Fibroepithelial stromal polyps

Clinical features
Fibroepithelial stromal polyps (FSP) of the vulvovaginal region exhibit a wide range of morphologic appearances. This morphologic spectrum has, in part, led to their underrecognition in some cases and, in those examples which exhibit worrisome histologic features, their misinterpretation as malignant. FSP usually occur in young to middle aged women in their reproductive years, presenting more commonly in the vagina, but also occurring in the vulva and rarely the cervix. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15] They can occur as a single lesion, or can be multiple, an occurrence particularly associated with pregnancy. [5, 7] FSP that occur during pregnancy tend to exhibit a greater degree of cellularity and nuclear pleomorphism, which contributed to use of the term "pseudosarcoma botryoides" by some authors. [2, 5, 6, 7, 8] These lesions are benign but have the potential for local non-destructive recurrence, particularly if incompletely excised. [1, 8, 15]

Histologic features
Histologically, FSP are characteristically polypoid, occasionally fronded and usually contain a conspicuous fibrovascular core; however, the most distinctive aspect is the stroma, which can exhibit a wide range of morphologic features. On one end of the spectrum, FSP can be bland and hypocellular, being composed of spindle shaped cells with indistinct cytoplasm set within a loose collagenous matrix. At the other end of the spectrum, FSP can be hypercellular, exhibit marked nuclear pleomorphism and frequent mitoses (>10 mitoses/ 10 hpf) including atypical forms [15]). These floridly pseudosarcomatous examples of FSP produce an especially worrisome histologic appearance and can easily be mistaken for a malignant neoplasm. Clues to the identity of both bland and more florid examples of FSP are the presence of characteristic stellate and multinucleate stromal cells, which tend to occur near the epithelial-stromal interface and the lack of any clear margin. These lesions extend right up to the mucosal-submucosal interface and essentially represent a form of localized stromal hyperplasia. Cellular FSP also tend to exhibit a greater degree of cellularity in the center of the lesion, becoming less cellular as the lesion extends up to the stromal-epithelial interface. The vascular component of FSP is variable, but usually composed of medium sized thick-walled vessels. The stromal cells of FSP exhibit a variable immunophenotype but, in general, they are desmin and vimentin positive, with actin positivity being less common. [8, 9, 10, 15] The stromal cells can also be positive for estrogen and progesterone receptor. [9, 13]

The pathogenesis of FSP is not well understood; however, there is copious indirect evidence suggesting that they represent reactive hyperplastic lesions that arise from the distinctive myxoid subepithelial zone of the distal female genital tract. The stellate and multinucleate cells characteristic of FSP can be seen in normal cervix, vulva and vagina and reactive states involving the female genital tract (such as uterine prolapse). Similar cells can also be seen in reactive states outside the female genital tract (such as nasal polyps and ulcers of the gastrointestinal tract), providing further evidence for the reactive rather than neoplastic nature of these cells. Evidence suggesting that hormonal influences play a role in their formation includes: (1) the propensity of these lesions to occur during pregnancy and spontaneously regress following delivery, (2) the association with hormone replacement therapy in the postmenopausal patient and (3) the stromal cells of FSP can be estrogen and progesterone receptor positive. Furthermore, FSP are extremely uncommon before the menarche.

Angiomyofibroblastoma

Clinical features
Angiomyofibroblastoma (AMF), first recognized in the early 1990s, occurs almost exclusively in the vulvovaginal region of women but can also occur occasionally in the inguinoscrotal region of men. [16, 17, 18, 19, 20, 21] It is a well-circumscribed tumor that clinically is often thought to represent a Bartholin's gland cyst. AMF usually measures less than 5 cm but can be larger, with tumors up to 12 cm reported in the literature. [16] Overall, AMF is a benign non-recurring lesion and local excision with clear margins is adequate treatment. There is one report of an angiomyofibroblastoma with sarcomatous transformation that recurred. [22] In this case, areas apparently typical of angiomyofibroblastoma merged imperceptibly with a high-grade sarcoma.

Histologic features
Histologically, AMF is characteristically a well-circumscribed lesion composed of alternating hyper- and hypocellular areas. Plump round-to-spindle shaped cells characteristically cluster, or are present in linear array, around numerous delicate capillary-sized vessels set within a variably edematous to collagenous matrix. The stromal cells can be somewhat epithelioid or plasmacytoid, and are often multinucleate, having moderate amounts of eosinophilic cytoplasm and nuclei with fine chromatin and inconspicuous nucleoli. Occasionally intralesional adipose tissue may be present. [20] Mitoses are not a prominent feature and are generally difficult to find. Stromal mast cells can be abundant. The stromal cells of AMF are typically desmin positive and actin negative, although they can occasionally exhibit actin positivity.

Cellular angiofibroma

Clinical features
Cellular angiofibroma (CA) is a more recently described benign stromal tumor that occurs mainly in the vulva or perineum of middle-aged women, [23, 24] however, it also occurs in the inguinoscrotal region of men [23, 24, 25] (where it was briefly known as angiomyofibroblastoma-like tumor [25]). Examples in retroperitoneum have also been recognized. [24] When CA occurs in the vulva, it is characterized by its generally small size (< 4 cm) and usually well-circumscribed margin; examples in men tend often to be larger and less clearly marginated. CA behaves in a benign fashion. To date, no case has either recurred locally or metastasized, although I have now seen three cases with clear histologic evidence of sarcomatous transformation, most often as a microscopic focus. Local excision with negative margins appears to be adequate treatment for these lesions.

Histologic features
Histologically, CA is usually well circumscribed, although focal extension into surrounding soft tissue can be seen. It is a cellular neoplasm, being composed of bland spindle shaped cells arranged in short intersecting fascicles, wispy collagen bundles and numerous thick-walled, often hyalinized, vessels. A usually minor component of adipose tissue is present in about 25% of cases. The spindle cells have bland oval to fusiform nuclei and scant, pale eosinophilic cytoplasm with indistinct borders, being rather similar in appearance to the spindle cells of spindle cell lipoma. Mitotic activity can be brisk but no tumor cell necrosis or pleomorphism is seen. Mild degenerative nuclear atypia may be a feature, more often in males. Mast cells are often abundant. The tumor cells are CD34 positive in 60% of cases and SMA positive in 20%. Occasional cases are desmin positive, but CAF is negative for S-100 protein, keratin and epithelial membrane antigen. ER and PR may be positive in 40-50% of cases.

Aggressive angiomyxoma

Clinical features
Aggressive angiomyxoma (AA) is a non-metastasizing, locally infiltrative tumor of the pelvi-perineal region that has the potential for local, occasionally destructive recurrence. [26, 27, 28, 29, 30, 31] Although originally thought to occur only in women, it is now well recognized to arise also in analogous sites in men. [29, 30, 31] In women, AA tends to occur most commonly in the reproductive years with a median incidence in the fourth decade. In men, the median age at presentation is in the sixth to seventh decades. Clinically, AA is most often thought to be a labial cyst, particularly a Bartholin's gland cyst. It characteristically has a myxoid or gelatinous appearance but can appear more fibrous, especially when it recurs. Local, sometimes destructive recurrence occurs in approximately 30-40% of cases, sometimes many years (even decades) after the initial excision. [26, 27, 28, 29, 30, 31] However, it is nowadays recognized that more than one recurrence is unusual and that most recurrences are cured by just one additional surgical intervention, suggesting that these lesions are not as "aggressive" as first thought. Except for positive surgical margins, there are no clinical or histological means for predicting which tumors are likely to recur. Intuitively one might think that size is associated with the potential for recurrence, with smaller lesions being less likely to recur; however, tumors as small as 3 cm have recurred multiple times over many years. [27] Treatment should be complete excision whenever possible.

Histologic features
Histologically, AA is characteristically poorly circumscribed with extension into surrounding soft tissue. It is generally a paucicellular neoplasm, being composed of bland spindle shaped cells set within a copious myxoid matrix containing variably sized, but most often medium to large-sized, thick walled, often hyalinized, vessels. The spindle shaped cells have bland, round-to-ovoid nuclei with dispersed chromatin and moderate amounts of pale eosinophilic cytoplasm discernible as delicate bi- or multi-polar cell processes. Delicate fibrillary collagen is dispersed throughout the myxoid stroma but characteristically condenses around the vascular component, forming loose cuffs. Another characteristic feature is the presence of bundles of eosinophilic smooth muscle cells (so-called myoid bundles) which are usually arranged in loose clusters or tight whorls adjacent to the blood vessels and which appear to 'spin off' into the surrounding stroma. Although originally thought to be desmin negative, it is now well known that the stromal cells of AA often exhibit desmin and actin positivity. Positivity for ER and PR is also common. Cytogenetic analysis, performed in only a few cases [32, 33, 34] has revealed clonal aberrations involving chromosome 12. One case of AA was found to have a clonal chromosomal translocation involving chromosome 12, specifically t(8;12)(p12;q15), [35] resulting in aberrant expression of HMGIC protein, a DNA architectural factor important in transcriptional regulation, which is rearranged in a variety of other benign mesenchymal neoplasms. [36]

Prepubertal vulval fibroma
Added to the list of seemingly site-specific distinctive vulvovaginal stromal lesions is the very recently described prepubertal vulval fibroma (PVF). [37]

Clinical features
As the name suggests, PVF [37] appears to occur exclusively in the vulva (principally labia majora) of prepubertal females, most often before the age of 10. It presents as a painless unilateral swelling, most often 3-5 cm in size, with margins which are hard to define surgically. Even with relatively limited follow-up data thus far, at least 30% of these lesions appear to recur locally, sometimes more than once. Such recurrences seem always to be the consequence of incomplete local excision.

Histologic features
PVF is invariably poorly marginated and is characterized by bland spindle-shaped fibroblastic cells with pale cytoplasm set in a variably collagenous to edematous stroma. These cells ramify between pre-existing structures, entrapping fat cells, variably sized vessels and nerve bundles. In come cases, the lesion extends right up to the mucosal-submucosal interface. Mitoses are scarce. Immunostains show positivity only for CD34. The unilaterality of these lesions, lack of any evident associated hormonal abnormality and tendency for local recurrence would suggest that these unusual lesions are neoplastic rather than reactive or hyperplastic in nature.

Superficial angiomyxoma
Superficial angiomyxoma, although not site-specific, is included here because of the tendency for it to be confused with both aggressive angiomyxoma and with stromal polyps.

Clinical features
Superficial angiomyxoma (SA), sometimes also known as cutaneous myxoma, can occur in a wide variety of cutaneous locations, particularly the head and neck region, the trunk and the genital area. [38, 39, 40] It occurs most commonly in the fourth decade, presenting as a slowly growing painless mass that usually measures less than 5 cm. SA is benign; however, it has an approximate 30-40% rate of local non-destructive recurrence and should be completely excised with a clear margin whenever possible. The presence of multiple cutaneous myxomas and angiomyxomas arising at certain sites, such as the breast or external ear, are highly associated with Carney's complex. This association is less clear with SA arising in the genital area. [39] However, if multiple SA are present, then the possibility of Carney's complex should be raised, particularly since patient's with Carney's complex may have cardiac myxoma(s) and are at risk for sudden death.

Histologic features
SA is characteristically centered in the dermis and subcutaneous tissue and, because of this feature, can often be clinically and histologically polypoid in appearance. SA is a myxoid neoplasm with a distinctive multilobulated growth pattern. It is composed of bland, slender spindle and stellate shaped cells set within a copious myxoid stroma that also contains delicate thin walled capillary sized vessels. Scattered inflammatory cells, particularly stromal neutrophils, are very often present – the latter being a helpful histologic clue, particularly in the absence of necrosis or ulceration. Nuclear pleomorphism and mitoses are uncommon. In approximately 25% of cases, SA contains an epithelial component, usually in the form of squamous epithelial-lined cysts, buds of basaloid cells or strands of squamous epithelium. These foci are presumed to result from entrapment of adnexal structures or secondary to stimulation of the overlying epithelium by the tumor. In our experience, the spindle cells of SA are negative for actin, S-100 and desmin.

Smooth muscle tumors

General features
Smooth muscle tumors occur infrequently in the distal female genital tract, being much more common in the uterus. In soft tissue, smooth muscle tumors were originally classified based upon their location – superficial or deep-seated. Genital smooth muscle tumors were originally placed in the category of superficial smooth muscle tumors, which included pilar leiomyoma and angioleiomyoma, and were believed to have similar criteria for malignancy. However, smooth muscle tumors of the distal female genital tract differ both clinically and histologically from pilar (cutaneous) smooth muscle tumors and these should not be co-classified. [41] Therefore, in soft tissue, three general categories of smooth muscle tumors are currently recognized, each with their own criteria for malignancy – superficial (including nipple), genital (vulva, scrotum) and deep-seated.

Clinical features
Smooth muscle tumors of the vulva occur over a wide age range, but they occur most commonly in the fourth and fifth decades. [41, 42, 43] As with other mesenchymal lesions occurring at this site, genital smooth muscle tumors are clinically often felt to represent a cyst. They typically present as a subcutaneous lump noticed either by the patient or by their physician during routine gynecologic examination. Of interest, these lesions can be present for many years. The tumors vary in size but when they are benign or of uncertain malignant potential, they are usually well circumscribed and between 3 and 5 cm, while those that are malignant tend to be infiltrative and of larger size, often greater than 5 cm. [41, 42, 43]

Histologic features
Smooth muscle tumors of the vulva exhibit three principal histologic patterns – spindled, epithelioid and myxohyaline. These patterns can be mixed or pure. The spindle cell pattern is comparable to that of leiomyomas in the uterine corpus, being composed of spindle shaped cells with moderate amounts of tapering eosinophilic cytoplasm and ovoid to elongate nuclei with rounded or blunt ends forming intersecting fascicles. In the myxohyaline pattern, which is curiously common in smooth muscle tumors of the vulvovaginal region, the neoplastic spindle cells are separated by myxohyaline material with entrapment of small fascicles imparting a lacy or plexiform appearance. Prominent myxoid change alone with mucin pooling can also be seen. [43] In the epithelioid pattern, a combination of spindle and epithelioid cells are often encountered, with the former having rounded cells with moderate amounts of eosinophilic or clear cytoplasm present in clusters or sheets.

Histologic criteria which predict recurrent potential
Because of the relative infrequency of smooth muscle tumors that occur in the vulva and the relatively limited series of cases with long-term follow-up, there is difficulty in reliably predicting recurrent potential. While a combination of size, circumscription and mitotic thresholds have been proposed to separate benign smooth muscle tumors from those with recurrent potential, [41, 42, 43] in my experience, any mitotic activity, nuclear pleomorphism or evidence of an infiltrative margin, regardless of the size of the tumor, is associated with locally recurrent potential. I have seen tumors of this type recur decades after the initial excision, often showing more worrisome histologic features in the recurrence, such as nuclear pleomorphism, increased mitoses or infiltrative margins. These observations raise the intriguing but troublesome possibility that smooth muscle tumors of the vulva (and perhaps those arising elsewhere) represent a biologic continuum without clearly definable cut-offs between benign and malignant. Lack of very long-term follow-up, which is understandably difficult to obtain, limits studies that propose criteria for recurrent potential. We therefore advocate the use of the concept of "atypical smooth muscle tumor" for lesions which do not fulfill the criteria for the diagnosis of sarcoma (see below) but which have one of the following features: infiltrative margin, nuclear atypia or any mitotic activity. The use of this term should also include a cautionary note that these lesions can be associated with late recurrence and that the patient should be followed-up. In all cases in which the diagnosis of an atypical smooth muscle tumor is rendered, at least a 1-cm margin of excision is recommended whenever possible with close, long-term clinical follow-up.

Histologic criteria for malignancy (metastatic potential)
Distinction between atypical smooth muscle tumors and leiomyosarcoma can also be difficult and remains a major diagnostic problem with important clinical consequences relative to potential differences in surgical management. In our opinion, the currently established criteria probably underdiagnose malignancy; nevertheless, they are useful and appear valid. We utilize the criteria proposed by Tavassoli and Norris, [42] which were more recently validated [41, 43] in which tumors with three or more of the following features are best classified as sarcomas: 1) > 5 cm in size 2) infiltrative margins 3) > 5 mitoses / 10 hpf 4) moderate to severe cytologic atypia. It is our view that the presence of coagulative tumor necrosis is also a histologic feature, which in combination with any of the four aforementioned ones, should seriously raise the possibility of sarcoma.

Vulvar leiomyomatosis
Vulvar leiomyomatosis is an unusual but interesting phenomenon that is characterized by multinodular mucosal-based masses that are the result of a diffuse, often multinodular proliferation of smooth muscle. [44, 45, 46, 47] This process can involve the clitoris leading to clitoral hypertrophy in some patients. Curiously, patients with vulvar leiomyomatosis can also develop numerous smooth muscle neoplasms in the esophagus (esophageal leiomyomatosis), which can occur either synchronously or metachronously. [44, 45, 46, 47] The pathogenesis of this unusual phenomenon is unclear; however, there is an association with Alport's syndrome. The molecular genetic basis for Alport's syndrome involves defects in type IV collagen, which is a major component in all basement membranes (including those of kidney and smooth muscle cells). Different subtypes of collagen type IV are present in basement membranes of different tissue types (such as COL4A6 in smooth muscle), and mutations/deletions of this area can sometimes, but not always, lead to Alport's syndrome in association with leiomyomatosis. [48]

Conclusions
Mesenchymal neoplasms of the vulva can be separated broadly into those that also occur outside the lower female genital tract and those that are relatively site-specific. The relatively site-specific lesions should be classified, whenever possible, as distinct entities based upon their clinical, histologic and biologic differences; however, they can be diagnostically challenging because not only can they exhibit superficial histologic similarities but also ancillary techniques, such as immunohistochemistry, are often not helpful. In addition, it is my experience that vulvovaginal stromal lesions are morphologically heterogeneous and a proportion of cases (particularly in consultation material) defy precise classification, necessitating the designation 'vulvovaginal stromal tumor NOS'. As more cases are gathered together, it seems possible that additional reproducible 'entities' may be described.

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