosis of aggressive angiomyxoma the lesion must be thoroughly sampled, homogeneously hypocellular and without significant atypia. Caution should be exercised on small biopsy specimens. Other potential mimics of aggressive angiomyxoma include: well differentiated liposarcoma, superficial angiomyxoma and myxoid liposarcoma. Well differentiated liposarcoma is characterized by atypical hyperchromatic stromal cells (Fig. 7C), and the presence of cytologic atypia would exclude the diagnosis of aggressive angiomyxoma. As these diagnostic cells may be focal, ancillary testing for MDM2 amplification by fluorescence in situ hybridization can be helpful, and if positive, would support the diagnosis of well differentiated liposarcoma. Superficial angiomyxoma, as its name implies, presents as a mass in the dermis or subcutis (Fig. 7D). Additionally, superficial
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Fig. 6. A,B) Aggressive angiomyxoma is an paucicellular neoplasm with no overt architecture other than sheets of mucin containing bland stromal cells and vessels, often with hyalinized walls (A, ×100). Aggressive angiomyxoma typically shows infiltration into surrounding soft tissues (B, ×40).
Fig. 7. A–D) Examples of vulvar tissue with reactive changes (A, ×40), smooth muscle tumor with marked myxoid change (B, ×100), well differentiated liposarcoma with atypical hyperchromatic stromal cells (C, ×100) and superficial angiomyxoma (D, ×100) are all potential mimics of aggressive angiomyxoma.
angiomyxoma tends to be small (less than 5 cm) and lobulated, whereas aggressive angiomyxomas are usually larger (exceeding 10 cm) and deep-seated with an infiltrative growth pattern. Myxoid liposarcoma is a malignant adipocytic
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tumor characterized by a distinct and prominent plexiform capillary network. Furthermore, the cells of myxoid liposarcoma are ovoid to round rather than spindled, and this tumor bears a unique t(12;16)(q13;p11) or FUS-DDIT3 fusion
Review Table 2. Clinicopathologic features of genital stromal tumors Key microscopic features Fibroepithelial stromal polyp Superficial myofibroblastoma Cellular angiofibroma
Polypoid growth with stellate stromal cells Superficial location; sieve-like pattern of spindle cells Spindle cells, wispy collagen and prominent medium-sized blood vessels Angiomyofibroblastoma Plasmacytoid cells that are clustered around small to medium-sized blood vessels Mammary-type myofibroblastoma Spindle cells in short fascicles with thick collagen bundles Aggressive angiomyxoma Uniformly paucicellular proliferation of bland spindle cells in myxomatous stroma
in the majority of cases with a minority harboring rearrangement of EWSR1. Genetic findings in genital stromal tumors Given the morphologic and immunophenotypic overlap among genital stromal tumors it is not surprising that a subset of these tumors seem to be linked genetically. Studies have shown that superficial myofibroblastoma, cellular angiofibroma and mammary-type myofibroblastoma share monoallelic loss of RB1/13q1427 – 32 Accordingly, RB1 immunoexpression is also lost in these tumors.33 Interestingly, studies to date have not shown similar findings in aggressive angiomyxoma, angiomyofibroblastoma or fibroepithelial stromal polyp.33,34 A practical approach to differentiating genital stromal tumors Genital stromal tumors are often diagnostically challenging specimens given their significant clinicopathologic overlap (Table 2). From a management prospective, aggressive angiomyxoma is the only genital stromal tumor which exhibits a significant risk for local recurrence. The extent of local infiltration in cases of aggressive angiomyxoma is not always clinically or surgically appreciable resulting in incomplete resection and traditional recurrence rates of 30–40% (Fig. 6B).26,35 Recent studies have shown that the recurrence rate can be reduced to less than 10% with aggressive surgical procedures.36,37 Complete local excision is the treatment of choice in addition to long term follow-up since recurrence may be as late as 7 years following resection.22,24,26 The remaining genital stromal tumors (fibroepithelial stromal polyp, superficial myofibroblastoma, cellular angiofibroma, mammary-type myofibroblastoma and angiomyofibroblastoma) generally do not recur unless incompletely excised, and simple excision is
Loss of RB1/13q14
Behavior
No Yes Yes
Minimal risk of recurrence Minimal risk of recurrence Minimal risk of recurrence
No
Minimal risk of recurrence
Yes No
Minimal risk of recurrence 30–40% recurrence rate
typically curative. Therefore, correct identification of aggressive angiomyxoma is critical. However, once aggressive angiomyxoma has been excluded, the label ‘benign genital stromal tumor’ is appropriate when definitive classification is not possible due to hybrid or indistinct features. While this approach is not always satisfying to the pathologist, it provides clinicians with information on how to treat and manage the patient. Of note, rare examples of sarcomatous transformation of cellular angiofibroma and angiomyofibroblastoma have been reported.14,38 Criteria for malignancy have not been established for genital stromal tumors, but malignant transformation usually manifests as an abrupt transition to a high grade or pleomorphic sarcoma. Therefore, thorough pathologic examination should be performed on all genital stromal tumors to exclude malignancy. Smooth muscle tumors of the external genitalia Smooth muscle tumors of the female (vulva, vagina) and male (scrotum) external genitalia have similar gross and pathologic features to their peripheral soft tissue and uterine counterparts, but criteria for malignancy vary depending on the specific site. General features of smooth muscle tumors of the external genitalia Gross features of smooth muscle tumors of the external genitalia are similar to those arising in the uterus and soft tissue. Leiomyomas of the vulva usually present as well circumscribed, whorled, dense masses whereas leiomyosarcomas may be well circumscribed or infiltrative and have a variegated cut surface with variable hemorrhage and necrosis.39 Grossly, scrotal smooth muscle tumors are typically ill-defined or infiltrative, and many have prominent lymphoid
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Fig. 8. A–D) Leiomyomas are composed of uniform spindle cells with blunt-ended nuclei and brightly eosinophilic cytoplasm (A, ×100). Occasionally, leiomyomas may exhibit an epithelioid morphology (B, ×100) or abundant myxoid change (C, ×100). An example of leiomyosarcoma with marked cytologic atypia and a brisk mitotic rate (D, ×100).
aggregates at the periphery.40 Upon histopathologic examination, leiomyomas are composed of spindled cells with cigar-shaped nuclei and brightly eosinophilic cytoplasm (Fig. 8A). Thick walled blood vessels are present throughout, and some cases may have hyaline plaques of varying thickness. Degenerative changes such as edema, dystrophic calcification or ischemic-type necrosis are sometimes seen.16 Variants include those tumors with predominantly epithelioid morphology (Fig. 8B) or significant myxoid change (Fig. 8C). Leiomyosarcomas show some combination of cytologic atypia, increased mitotic activity, increased size or infiltrative growth (Fig. 8D). Smooth muscle tumors show expression of desmin, smooth muscle actin and h-caldesmon. Smooth muscle tumors of the vulva Leiomyomas are one of the more common vulvar mesenchymal tumors, and generally present in the fourth or fifth decade as a small (less than 3 cm) mass. Patients who present with multiple
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leiomyomas of the vulva may be manifesting one of the signs of Alport syndrome, a hereditary disorder characterized chiefly by glomerulonephritis, ocular abnormalities and hearing loss that is caused by mutations in COL4A3, COL4A4 or COL4A5, genes responsible for collagen synthesis.41 In 1979, Tavassoli and Norris examined a series of vulvar smooth muscle tumors and found that lesions greater than 5 cm with infiltrative margins and five or more mitoses per 10 high power fields should be labeled as leiomyosarcomas.42 Nielsen et al. subsequently expanded these criteria to include moderate to marked cytologic atypia and proposed a risk stratification scheme based on these variables (Table 3).39 In this setting, the sole presence of cytologic atypia has no prognostic significance and should not be misinterpreted as leiomyosarcoma. Smooth muscle tumors of the vagina Although data for evaluation of vaginal smooth muscle tumors is limited, a study by Tavassoli and Norris suggest that tumors with significant
Review Table 3. Criteria to classify smooth muscle tumors of the vulva Features
Proposed classification
Gross size ≥ 5 cm Infiltrative margins Moderate-marked cytologic atypia Mitotic index ≥ 5 per 10 high power field
0 or 1 feature = leiomyoma 2 features = atypical leiomyoma 3 or 4 features = leiomyosarcoma
cytologic atypia and five or more mitotic figures per 10 high power should be considered leiomyosarcomas.43 Smooth muscle tumors of the scrotum Smooth muscle tumors of the scrotum are uncommon, and most are leiomyosarcomas exhibiting overt cytologic atypia, mitotic activity and necrosis. Smooth muscle tumors in this region without atypia or mitotic activity are rare, and only those lesions that have been extensively sampled may be cautiously labeled as leiomyoma with a recommendation of long-term clinical follow-up.44 Any mitotic activity in a scrotal smooth muscle tumor warrants classification as malignant.40 Although there is some limited evidence to suggest that scrotal smooth muscle tumors with only cytologic atypia (so-called symplastic leiomyomas) exist, long-term follow-up is lacking and most would advocate labeling these lesions as ‘atypical’ or ‘of uncertain biologic potential’.44 – 46 Differential diagnosis of smooth muscle tumors of the external genitalia The differential diagnosis of benign and malignant smooth muscle tumors at these sites includes entities such as neurofibroma, solitary fibrous tumor, inflammatory myofibroblastic tumor and sarcomatoid carcinoma. While careful morphologic examination is usually sufficient for distinguishing these entities, immunohistochemical stains may be helpful on biopsy specimens. The lesional cells of neurofibroma are classically S100 protein-positive
‘comma-shaped’ and embedded within a myxoid stroma with thin strands of collagen. Solitary fibrous tumor is a CD34-positive neoplasm composed of ovoid to spindle shaped cells surrounding prominent hemangiopericytic vessels admixed with keloid-type collagen. Recent work has found STAT6 to be a sensitive and specific marker for solitary fibrous tumor.47,48 Inflammatory myofibroblastic tumor is composed of fascicles of myofibroblasts and fibroblasts accompanied by a mixed population of inflammatory cells including plasma cells, lymphocytes and eosinophils. ALK immunohistochemistry is positive in 50–60% of cases and generally correlates with rearrangement of ALK .49 Finally, the differential diagnosis of leiomyosarcoma at these locations should include sarcomatoid carcinoma. Examination of the overlying epithelium for high grade squamous intraepithelial lesion and differentiated-type vulvar intraepithelial neoplasia (dVIN) is critical and would support the diagnosis of sarcomatoid carcinoma. While diffuse cytokeratin expression would favor sarcomatoid carcinoma, caution should be exercised because leiomyosarcomas may also aberrantly express this immunostain.50 Conclusion Genital soft tissue tumors are a rare group of mesenchymal entities, and both genital stromal tumors and smooth muscle tumors of the external genitalia present their own diagnostic challenges. Aggressive angiomyxoma is the only genital stromal tumor with significant risk of local recurrence necessitating accurate diagnosis. Fortunately, it is also one of the most microscopically distinctive tumors in this group. Fibroepithelial stromal polyp, cellular angiofibroma, mammary-type myofibroblastoma, superficial myofibroblastoma and angiomyofibroblastoma typically do not recur following complete excision and may be labeled ‘benign genital stromal tumor’ if definitive classification is not possible. Finally, pathologists should remember to use site-specific criteria for malignancy when evaluating smooth muscle tumors of the external genitalia.
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2. Ostor AG, Fortune DW, Riley CB. Fibroepithelial polyps with atypical stromal cells (pseudosarcoma botryoides) of vulva and vagina. A report of 13 cases. Int J Gynecol Pathol 1988; 7: 351.
3. Laskin WB, Fetsch JF, Tavassoli FA. Superficial cervicovaginal myofibroblastoma: fourteen cases of a distinctive mesenchymal tumor arising from the specialized subepithelial stroma of the lower female
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