—  SHORT COURSE #21  —

Mesenchymal Neoplasms of the Female Genital Tract

Case 6 - Deep (Aggressive) Angiomyxoma

Teri Longacre, Esther Oliva and Robert Soslow


Introduction
Deep (aggressive) angiomyxoma (AAM) is a distinctive soft tissue neoplasm occurring in the pelvis and perineum with a propensity for local-regional recurrence. Initially described by Steeper and Rosai in 1983 as a female gynecologic tumor, this uncommon specialized genital stromal tumor has also been recognized to occur in the inguinoscrotal region in men, and is characterized by a paucicellular spindle cell proliferation separated by loose myxoid stroma with a prominent thick-walled, hyalinized vascular component. Despite the bland histologic appearance, AAM is an infiltrative tumor with a propensity for aggressive local and regional recurrences, especially when incompletely excised. Due to involvement of the deep pelvic soft tissues and retroperitoneal regions, these tumors often attain a large size and may not be amenable to complete surgical excision.

While deep (aggressive) angiomyxoma can be very difficult to distinguish histologically from other myxoid soft tissue lesions of the vulvovaginal region, especially from benign angiomyofibroblastoma, differences in the clinical behavior between these various neoplasms requires accurate diagnosis to ensure proper treatment. A variety of immunohistologic strategies have been proposed to be of value in differentiating these various tumors, but in many instances their relative contribution is overemphasized. In problematic cases, careful evaluation of a few key histologic features in concert with attention to a series of practical considerations, including patient age, determination of adequacy of biopsy and tumor sectioning, tumor size, borders and location (superficial versus deep) should permit accurate classification.

Clinical Features
Deep (aggressive) angiomyxoma is a predominantly non-metastazing, locally infiltrative soft tissue neoplasm that is most commonly encountered in the vulvovaginal region of reproductively aged women during the third to fifth decades. [3, 12, 52] In men, the tumor occurs in analogous sites, but in a slightly older age group with peak incidence in the sixth to seventh decade. [22, 55] The most common site is the scrotum followed by the inguinal region, spermatic cord and perineum. Patients often present with vague symptoms secondary to pressure effects on the adjacent urogenital or anorectal tracts. The clinical impression frequently includes Bartholin's gland cyst or hernia and often underestimates the extent of disease.

AAM is typically large (> 5 cm; range 3-60 cm), poorly circumscribed and has a tendency to recur when incompletely excised. Reported recurrence rates vary from 36 to 72%, depending on size, anatomical location, and amenability to wide resection. The higher reported recurrence rates have been attributed to an enrichment of consultation cases. Most AAM are more superficially located and amenable to wide excision; recurrences, when they occur are effectively treated by a single re-exicison. Recurrence is uncommon in men, presumably due to improved surgical control. Most recurrences occur within 5 years after excision, but recurrences have been described as late as 14 years following initial diagnosis. [3, 12, 52] Re-excision is usually successful provided the margins are free of involvement, but patients with surgically inaccessible tumors may experience multiple recurrences with invasion into adjacent tissue structures, which may rarely include bone. [51] Rapid growth during pregnancy has been observed. [7, 59] AAM is considered to be non-metastasizing; however two reports have documented metastases to the lungs without apparent dedifferentiation and both patients died of their disease. [5, 50]

Histologic Features
Deep (aggressive) angiomyxoma typically has a macroscopic grey-colored, nonencapsulated gelatinous or myxoid appearance and is characterized microscopically by bland, spindle shaped cells with moderate pale-staining cytoplasm and round to oval nuclei. The vascular component is composed of small to medium-sized vessels, which may be thick-walled or hyalinized; areas of perivascular microhemorrhages may be present. Condensation of fibrillar collagenous material and bundles of smooth muscle may be seen around the blood vessels. Almost all AAM are paucicellular at initial presentation, but recurrent AAM may be more densely cellular and fibrotic.

Immunohistologic Features
Although once thought to be desmin negative, the stromal cells in AAM are now known to variably express actin, vimentin, CD34 and desmin, as well as estrogen and progesterone receptors, and are considered to be specialized genital myofibroblasts. [3, 12] Although fewer cases have been studied, expression of estrogen and progesterone receptors, as well as androgen receptors have also been reported in AAM in men. [8, 21] Expression of CD44, a cell surface receptor to hyaluronan in the extracellular matrix has also been recently detected in AAM. [2, 4] AAM do not stain for S100 or cytokeratin.

Molecular Studies
Deregulation of the HMGA2 (high mobility group A) protein, has been reported in AAM. HMGA2 is an architectural transcription factor that is expressed predominantly during embryogenesis and is activated by rearrangements of chromosome 12q13-15. [24, 33, 44, 47] Rearrangements affecting the HMGA2 gene have been implicated in a variety of other gynecologic mesenchymal neoplasms, including uterine leiomyomas, intravenous leiomyomatosis, endometrial polyps, as well as in lipomas, chondroid tumors, and fibroadenomas of the breast. HGMA2 transcripts have also been identified in at least one angiomyofibroblastoma. [20] High mobility proteins are believed to affect transcription by bending the DNA and by interacting with other transcription factors, influencing chromatin changes during the cell cycle. Normally, HMGA2 is expressed at low levels or not at all in adult tissue. The presence of overexpression in some AAM has led to the suggestion that immunostaining with this marker may assist in diagnosis or margin assessment, but this deserves further study. The role of HMGA2 deregulation in AAM and these other neoplasms is not known.

Clinical Management
Given the propensity for local recurrences and the isolated case reports of lung and in one case, lymph node metastasis, AAM should be classified with the group of soft tissue tumors that exhibit clinically intermediate behavior – i.e., risk of local recurrence but rarely metastasizes (Table 1). The traditional treatment of choice is wide local excision with attention to margins, but the recent literature suggests a more conservative approach based on a combination of surgical excision, arterial embolization and hormonal therapy with or without adjuvant radiation. [18] Lymphadenectomy is currently not indicated. Successful treatment with gonadotropin-releasing hormone agonists for small primary disease, residual disease and recurrent disease has been reported. [31, 49] Because of the risk of local recurrence, long-term follow-up with MRI or CT scan is recommended.

Differential Diagnosis
Because of its locally aggressive, but predominantly non-metastasizing clinical behavior, AAM should be distinguished from clinically benign genital stromal tumors with very low risk of recurrence (e.g., fibroepithelial stromal polyp, angiomyofibroblastoma, and cellular angiofibroma) on the one hand, and from clinically malignant tumors with significant metastatic potential of more general distribution (e.g., leiomyosarcoma, myxoid liposarcoma and low grade myxofibrosarcoma) on the other (Table 1). The vast majority of the clinically malignant neoplasms that occur in the vulvovaginal region exhibit substantially different demographic and histologic features from AAM and these neoplasms do not usually pose a significant differential diagnostic dilemma. In contrast, most of the clinically benign lesions that can potentially be confused with AAM are 1) also relatively site-specific, 2) uncommon, and 3) share similar histologic and immunohistologic features, and the differential diagnosis of these lesions can be quite challenging (Table 2).

Angiomyofibroblastoma vs Deep (Aggressive) Angiomyxoma
Angiomyofibroblastoma, one of the specialized genital stromal lesions most commonly confused with AAM, typically occurs in reproductively aged women and like AAM, may also occur in the inguinoscrotal region in men. [14, 27, 38, 46, 58] It presents clinically as a slowly growing mass, simulating a Bartholin gland cyst or hernia. Unlike AAM, this tumor is well circumscribed, non-recurring and characterized histologically by the presence of spindled and plump epithelioid or plasmacytoid cells that may be multinucleate and tend to cluster around the numerous small to medium caliber blood vessels. The vasculature is randomly arranged and may feature areas of perivascular fibrosis and thick walled vessels similar to AAM. Alternating hypocellular and hypercellular areas is considered to be one of the distinguishing features of this unusual neoplasm. Like AAM, angiomyofibroblastomas may exhibit immunoreactivity for actin, desmin, CD34, and estrogen and progesterone receptors. [38, 46] Although large lesions have been reported, most are less than 5 cm (range, 0.5-12 cm) and mitoses are not prominent. [14] Occasionally, these tumors may contain abundant mature adipose tissue, raising the consideration for an infiltrative process, but the borders of the tumor itself are circumspect, the tumor is usually located in the superficial soft tissue and local excision is usually curative. Recurrence has been observed in a case with sarcomatous transformation. [39]

Despite the apparent clinical and histological differences between AAM and angiomyofibroblastoma, overlap cases may occur. [17] There is limited clinical experience with these hybrid tumors, but they should probably be managed as if they had at least some potential for locally aggressive behavior, since local recurrence has been observed with at least one such tumor.

Cellular Angiofibroma vs Deep (Aggressive) Angiomyxoma
Cellular angiofibroma is a rare, recently described soft tissue neoplasm resembling spindle cell lipoma with an apparent predilection for the vulvovaginal region in middle-aged women. [43] Like AAM and angiomyofibroblastoma, this lesion can also present in the inguinoscrotal region of men; rarely, it occurs in extravulvar sites. [16, 27] When occurring in the vulva, the tumor is distinguished by its small size (<5 cm), circumscription, and a uniformly cellular, mitotically active proliferation of bland spindle cells arranged in short fascicles, admixed wispy bundles of collagen and numerous small to medium-sized thick-walled and often hyalinized blood vessels. [9, 11, 26, 30, 43] Occasionally, scattered multinucleate cells may be present. Entrapment of nerves and fat may be seen at the periphery of the tumors, but aggressive infiltration into adjacent structures has not been observed. Mast cells are often abundant and several cases have featured prominent perivascular lymphoid aggregates. Cellular angiofibroma is typically more cellular than AAM and does not feature elongated bundles of smooth muscle aggregated around blood vessels.

The histologic distinction between cellular angiofibroma and angiomyofibroblastoma is more controversial, but cellular angiofibroma is characterized by more spindled cells set in a collagenous stroma, whereas angiomyofibroblastoma has larger, more epithelioid cells aggregated around blood vessels. Fibroepithelial stromal polyp is typically less cellular and features more enlarged, atypical and multinucleate cells than cellular angiofibroma. The constituent cells of cellular angiofibroma can express CD34, estrogen and progesterone receptor, and occasionally, actin and desmin. [30, 43, 23] Few cases have been reported and follow-up information is limited, but complete excision with clear margins appears to be curative therapy for cellular angiofibroma in most instances. [30, 43] One local recurrence has been reported, suggesting that cellular angiofibroma may have limited potential for local recurrence. [32]

Superficial Cervicovaginal Myofibroblastoma (Myofibroblastoma) vs Deep (Aggressive) Angiomyxoma
This lesion occurs more frequently in the vagina, but may be seen in the cervix and vulva. [15, 28] Initially identified only in the cervix and vagina (hence the term, superficial cervicovaginal myofibroblastoma), this lesion is thought to arise from hormonally responsive mesenchymal cells in the subepithelial stromal layer normally present throughout the endocervix and vulva of adult women. Myofibroblastoma is small (< 5cm; range 0.2 to 6.5 cm), superficial, polypoid and well circumscribed but unencapsulated. The cells are ovoid or spindled and dispersed in a finely collagenized stroma. Lace-like, seive-like and fascicular patterns are often present within the same lesion. Thick-walled vessels may be distributed along the center of the lesion. Because of its small size and superficial location, myofibroblastoma is almost never mistaken for aggressive angiomyxoma.

Unlike the fibroepithelial polyp, a distinct uninvolved Grenz zone often separates the lesion from the overlying surface epithelium. Immunohistologic features do not differ significantly from other vulvovaginal lesions. Although metachronous lesions have been observed in one patient, no recurrences have been reported. An association with tamoxifen has been suggested. [29]

Superficial Angiomyxoma vs Deep (Aggressive) Angiomyxoma
Although superficial angiomyxoma should always be considered in the histologic differential diagnosis of AAM, this lesion is superficial, small (< 5cm), lacks infiltrative borders and is almost always desmin negative. [1, 6, 13] Superficial angiomyxomas often exhibit a multilobulated growth pattern and have a significant potential for local, but nondestructive recurrence (up to 40%). These lesions are centered in the dermis and superficial subcutaneous tissue, feature abundant myxoid stroma with bland fibroblasts, and scattered neutrophilic inflammatory cells. Up to a third contain an epithelial or adnexal component secondary to entrapment. [1] Necrosis is absent. Superficial angiomyxomas may arise in a wide variety of anatomic regions; when multiple or presenting in the external ear, an association with Carney's complex should be considered. [6]

Fibroepithelial Stromal Polyp vs Deep (Aggressive) Angiomyxoma
Fibroepithelial stromal polyp (so called pseudosarcoma botyroides) of the genital tract is another genital stromal lesion that may be misdiagnosed as a malignant process. Unlike AAM, this lesion is relatively common and typically presents as a small exophytic and polypoid mass in reproductive aged women, most commonly in the vagina, but also in the vulva and cervix. [35, 40, 45] Occasionally they have a fronded appearance simulating a condyloma. These lesions have a propensity to occur during pregnancy (many spontaneously regress following parturition) and may be single or occasionally, multiple. [37] When they occur on the vulva, these lesions are commonly small, but may grow to large, sometimes disfiguring proportions (up to12 cm). Histologically, they are characterized by variable cellularity and a notoriously wide range of morphologic appearances. Cell types range from small spindle cells to enlarged, bizarre angulated and multinucleated forms. The multinucleated atypical cells are often enriched along the stromal-epithelial interface. The vascular component is also variable, but medium thick-walled vessels, often coursing through the middle of the lesion are usually present. Mitotic figures may be prominent (> 10 MF/10 HPF), including atypical forms and in these cases, the lesion may be initially misinterpreted as malignant. The absence of a clear demarcation between the lesional cells and the stromal-epithelial interface and the presence of characteristic stellate multinucleate stromal cells facilitate the correct diagnosis. The stroma of these lesions is often pale and edematous or myxoid, mimicking AAM. Similar to AAM, the stromal cells are variably reactive for desmin, actin and estrogen and progesterone hormone receptors, but not S100. [19] Fibroepithelial stromal polyps appear to represent a reactive process rather than a neoplasm. Although occasional local, nondestructive recurrences have been documented, reexcision has been successful in all cases.

Exuberant Angiomyofibroblastic Stromal Response vs Aggressive Angiomyxoma
A variety of other secondary or reactive myofibroblastic proliferations can occur in the vulvo-vaginal soft tissue, giving rise to an inflamed and edematous or myxoid stroma, which on a small biopsy may be misinterpreted as a neoplastic process. Two pseudosarcomatous proliferations that should be considered in the differential diagnosis of AAM include nodular fasciitis and postoperative spindle cell nodule. [37] Both may undergo focal myxoid change, but are distinguished from AAM by areas of greater cellularity, plump spindle cells, numerous thin walled vessels, small size, and the presence of easily found mitotic figures. A history of recent operative procedure may facilitate recognition of the postoperative spindle cell nodule. The characteristic torn tissue paper pattern provides a clue to the diagnosis of nodular fasciitis with myxoid change.

Fallopian tube prolapse, which may occur from 2 months to 30 years following vaginal hysterectomy is especially prone to misdiagnosis. [34, 57] Clinical history of prior surgery with imaging studies may provide a clue to the underlying etiology of the process.

Vulvar hypertrophy with lymphedema may also mimic deep angiomyxoma. A history of prior surgery or lymphatic obstruction and attention to the ectatic lymphatic spaces in vulvar lymphedema will provide the correct diagnosis. [56] Lymphedema may also impart a verruciform or frondlike appearance to the overlying skin, which may raise the differential diagnosis of condyloma.

Leiomyomas with Hydropic or Myxoid Change vs Deep (Aggressive) Angiomyxoma
Leiomyomas of the vulva or vagina may undergo hydropic or myxoid change, especially during pregnancy and may be confused with AAM on a small biopsy. Tumors with epithelioid or myxohyaline features may also be a source of confusion, but most genital smooth muscle tumors can be recognized by the presence elsewhere of classic interlacing fascicles of elongate spindle cells with prominent eosinophilic cytoplasm and blunt ended nuclei.

Rarely, smooth muscle tumors featuring the histologic features of myxoid leiomyosarcoma has been reported in the vulva; as in other smooth muscle variants, these tumors can be recognized by the presence of additional foci with typical smooth muscle histology. [10, 54] Additional distinguishing features are the greater cellularity and nuclear atypia in the non-myxoid areas.

Vulvar smooth muscle tumors occur predominantly in premenopausal women and rarely present in women over 50 years of age. They are considered to be malignant when they have three or all four of the following features: 1) size > 5cm; 2) infiltrative margins; 3) moderate to severe cytologic atypia; and 4) > 5 MF/10 HPF. [36] Most vulvar smooth muscle tumors recur locally; less than one-fourth metastasize to the lungs or other distant sites causing death. However, long-term follow-up is limited in most series and the rate of metastasis may be higher than is currently appreciated.

Vaginal smooth muscle tumors, which also occur in premenopausal women (mean age, 40 years), are mostly benign and appear to be more common than their vulvar counterparts. Local recurrence is associated with tumors exhibiting mitotic index > 5 MF/10HPF. [53]

Although smooth muscle tumors with myxoid features can potentially be confused with AAM, the major difficulty in diagnosing smooth muscle tumors of the genital tract lies in predicting recurrent potential with a reasonable degree of accuracy. Since the presence of any mitotic activity, nuclear atypia, necrosis, or evidence of infiltration into adjacent tissue in a vulvar smooth muscle tumor may be associated with recurrent potential, regardless of size, such lesions should probably be completely excised with clear margins whenever possible. [41] Since almost all of these tumors express ER and/or PR, they may respond to hormonal therapy. Adjuvant chemotherapy should probably be reserved for those tumors exhibiting unequivocal sarcomatous features.

All tumors with unusual or atypical features should be fully evaluated using a broad immunohistochemical panel in order to exclude spindle cell variants of melanoma, carcinoma and other soft tissue neoplasms.

Other Clinically Benign Myxoid Mesenchymal Lesions
Clinically benign myxoid appearing neoplasms with a more generalized site distribution that can be confused with AAM include myxoid neurofibroma and schwannoma, spindle cell lipoma, myxoma and hemangioma. Myxoid neurofibroma is recognized by the characteristic darkly staining, wavy or buckled nuclei, immunoreactivity for S100, and absence of a prominent vascular pattern. Schwannomas are also uniformly and diffusely S100 positive. Because of its bland appearance, myxoma is often included in the differential diagnosis of AAM, but myxomas occur in skeletal muscle (intramuscular myxoma) or immediately adjacent to a large joint (juxta-articular myxoma), feature inconspicuous capillary-sized vessels and are almost never serious differential diagnostic considerations. Although spindle cell lipoma more closely resembles cellular angiofibroma, this lesion is also frequently mentioned in the list of differential diagnoses for AAM. Spindle cell lipoma differs from AAM on the basis of its small size, location in the dermis and subcutis and the presence of a denser spindle cell proliferation with eosinophilic ropy collagen bundles. [48] Cellular angiofibroma possesses a more richly vascularized stroma with wispy collagen as opposed to the classic ropy collagen in spindle cell lipoma. Additionally, the pelviperineal region is generally considered to be an unusual site for spindle cell/pleomorphic lipoma. The presence of a focally prominent vasculature and extravasation of red blood cells in AAM may suggest hemangioma on a limited biopsy, but hemangiomas are small, typically unassociated with a prominent myxoid stroma and do not commonly occur in the vulva. The recently described prepubertal vulval fibroma is unlikely to be confused with any of the typical vulvar mesenchymal lesions due to its predilection for prepubertal females (age range, 4-12 years; median, 8 years). This lesion, which most commonly involves the labia majora, presents as a unilateral, ill defined and painless subcutaneous vulvar mass with microscopic features that suggest a hamartomatous process. Histologic sections show a patternless, mitotically inactive and bland spindle cell proliferation that extends around vessels, nerve and mature fat with no clear interface. Mitotic activity is sparse. Recurrences may occur when incompletely excised, which is probably not infrequent given the poor demarcation of the lesion from the surrounding normal tissue. [23]

Other Clinically Intermediate Myxoid Mesenchymal Lesions
Other soft tissue neoplasms with clinically intermediate behavior that may be confused with AAM include dermatofibrosarcoma protuberans, pelvic fibromatosis, atypical lipomatous tumor and low-grade myxofibrosarcoma. [25] Dermatofibrosarcoma protuberans with paucicellular myxoid stroma can cause difficulty because the myxoid areas may be indistinguishable from bland myxoid areas in AIM; identification depends on finding the distinctive repetitive storiform pattern elsewhere in the tumor and the absence of desmin reactivity. Pelvic fibromatosis features a more collagenous stroma and atypical lipomatous tumor (well differentiated liposarcoma) with myxoid change is recognized by the presence of atypical cells with angulated hyerchromatic and dense nuclei. Low-grade myxofibrosarcoma has thin walled, curvilinear vessels and more nuclear atypia; it often exhibits a multinodular growth pattern and is usually desmin negative. Like AAM, low-grade fibromyxoid sarcoma is capable of repeated and locally aggressive recurrences, especially when incompletely excised. However, low-grade fibromyxoid sarcoma occurs predominantly in the torso, thigh and shoulder areas of young adults and contains areas of fibrous stroma arranged in a swirling or whorled pattern alternating with myxoid stroma. [25]

Other Clinically Malignant Myxoid Mesenchymal Lesions
Unlike these clinically benign stromal lesions, most of the clinically malignant myxoid appearing neoplasms that may be considered in the differential diagnosis of AAM either rarely occur in the pelviperineal region or occur in the pelviperineal region but in a different age bracket from AAM, and do not usually pose a significant differential diagnostic dilemma. Embryonal rhabdomyosarcoma (sarcoma botryoides) can present in the vulvovaginal area either as a primary tumor or due to metastasis or direct spread. Although it may contain myxoid, edematous and spindle cell areas, embryonal rhabdomyosarcoma is recognized by the presence of a characteristic cambium layer, differentiating rhabdomyoblasts, and is typically seen in a younger age group than AAM. [25] Myxoid liposarcoma is exceedingly rare in the genital region, but may present there as a primary tumor or following spread from the adjacent pelvic region through the inguinal canal or perirectal sheath. [42] Paucicellular variants may be confused with AAM, but most myxoid liposarcomas can be recognized by the presence of areas containing the characteristic 'chicken wire' arborizing vasculature and lipoblasts. Myxoid variants of malignant melanoma (neurotropic or desmoplastic) and malignant peripheral nerve sheath tumor are identified by the presence elsewhere of areas that are diagnostic of the respective tumors. Most melanomas can be excluded by an S100 stain and malignant nerve sheath tumors exhibit substantially more cytologic atypia compared to AAM. Primary or metastatic carcinoma with prominent myxoid and spindle cell change can be excluded by a good clinical history and cytokeratin stains.

Managerial Approach
AAM is a distinctive soft tissue neoplasm of the pelviperineal region with a proclivity for local recurrence and aggressive infiltration into adjacent deep organs and tissues. The rate of local recurrence and sometimes unpredictable behavior associated with AAM merit the distinction of this clinically intermediate tumor from the other clinically benign genital stromal tumors as well as the less common, but clinically malignant tumors with significant metastatic potential that may also occur in this site. Because of their relatively nonspecific mesenchymal features, significant morphologic overlap exists among the specialized genital stromal tumors and precise classification may not always be possible.

Since the distinction of these lesions usually makes little difference in terms of clinical management as long as they are separated from AAM, a practical approach utilizing key histologic features (Table 2) and the following clinical information is most useful in the individual case: 1) tumor size; 2) depth of involvement (e.g., cutaneous, subcutaneous, deep soft tissue); 3) margins (infiltrative versus well circumscribed); 4) imaging studies, if performed; and 5) history of prior malignancy. Whether the lesion is reactive or neoplastic should be considered; if neoplastic, the possibility of a metastasis or extension of a tumor from the nearby retroperitoneum or deep pelvic organs should be excluded, since this could significantly alter management and prognosis. Immunohistochemical studies should be utilized in a directed fashion. Since most specialized genital stromal tumors exhibit similar immunophenotypic patterns, immunohistochemistry is most useful in exclusion of melanoma (S100) and metastatic carcinomas with myxoid and/or spindle cell features (cytokeratin and EMA). Reactivity with S100 also helps to exclude most nerve sheath tumors in this setting.

The difficulties encountered in distinguishing these various entities is compounded by small biopsies, which may not be entirely representative, and/or inadequate sampling of the lesion. This can be controlled to a certain extent by submission of the entire biopsy when it is small and by adequate sectioning when the biopsy is large. In the problematic case, one section per cm should be obtained. In all cases, sections should be taken in order to document the tumor interface and the surgical margins; these should be obtained at right angles to the lesion (perpendicular margins), not tangentially (shave margins). When in doubt, correlation with imaging studies and complete, conservative excision with clinical follow up is warranted.

Table 1. Managerial Classification of Vulvovaginal Soft Tissue Tumors* [25]

Clinically Benign
(= local excision curative, recurrences may occur but are not destructive 		Clinically Intermediate
(= local recurrences common and may be destructive; metastases with or without dedifferentiation are rare 		Clinically Malignant
(= local recurrences common; metastases occur
Angiomyofibroblastoma Deep (aggressive) angiomyxoma Myxoid carcinoma
Fibroepithelial stromal polyp Dermatofibrosarcoma protuberans, myxoid variant Myxoid leiomyosarcoma
Cellular angiofibroma Pelvic (desmoid) fibromatosis Myxoid liposarcoma
Superficial angiomyxoma Atypical lipomatous tumor ("well differentiated liposarcoma") Myxoid embryonal rhabdomyosarcoma
Superficial myofibroblastoma of the lower female genital tract Low grade myxofibrosarcoma Myxoid malignant melanoma
Myxoid neurofibroma Atypical myxoid smooth muscle tumor Myxoid malignant peripheral nerve sheath tumor
Myxoid smooth muscle tumor (leiomyoma with hydropic change) Low grade fibromyxoid sarcoma
Myxoma
Hemangioma
Nodular fasciitis
Postoperative spindle cell nodule
Prepubertal vulval fibromaasfdVulvar hypertrophy with lymphedema

*Tumor is used in a generic sense. Some of these processes may be hamartomatous or reactive (e.g. prepubertal vulval fibroma, vulvar hypertrophy with lymphedema, nodular fasciitis, postoperative spindle cell nodule, etc.

Table 2. Differential Diagnosis of Specialized Genital Stromal Tumors* [30, 41, 45]

FESP Cellular Angiofibroma Angiomyofibroblastoma Superficial Myofibroblastoma Deep (Aggressive) Angiomyxoma
Age (years) Reproductive, associated with pregnancy (16-75; mean 32) Late reproductive (20-77; mean 47) Reproductive (23-71; mean 42) Reproductive (23-80; mean 55) Reproductive (16-70; mean 36)
Site Cutaneous Cutaneous and subcutaneous Subcutaneous Cutaneous and/or mucosal Subcutaneous and deep soft tissue
Size Small (<5 cm) Small (<5 cm) Small (<5cm) Small (<5cm) Large (>5cm)
Behavior No recurrence No recurrence No recurrence No recurrence Recurrences (30%)
Cellularity Variable, large atypical and multinucleate cells common Cellular, rare multinucleate cells Hypocellular and hypercellular areas Multipatterned, moderately cellular Paucicellular
Vasculature Medium caliber thick walled vessels in fibrovascular cores Numerous thick walled vessels Numerous small caliber vessels with perivascular epithelioid and plasmacytoid cells Numerous small caliber vessels, focal hyalinized vessels Medium to large caliber thick walled, hyalinized vessels with perivascular bundles of smooth muscle
Mitotic index Can be high (>10/10 hpf) Can be high (>10/10 hpf) Low Low Low
Margins No Grenz zone Circumscribed, can be focally infiltrative Circumscribed Circumscribed, Grenz zone Infiltrative
Expression present Actin, desmin, CD34, ER, PR CD34, ER, PR Actin, desmin, CD34, ER, PR Actin, desmin, CD34, ER, PR Actin, desmin, CD34, ER, PR

*Tumor is used in a generic sense. Fibroepithelial stromal polyp and possibly, cellular angiofibroma may not represent neoplasms in the strict sense of the term. Abbreviations: FESP, fibroepithelial stromal polyp; IHC, immunohistochemistry (Note: antibodies are listed if they have ever been reported to stain positively in lesional cells of the respective tumor. Most genital stromal tumors exhibit variable immunoreactivity with the markers listed); ER, estrogen receptor; PR, progesterone receptor.

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