Author’s reply to Krishnamurthy et al. and Thiagarajan

Abstract

It was encouraging to note the bolstering responses from experts in the field to the recently published editorial on second primary versus recurrent tumor.[1] The editorial discussed the inconsistencies in the currently used sets of diagnostic criteria and their practical implications, focusing mainly on head-and-neck squamous cell carcinoma (HNSCC). I thank Krishnamurthy et al.[2] and Thiagarajan[3] for their letters, which not only shed light on a few more crucial observations relevant to the topic but also incited further deliberation on possible solutions to the problem at hand. In addition to the peculiar statistical and clinical issues highlighted in the editorial arising from the lack of a standardized definition of a second primary tumor and uniform criteria to distinguish it from recurrence (locally) or metastasis (distantly), there is also the question of how to determine the pathological status of the intervening mucosa. Does this accurate diagnosis mandate invasive pathological sampling of normal-looking intervening mucosa? As raised by Thiagarajan, what would be the diagnostic stand if the intervening mucosa showed dysplasia?[3] Regarding the risk of a second primary tumor, as conjectured by Krishnamurthy et al.,[2] some of the recent studies have reported an apparent protective effect of human papillomavirus (HPV) positivity in HNSCC, that contrasts with the significant increase in the risk of second primary tumors conferred by traditional risk factors like tobacco and alcohol.[4–6] This is not surprising, given the remarkable differences in the molecular mechanisms of carcinogenesis between HPV-positive and HPV-negative tobacco-related HNSCC.[7] Interestingly, in these studies, patients with oral cavity primaries and those with comorbidities were noted to have a significantly higher rate of second primary tumors, suggesting that these factors are also important determinants of the risk of developing second primary tumors in HNSCC.[4,5] As highlighted by Thiagarajan,[3] although the works of Warren and Gates from the 1930s remain the most cited criteria for defining the second primary tumor in the literature, several articles cite Theodore Billroth’s work from the 1880s as the origin of the three-point criteria.[4,5,8] However, the inability to access the original work of Billroth, and consequently, the lack of clarity about the context and components of the criteria described by him, could be some of the reasons for it not being widely adopted or cited. Nevertheless, as highlighted in the editorial,[1] despite the presence of sets of criteria endorsed by the International Association of Cancer Registries and the Surveillance, Epidemiology, and End Results program for a few decades now, researchers still prefer using the Warren and Gates criteria to define second primary tumors, probably for their simplicity and comprehensibility.[4,5] Interestingly, as discussed in both letters,[2,3] a group of researchers from The Netherlands proposed a novel and intriguing classification scheme in 2002 intending to solve the clinical predicament of distinguishing a second primary tumor from recurrent disease with the help of molecular characterization of the tumors.[9] However, not many have explored this approach, probably owing to issues with feasibility, technical challenges, and practical applicability of such a scheme in patient care, as subsequently pointed out by the experts from the International Head and Neck Scientific Group, which also included authors of the 2002 study from The Netherlands.[10] In other words, the practical utility of molecular diagnostics is yet to be streamlined and has a long way ahead. Even if made available in most large centers, standardization and universal adherence may still be challenging.[11] Thus, although molecular profiling is the future, with several added advantages that could aid in therapeutic decision-making until a sensitive and standardized set of molecular criteria are established for separating second primary tumors from recurrent and metastatic tumors, the most feasible solution currently is to standardize the existing clinical guidelines and ensure universal adherence across cancer registries and research groups. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.