Endosialin expression in soft tissue sarcoma as a potential marker of undifferentiated mesenchymal cells

Abstract

Background: Soft tissue sarcomas are a group of neoplasms with differentiation towards mesenchymal tissue, many of which are aggressive and chemotherapy resistant. Histology and immunoprofiles often overlap with neoplasms of other lineages, and establishing an accurate histopathological diagnosis is crucial for correct management, and therapeutic stratification. The endosialin cell surface glycoprotein is predominantly expressed by stromal fibroblasts and pericytes in epithelial neoplasms; however, tumour cell expression has been reported in small series of sarcomas.

Methods: We assessed endosialin expression by immunohistochemistry in a large set of 514 human soft tissue sarcomas.

Results: Tumour cell endosialin expression was seen in 89% of undifferentiated pleomorphic sarcomas (104/117), 77% adult fibrosarcomas/spindle cell sarcomas (20/26), 62% synovial sarcomas (37/60), 51% leiomyosarcomas (94/185) and 31% rhabdomyosarcomas (39/126).

Conclusions: Endosialin immunohistochemistry has potential to distinguish undifferentiated and poorly differentiated sarcomas from other poorly differentiated, non-mesenchymal neoplasms. A Phase II trial randomising patients with advanced sarcomas to receive chemotherapy with/without an endosialin therapeutic antibody has recently completed enrolment. Endosialin expression could be used to select patients for such clinical trials. Based on our results, patients with undifferentiated pleomorphic sarcoma may be particularly suitable for such a therapeutic approach.

Figure 1

Endosialin expression in control human tissues. (A) Normal adult breast tissue shows strong endosialin expression on the stromal fibroblasts (black arrows) surrounding the endosialin-negative luminal and myoepithelial cells within the terminal duct lobular units (red arrowheads). (B) Placental tissue shows strong endosialin expression within the placental villi (black arrows), with absence of expression within the syncytiotrophoblastic cells (red arrowheads). (C, D) Normal skeletal muscle and liver tissue, respectively, show no endosialin expression. Scale bar, 100 μm. See Supplementary Figure S1 for higher power images.

Figure 2

Endosialin expression in undifferentiated pleomorphic sarcoma (UPS). (A) Haematoxylin and eosin-stained section shows markedly pleomorphic, cellular tumour composed of sheets of spindle cells (black arrowheads) interspersed with ovoid cells (white arrowheads). (B, C) Examples 1 and 2. Both these UPS specimens show strong endosialin positivity, which is uniform throughout the tumour cells in panel B, but has a more focal, heterogeneous tumour cell distribution in panel C. (D) Example 3. UPS showing strong but focal membranous expression of endosialin (black arrowheads) on approximately 40% of tumour cells interspersed with endosialin-negative tumour cell (red arrowheads). (E) Example 4. The neoplastic cells (top left of field) show focal endosialin expression (black arrowheads), but endosialin expression is stronger within the surrounding stroma (black arrows). (F) Example 5. UPS with endosialin-negative tumour cells (red arrowheads), but endosialin is strongly expressed by the pericytes (black arrows). (G, H) Confocal microscopy of UPS specimens with stromal endosialin expression but no tumour cell positivity. Panel G, illustrating tumour vasculature with endosialin-positive pericytes (arrows) closely apposed to endomucin-positive endothelial cells (arrowheads). Panel H illustrating co-localisation of endosialin and α-smooth muscle actin in stromal fibroblasts (arrowheads). Scale bars, 100 μm (panels A–F), 50 μm (panels G, H). See Supplementary Figure S2 for higher power images.

Figure 3

Endosialin in expression in non-UPS sarcomas. (A, C) Embryonal rhabdomyosarcoma. Panel A, Example 1 showing strong uniform expression of endosialin throughout the ovoid and spindle tumour cell populations. Panel B, Example 2 where the spindle and ovoid cells of the neoplasm show no expression of endosialin (red arrowheads), but strong endosialin expression on the pericytes of the tumour vasculature (black arrows). Panel C, Example 3–as in example 2 except additional expression of endosialin on stromal fibroblasts (black arrows). (D) Alveolar rhabdomyosarcoma showing focal expression of endosialin (black arrowheads) throughout the ovoid and spindle cell population, interspersed by endosialin-negative tumour cells (red arrowheads). Characteristic fibrous septa containing endosialin-positive fibroblasts (black arrows) divide the nests of round cells. (E, F) Biphasic synovial sarcoma. Panel E, haematoxylin and eosin-stained section showing spindle cell (black arrowheads) and glandular (white arrowheads) tumour cell components. Panel F illustrates an example with strong endosialin expression within the spindle cell component (black arrowheads), whereas the glandular component, composed of more rounded tumour cells, is largely endosialin-negative (red arrowheads). (G, H) Leiomyosarcoma. Panel G illustrates a tumour with high-level endosialin expression throughout. Panel H illustrates a tumour with focal endosialin expression. Scale bar, 100 μm. See Supplementary Figure S3 for higher power images.