Date Published: February 5, 2019
Publisher: Public Library of Science
Author(s): Elias Nerad, Andrea Delli Pizzi, Doenja M. J. Lambregts, Monique Maas, Sharan Wadhwani, Frans C. H. Bakers, Harrie C. M. van den Bosch, Regina G. H. Beets-Tan, Max J. Lahaye, Anthony F. Shields.
To investigate the role of the apparent diffusion coefficient (ADC) as a potential imaging biomarker to predict metastasis (lymph node metastasis and distant metastasis) in colon cancer based on the ADC-value of the primary tumor.
Thirty patients (21M, 9F) were included retrospectively. All patients received a 1.5T MRI of the colon including T2 and DWI sequences. ADC maps were calculated for each patient. An expert reader manually delineated all colon tumors to measure mean ADC and histogram metrics (mean, min, max, median, standard deviation (SD), skewness, kurtosis, 5th-95th percentiles) were calculated. Advanced colon cancer was defined as lymph node mestastasis (N+) or distant metastasis (M+). The student Mann Whitney U-test was used to assess the differences between the ADC means of early and advanced colon cancer. To compare the accuracy of lymph node metastasis (N+) prediction based on morpholigical criteria versus ADC-value of the primary tumor, two blinded readers, determined the lymph node metastasis (N0 vs N+) based on morphological criteria. The sensitivity and specificity in predicting lymph node metastasis was calculated for both readers and for the ADC-value of the primary tumor, with histopathology results as the gold standard.
There was a significant difference between the mean ADC-value of advanced versus early tumors (p = 0.002). The optimal cut off value was 1179 * 10−3 mm2/s with an area under the curve (AUC) of 0.83 and a sensitivity and specificity of 81% and 86% respectively to predict advanced tumors. Histogram analyses did not add any significant additional value.
The ADC-value of the primary tumor has the potential to predict advanced colon cancer, defined as lymph node metastasis or distant metastasis, with lower ADC values significantly associated with advanced tumors. Furthermore the ADC-value of the primary tumor increases the prediction accuracy of lymph node metastasis compared with morphological criteria.
Surgical resection of the primary tumor and regional lymph nodes is the cornerstone of curative treatment for colon cancer. After surgical resection, adjuvant chemotherapy is considered in patients with stage II or III disease to reduce the risk of disease recurrence (i.e. patients with locally advanced tumors and/or lymph node metastasis). In rectal cancer, neoadjuvant (i.e. preoperative) instead of adjuvant (i.e. postoperative) chemoradiotherapy has become the standard of care in the United States and Europe after the German rectal cancer trial, which showed improved local control and reduced toxicity with neoadjuvant chemoradiotherapy, compared to adjuvant chemoradiotherapy . Similar results were found in advanced colon cancer patients in several smaller studies [2–6]. Therefore a large multicenter study called FOXTROT-trial  is currently investigating whether these promising results of neoadjuvant therapy can improve the outcome for advanced colon cancer patients similarly as with rectal cancer patients. If so, preoperative imaging will play an important role in the selection of advanced colon cancer patients for neoadjuvant treatment. Currently, staging of colon cancer is performed with computed tomography (CT) however, a recent meta-analysis showed unsatisfactory results for CT in identifying high-risk factors such as T- and especially N-staging . MRI might be a logical alternative to CT because of its superior soft tissue contrast and the fact that MRI is already well known as a reliable staging modality to identify advanced tumors in rectal cancer . To date, only a small number of studies investigated MR imaging for the staging of colon cancer patients, with promising results considering T-staging. Unfortunately accurate N-staging (i.e prediction of lymph node metastasis) remains a problem [10–12]. It needs to be addressed that these studies focused solely on morphological changes for T and N staging (i.e. visible breach of the muscularis propria layer of the bowel wall for T3 tumors, short axis diameter/shape of lymph nodes for nodal staging). However predicting lymph node metastasis with this standard approach is thwarted by microscopic metastasis which increase false negative results and conversely enlarged benign (inflammatory) lymph nodes which increase false positive results. Functional MR imaging by obtaining additional quantitative imaging ‘biomarkers’, such as the Apparent Diffusion Coefficient (ADC) may aid radiologists in their diagnosis. The ADC value is a quantitative measure of the magnitude of movement of water protons within a given tissue. This movement due to diffusion is influenced mainly by tissue cellularity, integrity of cell membranes and viscosity of fluids, thereby providing an indirect measure of a tissue’s microcellular architecture. ADC measurements are reliably demonstrated to be a beneficial predictor of tumor aggression in rectal cancer[14–17] and other types of cancer such as breast [18–20] and prostate cancer[21–23]. Therefore, our study investigates the value of ADC as a biomarker to identify advanced colon cancer, defined as tumors with metastatic potential (lymph node metastasis and distant metastasis) and whether it can provide additional value in predicting lymph node metastasis compared with morphological staging only. Due to the heterogeneity of cancer tumors however, mean and median ADC values might not be representative. That is why our secondary aim is to evaluate if adding histogram ADC analyses as a post processing step could be of added value.
Due to the retrospective nature of the study informed consent was waived and the study was approved by the Maastricht University Medical Center Medical Review Ethics Committee.
This study suggests that the ADC value of a colon tumor can be used as a biomarker to predict tumor aggression. Advanced tumors (i.e. tumors with lymph node metastasis/distant metastasis) had significantly lower mean ADC values than early tumors. According to our results the optimal ADC cut off value to discriminate between early and advanced tumors is 1.179 * 10−3 mm2/s.
Our study demonstrates that colon cancer tumors with lymph node metastasis or distant metastasis have significantly lower ADC values than colon tumors without lymph node/distant metastasis. Furthermore, employing tumor ADC values seem more accurate in the prediction of lymph node metastasis instead of relying on the notoriously unreliable morphological characteristics. Consequently, ADC tumor values can help identify patients potentially eligible for neoadjuvant treatment using not only qualitative, but also quantitative biomarkers.