Colorectal
.jpg "Chelsea M. Knotts, MD photo")
Chelsea M. Knotts, MD
Complex General Surgical Oncology Fellow
Allegheny Health Network
Pittsburgh, Pennsylvania, United States
Chelsea M. Knotts, MD
Complex General Surgical Oncology Fellow
Allegheny Health Network
Pittsburgh, Pennsylvania, United States
Chelsea M. Knotts, MD
Complex General Surgical Oncology Fellow
Allegheny Health Network
Pittsburgh, Pennsylvania, United States
Rose Blodgett, n/a
Research Associate
Allegheny Health Network, United States
Catherine R. Lewis, MD, PhD (she/her/hers)
Peritoneal surface malignancy fellow
Allegheny Health Network Cancer Institute
Pittsburgh, Pennsylvania, United States
Hyun Park, n/a
Research Associate Senior
Allegheny Singer Research Institute, United States
Ashten Omstead, n/a
Manager Medical Technology & Research
Allegheny Health Network, United States
Neda Dadgar, PhD
Scientist Project Staff
Cleveland Clinic Foundation
Cleveland, Ohio, United States
Ali Zaidi, n/a
Medical Director Research
Allegheny Health Network, United States
.jpg "David L. Bartlett, MD photo")
David L. Bartlett, MD
Faculty
AHN
Pittsburgh, Pennsylvania, United States
Patrick L. Wagner
Director, Complex General Surgical Oncology
Allegheny Health Network Cancer Institute
Pittsburgh, Pennsylvania, United States
Intra-tumoral lymphocyte counts have been established as important biomarkers of prognosis in a number of digestive tumor types. CD3 and CD8 cell density, in particular, are known to impart favorable prognosis in colorectal cancer, and have been utilized to create commercial assays. The prognostic utility of lymphocyte density has not been studied in appendiceal cancer (AC), and may be challenged in settings of carcinomatosis by the inability to define and score a discrete primary tumor, or to identify a tumor center and peripheral edge. We hypothesized that CD3 and CD8 density, or combination metrics thereof, could provide prognostic information in AC.
Methods:
Archival tissue from 74 unique AC patients was subjected to immunohistochemistry for CD3 and CD8. 38 (51.4%) lesions were primary AC tumors, the remainder being peritoneal metastatic lesions. Cell counting using digitally scanned images was performed using the Aperio image analysis platform (Leica). CD3 and CD8 density was assessed individually and then combined into an averaged percentile metric (I-score). These variables, along with CD8:CD3 density ratio, were assessed for association with underlying clinicopathologic variables using linear regression; and with overall or progression-free survival (PFS) using Cox proportional hazards models.
Results:
CD3 and CD8 counts were associated with younger age and lower grade histology (Figure). The CD8:CD3 ratio was not associated with age or grade, but when stratified at its mean level of 0.835, was predictive of PFS. (HR 0.102, 95% CI [0.012, 0.882], p=0.048; Figure). This finding was independent of grade on multivariable analysis. No difference in CD3 or CD8 density was seen on the basis of primary AC tumors versus metastatic lesions. CD3 and CD8 density, as well as CD8:CD3 ratio, were right-skewed and kurtotic in their distributions, indicating the potential presence of outliers in the tail of the distribution with favorable prognosis (Figure).
Conclusions:
Lymphocyte density metrics hold prognostic value in AC, as they do in many other digestive tumors. Below-mean CD8:CD3 density ratio was a grade-independent predictor of poor PFS in this AC series. Follow-up studies will seek to validate these findings in larger datasets, and to further refine the categorization of lymphocytes into more specific functional subsets. These findings may hold increasing importance in predicting eligibility for or response to emerging immunotherapeutic strategies for patients with AC.