Low D2-40 immunoreactivity correlates with lymphatic invasion and nodal metastasis in early-stage squamous cell carcinoma of the uterine cervix

Abstract

Lymphatic invasion and nodal metastasis are predictors of shorter disease-free and overall survival in carcinoma of the uterine cervix. The monoclonal antibody D2-40, which reacts with the oncofetal membrane antigen M2A, is a new selective marker for lymphatic endothelium, and has been shown to be useful in identifying the presence of lymphatic invasion in various malignant neoplasms, including cervical carcinoma. However, the reactivity of the tumor cells with D2-40 has not yet been evaluated. In this study, we examined the pattern of D2-40 immunoreactivity in a series of 138 invasive squamous cell carcinomas of the uterine cervix. We correlated the presence and extent of D2-40 immunoreactivity in the tumor cells with various clinicopathologic features, the presence of lymphatic invasion, lymph node metastasis and outcome. Diffuse or focal D2-40 immunoreactivity was present in 17 (12%) and 81 (59%) tumors, respectively, while 40 (29%) tumors showed no immunoreactivity. Lymphatic invasion and nodal metastasis were present in 56 and 29% of tumors, respectively. Tumor emboli within lymphatic spaces and metastatic tumor foci in lymph nodes showed no immunoreactivity in 86 and 80% of the cases, respectively. Lymphatic invasion and nodal metastasis were significantly more common in tumors showing low D2-40 immunoreactivity (Po0.0001 and 0.022, respectively). D2-40 immunoreactivity showed no correlation with any other clinicopathologic features examined, including tumor size, grade and FIGO stage. In univariate analysis low D2-40 immunoreactivity was significantly associated with shorter recurrence-free, but not with overall survival. Our studies suggest that D2-40 immunostaining may serve as a marker for increased risk of lymphatic invasion and tumor recurrence in cervical biopsy material. Further study of the biological function of the M2A antigen may shed some light on the interaction of tumor cells with lymphatics.

The potential role of podoplanin in tumour invasion

“…The oncofetal M2A antigen expressed in testicular germ cell tumours is identical to podoplanin (Dumoff et al, 2005).…”

“…Interestingly, focal expression of podoplanin correlated with lymphatic invasion, metastasis and a shorter recurrence-free survival, whereas diffuse expression did not. Hence, podoplanin was proposed as a prognostic marker for cervical cancer (Dumoff et al, 2005(Dumoff et al, , 2006.…”

Low podoplanin expression in pretreatment biopsy material predicts poor prognosis in advanced-stage squamous cell carcinoma of the uterine cervix treated by primary radiation

“…12,13 It was shown to be a selective marker for lymphatic endothelium allowing the specific identification of lymphatic vessels and the study of lymphatic vessel density in solid tumors. [13][14][15][16][17] We have recently found that cells of cervical squamous cell carcinomas also express podoplanin and characterized the D2-40 immunostaining pattern in a series of tumors treated by radical surgery. 16 We found a highly significant correlation between the level of podoplanin expression and the presence of lymphatic invasion, nodal metastasis, and poor outcome in this cohort of patients with early-stage tumors.…”

Comparison of the diagnostic accuracy of lymphatic endothelium markers: Bayesian approach

“…1,5 It has been postulated that the density of the lymphatic vessels is a predictor of clinically meaningful outcomes in a number of malignancies. [6][7][8][9][10][11][12][13] One of the most critical steps in the assessment of lymphatic vessel density is the selection of the optimal lymphatic endothelium marker, 1,2,5,[12][13][14][15][16][17][18][19][20][21][22][23] in order to avoid spurious findings arising from the low accuracy of the staining. However, given the absence of a gold standard, the evaluation of the sensitivity and the specificity of the lymphatic endothelium markers is a daunting task.…”