Thank you for the opportunity to review this submission. This article sought to review the current evidence of the association of the oral mycobiome (specifically Candida albicans (C. albicans) and oral epithelial dysplasia (OED). This potential association has been the subject of investigation and debate over several decades and, despite advances in research methodology, the relationship between C. albicans and oral carcinogenesis remains equivocal. Nevertheless, review articles on this subject are worthwhile in order to advance and clarify this debate. However, I am unable to recommend publication of this article in its current form for the following reasons (in order in which these issues are raised in the manuscript):
1. Page, lines 16-19. The description that ‘… the multistep process of oral carcinogenesis with a gradual transition from normal lining epithelium to hyperplastic, dysplastic, and finally malignant epithelial changes’ is an oversimplification. There is little evidence to indicate that hyperplasia precedes dysplasia in the clinical situation. Do the authors mean that molecular changes in early (assuming a temporal relationship) carcinogenesis do not correlate with morphological features? Do the authors not concede that malignancy may present without any prior morphological evidence of (so-called) hyperplasia and dysplasia?
2. Page 4, lines 54-56. Is there a particular reason why the authors have opted for the term ‘candidiasis’ instead of ‘candidosis’?
3. Page 5, lines 44-46. The authors cite PMID: 12076705 when stating ‘Previous findings have indubitably shown increased Candida colonization as the epithelial lining of the oral mucosa transforms from normal to hyperplastic and subsequently to dysplastic or invasive’. In my reading of this citation, it would seem that this was a study into oral yeast carriage rather than ‘colonization’. Since the molecular profile of this fungus varies depending on whether the yeast or hyphal form dominates (PMID: 20833374), the authors should distinguish between these forms. This is especially important in the proposed models (Figure 1).
4. Page 5, lines 49-51. ‘ …when comparing patients with different solid or hematological malignancies, head and neck cancer features the highest Candida carriage rate’. Might this not be explained, at least in part, by the effects of treatment i.e. a consequence rather than a cause?
5. Page 6, lines 12-14. Readers might be interested in potential mechanisms of fungal dysbiosis in colorectal cancer, and whether these could be extrapolated to head and neck cancer.
6. Pages 6-7. In their first hypothesis of ‘The oral mycobiome as an initiator of oral carcinogenesis’, how do they authors differentiate the ‘initiator’ and ‘promoter’ roles of C. albicans? Are they using these terms interchangeably?
7. Page 7, lines 19-21. How does the ‘… upregulation of the complement pathway… result in carcinogenesis?
8. Page 7, lines 34-35. The word ‘does’ appears to be missing after ‘OED’.
9. Page 7 lines 53-54. Do they authors really mean ‘Transfection’?
10. Page 8, lines 4-5. Capitalize ‘However’.
11. Page 8, lines 1-8. Readers would benefit from greater detail of the molecular mechanisms postulated in this model. What were the shared pathways between fungal infection and carcinogenesis? Were there any overlapping pathways between these and reactive (hyperplasia/wound healing) processes? Since reactive and oncogenic pathways often overpal, how would the authors distinguish between the two?
12. Page 8, lines 14-18. The authors state that ‘This setting implies that treatment with antifungals cannot resolve the lesion and is not sufficient to treat this multifactorial process, and thus the lesion should be managed as a leukoplakia’. This statement seems overly prescriptive since antifungals may be one (of many) tools in the armamentarium of devices for preventative measures against malignant transformation. Should not the managing physician take into account multiple factors include patient factors and the degree of dysplasia?
13. Pages 8-9. The third hypothesis may be better phrased along the lines of altered epithelial changes (here the authors can posit structural and functional/metabolic according to literature) which create a suitable milieu for the colonization of C. albicans.
14. Page 8, lines 47-49. APECED needs to be defined. How does this support the hypothesis of passive or secondary colonization?
15. Page 9, lines 16-17. ‘…regards...’ should be ‘…regard…’.
16. Page 9, lines 23-28. When the authors state ‘Well-defined non-traumatic white plaques of the oral mucosa, microscopically displaying cytologic and architectural alterations with concomitant Candida infection should be treated with antifungals to facilitate the diagnosis’, does this also apply to those lesions on the severe end of the dysplastic spectrum? Should severe dysplasia/carcinoma in-situ be also subject to antifungals prior to definitive management? In my opinion, the failure to address the full spectrum of dysplastic changes is a shortcoming of this paper. Where is the histomorphological boundary between chronic hyperplastic candidosis and mild epithelial dysplasia with candidosis? At the other end of the dysplasia spectrum bordering on carcinoma in-situ, are the authors suggesting that surgical management should be delayed pending histological assessment of the epithelial response to antifungals? Criteria for separating equivocal from unequivocal dysplasia in the presence of C. albicans would be helpful for physicians and pathologists alike.
17. Page 9, lines 41-42. ‘…sing-out…’ should be ‘…sign-out…’.
18. Page 14, lines 55-60. Reference number 42 is now published and the bibliography should be updated.
19. Page 17, legend to Figure 3. In Case 2, stating that the lesion is mildly dysplastic because it persisted clinically is an assumption, especially since it was not re-biopsied. How would the authors regard this lesion if it was re-biopsied and showed features of hyperkeratosis only? Would they be still confident to state that all the features observed prior to antifungal treatment was still dysplastic and stepwise carcinogenesis had been reversed? How would they know that it was not a case of dysplasia being ‘overcalled’?

It is my view that the authors have satisfactorily addressed the reviewers' comments and that the revised manuscript is substabtially improved.