CORRELATION OF TUMOR ASSOCIATED MACROPHAGES (TAMS) DENSITY AND M2 PROPORTION WITH THE PATHOLOGICAL STAGE OF COLORECTAL CANCER

Abstract

Colorectal cancer (CRC) is the second most common malignancy among adults in Pakistan. With increasing focus on precision medicine and personalized chemotherapy, focus has shifted to finding a finer print in the pathological assessment. Tumor Associated Macrophages (TAMs) can serve as an additional pathological marker to enable further therapeutic targets and improve cancer therapy for CRC. TAMs have two polarization states – anti-tumor M1 and protumor M2. This cross-sectional study was conducted to determine statistical correlation of M2-macrophage proportion among all TAMs and TAM density in tumor stroma and tumor front, with the pathological stage of colorectal cancer, at the PNS Shifa Hospital, Karachi, during a period of six months. Clinical and pathological records were reviewed. With anti-CD68+ determining the total TAMs infiltrate and anti CD163+, the M2 polarized macrophages, the proportional distribution of M2 was ascertained and correlated with tumor histological stage along with other clinico pathological parameters. Histopathology specimen of 43 patients were selected. Among the included patients, two-thirds were male patients (n=30, 69.8%) with a median age of 54 years (Range 18-80 years of age). Tumors were most commonly found in cecum, sigmoid colon and rectum (combined n= 29, 67.4,%) with overall propensity toward the left side of the colon, along with rectum (n=25, 58%). The tumor were mostly well differentiated (n=21, 48.8%) adenocarcinoma (n=36, 83.7%), staged as pT3 (n=26, 60.5%), pN1 (n=23, 53.3%) with a median size of 4.5 cm in the greatest dimension. A small proportion of tumor had identified tumor perforation (n=3, 7%) and perineural invasion (n=9, 20.9) but more than half the specimen showed lympho-vascular invasion (n=24, 55.8%). Overall TNM stage III was more prevalent (n=26, 60.5%). The tumor grade and dimensions were independently distributed in relation to the age groups. There was a higher frequency of cancer in right colon among males (n=15, 50%), compared to females. The two measures that showed significant difference between the two genders were macroscopic tumor perforation and lympho-vascular invasion. There was no significant difference in TAMs 2 density and M2 proportion, in the tumor stroma and tumor front, tumor size, pathological tumor grade and pathological tumor stage. Lympho-vascular infiltration showed significant statistical difference in the TAMs density, at the tumor front. Otherwise, no difference was found for macroscopic tumor perforation, perineural invasion as well as the lympho vascular invasion in the tumor stroma. For M2 proportion also no difference was found in any of these categories. Comparison of TAMs density and M2 proportion, for early versus late-stage CRC also did not reveal any statistical difference. Based on logistic regression analysis, sensitivity was calculated to be 84.6% with a specificity of 76.5% for modified model. In conclusion, TAMs density and M2 proportion, in the tumor stroma and the tumor front of colorectal cancer specimens, did not reach statistically significant correlation in this study with the tumor stage. The predictability of advanced tumor stage (TNM stage 3 or 4) when assessed based on TAMs density and M2 proportion only, had a low sensitivity and specificity and was not statistically significant but the predictability improved remarkably for the model that also included the tumor grade and lympho-vascular invasion, reaching statistical significance