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Is there any correlation between tumor infiltrating lymphocytes and expression of EGFR in squamous cell carcinoma of head and neck? A retrospective observational study Dasgupta S, Biswas N, Deb AR, Chakrabarti S



   Abstract  

Background: The dismal survival of one of the commonest malignancies of the world, head neck squamous cell carcinomas (HNSCC), has prompted researchers to probe into its various characteristics, especially those which reflect the outcome. Over the years, even though epidermal growth factor receptor (EGFR) and tumor-infiltrating lymphocytes (TIL) have emerged as useful biomarkers of the disease, the two parameters have rarely been considered in conjunction. Aims and Objectives: The study aimed to assess if there is any correlation between TIL levels (both stromal and intratumoral) and site, grade, stage, and EGFR score of HNSCC. Materials and Methods: A retrospective observational study was conducted in which histopathologically confirmed cases of HNSCC were included. The site of tumor, grade, stage, stromal and intratumoral TIL levels, and EGFR score were noted for each case. The data were analyzed using standard statistical tests. Results: The study population consisted of 122 patients with a mean age of 53.8 ± 9.2 years. The oral cavity was the commonest site of tumor (109 cases, 89.3%). Most cases were moderately differentiated (75, 61.5%). Pathological staging showed 66 cases (54%) to be in pT1, and 92 cases (75.4%) to be in pN0. In 68 cases (55.7%), stromal TIL level was high, and intratumoral TIL was low in 102 cases (83.6%). A statistically significant correlation was found between TIL levels and site, grade, pathological stage, and EGFR score of HNSCC. Conclusion: This pioneering study is unique in its exploration of the correlation between two significant biomarkers of HNSCC – TIL and EGFR score.

Keywords: Epidermal growth factor receptor score, head neck squamous cell carcinoma, tumor-infiltrating lymphocytes

How to cite this article:
Dasgupta S, Biswas N, Deb AR, Chakrabarti S. Is there any correlation between tumor infiltrating lymphocytes and expression of EGFR in squamous cell carcinoma of head and neck? A retrospective observational study. Indian J Pathol Microbiol 2022;65:262-7



How to cite this URL:
Dasgupta S, Biswas N, Deb AR, Chakrabarti S. Is there any correlation between tumor infiltrating lymphocytes and expression of EGFR in squamous cell carcinoma of head and neck? A retrospective observational study. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 4];65:262-7. Available from: https://www.ijpmonline.org/text.asp?2022/65/2/262/343179

   Introduction   Top

Evasion of the immune response of the host is one of the hallmarks of cancer progression.[1] Immune infiltrates have in the process, emerged as one of the important prognostic indicators in many solid tumors. The hallmark of these infiltrates constitutes lymphocytes that traverse their way from the bloodstream to enter the tumor, thereby referred to as tumor-infiltrating lymphocytes (TIL).[2]

Head neck carcinomas are one of the commonest solid tumors encountered today with approximately 635,000 new cases being diagnosed worldwide every year. Of these cases, more than 90% are histologically squamous cell carcinomas.[3] The treatment of head neck squamous cell carcinoma (HNSCC) is mainly dependent on the stage of the tumor and consists of various combinations of surgery, radiotherapy, and chemotherapy. Novel therapies such as antibody therapies, cancer vaccines, T-cell transfusions, and cytokine therapies have also been recommended in advanced cases.[4],[5] The dismal prognosis of most HNSCC cases has prompted researchers to focus on the tumor microenvironment in recent times. TIL in HNSCC reflects anti-tumor response by the host, and studies reveal that higher levels of TIL are associated with better prognosis.[6]

Epidermal growth factor receptor (EGFR) is one of the oncoproteins that play a vital role in the pathogenesis of HNSCC. EGFR expression in HNSCC has been associated with tumor progression, metastasis, and refractoriness to conventional therapies. However, this also paves the path for anti-EGFR therapy. EGFR has emerged over the years not only as a prognostic marker but also as a promising therapeutic target.[7]

Both EGFR and TIL are prognostic parameters, and the correlation between the two has been explored in carcinomas of other organs. Cases of -non-small cell carcinoma of the lung with high EGFR expression and low CD8 positive TILs demonstrate a poor response to immunotherapy.[8] It has been stressed in some studies that for combating drug resistance encountered during treatment of EGFR-mutant lung carcinomas with anti-EGFR drugs, it is essential to understand the tumor microenvironment reflected by the TILs.[9] EGFR overexpression has been associated with poor prognosis in carcinomas of the brain, breast, colon, pancreas, and lung. It has been demonstrated that intratumoral CD8 positive TIL level in triple-negative breast carcinoma can predict response to anti-EGFR agents.[10]

It is evident that assessment of correlation, if any, between EGFR expression and TIL score in various solid tumors is important. This helps to understand the tumor microenvironment better and provides valuable information regarding prognosis and therapeutic response. Even though both TIL level and EGFR score are significant biomarkers of HNSCC, a thorough search of the literature revealed very few studies that have taken into account the two parameters together. Hence, a study has been conducted to find out the correlation between TIL level and anatomic site, grade, stage, and EGFR score of HNSCC.

   Materials and Methods   Top

The present study was a retrospective, observational study, conducted over a time span of 1 and a ½ years. All patients with histologically confirmed squamous cell carcinoma (SCC) of the head and neck region were included in the study. Patients having any variant of malignancy of head and neck region besides squamous cell carcinoma, recurrence cases, recipients of chemotherapy or radiotherapy, cases with metastatic deposits of carcinoma to head-neck region from unknown primary sites, and tumors diagnosed by cytological methods only were excluded from the study group.

For each case, detailed clinical history was elicited, and thorough general, systemic, and local examinations were undertaken. The gross and microscopic findings of the cases were noted meticulously. In accordance with WHO criteria, each case was classified as well-differentiated (WD), moderately differentiated (MD), or poorly differentiated (PD) tumors.[7]

The tumor area was delineated in each slide under low power. Degenerated and necrotic areas were excluded. The mononuclear cells were taken into account only in the stromal area of the tumor. Neutrophils, macrophages, and dendritic cells were excluded. Only lymphocytes and plasma cells were counted. The TIL level was classified as “high level ” in cases with 71% to 99% TIL, “moderate level ” in those with 31% to 70% TIL, and “low level ” when the TIL level was between 0% and 30%. Five typical views were chosen under high power, (× 400) for each slide, and the total area of tumor stroma was divided by the area occupied by lymphocytes to arrive at the final score.[11] A “hotspot ” approach was followed so as to ensure that the chosen fields were the most heavily infiltrated areas of the slide. The same method was applied to assess the intratumoral TIL level. Both stromal TIL and intratumoral TIL levels were recorded in each case. The scoring was done independently by two pathologists, and the results were accepted if the differences between the individual scores were less than 10%. When the difference was more, the two pathologists reached an agreement by re-evaluating the slides together.

Immunohistochemical analysis was performed with EGFR using the same method as in previous studies.[12],[13] Normal skin tissues were used as positive controls. Primary antibody was omitted to obtain negative controls. The EGFR clone 2-18C9, (manufactured by Dako) was used in all the cases. Scoring was done after noting the percentage of positive cells and the intensity of staining. The staining intensity was scored as 0, 1, 2, or 3 for negative, weak, moderate, or strong intensity, respectively. The percentage of positive cells was scored in the following manner: <1%: 0; 1%–20%: 1; 20%–50%:2; 50%–80%: 3; >80%; 4. Each slide was independently scored by two observers, and the scores were combined to obtain the final score of expression of EGFR – score 0 to 2 was noted as low expression, 3 to 4 as intermediate, and 5 to 7 as high expression.

All the data were recorded and analyzed using Graph Pad software. Statistical analysis was performed to find out the correlation between stromal and intratumoral TIL levels and site of tumor, grade, stage, and EGFR score using Chi-square test. P value of <0.05 was considered to be statistically significant. The Ethics Committee was obtained. The date of approval is 15th January, 2020.

   Results   Top

At the onset, 149 patients were included in the study. Later, 27 patients were excluded on the basis of the previously defined exclusion criteria. A total of 122 subjects were finally included.

The age of the patients ranged between 31 and 82 years with a mean of 53.8 ± 9.2 years. Most of the subjects were male (76, 62.3%) and the rest female (46, 37.7%). The ratio of males to females was 1.7:1. The commonest location of the tumor was the oral cavity (109 cases, 89.3%). Other sites like the larynx and nasal cavity constituted only 13 cases (10.7%).

Histologically, most of the tumors were found to be moderately differentiated SCC (75, 61.5%). Well differentiated SCC constituted 32 cases (26.2%), and 15 cases (12.3%) were poorly differentiated. On pathological tumor staging, 66 cases (54%) were noted to be in pT1, 36 (29.5%) in pT2, 6 (4.9%) in pT3, and 14 (11.6%) in pT4. Pathological nodal staging revealed 92 cases (75.4%) to be in pN0, 18 (14.8%) in pN1, 9 (7.4%) in pN2, and 3 (2.4%) in pN3.

Stromal TIL level was low in 9 cases (7.4%), moderate in 45 (36.9%), and high in 68 (55.7%). Intratumoral TIL level was found to be low in 102 cases (83.6%). Moderate and high intratumoral TIL levels were found in 10 cases each (8.2%). Chi-square test was used to find out if there is any correlation between the stromal and intratumoral TIL levels. The Chi-square statistic was 143.3199, and the P value was <0.00001. The result was therefore significant at P < .05. EGFR expression was noted to be low in 20 (16.4%), moderate in 32 (26.2%), and high in 70 cases (57.4%) [Figure 1] and [Figure 2].

Figure 1: Low expression of EGFR with high stromal TIL level in a case of moderately differentiated SCC (EGFR, × 100)

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Figure 2: A case of moderately differentiated HNSCC showing high EGFR expression and low stromal TIL level (EGFR, × 400)

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A statistically significant correlation was noted between both stromal and intratumoral TIL levels and the site of tumor. [Table 1] The subsites of the oral cavity involved, and their associations with TIL level and EGFR score have been shown in [Table 2]. Buccal mucosa was the commonest site involved (39 cases, 35.8%), followed by the dorsal surface of the tongue (28 cases, 25.7%). Most of the tumors of the oral cavity showed high stromal TIL levels (63 cases, 57.8%), low intratumoral TIL levels (96 cases, 88.1%), and high EGFR scores (63 cases, 57.8%).

Table 1: Association between stromal and intratumoral TIL levels and site of tumor. The correlation between both stromal and intratumoral TIL levels and site is statistically significant

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Table 2: Distribution of cases in various subsites of oral cavity and their association with stromal and intratumoral TIL levels and EGFR score. Most of the cases located in the oral cavity are associated with high stromal TIL levels, low intratumoral TIL levels, and high EGFR scores

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The correlation between TIL levels and the grade of tumor was also found to be statistically significant. [Table 3] Stromal TIL level and pT stage when compared, a P value <0.00001 was obtained, which is statistically significant. Similar results were noted with intratumoral TIL levels as well. [Table 4] Statistically significant correlation was found between TIL levels (stromal and intratumoral) and pN stage. [Table 5] The P value obtained while comparing EGFR score and stromal TIL level was <0.00001 (statistically significant). The correlation between intratumoral TIL level and EGFR score was also found to be statistically significant (P-value 0.000249) [Table 6].

Table 3: Relationship between stromal and intratumoral TIL levels and tumor grade. Statistically significant correlation was noted between both stromal and intratumoral TIL levels and tumor grade

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Table 4: Correlation between stromal and intratumoral TIL levels and pT stage. The correlation between TIL levels (both stromal and intratumoral) and pT stage is statistically significant

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Table 5: Relationship between stromal and intratumoral TIL levels and pN stage. The association between both stromal and intratumoral TIL levels and pN stage is statistically significant

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Table 6: EGFR score in relation to stromal and intratumoral TIL levels. Statistically significant correlation was observed between both stromal and intratumoral TIL levels and EGFR score

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   Discussion   Top

Many authors have suggested that TIL levels provide more prognostic information than the TNM stage in HNSCC. Others are of the opinion that more detailed prognostic categorization can be achieved by taking both TIL levels and tumor stage into consideration.[11] Faraji F et al.[14] found TIL level to be an independent prognostic marker for recurrence of stage I HNSCC. They also reported that depletion of TIL is an independent high-risk factor for recurrence of human papillomavirus (HPV) associated with oropharyngeal carcinoma.

In the present study, a statistically significant correlation was found between TIL levels (both stromal and intratumoral TIL levels) and the site oftumor. Nguyen N et al.[15] found similar results when they correlated the site of tumor with CD4, CD8, and FoxP3 positive TILs. The correlation between TIL levels and grade and stage of HNSCC was also found to be statistically significant in the present study. This corroborates with the findings of Xu Q et al.[11] who stated that TIL levels are associated with the tumor stage of HNSCC. They reported lymphocytic infiltration to be significantly less in an advanced stage of HNSCC. de Ruiter EJ et al.[16] conducted a meta-analysis including 19 studies, and they concluded that higher TIL levels are indicators of a good prognosis in HNSCC.

The present study was based on the morphologic evaluation of lymphocytic infiltration. It was not possible to undertake immunohistochemical analysis of the lymphocytes to define their subpopulations due to the availability of limited resources. Although that is a limitation of the study, it is interesting to note that other studies have pointed out it may not be necessary to use immunostains in the first place. The authors were of the opinion that subpopulations of TIL do not improve the predictive power of prognosis in HNSCC, rather a simple scoring by morphologic evaluation is sufficient.[17]

It has been pointed out that 40% to 80% of cases of HNSCC show overexpression of EGFR. High positivity for EGFR is a poor prognostic factor, and it is associated with a higher probability of recurrence of HNSCC.[18] In the present study, EGFR was found to be high in 70 cases (57.4%). The EGFR score was noted to have a statistically significant correlation with both stromal and intratumoral TIL levels. Issa HI reported EGFR expression to be associated with a higher stage of HNSCC and lymph node metastases.[19] That EGFR expression is a poor prognostic indicator has also been corroborated by Reimers et al.[20] Verma J et al.[18] noted statistically significant correlation between tumor grade of HNSCC and EGFR score.

Kong CS et al.[21] stated in their study that HPV status of HNSCC does not influence EGFR expression, but the same is not true for intratumoral TIL levels. According to them, the intratumoral TIL level serves as a prognostic indicator only in the case of HPV-negative tumors. This may be the reason why Uppaluri R et al.[22] had suggested a re-evaluation of TIL levels taking into consideration that HPV positive HNSCC is a unique clinical entity. Wansom D et al.[23], however, did not find any association between TIL and HPV status or EGFR score. They reported blood CD8 positive T-cells to have favorable prognostic influence. They found increased blood CD 8 lymphocytes were associated with low EGFR expression, positive HPV status, and better response to chemotherapy in HNSCC. They concluded that blood lymphocytes could not be used as surrogate markers for TIL.

Immunotherapy has been found to be successful in some advanced cases of HNSCC. TIL assessment helps to delineate which patients would benefit from immunomodulation.[24] On the other hand, the importance of the EGFR score also lies in the fact that over the years, it has emerged as a target for monoclonal antibody treatment.[19] Consolidated information regarding EGFR score and TIL level is important in predicting prognosis and response to therapy not only in HNSCC but also in other solid tumors. Feng W et al.[25] reported a statistically significant association between TIL level and EGFR mutation in adenocarcinoma of the lung. They opined that further studies are warranted to delineate the molecular pathways that relate EGFR mutations with the level of infiltration of lymphocytes. Matsumoto Y et al.[26] stressed in their study that the presence of EGFR mutation alone is not sufficient to guarantee a response to anti-EGFR therapy. The tumor microenvironment, (of which TIL is an integral part), is responsible for varied responses among these cases. Garbar C et al.[27] stated that EGFR is one of the membrane glycoproteins that serve as regulatory signals between breast carcinoma cells and TILs, and this is potentially one of the mechanisms that cause therapeutic resistance. In EGFR-mutant colorectal carcinomas, response to immunotherapy is guided by the tumor microenvironment.[28]

In the present study, tumors were found to originate from varied sites and belong to different stages. The oral cavity was the most common site (109 cases, 89.3%) followed by others like the nasal cavity and larynx (13 cases, 10.7%). Similar limitations have also been highlighted in other studies.[16],[22] However, exploration of the correlation between TIL levels and EGFR scores is the novelty of the study. Reporting of TIL is an emerging concept and studies like this are necessary to establish its importance in a malignant condition as heterogeneous as HNSCC.

   Conclusion   Top

The present study is a pioneer work from the eastern part of India. It is unique in its attempt to explore the correlation between TIL level (both stromal and intratumoral TIL levels) and EGFR score in HNSCC. The association between the two was found to be statistically significant. This study also found both stromal and intratumoral TIL levels to have a statistically significant correlation with the anatomic site of tumor, grade, and stage of HNSCC. When these two parameters (TIL level and EGFR score) are taken into account, they provide valuable prognostic information.

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Conflicts of interest

There are no conflicts of interest.

 

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Correspondence Address:
Sudipta Chakrabarti
Department of Pathology, ESI PGIMSR, Manicktala Kolkata, 54 Bagmari Road, Kolkata – 700054, West Bengal
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_1251_20

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[Figure 1], [Figure 2]
 
 
 
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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