Case of the Month: Vulva

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2014, case 16 and is an aggressive angiomyxoma.

The slides show a paucicellular lesion with abundant myxoid stroma and infiltrative borders. Bland ovoid and spindle shaped cells are embedded within the stroma; mitotic activity is absent. Thin bands, bundles, or whorls of eosinophilic smooth muscle can be seen near blood vessels, sometimes radiating from vessels. Numerous, variably sized vessels are present, ranging from thin-walled, capillary-sized to large vessels with thick muscular walls. Mast cells are readily identified and extravasated red blood cells may also be seen in this lesion. The histologic features are characteristic of an aggressive angiomyxoma (AA), a deep-seated tumor arising in the vulvar soft tissue of reproductive age women. The tumors are generally large (greater than 5.0 cm) and grossly can be rubbery, gelatinous, or fibrous. AA is a nonencapsulated lesion and its infiltrative edge frequently entraps surrounding adipose tissue and skeletal muscle.

Immunohistochemically the tumor cells of AA are positive for estrogen receptor (ER), progesterone receptor (PR), and vimentin. Most cases are positive for desmin and in some cases smooth muscle actin (SMA) and CD34 are expressed. This variable immunophenotype overlaps with that of many histologic mimics of AA, as these vulvar soft tissue lesions arise from the subepithelial myxoid stroma of the lower female genital tract that extends from the cervix to the vulva and contain stromal cells that are immunoreactive to hormone receptors. Cytogenetic analyses of AAs have revealed many cases with rearrangements involving the chromosomal gene locus 12q15 resulting in aberrant protein expression of the architectural transcription factor HMGA2. Immunohistochemistry for HMGA2 is positive in up to an estimated 50% of cases while its histologic mimics are generally negative; therefore HMGA2 is emerging as a potentially useful marker in the differential diagnosis of aggressive angiomyxoma. As blood vessels and native vulvovaginal connective tissue are negative for HMGA2, this marker may also be useful to help evaluate surgical margins, as well as in re-excision specimens to help distinguish between residual/recurrent tumor and native connective tissue, which may have a vague myxoid consistency and contain numerous blood vessels.

Metastasis of AA is an extremely rare phenomenon; however the infiltrative nature of the tumor gives it a propensity for destructive local recurrence, occurring in approximately 30% of cases, particularly if the lesion is incompletely excised. A few reports in the literature have demonstrated response of AAs to gonadotropin releasing hormone agonists leading to reduction in tumor size. This therapy may be useful to obtain clear margins with less radical surgery or as an alternative to re-excision for a tumor with close or positive margins.

Angiomyofibroblastoma resembles AA with its bland ovoid to spindle-shaped nuclei, stromal mast cells, rare or absent mitotic figures, and numerous blood vessels. However, it may be distinguished by its alternating hypocellular and hypercellular regions, lack of thick walled blood vessels, and aggregation of tumor cells around capillary-like vascular channels. While the stroma of angiomyofibroblastoma may be myxoid or edematous, it is commonly more fibrous than that of AA. Angiomyofibroblastoma is more superficially located and well-circumscribed than AA, with a very low tendency for non-destructive local recurrence. Angiomyofibroblastoma may show variable immunoexpression with the same markers that characterize AA, with the exception of HMGA2, which has not been demonstrated in angiomyofibroblastoma. A single case reported in the literature did demonstrate the presence of HMGA2 transcripts; however immunohistochemical characteristics were not reported.

Cellular angiofibroma is another vulvar tumor comprised of bland spindled cells and thick-walled vessels which may mimic AA. Findings that differentiate cellular angiofibroma include its more superficial location, well-circumscribed nature, increased cellularity, more fibrous stroma, and greater tendency for hyalinization of its vessel walls. Cellular angiofibromas are less likely to be immunoreactive for SMA and desmin; the absence of such staining may be helpful in conjunction with the gross and microscopic features. Cellular fibromas have no reported metastatic potential and a very low risk of local recurrence.

Fibroepithelial stromal polyps are usually exophytic or pedunculated lesions with spindled stromal cells and a central component of thick or thin-walled blood vessels. The variable nature of the stroma in these lesions may lead to consideration of other diagnoses in some cases. The stroma is often fibrous but may be edematous or myxoid, resembling AA. Marked hypercellularity, nuclear atypia, and numerous mitoses may occasionally be seen. The presence of multinucleate stromal cells, often near the ill-defined epithelial-stromal interface, is a clue to the diagnosis of fibroepithelial stromal polyp. Although worrisome pseudosarcomatous histologic features may be present, local excision is generally curative for these benign lesions.

Obesity and immobilization have been described as predisposing clinical factors of massive vulval edema. The underlying pathogenesis is thought to involve chronic lymphedema, therefore some authors prefer the diagnostic term "localized vulvar lymphedema."" It is characterized by bilateral swelling of the vulva with marked stromal edema, rather than true myxoid stroma, and perivascular cuffing by lymphocytes and plasma cells. Similarities to AA include a lack of well-defined borders and hypocellularity. The edematous stroma of massive vulval edema may mimic myxoid material, however it is alcian blue negative, in contrast to the alcian blue positive stromal myxoid ground substance of AA. In addition, overlying secondary skin changes such as dermal lymphangiectasia, dermal fibrosis, and lichenoid inflammatory infiltrates are not typically seen in AA and may be a clue to the diagnosis of massive vulval edema. Excision is generally curative.

Superficial angiomyxoma is composed of bland spindled and stellate cells with rare mitoses set within a copious myxoid stroma bearing a resemblance to AA. However it differs from AA by its superficial, subcutaneous location, multinodular pattern, and predominance of thin-walled capillary sized vessels. Other findings characteristic of superficial angiomyxoma are the presence of stromal neutrophils and entrapped epithelial elements from the overlying skin or adnexal structures, which are not seen in AA. Although these lesions also have no metastatic potential, the rate of local non-destructive recurrence is approximately 30–40%, therefore should be completely excised with clear margins whenever possible. There is no specific immunophenotype for superficial angiomyxoma; however the lesional cells are generally positive for vimentin and CD34, negative for ER and desmin, with variably reported expression of SMA and S100.

1. Which of the following histologic features is most characteristic of aggressive angiomyxoma?
   
   1. Alternating hypocellular and hypercellular areas
   2. Multinucleate stromal cells
   3. Predominantly hyalinized thick-walled blood vessels
   4. Smooth muscle fibers radiating from blood vessels
   5. Stromal neutrophils
2. Which of the following is useful to distinguish aggressive angiomyxoma from angiomyofibroblastoma?
   
   1. Identification of numerous thick-walled blood vessels
   2. Identification of stromal mast cells
   3. Immunohistochemistry for desmin, SMA, CD34, and ER
   4. Lack of mitotic figures
   5. Presence of myxoid stroma
3. In which of the following vulvar soft tissue lesions is destructive local recurrence most likely to occur?
   
   1. Aggressive angiomyxoma
   2. Angiomyofibroblastoma
   3. Fibroepithelial stromal polyp
   4. Massive vulval edema
   5. Superficial angiomyxoma

1. Fadare O, Brannan SM, Arin-Silasi D, Parkash V. Localized lymphedema of the vulva: a clinicopathologic study of 2 cases and a review of the literature. Int J Gynecol Pathol. 2011;30:306-313.
2. Horiguchi H, Matsui-Horiguchi M, Fujiwara M, et al. Angiomyofibroblastoma of the vulva: report of a case with immunohistochemical and molecular analysis. Int J Gynecol Pathol. 2003;22:277-284.
3. McCluggage WG. A review and update of morphologically bland vulvovaginal mesenchymal lesions. Int J Gynecol Pathol. 2004;24:26-38.
4. McCluggage WG. Recent developments in vulvovaginal pathology. Histopathology. 2009;54:156-173.
5. Nucci MR, Fletcher CDM. Vulvovaginal soft tissue tumours: update and review. Histopathology. 2000;36:97-108.

2014
Rochelle A. Simon, MD FCAP
Surgical Pathology Committee
Women & Infants Hospital of Rhode Island
Providence, RI

1. Smooth muscle fibers radiating from blood vessels (d). 
2. Identification of numerous thick-walled blood vessels (a). 
3. Aggressive angiomyxoma (a).