Characterisation and prognostic value of tertiary lymphoid structures in oral squamous cell carcinoma
© Wirsing et al.; licensee BioMed Central Ltd. 2014
Received: 31 March 2014
Accepted: 18 August 2014
Published: 23 August 2014
Oral squamous cell carcinomas are often heavily infiltrated by immune cells. The organization of B-cells, follicular dendritic cells, T-cells and high-endothelial venules into structures termed tertiary lymphoid structures have been detected in various types of cancer, where their presence is found to predict favourable outcome. The purpose of the present study was to evaluate the incidence of tertiary lymphoid structures in oral squamous cell carcinomas, and if present, analyse whether they were associated with clinical outcome.
Tumour samples from 80 patients with oral squamous cell carcinoma were immunohistochemically stained for B-cells, follicular dendritic cells, T-cells, germinal centre B-cells and high-endothelial venules. Some samples were sectioned at multiple levels to assess whether the presence of tertiary lymphoid structures varied within the tumour.
Tumour-associated tertiary lymphoid structures were detected in 21 % of the tumours and were associated with lower disease-specific death. The presence of tertiary lymphoid structures varied within different levels of a tissue block.
Tertiary lymphoid structure formation was found to be a positive prognostic factor for patients with oral squamous cell carcinoma. Increased knowledge about tertiary lymphoid structure formation in oral squamous cell carcinoma might help to develop and guide immune-modulatory cancer treatments.
KeywordsOral squamous cell carcinoma Prognostic factor Tertiary lymphoid structure B-cell High-endothelial venule Follicular dendritic cell Germinal centre
Oral squamous cell carcinomas (OSCCs) are tumours known to metastasize to lymph nodes at an early stage of their development . Despite current improvements in clinical management of this cancer type, mortality and morbidity rates of OSCC patients have remained high over the last decades, with an average 5-year survival rate of about 50% [2, 3]. The TNM staging of the tumour, and especially the presence and extent of lymph node metastasis (N stage), have considerable prognostic importance for patients with OSCC  and are used to guide treatment strategies. However, tumours of the same clinical stage may respond differently to the same treatment and may also have distinct clinical outcomes .
Considerable interest has been devoted to the complex interplay between tumour cells and host-immune response, and especially to how infiltrating immune cells might affect the clinical outcome of cancer patients. Anti-tumour functions of tumour-infiltrating lymphocytes (TILs), particularly of T-cells, have been observed in numerous types of cancer . Accumulating evidence indicates that infiltrating immune cells may also be involved in the development and progression of oral cancer, where they have shown both favourable and detrimental effects . It is well established that immune cells infiltrating to sites of chronic inflammation organize themselves both anatomically and functionally similar to secondary lymphoid organs (SLOs), a phenomenon called tertiary lymphoid structure (TLS) formation . Similar to lymphoid follicles, TLSs typically comprise aggregates of B-cells in a meshwork of follicular dendritic cells (FDCs) that are then surrounded by T-cells as well as specialized blood vessels referred to as high-endothelial venules (HEVs) . HEVs express the lymphoid chemokine peripheral node addressin (PNAd), which binds to L-Selectin on naive lymphocytes and thus promote lymphocyte recruitment to sites of chronic inflammation . Furthermore, a complex interplay between different lymphotoxin- and chemokine-induced signalling pathways is required for the initiation of TLS formation . In contrast to lymph nodes, TLSs are not encapsulated, resulting in constitutive, direct antigenic stimulation from their surrounding microenvironment . Lymphatic vessels have also been found in association with TLSs, but their functional interplay is not yet fully clarified . The presence of ongoing germinal centre (GC) reactions in B-cell clusters of ectopic lymphoid structures has been reported, indicating that adaptive immunity can be triggered at sites different from SLOs . In autoimmune disorders, formation of ectopic lymphoid tissue is associated with disease progression , whereas TLS development in breast, ovarian, non-small-cell lung, renal and colorectal cancer is reported to be associated with a favourable prognosis [13–23].
The aim of the present study was to evaluate the incidence of TLSs in OSCCs, and if present, analyse whether they were associated with clinical outcome. The study included tissue samples and clinical data from 80 patients diagnosed with OSCCs between 1986 and 2002 at the Diagnostic Clinic – Clinical Pathology, University Hospital of North Norway (UNN). The presence of TLSs was determined based on immunohistochemical staining patterns of B-cells, FDCs, GC B-cells, T-cells and HEVs. We established that the presence of TLSs is a positive prognostic factor for patients with OSCC. Understanding and interpreting TLS formation in OSCC might help to implement and guide immunotherapeutic interventions. In terms of individual clinical management, reliable prognostic markers together with targeted anticancer therapies might improve the consistently low survival rates in patients with oral cancer.
Comparison of clinicopathological variables between 80 OSCC patients with and without TLSs using Pearson’s Chi-square test
(N = 63) (no. (%))
(N = 17) (no. (%))
Age at diagnosis, years
≤ 1 times weekly
> 1 times weekly or daily
Floor of mouth
Surgery local +/− neck resection
Surgery and radiotherapy
Radiotherapy +/− chemotherapy
None or palliative
Antibodies for immunohistochemistry
Mouse anti-CD20, clone L26, Ventana Medical Systems, France
Mouse anti-CD21, clone 2G9, Ventana
Mouse anti-bcl-6, clone GI191E/A8, Ventana
Mouse anti-Podoplanin, clone D2-40, Dako, Glostrup, Denmark
Mouse anit-CD34, clone QBEnd/10, Ventana
Rabbit anti-CD3, clone 2GV6, Ventana
Rat anti-PNAd, clone MECA-79, Biolegend, San Diego
Goat anti-rat light chain antibody, #AP202P, Millipore, Temecula, CA
Manual staining with the PNAd primary antibody was performed as previously described , using HRP-labelled goat anti-rat light chain secondary antibody (#AP202P, Millipore, Temecula, CA) and diaminobenzidine (Dako EnVision + System-Horseradish Peroxidase, Dako) for detection. Counterstaining was done with Harris hematoxylin (Sigma-Aldrich, St. Louis, MO). Finally, the sections were dehydrated in graded alcohol and xylene baths, and mounted with Histokit (Chemi-teknikk, Oslo, Norway). Negative controls were treated identically but with the primary antibodies replaced by the antibody diluting solution. Formalin-fixed, paraffin-embedded human lymph nodes served as positive controls for the PNAd staining. Negative control sections never showed any staining, whereas the positive control sections (lymph nodes) always showed positive staining confined to the cells that were supposed to be positive (data not shown). The specificity of the PNAd antibody was evaluated on consecutive sections from six different OSCC samples and three samples of normal oral mucosa. These OSCC and normal tissue sections were assessed for overlapping immunohistochemical staining for the PNAd antibody, the blood vessel marker CD34 and the lymphatic endothelial cell marker D2-40. In the OSCC samples, sporadic CD34+ blood vessels were to a minor degree positive for PNAd, whereas no D2-40+ lymphatic vessels were positive, indicating a high degree of antibody specificity. No HEV staining was seen in the three samples from normal oral mucosa.
Eighty patients were included in the study. In 25 of the patients, the presence of TLSs was evaluated at a single level in the tumour tissue block. In 45 of the patients – randomly chosen from the 80 patients – TLS formation was evaluated at two discrete levels at about 100 μm distance in the tissue block. Additionally, tumour tissue blocks from 10 of the patients – nine of them negative for TLSs in the superficial level – were cut down completely and presence of TLSs was evaluated at 100 μm distance throughout the tumour sample.
We used a two-step method for TLS detection. First, the tissue sections were immunohistochemically stained for the pan B-cell marker CD20 and assigned to three different groups based on their staining pattern: obvious B-cell aggregates, indistinct aggregates of B-cells and no or scattered B-cells. Second, staining for the FDC marker CD21, the T-cell marker CD3 and the HEV marker PNAd was performed on consecutive sections of those with obvious and indistinct B-cell aggregates. For FDC evaluation, areas with clusters of B-cells were examined at high-power magnification (400×). All tumours that had one or several accumulations of B-cells containing CD21 positive FDCs were defined as TLS-positive. All TLSs also contained HEVs and T-cells. The TLS-positive tumours were further subdivided into classical and non-classical TLSs. A classical TLS was defined as a B-cell aggregate containing a continuous FDC meshwork, and a non-classical TLS as a B-cell aggregate with a more diffuse distribution of the FDCs. Sections from seven of the TLS-positive tumours were stained with BCL-6 to verify the presence of GC B-cells in B-cell clusters of TLSs.
All statistical analyses were performed with the SPSS software version 22.0 for Windows (IBM, Armonk, NY). The association between various clinicopathological variables was examined by the Pearson’s Chi-square test. Disease-specific death (DSD) and disease-specific survival (DSS) curves were estimated in univariate analyses and by Kaplan Meier method. The log-rank test was used to evaluate significant differences between the groups of patients. Variables that were statistically significant in the univariate analysis were entered into multivariate Cox regression analyses to identify independent prognostic factors in the presence of other variables. Validity of the proportionality assumption was verified by plotting log-minus-log plots. P-values less than 0.05 were considered statistically significant.
Presence of TLSs in OSCC
Clinicopathological characteristics and prognostic value of TLSs
Clinicopathologic variables as predictors for 5-year disease-specific death in univariate analysis for 80 patients with OSCC
Patients (N = 80)
5-Year death (%)
Age at diagnosis, years
≤ 1 times weekly
> 1 times weekly or daily
Floor of mouth
TLS single level
TLS multiple level
Results from multiple level analysis: multivariate analysis of 5-year disease-specific death according to Cox’s proportional hazards model*
T stage (1) (T1 [n = 29] v. T2 [n = 27])
0.134 - 2.151
T stage (2) (T1 [n = 29] v. T3/T4 [n = 23])
2.814 - 18.612
N stage (1) (N0 [n = 54] v. N + [n = 20])
0.742 - 4.461
N stage (2) (N0 [n = 54] v. unknown [n = 5])
0.290 - 18.900
TLS (negative [n = 62] v. positive [n = 17])
0.556 - 10.448
In the present study, we have demonstrated TLSs in OSCC by immunohistochemical analyses. To the best of our knowledge, this is the first report of TLSs in OSCCs. TLSs were found in 16% of the patients when a single level of the tumour was assessed, and in 21% of the patients when multiple levels of the tumours were analysed. This is a rather low occurrence compared to what has previously been reported in colorectal cancer and lung cancer, suggesting that the occurrence of TLSs varies among different types of tumours [14, 19, 26]. When assessed at a single level, presence of TLSs was not a significant predictor of survival. However, when analysed at multiple levels, their presence in the tumour was a positive prognostic factor. This indicates that the prognostic value of TLSs depends on the type of analysis, probably due to their rather infrequent occurrence and tumour heterogeneity. In multivariate analyses, only T stage turned out to be an independent prognostic factor. TLS status, however, performed better than N stage, which is recognized as one of the best prognostic factors in OSCCs . In the TLS-positive tumours, either single or multiple TLSs were found in the same tissue section. In some of the TLSs, GC B-cells and FDC meshworks were observed, providing evidence that the TLSs comprised all cells needed to generate a functional immune response. We called lymphoid structures with defined FDC meshworks and GCs classical TLSs, as this phenotype has been mostly described for TLSs in literature. Besides the classical TLSs, we also found TLSs with diffuse accumulations of FDCs and scattered or absent GC B-cells that we termed non-classical TLSs. It remains elusive whether non-classical TLSs have the same immunological properties as classical TLSs. Immunohistochemistry on multiple tissue planes of the same tumour showed in some cases that classical and non-classical phenotypes corresponded to the same ectopic lymphoid structure. This implies that the two different patterns may be artefacts of the methodical approach of TLS detection. This is also supported by the fact that both classical and non-classical TLSs were found on the same tissue plane. Moreover, patients with TLSs showed prolonged survival regardless of TLS subtype, indicating that none of the TLS subtypes alone are particularly associated with survival. However, we found a trend towards better prognosis for patients with classical TLSs or with both classical and non-classical TLSs compared to patients with non-classical TLSs only. This indicates that, in some cases, non-classical TLSs could also represent immature follicles that may later develop into classical TLSs with full immunogenic properties. Previous studies have already reported the presence of fully and not fully mature TLSs in cancer and other inflammatory diseases .
Many questions about TLS development in oral cancer remain to be elucidated. Ectopic lymphoid formation is a common feature in chronically inflamed tissues and has been found in a number of different diseases at various anatomical sites . After the switch from acute to chronic inflammation, gradual accumulation of lymphocytes as well as promotion of lymphangiogenesis and transformation of blood vessels into lymphocyte-guiding HEVs has been observed . In oral cancer, chronically inflamed tissue precedes most of the tumours , providing favourable sites for TLS formation. In our OSCC samples, the TLSs were mainly located in the subepithelial lymphocytic infiltrate close to the tumour front. It would be of great interest to find out why the chronic infiltrate sometimes organizes into these structures. Disclosing the mechanisms that regulate TLS development may give important information on how to improve immune-modulating cancer therapy. Lymphoid neogenesis has been most extensively studied in autoimmune disorders such as rheumatoid arthritis, Sjögrens’ syndrome and Hashimoto’s thyroiditis, where TLSs might contribute to disease progression . In some ectopic GCs, B-cells producing antibodies against self-antigens have been recognized, but data are still sparse . In OSCC, it is not yet clear which antigenic targets the lymphocytes might react to and whether auto-antigens play a role in the induction of TLSs. In terms of viral agents that are linked to human tumours, human papillomavirus (HPV) has become a topic of interest during the last years. While HPV is a known risk factor for oropharyngeal cancer, it probably plays only a minor role in cancers arising in the oral cavity . In the present study, there was no correlation between HPV-status and TLS formation. Although the antigenic stimuli directing TLS formation in OSSC are unknown, it seems likely that the immune-modulating factors that promote TLS development derive from the cancer cells rather than from autoimmunity or infection. Our results show that TLSs are most likely to form in well-differentiated tumours. It has been proposed that tumour growth might be related to stem and amplifying cell patterns, and that dedifferentiation may play a role in the origin of cancer stem cells (CSCs) in OSCC . CSCs are a minority of malignant cells that are thought to be able to attenuate host anti-tumour immune responses . Thus, one could speculate that dedifferentiation makes the tumour cells less antigenic and thereby elicits a milder inflammatory reaction with lower induction of TLSs. Previous studies on lymphoid neogenesis have revealed that clearance of the inflammation-inducing antigen or clinical therapy are able to cause a complete remission of the ectopic lymphoid structure . This might be advantageous in autoimmune diseases to stop aggravation of the disease. However, as TLSs are thought to be conducive for patient survival in OSCC, characterization of stimulating agents might be used therapeutically to promote TLS formation by presentation of the causative agent. Investigation of circulating lymphocytes in blood samples of OSCC patients may provide new insights into the involvement of the host immune reaction in TLS development. A long-lasting chronic inflammation, as in larger tumours, could promote TLS development. In the present study, however, more TLSs were found in smaller tumours, clearly indicating that TLS formation can also take place in the early phases of tumour growth.
We found TLS formation to be a positive prognostic factor for patients with OSSC when tumours were analysed at multiple levels. Thus, patients with TLS-positive tumours might benefit from more restrictive treatment while a closer follow-up and more aggressive therapy should be considered for patients with TLS-negative tumours. However, before we can envisage TLSs as prognostic factors in individual clinical management of OSCC patients, larger studies on ectopic lymphoid structures are needed. Our study shows that correct assessment of TLS by immunohistochemistry requires careful analyses. When assessing CD20 B-cell staining, both dense and more diffuse aggregates of B-cells should be considered as putative TLSs. We found however, that about a third of the TLS-positive patients were missed when analysing only one level in the tissue block. This may be due to the fact that we selected blocks with representative tumour material rather than the tumour blocks with most intense inflammation. By selecting differently, the chance of discovering TLSs on a single tissue level might have increased. PCR-based approaches, such as combining analyses of a combination of mature FDC markers, HEV markers and TLS associated chemokines such as CCL19, CCL21 and CXCL13 , could also decrease the chance of missing TLS-positive tumours. Furthermore, analyses of TLS associated chemokines in serum from cancer patients could be a possible indicator of TLS formation.
The future trend in clinical cancer management points to personalized treatment. The use of biomarkers to guide treatment decisions along with development of immunotherapy may benefit the patient. Thus, understanding TLS formation in OSCC might help to guide targeted anti-cancer therapies and improve the dismal survival rates of patients with oral cancer.
Oral squamous cell carcinomas
Secondary lymphoid organ
Tertiary lymphoid structure
Follicular dendritic cells
Peripheral node addressin
Cancer stem cell.
This work was supported by grants from The Norwegian Cancer Society, The North Norwegian Regional Health Authorities and The Erna and Olav Aakre Foundation for Cancer Research. We are also grateful for advice from Dr. Kristin A. Fenton, Dr. Elin Mortensen and M.Sc. Stine Figenshou at the Department of medical Biology, UiT, and for excellent technical help from Anne-Lise Klodiussen at the Diagnostic Clinic - Clinical Pathology, UNN and Bente Mortensen and Marit Nina Nilsen at the Department of Medical Biology, UiT. We also thank Dr. Gunbjørg Svineng and M.Sc. Maarten Beerepoot for advice and critical revision of the manuscript.
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