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Revista Española de Cirugía Oral y Maxilofacial

On-line version ISSN 2173-9161Print version ISSN 1130-0558

Rev Esp Cirug Oral y Maxilofac vol.28 n.1 Madrid Jan./Feb. 2006




Early stage oral cancer: prognosis with regard to histological grading, intratumoral lymphangiogenesis, and the expression of vascular endothelial growth factor-C (VEGF-C)

Estadios precoces de cancer oral: pronóstico en relación con gradación histológica, linfagiogénesis intratumoral y expresión de factor de crecimiento endotelial vascular Tipo-C (VEGF-C)



Jatin P. Shah

Jefe de Servicio. Servicio de Cirugía de Cabeza y Cuello
Memorial Sloan-Kettering Cancer Centrer. New York, EE.UU.


We have read with great interest the study by Munoz- Guerra and colleagues regarding the evaluation of prognostic markers for recurrence in T1 and T2 oral squamous carcinomas. In their article, the authors discuss intratumoral lymphangiogenesis (IL) and the identification thereof, via immunohistochemical labeling of PA2.26, a transmembrane glycoprotein originally identified as a cell-surface antigen induced in epidermal carcinogenesis and skin remodeling.1 Previously, the authors were able to demonstrate that patients with IL+ tumors had a less favorable disease free pattern compared to those with IL- tumors, but that IL was not a statistically significant influential variable in overall survival.2 The results of the current study once again demonstrate that those patients with oral squamous cell carcinoma (OSCC) demonstrating IL-, showed a better prognosis in terms of both survival and disease free pattern, however the difference was not statistically significant.

In spite of the elaborate application and evaluation of various histological tumor grading schemes employed by the authors, they failed to demonstrate overall clinical utility.

If one accepts the supposition that tumors contain functional lymphatics of their own creation, that is to say that lymphangiogenesis occurs within malignant neoplasms, a question which comes to mind is, how does one establish that these new channels are interconnected and anastomose with native lymphatic networks? The authors were able to immunohistochemically identify intratumoral lymphatics, and yet all ninety-six patients in the current study were N0. Given that the study at hand wishes to evaluate IL+ as a predictor of pN+, the cohort is inadequate. Selection of all patients undergoing elective neck dissection to attempt to identify the predictive value of IL+ would seem more appropriate. Furthermore, as it has been previously shown, the risk of occult metastases in T1 and T2 OSCC ranges between 7 and 41%.5,6 Therefore, the complete absence of nodal metastases in this population is somewhat unusual.

Other molecular markers show similar promise. For instance, Hassan et al demonstrated head and neck squamous carcinomas with cyclin B1 overexpression more frequently had tumor recurrence or metastasis, as compared with those tumors without.3 Similarly, there are recent data to support that activation of phsphorylated-Akt, a kinase involved in cell survival, is a significant prognostic indicator of shorter disease-free survival in patients with tongue carcinoma, independent of stage and nodal status.8

Clearly there is a need for continued search for biomakers, predictive of tumor behavior and patient outcome. It is far more than just an academic pursuit, since promising novel epitopes are continuously surfacing, which may one day be of routine clinical utility. We encourage the authors to continue their work, with follow-up of longer duration, and in a subsequent investigation, evaluate patients that are clinically N0 and determine whether IL+ correlates with occult micro-metastases. Similarly, continued monitoring of those patients treated conservatively, i.e., who did not undergo elective neck dissection, and determine if IL+ correlates with subsequent development of nodal metastases. Additionally, identification and quantification of the presence or absence of tumor emboli may be of value and could be incorporated into future work.



1. Martin-Villar E, Scholl FG, Gamallo C, Yurrita MM, Munoz-Guerra M, Cruces J, Quintanilla M. Characterization of human PA2.26 antigen (T1á-2, podoplanin), a small membrane mucin induced in oral squamous cell carcinomas. Int J Cancer 2004;113:899-910.

2. Munoz-Guerra MF, Marazuela EG, Martin-Villar E, Quintailla M, Gamallo C. Prognostic significance of intratumoral lymphangionenesis in squamous cell carcinoma of the oral cavity. Cancer 2004;100:553-60.

3. Hassan KA, El-Naggar AK, Soria JC, Liu D, Hong WK, Mao L Clinical significance of cyclin B1 protein expression in squamous cell carcinoma of the tongue. Clin Cancer Res 2001;7:2458-62.

4. Scholl FG, Gamallo C, Vilaro S, Quintanilla M. Identification of PA2.26 antigen as a novel cell-surface mucin-type glycoprotein that induces plasma membrane extensions and increased motility in keratinocytes. J Cell Sci 1999;112:4601- 13.

5. Shah JP. Head and Neck Surgery and Oncology. 3rd ed. Mosby, New York, 2003.

6. Sprano A, Weinstein G, Chalian A, Yodul M, Weber R. Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolayngol Head Neck Surg 2004;131:472-6.

7. Beasley NJP, Prevo R, Banerji S, Leek RD, Moore J, Van Trappen P, Cox G, Harris AL, Jackson DG. Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Research 2002;62:1315-20.

8. Massarelli E, Liu DD, Lee JJ, El-Naggar AK, Lo Muzio L, Staibano S, De Placido S, Myers JN, Papadimitrakopoulou VA. Akt activation correlates with adverse outcome in tongue cancer. Cancer 2005;104:2430-6.

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