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Year : 2018  |  Volume : 61  |  Issue : 2  |  Page : 181-186
Interobserver reproducibility of tumor-infiltrating lymphocyte evaluations in breast cancer

1 Department of Pathology, Istanbul Bilim University, Istanbul, Turkey
2 Department of Pathology, Gayrettepe Florence Nightingale Hospital, Istanbul, Turkey
3 Department of Pathology, Acibadem Hospital, Istanbul, Turkey
4 Department of General Surgery, Istanbul Florence Nightingale Hospital, Istanbul, Turkey
5 Department of General Surgery, Istanbul University, Istanbul, Turkey

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Date of Web Publication20-Apr-2018


Aim: Tumor-infiltrating lymphocytes (TILs) have a prognostic value in breast cancer (BC); however, because of the lack of standard evaluation methods, we aimed to assess the interobserver agreement of stromal TILs (sTILs) and intratumoral TILs (iTILs) as well as the effect of hot spot areas and molecular subtyping on the overall agreement. Methods: The study consisted of 121 haematoxylin and eosin (H and E)-stained slides of invasive BC samples obtained from the pathology archives. The TIL assessment was based on the International TIL Working Group recommendations for the percentage of sTILs and was conducted by four pathologists. The percentage of iTILs, the number of lymphocytes in hot spot areas (iTILs-HS), and the overall interobserver agreement for the molecular subtypes were evaluated. The interclass correlation coefficient (ICC) was used to assess interobserver agreement among the four pathologists. Results: The ICC score among the observers for the sTIL percentages was 0.74, and the individual ICC values for each molecular subtype were 0.55, 0.88, and 0.79 for luminal, HER2-positive, and triple-negative tumors, respectively. The compliance value for the iTILs was 0.29 (95% confidence interval (CI) = 0.06–0.48], whereas the compliance value for the iTILs-HS was 0.63 (95% CI = 0.49–0.71). The compliance values for the iTILs-HS subtypes were 0.72, 0.43, and 0.55 for luminal, HER2-positive, and triple-negative tumors, respectively. Conclusion: The IWTILG recommendations are reproducible and reliable. The interobserver agreement of the sTIL percentages was considerably higher for the triple-negative and HER2-positive cases than the luminal cases, whereas the interobserver agreement for the assessment of iTILs-HS in tumors was higher for the luminal subtype.

Keywords: Breast cancer, breast pathology, tumor immunity, tumor-infiltrating lymphocyte

How to cite this article:
Cabuk FK, Aktepe F, Kapucuoglu FN, Coban I, Sarsenov D, Ozmen V. Interobserver reproducibility of tumor-infiltrating lymphocyte evaluations in breast cancer. Indian J Pathol Microbiol 2018;61:181-6

How to cite this URL:
Cabuk FK, Aktepe F, Kapucuoglu FN, Coban I, Sarsenov D, Ozmen V. Interobserver reproducibility of tumor-infiltrating lymphocyte evaluations in breast cancer. Indian J Pathol Microbiol [serial online] 2018 [cited 2021 Mar 4];61:181-6. Available from: https://www.ijpmonline.org/text.asp?2018/61/2/181/230531

   Introduction Top

Breast cancer (BC) is the most common form of cancer among women [1] and is the leading cause of cancer-related death in women.[2] The interaction between stromal cells and cancer cells is critical during the development and growth of several types of cancer.[3] Recently, several studies have reported associations between tumor-infiltrating lymphocytes (TILs) and both disease outcome and treatment response.[4],[5],[6],[7],[8],[9],[10] The role of the immune response in BC is not fully understood, but some reports have demonstrated that elevated lymphocytic infiltration can predict a better prognosis and more robust response to neoadjuvant chemotherapy.[11],[12],[13],[14],[15],[16],[17],[18],[19]

Recently, immune-related therapy has emerged as an effective therapeutic strategy for malignancies such as melanoma, nonsmall cell lung carcinoma, and prostate carcinoma.[20],[21],[22],[23] Thus, objective evaluation criteria to assess prognostic immune response indicators for such treatments are needed. Several studies have shown that there exists a relationship between the presence of TILs in BC (especially in triple-negative cancer) and a complete pathologic response after neoadjuvant chemotherapy.[12],[15],[16],[18],[19] The presence of TILs could serve as an indicator of the individual antitumor immune response in BC; thus, an immunological grade or score should be included in pathology reports.[12] However, evaluating a TIL score in BC is an uncommon pathology practice and is often conducted semiquantitatively based on the subjective assessment of the pathologist because there is no clear consensus on how to conduct objective TIL scoring. Thus, easy, practical, and reproducible criteria to evaluate TILs for predicting the patient response to chemotherapy and immunotherapy are highly desirable. For this purpose, in 2014, the International TIL Working Group (ITILWG) proposed such guidelines that could be used by pathologists.[12] Many studies on TILs in BC have evaluated stromal and intratumoral lymphocytes and have concluded that either or both of these cell types have prognostic significance.[10],[11],[15],[17] Stromal TILs (sTILs) are defined as lymphocytes outside the tumoral nests, and intratumoral TILs (iTILs) are mononuclear cells within tumor nests that directly contact tumor cells.[12]

The expression status of the oestrogen receptor (ER), progesterone receptor (PR), and HER2 receptor is important in determining the chemotherapeutic protocol for treating BC. The presence of both sTILs and iTILs is important for predicting the efficacy of platinum-based neoadjuvant chemotherapy and the prognosis of patients, especially those with triple-negative BC.[11],[16] Although the ITILWG suggests to only evaluate sTILs as the primary parameter and recommend criteria to standardize their evaluation,[12] iTILs are also important in determining the prognosis.[11],[16]

There are some concerns of the ITWILG recommendations. First, the method is too detailed to use routinely, and second, sTILs are difficult to estimate in diffuse tumors. For these reasons, evaluation of only hot spot areas, where TILs are most dense in the tumor, was recommended. This approach could predict the prognosis as well as ITILWG recommendations.[24]

There are many studies that have highlighted the importance of TILs in the prognosis of BC, but only a few have reported the interobserver agreement.[25],[26] In this study, we aimed to evaluate the interobserver agreement of sTILs and iTILs as well as the effectiveness of identifying hot spot areas and molecular subtyping on the overall agreement.

   Methods Top

This study consisted of 169 Haematoxylin and Eosin (H and E)-stained slides of invasive BC samples obtained from the archives of the Department of Pathology at Florence Nightingale Hospital. Tru-cut biopsies, specimens obtained from patients treated with neoadjuvant chemotherapy, and consultation cases were excluded from our analysis. The final study cohort consisted of 121 tissue specimens. The TIL assessment was performed by four pathologists (F. K. C., I. C., F. A., N. K.; experience ranging between 3 and 24 years), two of whom had expertise in breast pathology. The recommendations of the ITILWG were studied in detail by all four pathologists before participation in the study.

For each case, a representative 5-mm-thick H and E-stained slide was selected from the pathology archives. For multifocal tumors, a representative slide from the largest tumor was selected. All 121 slides of invasive tumors in the final cohort were circulated among the four participating pathologists. The data regarding the clinicopathological features of the corresponding patients were collected from pathology reports and maintained in a separate file.

The percentage of sTILs was determined using a light microscope with a ×200 magnification field according to the proposed guidelines set by the ITILWG [Figure 1]a, [Figure 1]b and [Figure 2]. According to the ITILWG, TILs should be evaluated within the borders of the invasive tumor. A full assessment of average TILs in the tumor area by the pathologist should be used. They do not recommend to focus on hotspots areas. The percent of lenfoid cells to the stromal area was assessed in stromal area between tumor nests.
Figure 1: Distribution of stromal tumor-infiltrating lymphocytes according to percentage (a) small stromal area between tumoral nests. Pay attention to small number of lymphocytes in this stroma. When you accept the stromal area as 100% the percentage of area occupied by lymphocytes as accepted as stromal tumor-infiltrating lymphocytes. It is %5 in figure a (b) Large stromal area between tumoral nests. This stromal area is occupied by more lymphocytes than the figure a, it is accepted as 40%

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Figure 2: Dense mononuclear lymphocyte infiltration in stromal areas outside the tumoral areas encircled in red (stromal tumor-infiltrating lymphocytes 80%) (H and E, ×200)

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Because TILs should be assessed as a continuous parameter, the percentage of sTILs is a semiquantitative parameter; for example, 80% sTILs corresponds to 80% of the stromal area presenting a dense mononuclear infiltrate. To assess the percentage values, the dissociated growth pattern of lymphocytes should be accounted. Lymphocytes do not typically form solid cellular aggregates; therefore, a designation of “100% sTILs” would still allow for some empty tissue space between the individual lymphocytes.[12]

Although the ITILWG does not recommend evaluating iTILs, the percentage of iTILs was determined using a light microscope at ×200 magnification in fields inside tumor nest [26] [Figure 3]. In addition to the iTIL evaluation, the entire slide was first viewed under low-power microscopy and then focused on hot spot areas inside the tumor nest, and lymphocytes counted in a single high-power (×400) field within the hot spot were defined as iTILs-HS.
Figure 3: Intratumoral tumor-infiltrating lymphocytes are defined as mononuclear cells either within tumor nests or in direct contact with tumor cells (H and E, ×400)

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To identify the luminal subtypes, the levels of established immunohistochemical markers (i.e., ER, PR, HER2, and Ki-67) were used. The tumor samples were classified as follows: luminal, HER2-negative (ER-and/or PR-positive); HER2-positive, HER2-positive and either ER-and PR-negative or ER-and/or PR-positive; and triple-negative (ER-, PR-and HER2-negative).[27]

The interobserver agreements regarding the sTILs, iTILs, and iTILs-HS were separately and blindly evaluated by each pathologist. The effect of molecular subtypes on the interobserver agreement was also assessed. Analysis of the interobserver agreement for the evaluation of sTILs was performed using an interclass correlation coefficient (ICC) analysis within the SPSS software package version 20 (SPSS Inc, Chicago, IL). To evaluate the agreement among the four pathologists, the formulas reported by Fleiss [28] were used. The interobserver agreement for the sTILs, iTILs, and iTILs-HS was assessed using the ICC with a 95% confidence interval (CI) based on two-way random models. There are no standard criteria available for ICC analysis, but similar criteria are generally used with kappa statistics. In general, kappa values <0.4 are associated with the relatively poor agreement, values of 0.4–0.6 indicate moderate agreement, values of 0.6–0.8 indicate substantial (good) agreement and values >0.8 are associated with excellent (almost perfect) agreement.[29]

The study was approved by the Regional Ethics Committee at Bilim University in İstanbul, Turkey (IRB No.: 47-05).

   Results Top

The patients' ages ranged from 23 to 91 years (mean 54.50 ± 13.52 years). The distribution of the molecular subtypes of the patients was as follows: 76 luminal (71.1%), 23 HER2-positive (19%), and 12 triple-negative (9.9%) cases. The pathological features of the patients are summarized in [Table 1].
Table 1: Histopathological characteristics of the patients included in the study

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According to the ITILWG recommendations, the overall ICC of the sTILs among the four pathologists was 0.78 (95% CI = 0.71–0.84), with ICC values for the individual molecular subtypes of 0.55, 0.88, and 0.79 for luminal, HER2-positive, and triple-negative tumors, respectively. The distribution of the cases based on the TIL category and molecular subtype is shown in [Table 2].
Table 2: The interclass correlation coefficient and 95% confidence interval of the percentage of stromal tumor-infiltrating lymphocytes in tumors based on molecular subtype

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The ICC of sTILs according to tumoral subtypes was 0.73 (95% CI = 0.63–0.81) in invasive ductal carcinomas, 0.78 (95% CI = 0.54–0.91) in lobular cacinomas, and 0.67 (95% CI = 0.30–0.87) among other subtypes. The subgroup analysis of ICC of sTILs according to tumor grade was 0.61 (95% CI = 0.09–0.86) in grade 1, 0.64 (95% CI = 0.48–0.76) in grade 2, and 0.79 (95% CI = 0.66–0.87) in grade 3.

The tumor ratio of the iTIL evaluation and the ICC calculated to determine the agreement correlation was relatively poor (0.29 [95% CI = 0.06–0.48]). The ICC of the iTILs-HS was higher (0.63 [95% CI = 0.49–0.71]) than the ratio of the iTILs. Regarding the iTIL evaluation, the results of our ICC analysis stratified by molecular subtype are presented in [Table 3] and [Table 4].
Table 3: The interclass correlation coefficient and 95% confidence interval of the percentage of intratumoral tumor-infiltrating lymphocytes in tumors based on molecular subtype

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Table 4: The interclass correlation coefficient and 95% confidence interval of the presence of intratumoral tumor-infiltrating lymphocytes by average hot spot score based on molecular subtype

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   Discussion Top

In this study, the overall interobserver agreement for sTILs was good based on the ITILWG guidelines. Swisher et al.[26] published data on the interobserver agreement of this methodology. Despite evaluating sTILs as a continuous variable as suggested by the ITILWG, this group categorized the percentage of sTILs as <10%, 10%–50%, or >50% and observed moderate interobserver agreement (kappa = 0.57). However, another study that strictly adhered to the ITILWG recommendations using a software program reported the near-perfect interobserver agreement.[25]

Studies on interobserver agreement among pathologists assessing TILs in BC have only been investigated for triple-negative tumors;[24],[26] however, in our study, all the BC molecular subtypes were included. On evaluation of the sTILs, the kappa statistics for interobserver agreement according to molecular subtype were 0.55, 0.88, and 0.79 for luminal, HER2-positive, and triple-negative tumors, respectively, with a lower kappa value for the luminal subtype than the other subtypes. This could be due to the more heterogeneous nature of the luminal subtype, as it consists of a mixture of ductal, lobular, and special types of breast carcinoma. Because the number of triple-negative samples was low, a higher interobserver agreement among the triple-negative tumors was observed but likely skewed.

In the literature, iTILs are as important as sTILs, especially regarding disease-free survival.[16] Pathological sections also provide a temporal view of the tumor. Lymphocytes are mobile elements of tissue, and a lymphocyte in the stromal area might migrate into the tumor a short time later.[12] Thus, although not recommended by the ITILWG, evaluation of the iTILs was also conducted by our group. In our study, the interobserver agreement for the evaluation of iTILs was extremely low (ICC, 0.29 [95% CI = 0.06–0.48]) when reported as a percentage. Swisher et al.[26] did not distinguish iTILs and sTILs and found a moderate agreement (ICC = 0.62). However, Hida and Ohi.[24] reported that the method described by the working group was too detailed; rather, they proposed the evaluation of TILs at hot spots and classified the results as low (<10%), intermediate (10–50%), and high (>50%). They argued that this method is easier and more applicable. In our study, the interobserver agreement increased when including the iTILs-HS count (ICC, 0.61 [95% CI = 0.49–0.71]). However, the interobserver agreement of the iTIL percentage in tumors based on molecular subtype was the lowest in triple-negative tumors. The difficulty in the distinguishing iTILs from individual cell necrosis or apoptosis while using H and E-stained slides could explain the low interobserver agreement in iTILs. In contrast, the higher interobserver agreement of the hot spot areas could be due to the evaluation of a smaller area.

Most of the studies in the literature that determined the prognosis and assessed the interobserver agreement of TILs only evaluated triple-negative tumors.[17],[19],[24],[26],[30] In the BIG 2–98 trial study, each 10% increase in intratumoral and sTILs was associated with a 17% and 15% reduced risk of relapse, respectively, and 27% and 17% reduced risk of death, respectively.[15] In another study, for every 10% increase in TILs, the BC-free interval risk reduction was 13% in triple-negative BC.[31] TILs have been associated with higher rates of pathological complete response (pCR) to neoadjuvant therapy especially in triple negative and HER2 positive BC.[32],[33] In primary node negative triple-negative BC patients with TILs 20% or more had excellent 5-year distant metastases-free survival.[31],[34] This could result in studies suggesting that the prognostic significance of TILs is the highest in triple-negative and HER2 positive tumors. However, all the molecular types of BC could be important in standardizing the TIL evaluation criteria; therefore, all the molecular subtypes of BC were included in our study. To the best of our knowledge, this is the first study that evaluated the interobserver variation in assessing TILs in all the molecular subtypes of BC.

The grade of tumor in BC is associated with outcomes of patients. In our study, we find a good ICC between observers in grade and subtypes. In the literature, we found no study that check the ICC in grade and subtypes, but Sawe et al. concluded that there is no correlation between tumoral grade and subtypes with TILs. They accept the immune response to tumoral cells as an independent prognostic factor than grade or subtypes of BC.[35]

The primary limitation of our study was the small number of pathologists who participated. Also, the number of triple-negative and HER2-positive cases included was low. A software program could increase the interobserver agreement, but many programs are only used in scientific studies and are not available in daily clinical practice.

   Conclusion Top

In conclusion, for the evaluation of sTILs, the IWTILG recommendations are reproducible and reliable without stratifying the percentages of sTILs into groups. The interobserver agreement of the sTILs percentage was considerably higher for triple-negative and HER2-positive cases than luminal cases, whereas the interobserver agreement for the assessing iTILs-HS in tumors was higher for the luminal subtype. We suggest that if TILs were evaluated for each molecular subtype of BC, sTILs should be the standard for HER2 and triple-negative tumors, whereas the iTILs-HS is a better metric for evaluating luminal subtypes.

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Correspondence Address:
Fatmagul Kusku Cabuk
Cumhuriyet Avenue, No: 4A -13 Gokturk, Eyup Istanbul
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_131_17

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  [Table 1], [Table 2], [Table 3], [Table 4]

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