Even when the molecular structure of CD34 is well recognized, its function is far from being completely understood. In hematopoiesis, CD34 has roles of cytoadhesion and the regulation of cell differentiation. CD34
+ cells represent a proportion of the total mesenchymal stem cells (MSCs), and are associated with high colony forming efficiency and long-term proliferative capacity [
39,
40]. Moreover, CD34
+ MSCs have exhibited a propensity for endothelial transdifferentiation. Thus, CD34
+/CD90
+ cells of human adipose tissue were able to form a sphere cluster and be differentiated in endothelial cells that form capillary-like structures producing a high level of VEGF [
41]. A diffuse cytoplasmic with perinuclear enhancement of bcl-2 staining has been constantly described in SFT [
42]. The level of bcl-2 positivity ranges from 70 to 86% in the largest series of SFT [
37,
43]. Of note, bcl-2 immunostaining was positive in benign conditions with spindle cellularity (). Further, apart from SFT, it is expressed in some fibroblastic spindle cell sarcomas and in the spindle component of DD-LPS or in synovial sarcoma. A close relationship of CD34 staining is seen with bcl-2, being coincident in several tumors such as SFT, dermatofibrosarcoma protuberans, Kaposi sarcoma or gastro-intestinal stromal tumor (GIST), as well as in other previously mentioned benign conditions [
44]. In SFT, bcl-2 expression was seen regardless of the mitotic activity or the cellularity. Analyses in mammalian tissues determined that bcl-2 protein expression is common in stem cells, endocrine tissue, and long-lived cells [
45]. Considered together, this raises the possibility that the pathogenesis of SFT could be explained as a result of neoplastic transformation of a fibroblastic precursor CD34
+/bcl-2
+. In addition, bcl-2 expression could be induced by STAT6 through IL-4. This mechanism is physiologically activated in lymphocytes where this signaling pathway would maintain the T cells activated, avoiding apoptosis [
46]. The overexpression of bcl-2 in SFT could explain the chemo-resistance seen in this entity. Additionally, the bcl-2 expression detected in synovial sarcoma could be explained by the characteristic translocation t (X, 18) that would affect the bcl-2 gene allocated in chromosome 18 [
47]. The positive expression of bcl-2 seen in neural neoplasms could be due to the fact that these tumors stem from the neural crest cell lineage, which also expresses bcl-2. The protein expression of CD99 is extensively present in SFT, showing strong membranous predominant staining, or membranous cytoplasmic, in more than 80% of cases. The glycosylated transmembrane protein CD99 is implicated in several cellular functions such as cell adhesion, migration, differentiation, endo and exocytosis among others [
48]. In malignancy, CD99 has been demonstrated to have a remarkable role in migration, invasion and metastasis. In this sense, CD99 has behaved as an oncogene in several tumors including some sarcomas such as Ewing sarcoma, synovial sarcoma or rhabdomyosarcoma. However, there is an increasing number of tumors in which CD99 expression is diffuse in an early stage or in benign conditions, but is lacking or reduced in an advanced stage or in the malignant counterpart [
49,
50]. In this latter subset of tumors, which includes osteosarcoma, CD99 acts as a suppressor gene. In addition, two isoforms of CD99 (wild type and truncated forms) have been described with opposite functions. While CD99
wt inhibits migration, metastasis, anoikis resistance and anchorage-independent growth, the truncated form exhibits the opposite functions [
51]. CD99 is highly expressed in CD34
+ bone marrow cells and in leukocytes, whatever the lineage, and it is a determinant in the orientation of immune response [
52]. As CD99 expression is usually lost in the dedifferentiated SFT (in the DD zones), it is probable that CD99 would act also as a tumor suppressor in the context of SFT [
53].
In all, one might speculate that precursor cells of SFT would harbor an early expression of CD34+ and bcl-2, probably a progenitor of fibroblasts or myofibroblasts, along with CD99+ upon which other genetic early hits had been added, such as the characteristic NAB2–STAT6 transcript. The latter would ultimately facilitate proliferation through EGR1 signaling.