Tumor invasion depth is a useful pathologic assessment for predicting outcomes in cervical squamous cell carcinoma after neoadjuvant radiotherapy

In this study, we assessed the prognostic value of different clinical and pathologic assessment parameters using data of 173 cervical squamous cell carcinoma patients who underwent neoadjuvant RT or CCRT prior to radical hysterectomy. Although no standard procedures for neoadjuvant therapy plus surgery have been confirmed yet and more supporting data are still needed, especially data regarding CCRT, some studies have suggested that pre-operative CCRT is associated with significantly improved PFS and OS compared with RT alone [21, 22], whereas other studies have provided evidence suggesting almost the same clinical outcomes following these different treatment modalities [13, 23]. Our data also did not show significant differences in the outcomes of patients who received RT alone or CCRT, which is consistent with the results of the study by Keys et al. [24]. Moreover, improvement of the 5-year OS rate with neoadjuvant CCRT over that achieved with RT alone remains to be proven. In our study, the 60.0 % 5-year survival rate of stage IIIb patients is similar to the rates previously reported, whereas the 96.7 % 5-year survival rate of stage IIb patients in our study seems to be higher than rates previously reported (e.g., 71.0 %) [25, 26]. These findings may suggest the benefit of neoadjuvant RT or CCRT, but further studies are still needed to draw such conclusions.

Before radical hysterectomy, we obtained the tumor size measurements used in the clinical FIGO staging system and WHO and RECIST 1.1 evaluation criteria by TVS examination, which has been shown to be highly accurate for detecting tumor presence and evaluating the local extension of cervical carcinoma [27, 28]. Because this imaging technique is faster, cheaper, and more widely available than other imaging techniques [27, 28], its use is consistent with our objective of establishing prognostic criteria for cervical carcinoma underwent neoadjuvant treatment that are easily applied in most hospitals. However, TVS is a painful and time-consuming procedure, especially for the patients who have undergone RT or CCRT.

The FIGO staging system [16, 17], especially the revised FIGO (2009) staging system, is widely used in standard clinical and pathologic staging procedures for many types of cancer, including cervical carcinoma. Similar to the results of previous clinicopathologic studies on cervical carcinoma [29], our data demonstrate that the clinical FIGO staging prior to radical hysterectomy serves as a valuable independent predictor of distant metastasis and survival outcomes (Table 1 and Fig. 2) in patients with FIGO stage III carcinomas, whereas it is not a very effective predictor of outcomes for stage I and II carcinomas. In addition, our results showed that post-operative pathologic FIGO staging is a less effective predictor compared with the clinical stage. Use of the FIGO staging system both before and after surgical treatment are dependent on the assessment of tumor size and invasion of the parametrium and pelvic side wall as well as the evaluation of adjacent organs and lymph node involvement [30]. Thus, high accuracy of FIGO staging prior to radical hysterectomy for cervical carcinoma prognosis is not easily obtainable and depends heavily on accurate clinical examinations [28‐32].

The WHO (double diameter measurement evaluation) criteria and RECIST 1.1 criteria are widely used and also were found to be effective in our study (Table 1 and Additional file 2: Figure S2 & Additional file 3: Figure S3). However, these two sets of criteria clearly state that tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are not usually considered measurable unless evidence of progression in the lesion has been demonstrated [31]. Moreover, both sets of criteria also suggest the ultrasound examinations should not be used for imaging-based evaluation measurements, because ultrasound is regarded as operator dependent and therefore of limited reliability [32]. However, the effective application of these two sets of criteria in our study indicated that the use of TVS is more reliable than ordinary ultrasound examination with respect to the accuracy of the results.

In our study, to find useful prognostic factors for cervical carcinoma treated with neoadjuvant RT or CCRT, we also included the TNR in our analyses and showed that the TNR cannot be considered an effective prognostic factor (Table 1). This is likely because the degree of necrosis within tumor tissue is not apparent until some time after treatment. Moreover, TNR also can be easily affected by tumor heterogeneity, artery dilatation, and vascular proliferation within the tumor [33]. We also applied the 5-point TRG scoring system to determine whether the TRG is correlated with outcomes in these patients. Based on the hypothesis that a shorter tumor cell doubling time indicates a more aggressive tumor, the regression grade is in general considered to be related to patients’ prognosis. However, the TNR is a subjective criterion not based on an objective measurement and thus does not offer good reproducibility, and our results showed no clear prognostic significance for patients with cervical carcinoma treated with neoadjuvant therapy (Table 1).

Residual tumor cells are generally considered aggressive, and the area containing such cells may be important for the determination of invasive and metastatic capacity. Dipen et al. proposed “tumor thickness” as a new prognostic factor for therapy response and survival outcome in patients with resected hepatic colorectal metastases [34], and other studies also indicated that the tumor thickness remains the most important determinant of melanoma patient survival [35, 36]. For cervical carcinoma, tumor diameter and volume, as determined by pre-surgery imaging examinations, can predict progression-free survival [37], and previous studies confirmed that the tumor size on T2-weighted magnetic resonance images is a useful index for evaluating parametrial involvement of cervical carcinoma with full-thickness stromal invasion [38]. Therefore, based on the hypothesis that the existence of residual tumor cells correlates with the outcomes of patients, the TID was designed to measure the length perpendicular to the cervical internal surface in the maximal cutting plane. Measurement of this dimension was less time consuming and more reproducible, because few parameters are considered and major parts of the tumor cannot be disregarded [34, 39].

In practice, nest-like or cord-like scattered tumor cells and continuous tumor tissue invading to different depths with different degrees of necrosis and inflammatory reactions can be identified easily under a microscope. Also, the reproducibility of such objective measurements could not be easily influenced by the pathologist’s experience. In the present study, cytokeratin immunostaining was used to identify some uncertain residual tumor tissue and obtain TIDC measurements. The positive results demonstrated the existence of residual tumor tissue and inevitably changed the measured invasion depth. Even after we eliminated the major influence of patients’ pre-operative clinical FIGO stages on survival outcomes, both the TID and TIDC were found to be significantly correlated with distant metastasis and survival outcomes in cervical squamous cell carcinoma patients who had undergone adjuvant RT or CCRT.