Immune Cells Inside Breast Tumours May Signal Spread to Lymph Nodes

When a woman is diagnosed with early breast cancer, one of the most consequential questions her surgical team must answer is whether the disease has already begun its silent march through the lymphatic system. The answer determines everything from the extent of surgery to the intensity of adjuvant therapy, yet predicting nodal involvement before operation remains stubbornly imprecise. Now, a new study from Malaysia suggests that the answer may be written, in part, by the immune system itself — specifically, by the armies of lymphocytes that infiltrate the tumour and its surrounding stroma.

The research, conducted at Hospital Canselor Tuanku Muhriz of Universiti Kebangsaan Malaysia and published in BMC Cancer, examined 241 women with clinically node-negative early breast cancer, all staged cT1–2N0M0, who underwent sentinel lymph node biopsy between January 2018 and December 2025. The team, led by surgeon Hadija Mustamin together with pathologists and community health researchers, asked a deceptively simple question: does the density of tumour-infiltrating lymphocytes, or TILs, in the tumour stroma correlate with whether cancer cells are found in the sentinel node?

The findings were striking. Among the cohort, 67 patients — 27.8 percent — had metastasis to the sentinel lymph node. But the distribution of that risk was far from even. When pathologists graded stromal TIL levels according to the internationally accepted 2014 guidelines of the International TILs Working Group, they found that two-thirds of the patients fell into the low-TIL category, 17.4 percent into the intermediate category, and 16.6 percent into the high category. Critically, the highest proportion of nodal metastasis occurred in the group with the fewest infiltrating lymphocytes, a statistically significant association with a p value of 0.023.

To understand why this matters, one must appreciate what TILs actually represent. Tumour-infiltrating lymphocytes are immune cells — predominantly T cells — that have migrated from the bloodstream into the tumour microenvironment, a biological indication that the host immune system has recognised the malignancy and mounted a response. In recent years, TIL assessment has graduated from a curiosity of tumour immunology to a practical, reproducible pathology metric. In triple-negative and HER2-positive breast cancers, high TIL counts are already associated with better responses to neoadjuvant chemotherapy and improved survival. What this new study adds is a potential role in the preoperative and perioperative decision-making around the axilla.

The statistical backbone of the study was a two-stage logistic regression strategy. The researchers first screened clinicopathological variables — tumour size, histological type, grade, lymphovascular invasion, hormone receptor status and TIL category — using univariable analyses, and then entered any variable with a p value below 0.25 into a multivariable model. After adjustment, two factors emerged as independent predictors of sentinel node involvement. Higher TIL levels were associated with lower odds of metastasis, with an adjusted odds ratio of 0.977 per unit increase (95 percent confidence interval 0.961–0.994; p = 0.007). Lymphovascular invasion, the histological evidence of tumour cells invading blood or lymphatic vessels, was independently associated with nodal spread, carrying an adjusted odds ratio of 0.290 (95 percent CI 0.156–0.537; p < 0.001), meaning its presence substantially raised the odds of metastasis.

Interestingly, tumour size — long regarded as a cornerstone of nodal risk prediction — was associated with sentinel lymph node metastasis in the univariable analysis but lost its significance once other factors were accounted for. That statistical humility is itself informative: it suggests that within this cohort of small, clinically node-negative tumours, the biology of the tumour microenvironment and the presence of lymphovascular invasion may carry more predictive weight than size alone. If validated, such a shift could change how pathologists’ reports are weighted in surgical planning.

The clinical implications are potentially significant. Sentinel lymph node biopsy, while far less morbid than full axillary dissection, still carries risks of lymphoedema, seroma, nerve injury and infection. A reliable, cheap, microscope-based biomarker that stratifies nodal risk before surgery could, in principle, help identify patients in whom biopsy yields the greatest information, or in the longer term, support more selective approaches to axillary staging. Because TIL scoring requires only routine haematoxylin and eosin slides and a trained pathologist, it is vastly more accessible than genomic assays or advanced imaging, an especially important consideration in resource-constrained health systems such as much of Southeast Asia.

The authors are careful, and appropriately so, about the limits of their work. This was a single-centre, cross-sectional study, which captures association but cannot establish that low TIL levels cause nodal spread. Only a single pathologist scored the slides, raising questions about inter-observer reproducibility that multi-reader studies would need to resolve. The cohort spans tumours of all molecular subtypes, and TIL biology differs markedly between triple-negative, HER2-positive and luminal cancers; subtype-specific analyses in larger, prospective cohorts with external validation will be required before TIL assessment can be folded into clinically useful prediction models for nodal status. The study received no external funding, and the analysis reflects institutional records from one Malaysian tertiary centre.

Nevertheless, the study joins a rapidly expanding body of evidence that the immune microenvironment is not merely a bystander in cancer progression but an active determinant of how tumours behave. A tumour bristling with lymphocytes appears, in this data, to be a tumour less likely to have seeded the regional nodes — a biological narrative that makes intuitive sense, since a robust local immune response may constrain the earliest steps of dissemination. Conversely, an immunologically cold tumour, walled off from immune attack, may enjoy freer rein to invade lymphatic channels and establish footholds downstream.

For patients, the message is not one of immediate change in care — no guideline today spares anyone a sentinel node biopsy on the basis of TIL counts. But it is another step toward a future in which the pathology report of a breast cancer describes not just what the tumour is, but what the body is doing about it. As immunotherapy reshapes oncology and immune biomarkers move from research benches to clinical reports, studies like this one map the terrain where tumour immunology and surgical decision-making converge. Whether the quiet presence of lymphocytes in a tumour’s stroma can one day spare a woman an unnecessary procedure remains to be proven, but this Malaysian cohort offers a compelling early signal that the immune system has been keeping records all along — records pathologists are only now learning to read.

Subject of Research: Association between stromal tumour-infiltrating lymphocyte levels and sentinel lymph node metastasis in early breast cancer

Article Title: Tumour-infiltrating lymphocytes are associated with sentinel lymph node metastasis in early breast cancer: a cross-sectional study

Article References: Tumour-infiltrating lymphocytes are associated with sentinel lymph node metastasis in early breast cancer: a cross-sectional study. (n.d.). https://doi.org/10.1186/s12885-026-17012-z

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17012-z

Keywords: breast cancer, tumour-infiltrating lymphocytes, sentinel lymph node metastasis, tumour immune microenvironment, lymphovascular invasion, sentinel lymph node biopsy, cancer metastasis, tumour immunology, early breast cancer, pathology biomarker, logistic regression, BMC Cancer