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Some studies have reported higher TIL amounts in atypical and malignant meningiomas as compared with benign meningiomas, while other studies have observed lower TIL numbers with higher meningioma grade [ , , ]. The biological and clinical significance of TILs in meningioma is unclear and further study is required.
However, as for gliomas, the methodology of TIL assessment is non-standardized and needs to be elaborated in systematic investigations. In this review, we have focused on common solid tumors in which data about the potential significance of TILs is available or emerging.
The importance of TILs and host-tumor immune interactions is clearly not limited to these tumor types, and further exploration of less common or less well-studied tumors such as cervical carcinoma, sarcomas, and pediatric malignancies is anticipated with interest. As can be seen from the above discussion, approaches to TIL scoring have varied both between and within tumor types.
Through the efforts of researchers, clinicians and pathologists, the significance of TILs is gaining increasing recognition. However, a standardized methodology would help to increase the quantity and quality of comparable evidence and enable the implementation of TIL scoring in large-scale clinical trials and routine histopathological practice.
The consensus methodology we propose has limitations and many open questions remain, as discussed in part 1 of this review. These methods should be considered a tool for further research, to investigate both the significance of TILs in solid tumors and how we can best assess and describe the host immune response to tumors.
They can be used as a reference against which other methods can be tested, and should be thoroughly validated for reproducibility and utility. Significant results have already been demonstrated using this methodology in diverse tumor types including gastric cancer, lung cancer and laryngeal squamous cell carcinoma.
However, these recommendations may not be translatable into other tumor types, such as gliomas, for which further work is required to develop a standardized, reproducible and valid methodology. As more evidence becomes available, recommendations will be reviewed, expanded and clarified.
It is hoped this proposed standardized methodology will help clinicians, researchers and pathologists to evaluate the utility of TILs assessment with a view to both prognosis and prediction of response to treatment. The authors have no conflicts of interest to disclose. No specific funding was obtained for this project. National Center for Biotechnology Information , U. Adv Anat Pathol. Author manuscript; available in PMC Nov 1. Part 2: TILs in melanoma, gastrointestinal tract carcinomas, non-small cell lung carcinoma and mesothelioma, endometrial and ovarian carcinomas, squamous cell carcinoma of the head and neck, genitourinary carcinomas, and primary brain tumors.
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Abstract Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. Introduction Assessment of tumor infiltrating lymphocytes TILs is growing in importance as evidence emerges of the prognostic and potentially predictive significance of TILs in many different tumor types, and as immunotherapies show exciting results in clinical trials and clinical practice.
TILs in melanoma Reporting of TILs in primary cutaneous melanoma has long been routine in histopathology practice, following the early recognition of their prognostic significance [ 3 — 5 ]. Open in a separate window. Figure 1. TILs in colorectal carcinoma Recognition of the prognostic impact of TILs in colorectal carcinoma dates back to the s [ 40 ].
TILs in upper gastrointestinal tract carcinomas As a group, carcinomas of the stomach, pancreas, and liver are relatively common, and also account for a disproportionately high number of cancer deaths [ 84 ]. Gastric carcinoma Gastric cancer is notable for its associations with infection Helicobacter pylori, Epstein-Barr virus EBV , chronic inflammation, and genomic instability both microsatellite instability and chromosomal instability [ 87 ].
Pancreatic carcinoma Pancreatic ductal adenocarcinomas typically have abundant desmoplastic stroma, which contributes to tumorigenesis [ ], interacts with immune and inflammatory cells [ ], and will be important to consider in the histological assessment of TILs. Hepatocellular carcinoma Many cases of hepatocellular carcinoma are causally linked to chronic inflammation, with viral hepatitis, alcohol, and non-alcoholic steatohepatitis as major underlying contributors. TILs in non-small cell lung carcinoma The immune microenvironment in non-small cell lung cancer has been extensively studied and detailed descriptions exist in the literature [ , ].
Figure 2. Figure 3. Ovarian carcinoma A seminal paper published in by Zhang et al established the prognostic significance of TILs in ovarian carcinoma [ ]. Figure 4. TILs in head and neck squamous cell carcinoma Head and neck squamous cell carcinoma encompasses a heterogeneous group of tumors arising in different sub-sites within the upper aerodigestive tract, including the oral cavity, the oropharynx, larynx and hypopharynx. TILs in genitourinary carcinomas Urothelial carcinoma The successful introduction of intravesical bacillus Calmette-Guerin BCG therapy for high-risk non-muscle invasive urothelial carcinoma over the past decades can be regarded as early proof of the potential effectiveness of immunotherapy in urothelial carcinoma [ , ].
Prostate carcinoma Traditionally, prostate cancer has not been associated with a florid immune response and the potential of prostate cancer to respond to immunotherapy is still questioned [ ]. Renal cell carcinoma Prior to the introduction of tyrosine kinase inhibitors with anti-angiogenic actions such as sunitinib, and mTOR inhibitors such as everolimus, immunotherapy was the mainstay of systemic treatment for metastatic renal cell carcinoma [ ].
TILs in brain tumors The central nervous system has long been considered an immune-privileged organ, but this view is being increasingly challenged as it has become clear that the immune system is active and important in many central nervous system disorders, including neoplastic disease. Gliomas TILs are frequently present in gliomas, although in most cases at relatively low densities [ ]. Meningiomas Lymphocyte infiltration of variable extent is commonly found in meningiomas. Discussion In this review, we have focused on common solid tumors in which data about the potential significance of TILs is available or emerging.
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