Oral cancer (OC) affects the lips, oral cavity, nasopharynx, and pharynx, according to the World Health Organization (WHO) and ranks 17th among all malignancies with a suggested 5-year survival rate of around 50%. As with any cancer, early diagnosis is crucial and therefore many diagnostic markers have been developed, specifically salivary biomarkers to enable early diagnosis; the benefits of this are that it is simple, non-invasive, not painful and can be repeated. Examples of these include cytokines (IL-6 and IL-8), immunoglobulin G, insulin growth factor, and lactate dehydrogenase (LDH).
Although salivary LDH can be increased due to multiple reasons, several investigations have found that oral epithelial cells produce the majority of salivary LDH, particularly when oral diseases such as OC and Oral potentially malignant diseases (OPMD) cause increased tissue necrosis.
When compared to a healthy control group, the aim of this study was to see if salivary lactate dehydrogenase (LDH) levels are higher in individuals with oral cancer or oral potentially malignant disorders.
A meta-analysis was carried out. PubMed/MEDLINE, The Cochrane Library, Web of Science, Scopus, and OpenGrey were all searched with certain inclusion criterion that had to be fulfilled to become part of this review. These included:
- Original longitudinal, or case–control studies published in scientific journals
- Studies comparing patients diagnosed both clinically and histologically with OC and/or OPMD affecting the oral cavity
- Unstimulated whole saliva
- Studies written in English and performed on humans only.
Search results were checked by two different researchers to make sure they were comprehensive, and duplicates were eliminated. All complete titles and abstracts of the identified papers were individually reviewed by both reviewers. Any discrepancies were discussed with a third reviewer. The Newcastle-Ottawa Quality Assessment Scale tool (NOS) for case-control studies was used to assess the methodological quality of the chosen studies which showed twelve of the studies were of good quality and one was of fair quality. The standardised mean difference of salivary LDH levels was used as a metric to measure effect. The SD was calculated for studies that displayed the mean and standard error of the and for research where the standard deviation could be computed using the formulas for combining groups.
Ten studies were ultimately included in total for the meta-analysis, all of which were case-control studies. All of the articles that were chosen were published between 2007 and 2020 and included a total of 755 patients in all; of them, 303 had OC, 80 had Oral Leukoplakia (OL), 60 had Oral Submucous Fibrosis (OSMF), 9 had other OPMD, and 303 were in the control group (CG). The groups’ ages ranged from 18 to 86.
The main findings were as follows:
- The results of the meta-analysis revealed that salivary LDH levels in OC patients were significantly higher than in the CG (specifically, that the Oral Leukoplakia (OL) group had higher salivary LDH levels than the CG group, with these differences statistically significant).
- The OSMF group had greater LDH levels than the CG group, even though the difference was not statistically significant
- The study also revealed that LDH levels in the OC group were significantly greater than in the OL group with a SMD of 9.49 (95%CI; 6.97 to 12) p < .00001.
The present systematic review and meta-analysis show that patients with OC have significantly higher salivary LDH levels than CG. In relation to OPMD, the results of this study reflect how salivary LDH levels are also higher in patients with OL compared to the CG. Similarly, it could also be observed how salivary LDH values in patients with OSMF are higher than in the CG, but not significantly. In addition, LDH values were found to be higher in the OC group than in the OL patients.
This is a first of its kind study looking at LDH levels in the saliva and what use it may have as a diagnostic marker for oral cancer. It has been hypothesised that the increase in LDH levels is likely linked to higher lactate generation by tissue, whose cells receive less oxygen because of their altered arrangement, and so rely on anaerobic glycolysis for energy production. The findings of another study that consolidate the results of this study is by Pathiyil and D’Cruz (2017). This showed that salivary LDH may be useful not only in OC and OPMD screening, but also in the post-treatment evaluation of patients, as this study noted a reduction in LDH post treatment.
There are certain limitations of this review that must be considered. The review only reviewed papers written in English, therefore any studies on the issue written in languages other than English may have been overlooked and could be significant. Additionally, the included studies had a lot of clinical and methodological heterogeneity in terms of sample size and actual disparities between studies. Furthermore, all the studies included were case–control studies, which have several drawbacks, including the ease with which selection or reporting bias can be introduced and the retrospective nature of the studies.
Overall, the non-invasive nature of this diagnostic test and the results from this review show that there may be a place for LDH detection in saliva to become more widespread as a screening tool, but likely only as an adjunct to diagnose OC or OPMD and further research is needed on an exact protocol with reference values that would indicate disease.
Iglesias-Velázquez Ó, López-Pintor RM, González-Serrano J, Casañas E, Torres J, Hernández G. Salivary LDH in oral cancer and potentially malignant disorders: A systematic review and meta-analysis. Oral Dis. 2022 Jan;28(1):44-56. doi: 10.1111/odi.13630. Epub 2020 Oct 16. PMID: 32881152.
Pathiyil V, D’Cruz AM. Salivary lactate dehydrogenase as a prognostic marker in oral squamous cell carcinoma patients following surgical therapy. J Exp Ther Oncol. 2017 Sep;11(2):133-137. PMID: 28976136.
Dental Elf -23rd July 2021