Research ArticleClinical Studies

Associations Between ADC Texture Analysis and Tumor Infiltrating Lymphocytes in Brain Metastasis – A Preliminary Study

HANS-JONAS MEYER, ANNE-KATHRIN HOHN, GORDIAN PRASSE, KARL-TITUS HOFFMANN and ALEXEY SUROV
Anticancer Research September 2021, 41 (9) 4549-4554; DOI: https://doi.org/10.21873/anticanres.15267

Abstract

Background/Aim: Tumor infiltrating lymphocytes (TILs) are an important prognostic factor in brain metastasis (BM). This study elucidated associations between apparent diffusion coefficient (ADC) texture analysis and TIL in BM. Patients and Methods: Eleven patients with BM were retrospectively included into the study. TIL levels were analyzed with Leucocyte-common antigen staining. Clinical routine magnetic resonance imaging was used to calculate the texture features. Results: ADC GrayLevelNonUniformity correlated with TILs of the stromal compartment (r=0.67, p=0.02). ADC HighGrayLevelRunEmphasis and ADC Coarseness showed associations with TILs of the tumoral compartment (r=-0.60, p=0.04 and r=0.68, p=0.02, respectively). Conclusion: ADC texture features correlated with TIL levels in BM. ADC texture features could aid in reflecting the complex tumor-micromilieu in a non-invasive manner.

Key Words:

Brain metastasis (BM) is the most common intracerebral malignancy with still a poor prognosis and a median survival of 6 months (1-3). BM represents a heterogeneous tumor group caused by various primary tumors. The common primary tumors comprise lung cancer, breast cancer and malignant melanoma in this order (1).

The levels of tumor infiltrating lymphocytes (TIL) are known to be of prognostic relevance in BM (4). Berghoff et al. showed that CD8+-TIL levels were associated with perifocal edema and with a better median overall survival of BM patients (4). Moreover, TIL levels are also highlighted as an important prognostic marker in several tumor entities throughout oncology (5-7).

Diffusion-weighted imaging (DWI) is a functional imaging sequence, which reflects random water movement (8, 9). The apparent diffusion coefficient (ADC) is the quantification of this water movement. In various investigations, it was shown that ADC value is inversely correlated with cellularity and other important histopathological features in several tumors (8-13).

Regarding BM, the ADC values show a relatively wide range in different primary tumors with corresponding different underlying histological composition (14-18). Nevertheless, ADC values were of prognostic relevance in several studies, which highlights the importance of this imaging sequence in BM (15, 16, 19).

For BM, there is data that ADC values are inversely associated with cell density and cellularity (15, 17). Notably, for BM of lung cancers there were statistically significant differences between EGFR positive and negative tumors (20).

To further analyzed ADC values, texture analysis can be employed, which is a method to quantify the spatial heterogeneity of the ADC values in a defined region of interest (21, 22). With this method, various parameters can be calculated, which show also different correlations with the underlying histopathology of tumors (22).

However, little is known regarding the associations between ADC texture analysis and TIL expression in BM.

Therefore, the purpose of the present study was to elucidate whether TIL levels in surgical specimens are associated with ADC texture parameters of BM calculated by routinely obtained MRI.

Patients and Methods

This study was approved by the institutional review board (Ethic committee of the University of Leipzig) and informed consent was waived. The radiological database of the university hospital was retrospectively screened for patients with BM between 2016 and 2017.

The following inclusion criteria were defined: magnetic resonance imaging (MRI) of the head including DWI sequence– and available histopathology specimen acquired by surgical resection. The following exclusion criteria were defined: previous systemic or local treatment of BM– and insufficient image quality

Patients. Overall, 11 patients with BM were included into the present study. There were 5 (45.5%) women and 6 (55.5%) men with a mean age of 57.1±14.7 years, range=28-78 years.

Imaging acquisition. MRI was performed for surgical planning in clinical routine using a 1.5T scanner (Aera 1.5T, Siemens, Erlangen, Germany) with a standard head coil. DWI was obtained as a multi-slice single-shot echo-planar imaging sequence (TR/TE: 5,900/96 ms; FOV: 250×250 mm; slice thickness: 5 mm; acquisition matrix: 128×128. B-values of 0, 500, and 1,000 s/mm2 were used.

Image analysis. The images were analyzed by a neuroradiology resident (G.P., 5 years of neuroradiology experience) blinded to the histopathology. Texture analysis was performed using validated software (23, 24), resulting in 95 features per case. A polygonal volume of interest (VOI) was placed on all tumor displaying slides according to the boundaries of the T1w contrast media enhancement. Gray-level normalization was performed to minimize the influence of contrast and brightness variation (μ±3 SD), as previously performed (25). Figure 1 displays a representative patient of our cohort.

Figure 1.
Figure 1.

Representative case of a patient sample with a known non-small cell cancer of the lung and a brain metastasis located in the left frontal lobe. A. Postcontrast T1-weighted image in axial plane. A strong contrast media enhancement can be appreciated with small central necrosis. A severe surrounding edema can also be observed. B. The corresponding DWI image of this patients (b-value of 1,000 s/mm2). C. The corresponding apparent diffusion coefficient map with a drawn ROI. The measurement was performed as a whole lesion measurement on every tumor displaying slide. D. The Leucocyte common antigen-stained specimen of this patient. The tumor infiltrating lymphocyte levels in the tumor are 40 per high-power field and in the stromal compartment is 80 per high-power field.

Histopathology analysis. The diagnosis was confirmed by histopathology after tumor resection in every case. Histopathology analysis was performed by an experienced board-certified pathologist (A.K.H.) with 14 years of experience blinded to the imaging results. The histological specimens were deparaffinized, rehydrated, and cut into 5 μm slices. First, the standard Hematoxylin and eosin (HE) staining was evaluated. Then, the histological slices were stained for Leucocyte common antigen (LCA) (CD45, DAKO, dilution 1:150). All histopathology quantifications were performed on a 20-fold magnification. TIL levels were evaluated per high power field.

Statistical analysis. Statistics and graphics creation was performed with Graph Pad Prism 5 (GraphPad Software, La Jolla, CA, USA). Collected data were evaluated by means of descriptive statistics. For correlation analysis, Spearman’s correlation coefficient (r) was used to analyze possible associations for the investigated parameters. Mann-Whitney test was used for group discrimination analysis. In every instance, p-values <0.05 were taken to indicate statistical significance.

Results

The tumors were localized supratentorial in 8 cases (72.7%) and infratentorial in 3 cases (17.3%).

Primary tumors were as follows: 7 patients had non-small cell lung cancer (NSCLC) (63.6%), one patient (9.1%) had colorectal cancer, urothelial cancer, malignant melanoma, and nasopharynx carcinoma, respectively.

The mean TIL levels of the tumoral compartment were 9.5±13.9% and of the stromal compartment 44.4±24.9%. TIL levels in the stromal compartment were significantly higher than TIL levels in the tumor compartment (p=0.001).

The correlation analysis between TIL levels in the tumor compartment revealed statistically significant correlations with ADC HighGrayLevelRunEmphasis and ADC Coarseness (r=-0.60, p=0.04 and r=0.68, p=0.02, respectively; Figure 2).

Figure 2.
Figure 2.

Correlation analysis between apparent diffusion coefficient (ADC) texture analysis and tumor infiltrating lymphocyte (TIL) levels of the tumoral compartment. A. Spearman’s correlation analysis between ADC. HighGrayLevelRunEmphasis and TIL levels in the tumoral compartment (r=–0.60, p=0.04). B. Spearman’s correlation analysis between ADC Coarseness and TIL levels in the tumoral compartment (r=0.68, p=0.02).

TIL levels in the stromal compartment were correlated significantly with ADC GrayLevelNonUniformity (r=0.67, p=0.02). Figure 3 displays the corresponding correlation graph.

Figure 3.
Figure 3.

Spearman’s correlation analysis between apparent diffusion coefficient GrayLevelNonUniformity and tumor infiltrating lymphocyte expression of the stromal compartment (r=0.67, p=0.02).

Discussion

The present study analyzed associations between ADC texture analysis and TIL levels in BM. Presumably, ADC texture analysis can reflect complex tissue compositions of the tumor micromilieu. As shown, different ADC texture features seem to reflect TIL levels in tumoral and stromal compartments. However, there is definite need to confirm the present results in a larger patient sample.

Only few studies investigated possible associations between imaging and histopathology features in BM (15-17, 26-29). In a noteworthy study, Berghoff et al. have investigated the role of different TIL subtypes in patients with BM undergoing surgery (4). One key finding was that CD8+ lymphocytes were inversely associated with the extension of perifocal edema, being more expressed in the patients with less edema (4). Other subtypes including CD3+, CD45RO+, FOXP3+ and PD1+ TIL subtypes were not correlated with edema extension (4). As another key finding of this study, CD3+, CD8+ and CD45RO+ TIL levels were associated with survival, even in multivariate analysis (4). In short, increased levels of TIL are associated with a better outcome in BM.

In a first study, Hayashida et al. investigated the ADC values of 26 patients with BM and could show a clear inverse correlation between ADC and cellularity (17). In other studies, correlations between cell density, ADC values (15) and signal intensities of the DWI sequence were identified (16). Of further note, differences in ADC values were identified between different primary tumors with small cell lung cancer showing the lowest ADC values compared to other primary tumors (14). In another study, the frequencies of metastasis displaying a diffusion restriction, defined by hyperintensity of the DWI sequence, was evaluated. This frequency differed significantly between different primary tumors and was primarily identified in patients with lung cancer (18). Importantly, these studies also identified significant associations of ADC values with overall survival in BM (15, 16, 19).

Another study has investigated associations between T-cell densities with ADC metrics in 26 resected BM (29). It was found that only increased density of CD3+ lymphocytes correlated with decreased fraction anisotropy values derived from diffusion tensor imaging (p=0.037). Moreover, the authors concluded that T-cell response to brain metastases is associated with patient survival time regardless of other different biological factors investigated in this study (29).

Interestingly, there are histological differences of the tumor microenvironment between the primary tumor and the BM. Most evidence has been published for lung cancer. It was shown that BM had higher PD1+ TIL compared to the primary tumor (30), whereas CD8+ TIL levels were significantly lower in BM (31).

For renal cell cancer, most TIL subtypes were equally expressed in the primary tumor and the corresponding BM (32). For other primary tumors, no reliable data is available.

ADC texture analysis was employed to discriminate solitary brain metastasis from glioblastoma multiforme (33).

One can assume that virtual biopsy performed by MRI texture analysis can aid to characterize tissue microstructure including the immune microenvironment, especially when combining different MRI sequences in a radiomics signature. This was shown in another study on glioblastoma in which different sequences could reflect distinctive tissue features (34).

There are some limitations to the present analysis. First, it is a retrospective study with possible inherent bias. However, imaging and histopathology were performed independently and blindly. This should reduce possible bias. Second, the study design allowed only the inclusion of surgical resected metastases. There might be resulting selection bias. Third, the patient sample is small and compared to other patient samples, cases of breast cancer and malignant melanoma patients are underrepresented.

In conclusion, ADC texture parameters could aid in reflecting the complex tumor-micromilieu in a non-invasive manner. Different ADC texture features seem to reflect TIL levels in tumoral and stromal compartment.

Footnotes

  • ↵* These Authors contributed equally to this study.

  • Authors’ Contributions

    Study design: Hans-Jonas Meyer, Alexey Surov; Data collection: Gordian Prasse, Anne Kathrin Höhn; Data processing: Hans-Jonas Meyer, Gordian Prasse, Anne Kathrin Höhn, Karl-Titus Hoffmann; Article preparation and review: Hans-Jonas Meyer, Alexey Surov.

  • Conflicts of Interest

    The Authors report no conflicts of interest in relation to this study.

  • Received July 16, 2021.
  • Revision received August 5, 2021.
  • Accepted August 6, 2021.

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