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The prognostic role of microarchitecture in tumour-positive lymph nodes in oesophageal cancer patients: Results from the UK MRC OE02 trial
Background
Patients with resectable oesophageal cancer (OeC) have a 25-47% 5-year overall survival (OS). The strongest prognostic factor is pathological lymph node (LN) status. Regional tumour-draining LNs play an important role in the host anti-tumour immune response. We previously demonstrated that the microarchitecture in tumour-negative LNs (LNneg) changes after chemotherapy and predicts OS. It is currently unknown whether neoadjuvant chemotherapy induces microarchitectural changes in regional tumour-positive LNs (LNpos) which might impact patient's OS. We hypothesized that (1) LNpos in OeC patients treated with chemotherapy and surgery contain fewer germinal centres compared to patients treated by surgery alone and (2) that patients with an activated anti-tumour immune response (e.g. more germinal centres and more lymphocytes) in the regional LNpos have a better OS.
Methods
Digitized haematoxylin/eosin-stained sections of 129 OE02 trial patients with at least one LNpos were analyzed (70 treated with surgery alone (S patients), 59 treated with chemotherapy and surgery (CS patients)). The area of the different histological components (lymphocytes, germinal centres, histiocytes, tumour tissue) of the largest LNpos per patient was manually quantified by point counting as surrogate of LNpos microarchitecture. The %area of individual immune features in the tumour-free LN area and %area of tumour were calculated. The relationship between individual histological LN components, largest LNpos diameter, treatment and clinicopathological variables was analyzed. Kaplan Meier method was applied for univariate OS from time of surgery and Cox proportional hazard model for multivariate survival analysis including (y)pT status in the model.
Results
There was no difference in LNpos microarchitecture between treatment arms. Combined analysis showed that tumour tissue occupied (median(range)) 8.9% of the largest LNpos area (0.01-44.4%). Lymphocytes occupied most of the tumour-free LNpos area (median (range) 65.2% LN area (2.1%-87.7%), followed by histiocytes (9.7% LN area (0%-59.3%)) and germinal centres (1.8% LN area (0%-16.9%)). No relationship between individual LNpos components and clinicopathological parameters was found. S patients with a high %area of histiocytes in the LNpos had a poorer survival in univariate (p=0.008; HR 1.05 95% CI (1.01-1.09)) and in multivariate analysis (p=0.04; HR 1.06 (1.02-1.09)). CS patients with a larger area of tumour in the LNpos showed decreased OS in univariate (p=0.04; HR 2.27 (1.29-3.99)) and in multivariate analysis (p=0.01; HR 2.11 (1.19-3.75). No other relationships with survival were seen.
Conclusions
This is the first study to quantify LNpos microarchitecture on haematoxylin/eosin-stained sections and show that LNpos microarchitecture is similar between oesophageal cancer patients treated with chemotherapy and surgery or surgery alone. This might indicate that chemotherapy does not alter the quantitative immune response in tumour-positive lymph nodes of oesophageal cancer patients. Nevertheless, there are differences in prognostic value of histiocytes in tumour-positive lymph nodes in surgery alone patients and residual tumor burden in tumour-positive lymph nodes in chemotherapy patients. The underlying molecular mechanisms of these novel findings warrant further investigations by for example detailed immune-cell phenotyping within lymph nodes and matched primary tumour. Our results need to be confirmed in a second independent series to translate findings into post-surgery patient treatment decisions in the future.
Clinical trial identification
OE02.
Legal entity responsible for the study
The author.
Funding
Cancer Research UK.
Disclosures
D. Cunningham: Research grant / Funding (institution): MedImmune / AZ, Celgene, Bayer, 4SC, Eli Lilly, Clovis, Roche. D. Magee: Shareholder / Stockholder / Stock options: HeteroGenius Limited, HeteroGenius Limited, HeteroGenius Limited; Licensing / Royalties: HeteroGenius Limited, HeteroGenius Limited, HeteroGenius Limited; Full / Part-time employment: HeteroGenius Limited, HeteroGenius Limited, HeteroGenius Limited; Officer / Board of Directors: HeteroGenius Limited, HeteroGenius Limited, HeteroGenius Limited. All other authors have declared no conflicts of interest.
