Discussion
Cellular angiofibroma is a quite recently described rare, benign stromal tumour that occurs equally among men and women: in female patients, CA most frequently arises in the vulvo-vaginal region, although there are described a lot of pelvic and extra-pelvic cases. Women are affected most often in the fifth decade (mean age 46.1 years), earlier than men, affected in the seventh decade. CA is characterized by its small size (mean value 3.6 cm) and usually well-circumscribed margins; it tends to be an asymptomatic and slowly enlarging mass, so CA tends to gradually increase in size after approximately 1–2 asymptomatic years, inducing women to check with their doctor long time after the tumour onset. CA is usually misdiagnosed with a Bartholin’s cyst (12/25, 48 % of cases), a not-specific solid mass (7/25, 28 % of cases), vulval cyst (3/25, 12 % of cases), leyomioma (2/12, 8 % of cases) and lipoma (1/25, 4 % of cases). Six extra-pelvic CA are reported in literature. Exceptionally, a young woman presented both vulvar and extra-pelvic CA, particularly two vulvar CA on the right and the left labia majora and three extravulvar CA on the left axilla and both breasts were reported [
10].
Nevertheless exist exceptional early symptomatic forms, as well as our described case-report [
11] in which the woman complained coxalgia due to tumour’s position, in retroperitoneal site, very near to obturator nerve.
There are many mesenchymal tumour which enter into the differential diagnosis with CA as spindle cell lipoma, solitary fibrous tumour, mammary-type myofibroblastoma, angiomyfibroblastoma, aggressive angiomyxoma and smooth muscle tumour (Table
4). Exceptionally, CA has been diagnosed with these mesenchymal tumours, such as with lipoma [
19].
Spindle cell lipoma was first described by Enzinger and Harvey [
20] in 1975 as a benign lipomatous tumour with a predilection for shoulder, back and posterior neck region of middle-aged to elderly men. Occasional cases may occur in a wide variety of sites, including one reported case arising in the vulva [
21]. The tumour consists of mature adipocytes, bland spindle cells and short bundles of brightly eosinophilic ropy collagen [
7]. In fact, CA and spindle cell lipoma have similar histological features, but can be distinguished by the rarity of spindle cell lipoma in vulvovaginal region and the presence, in CA, of more numerous vessels with thickened, hyalinized walls, compared with capillary-sized thin-walled vessels in spindle cell lipoma. The immunostaining is not helpful because the spindle cells of both tumours are CD34 positive, in particular CD34 is positive in about 60 % of CA and in 100 % of spindle cell lipoma [
8].
Solitary fibrous tumour has been reported in a wide variety of locations, including vulva and perineum [
22,
23]. This tumour shows a patternless spindle cell proliferation of alternating hypercellular and hypocellular areas, associated with dense collagen bundles, stromal keloidal-type hyalinization and hemangiopericytoma-like vessels [
8]. Both solitary fibrous tumour and CA may contain fat in the lesion [
24] and show often positivity for CD34 [
8], but CA differs due to more evenly distributed cellularity, bland spindle cells with short bundles of collagen and more rounded small- to medium-sized vessels.
Mammary-type myofibroblastoma, as we know for its typical breast localization, has been described also at extramammary locations, especially in the inguinal region, with a male predominance [
25]
. Grossly, this lesion appears as a well circumscribed, nodular mass and, microscopically, it is composed of spindle cells and adipose tissue, separated by coarse bundles of hyalinized collagen. In comparison of CA, the vessels in mammary-type myofibroblastoma are incospicuous and the spindle cells have a more fascicular arrangement. The tumour cells consistently exhibit coexpression of desmin and CD34 [
25].
All these described tumours share similar morphologic features and are characterized by bland ovoid to spindle-shaped cells with wispy collagen, variably sized thick-walled blood vessels and immunoreactivity to CD34.
In consideration of the clinical features,
aggressive angiomyxoma (AA) and
angiomyofibroblastoma (AMF) should also be included in the differential diagnosis of CA. The former is a typical locally recurring tumour of the vulvo-vaginal/perineal/inguinal regions, which occurs mainly in women in third to fifth decades [
26‐
28]. It is easily distinguishable from CA because it is generally a large deep-seated lesion, poorly circumscribed with infiltrative edges: AA tends to display an infiltrative growth with entrapment of mucosal glands, fat, muscle and nerves. Microscopically, aggressive angiomyxoma is hypocellular, compared with CA, and it is composed of short spindle tumour cells with minimal atypia in myxoid stroma. Small clusters of smooth muscle cells surrounding or “spinning off from” blood vessels are a characteristic feature of AA [
3]. There is a variable positivity for desmin, smooth muscle actin and CD34 [
7,
27,
28].
Angiomyofibroblastoma is a benign tumour most commonly occurring in the vulva of peri- and post-menopausal women [
29,
30]. Like CA, AMF is well circumscribed, even well demarcated, usually with a thin fibrous capsule but, unlike to CA, it is characterized by alternating hypocellular and hypercellular areas, together with multinucleate cells and epithelioid or plasmacytoid cells arranged in cords and nets around vessels. In fact, the characteristic feature of angiomyofibroblastoma is the perivascular accentuation of tumor cells [
29,
30]. In aid to differential diagnosis, the immunochemistry is very useful because the tumour cells of AMF express desmin and rarely CD34 and smooth muscle actin [
7,
29,
30].
Finally, vulvar smooth muscle tumours can be easily distinguished from CA because the latter lacks typical features of smooth muscle differentiation and it is usually desmin negative. The smooth muscle neoplasm are classically composed of cells with blunt-ended nuclei and eosinophilic cytoplasm, although these histological features could be absent when the tumour is localized in the vulvovaginal region.
The immunohistochemical features of CA may be helpful in differential diagnosis with the other vulvovaginal soft tissue tumours. An interesting immunohistochemical finding is the Estrogen and/or Progesterone receptors (ER/PR) expression by the CA. The occurrence of CA during menopausal transition and post-menopausal period and the description of a two cases associated with long-term estrogen replacement therapy [
11,
15] support the hypothesis of an hormonal pathogenetic origin. However, the direct role of these steroids in the CA pathogenesis still remains unclear, since a subset of mesenchymal cells of the distal female genital tract normally expresses these receptors and, at the same time, the neoplastic cells in other soft tissue disorders, arising from the vulva, may also show immunoreactivity for ER and/or PR [
31].
Immunohistochemistry may be also helpful in differential diagnosis between
usual CA and CA with
atypia or sarcomatous transformation. p16 expression is commonly negative in
usual CA whilst is multifocal or diffuse in CA with
atypia or sarcomatous transformation [
9]. The p16 and p53 represent tumour suppressor genes involving in the regulation of molecular pathways that may play a role in the tumour progression in sarcomas: overexpression of p16 may participate in the molecular mechanisms underlying the atypical or sarcomatous transformation seen in some subset of CA [
9].
Recently fluorescent
in situ hybridization (FISH) [
13] has shown a genetic relationship between CA, mammary-type myofibroblastoma and spindle cell lipoma. The same monoallelic or biallelic loss of retinoblastoma (RB) 1 (13q14), suggested a spectrum of one entity with morphological variations dependent on anatomic location. This argument doesn’t apply to solitary fibrous tumour as pubblished by Fritchie et al. [
26] that shows the absence of monoallelic/biallelic RB1 loss by FISH, arguing against the concept the solitary fibrous tumour is genetically related to the other three entities.
RB is an important tumor suppressor protein that plays a crucial role in cell cycle progression [
32]. RB gene is located at 13q14. Disruptions to the RB protein and to the pathway controlled by RB confer proliferative advantage to tumor cells [
33]. In 13q14 gene is located also a tumor suppressor called Forkhead box protein O1 (FOXO1) [
34]. FOXO1 is a transcription factor associated with apoptosis, cell cycle regulation, DNA repair and resistance to oxidative stress [
34]. A loss of FOXO1 expression was recently associated with CA [
35]. FOXO1 transcription factor induces an increased expression of manganese superoxide dismutase (MnSOD) resulting in an elimination of the reactive oxygen species (ROS) [
36]. Hence, loss of FOXO1 expression is associated with a decreased expression of MnSOD and, as consequence, an increased intracellular ROS generation causing mutations in proto-oncogenes and tumor suppressor genes [
37]. In fact, increased intracellular ROS induces p38 mitogen-activated protein (MAPK) pathway and may be linked to the tumorigenesis [
36‐
38].
ROS can cause tumor development through cellular proliferation, tumor cell invasion, angiogenesis and cancer stem cell survival [
37]. Also mammary and vaginal myofibroblastomas can present a monoallelic deletion of FOXO1 [
31]. Hence, RB1 and FOXO1 loss of expression could be implicated in the pathogenesis of CA [
13,
39]. RB1 and FOXO1 FISH analysis could be used to support CA diagnosis but the specificity is uncertain [
13].
Also CA pathogenesis is still unclear, both sexual hormones and ROS has been proposed. Although human papillomavirus (HPV) E7 oncoprotein bind RB protein causing a loss of function [
40], to our knowledge no role of infections in the pathogenesis of CA has been studied.
CA appears to behave in a benign fashion, since there is no report of tumours that progressed with metastasis and there is described only a recurrent case [
12]. The primary and the recurrent CA consisted of a well circumscribed solid white mass of 4 and 6.5 cm respectively. The histology of both lesions didn’t consistently differ: the recurrent lesion showed foci of increased cellularity and decreased vascularity compared with the original specimen although there were no histological features to suggest malignancy and 33 months after the excision of the recurrent CA, there were no evidences of further local recurrence.
In the majority of the analysed cases, the surgical approach consists of a simple local excision or a “shelling out” and these treatments seem to be adequate also in case of atypia and/or sarcomatous transformation where the literature suggests a radical excision with free margins [
9,
12]. To date, we are not aware of any cases of metastases of these tumours with atypia/sarcomatous features, suggesting that morphological atypical or sarcomatous aspects don’t necessarily confer an aggressive biologic behaviour to CA. Moreover, only 5 cases (5/18, 27.8 %) of re-excision because involved surgical margins has been reported but this method doesn’t represent an elective procedure because the tumour is usually treated with a local excision also when there are positive surgical margins, as showed in the remaining 13 cases (13/18, 72.2 %) with positive surgical margins, although no recurrences or metastasis have been reported. Therefore, considering that also cases of CA with positive margins don’t recur, no wide excision should be required. Given the relative sensitivity of the most frequently affected anatomic sites, there seems to be no justification for attempting to obtain a larger surgical margins [
3].