Clin Exp Otorhinolaryngol.  2016 Dec;9(4):374-381. 10.21053/ceo.2015.01683.

Parameters of Stromal Activation and Epithelial to Mesenchymal Transition as Predictive Biomarkers for Induction Chemotherapy in Patients With Locally Advanced Oral Cavity and Oropharyngeal Squamous Cell Cancer

• Geweiler J
• Inhestern
• Berndt A
• Guntinas-Lichius O

• KMID: 2360771
• DOI: http://doi.org/10.21053/ceo.2015.01683

Abstract

OBJECTIVES
Induction chemotherapy (IC) is likely to be effective for biologically distinct subgroups of oral cancer and biomarker development may lead to identification of those patients.
METHODS
We evaluated immune cell infiltration, stroma formation and structure of the invasive front as well as the immunohistochemical expression of alpha smooth muscle actin (ASMA), CD163, E-cadherin, N-cadherin, and the laminin gamma 2 chain in pretreatment biopsy specimens and surgical resections after IC in 20 patients with locally advanced oral cancer who were treated in a prospective, ongoing, phase II trial on IC using docetaxel, cisplatin, and 5-fluorouracil (TPF).
RESULTS
Significant negative prognostic factors for incomplete pathological tumor response to IC were alcohol abuse (P=0.032), cN+ (P=0.042), and <30% tumor reduction after first cycle of IC (P=0.034). Of the investigated histological parameters and biomarkers only a low membrane-bound expression of E-cadherin showed a trend to be associated with incomplete response to IC (P=0.061). Low expression of ASMA in stromal vessels and a strong tumor invasion front were significantly associated to tumor recurrence (P=0.024 and P=0.004, respectively). The median follow-up of all patients was 35 months. Alcohol abuse (P<0.001), <30% tumor reduction after first cycle of IC (P=0.005), and a strong tumor invasion front (P=0.019) were negative prognostic factors for overall survival.
CONCLUSION
A strong predictive biomarker among the investigated parameters for benefitting from TPF IC could not be found. The extent of the tumor invasion front was a negative prognostic marker for recurrence and survival in oral cancer treated by TPF IC followed by surgery and postoperative radiochemotherapy.

Keyword

Induction Chemotherapy; Mouth Neoplasms; Docetaxel; Neoplasm Invasiveness; Survival

MeSH Terms

Actins
Alcoholism
Biomarkers*
Biopsy
Cadherins
Chemoradiotherapy
Cisplatin
Epithelial Cells*
Fluorouracil
Follow-Up Studies
Humans
Induction Chemotherapy*
Laminin
Mouth Neoplasms
Mouth*
Muscle, Smooth
Neoplasm Invasiveness
Neoplasms, Squamous Cell*
Prospective Studies
Recurrence
Actins
Biomarkers
Cadherins
Cisplatin
Fluorouracil
Laminin

Figure

• 

  Fig. 1. Histological and immunohistological examples of tumor stroma and epithelial-mesenchymal transition activation in oral cancer prior to induction chemotherapy. (A) H&E, case 11; mode of invasion, score 3 (detached island/disseminated); Inflammation, score 2 (moderate). (B) H&E, case 3; mode of invasion, score 1 (pushing borders); inflammation, score 2–3 (moderate – distinct inflammatory reaction). (C) E-cadherin immunohistochemistry (IH), case 21; membranous positivity, score 3 (positive >30% tumor area)/red staining. (D) Laminin gamma 2 chain IH, case 20; cytoplasmic positivity, score 3 (tumor cells more or less all positive)/red staining. (E) Alpha smooth muscle actin IH, case 3; stromal positivity, score 2–3 (distinct stroma positivity, note the accentuation of the tumor borders)/red staining. (F) CD163 IH, case 3; CD163 positivity, score 2 (many positive cells detectable)/brown staining.

• 

  Fig. 2. Kaplan-Meier curves on overall survival, related to alcohol abuse (A), response to first cycle of induction chemotherapy (B), and structure of the tumor invasion front (C). Results of the log rank tests are shown.

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