Stromal features are predictive of disease mortality in oral cancer patients

Abstract

Worldwide, approximately 405 000 cases of oral cancer (OSCC) are diagnosed each year, with a rising incidence in many countries. Despite advances in surgery and radiotherapy, which remain the standard treatment options, the mortality rate has remained largely unchanged for decades, with a 5-year survival rate of around 50%. OSCC is a heterogeneous disease, staged currently using the TNM classification, supplemented with pathological information from the primary tumour and loco-regional lymph nodes. Although patients with advanced disease show reduced survival, there is no single pathological or molecular feature that identifies aggressive, early-stage tumours. We retrospectively analysed 282 OSCC patients for disease mortality, related to clinical, pathological, and molecular features based on our previous functional studies [EGFR, αvβ6 integrin, smooth muscle actin (SMA), p53, p16, EP4]. We found that the strongest independent risk factor of early OSCC death was a feature of stroma rather than tumour cells. After adjusting for all factors, high stromal SMA expression, indicating myofibroblast transdifferentiation, produced the highest hazard ratio (3.06, 95% CI 1.65-5.66) and likelihood ratio (3.6; detection rate: false positive rate) of any feature examined, and was strongly associated with mortality, regardless of disease stage. Functional assays showed that OSCC cells can modulate myofibroblast transdifferentiation through αvβ6-dependent TGF-β1 activation and that myofibroblasts promote OSCC invasion. Finally, we developed a prognostic model using Cox regression with backward elimination; only SMA expression, metastasis, cohesion, and age were significant. This model was independently validated on a patient subset (detection rate 70%; false positive rate 20%; ROC analysis 77%, p < 0.001). Our study highlights the limited prognostic value of TNM staging and suggests that an SMA-positive, myofibroblastic stroma is the strongest predictor of OSCC mortality. Whether used independently or as part of a prognostic model, SMA identifies a significant group of patients with aggressive tumours, regardless of disease stage.

SERPINE1 and SMA expression at the invasive front predict extracapsular spread and survival in oral squamous cell carcinoma

“…The intense SMA expression at the tumouradvancing front, was significantly associated with the N-stage and presence of nodal metastasis and its patterns are in keeping with previous studies (Kellermann et al, 2007;Surowiak et al, 2007;Marsh et al, 2011;Thode et al, 2011). The distribution of SMA immunoreactivity in the tumour stroma varies widely between different tumours and between different areas in the same tumour, and reflects heterogeneity (Vered et al, 2010).…”

“…Similarly, a combined approach using both SMA and SERPINE1 expression at the advancing front showed greater ability to predict survival than expression of the individual proteins. The most recent and largest study of prognostic stromal features in OSCC reported a greater prognostic significance for SMA expression in the stroma of OSCC than the presence of ECS (Marsh et al, 2011). Our study, however, suggests that ECS is of greater prognostic value, but that SMA plus SERPINE1 expression in combination was highly significantly associated with adverse outcomes.…”

“…Recent studies have also shown that the presence of activated fibroblasts, otherwise known as myofibroblasts, in the tumourassociated stroma are of high prognostic value in OSCC (Kellermann et al, 2007;Vered et al, 2010;Marsh et al, 2011). Myofibroblasts are usually demonstrated by the presence of alpha smooth muscle actin (SMA) expression, and their presence has also been shown to predict for disease recurrence across a number of tumour types (Surowiak et al, 2007;Tsujino et al, 2007).…”

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

“…4 In a number of different cancer types, stromal properties have demonstrated importance in disease identification, progression, and patient prognosis. [5][6][7][8][9][10][11][12] Given the pronounced desmoplastic reaction in pancreatic ductal adenocarcinoma, a large number of recent research efforts have focused on elucidating stroma-cancer interactions for both nuanced insight into disease progression and for potential diagnostic, prognostic, or therapeutic targets. 13 The dominant extracellular matrix component of most tumor stromas, including that of pancreatic ductal adenocarcinoma, is fibrillar collagen.…”

Epidemiology and pathological trends in oral squamous cell carcinoma in a local tertiary care hospital

“…Even with advancements in surgery and radiotherapy, mortality still is very high with a 5-year survival rate of only 50%. 11 The prognosis in the initial stages (I and II) is relatively good with surgery and/or radiotherapy. While in the 3 rd or 4 th stage of OSCC, combined surgery and radiotherapy or chemotherapy is the treatment of choice.…”