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
