Discussion

The rate of distant metastasis at the time of presentation of head and neck SCC was ten per cent in our study cohort, which is comparable to literature-reported rates (3.1–16.5 per cent).^{Reference Liu, Bhayani, Kuchta, Galloway and Fundakowski14–Reference Spector, Chinn, Rosko, Worden, Ward and Divi16} Interestingly, most of our patients with distant metastasis were men and 50 years old or older.

Neither age nor gender showed any statistically significant association with the presence of distant metastasis at the time of diagnosis. Oral cavity, laryngeal, and hypopharyngeal tumours exhibited a greater rate of distant metastasis in our group. However, this study had large number of patients in oral-cavity and laryngeal malignancy groups. When the pattern of distant metastasis was considered with the proportional distrubtion of cases in each site, it was shown that the hypopharyngeal tumours have a greater incidence of distant metastasis than the laryngeal cancers, although this link was not statistically significant. A recent United States population-based study using the American College of Surgeons National Cancer Data Base reported that distant metastasis was seen more often in nasopharyngeal cancers followed by hypopharynx cancers.^{Reference Liu, Bhayani, Kuchta, Galloway and Fundakowski14} Our study included a smaller number of nasopharyngeal cancers, so this variation in the distribution of nasopharyngeal cancer between United States and southern part of India could be attributed to differential rates of distant metastasis reported in nasopharyngeal cancers.^{Reference Haleshappa, Thanky, Kuntegowdanahalli, Kanakasetty, Dasappa and Jacob17}

Factors such as poor differentiation of the tumour, advanced T stage and advanced N stage exhibited significant association with distant metastasis at the time of presentation of head and neck SCC. The results of the present study echo the conclusions of the National Cancer Data Base study from United States, in which, the advanced T stage, positive N stage and N3 status were predictive of the presence of distant metastasis at the time of presentation of head and neck SCC, both by univariate and multivariate analyses.^{Reference Liu, Bhayani, Kuchta, Galloway and Fundakowski14}

Of the various subsites of the head and neck, even though oral cancers are much more common than pharyngeal and laryngeal tumours in our study, the hypopharyngeal and laryngeal cancers had the highest propensity to have distant metastasis at the time of presentation (almost three times more than that of oral and oropharyngeal cancers). This is also reflected by other reports in the literature, suggesting a vigorous pre-treatment workup for distant metastasis in hypopharyngeal cancers.^{Reference Liu, Bhayani, Kuchta, Galloway and Fundakowski14,Reference Chiesa-Estomba, Lechien, Ayad, Calvo-Henriquez, González-García and Sistiaga-Suarez18} Although the exact reasons for the higher propensity of distant metastasis among hypopharynx and larynx cancers are not well understood, the rich lymph–vascular supply of these regions might have a role to play in this regard.^{Reference Pisani, Airoldi, Allais, Aluffi Valletti, Battista and Benazzo19} Nevertheless, since these above-mentioned clinical and histopathological risk factors are also the established risk factors for the occurrence of distant metastasis after curative therapy of head and neck SCC, the presence of these factors should prompt a strict post-therapy surveillance.^{Reference Chiesa-Estomba, Lechien, Ayad, Calvo-Henriquez, González-García and Sistiaga-Suarez18,Reference Liu, Wang, Wu, Zhang and Peng20}

The lung is by far the most common site of distant metastasis, even at the time of presentation of head and neck SCC, as seen in our report as well as in previous studies.^{Reference Liu, Bhayani, Kuchta, Galloway and Fundakowski14,Reference Chiesa-Estomba, Lechien, Ayad, Calvo-Henriquez, González-García and Sistiaga-Suarez18} The other common sites of distant metastasis include the liver and bone, but rarely does head and neck SCC also present with isolated metastatic lesions in the stomach, duodenum, or peritoneum.^{Reference Liu, Bhayani, Kuchta, Galloway and Fundakowski14,Reference Ahmed and Lenza21–Reference Wakasaki, Omori, Sueyoshi, Rikimaru, Toh and Taguchi23}

There are several challenges concerning the choice of investigation that is sensitive as well as cost-effective for detecting the distant metastasis in head and neck SCC.^{Reference Usman, Shetty, Dikhit, Dinker, Kumar and Palod13–Reference Kim, Roh, Kim, Lee, Choi and Nam15} The routine use of computed tomography of the thorax to screen for the most likely site of distant metastasis is not cost-effective in all cases of head and neck SCC, particularly in low- and medium-income countries.^{Reference Usman, Shetty, Dikhit, Dinker, Kumar and Palod13,Reference Khan24} Similarly, although ¹⁸F-FDG-PET/CT could have higher chances of detecting distant metastases compared to chest radiograph or computed tomography, their use as a routine investigation to diagnose distant metastasis at the time of presentation of head and neck SCC is not justifiable in all cases.^{Reference Liu, Bhayani, Kuchta, Galloway and Fundakowski14,Reference Kim, Roh, Kim, Lee, Choi and Nam15} Our findings, which are similar to previous studies, highlight the utility of multiple imaging modalities for examining the pattern of distant metastases.^{Reference Kim, Roh, Kim, Lee, Choi and Nam15,Reference Spector, Chinn, Rosko, Worden, Ward and Divi16}

One of the solutions to detecting distant metastases could be the development of novel and reliable models based on the known clinical and pathological risk factors that could predict the risk of distant metastasis at the time of presentation. In fact, attempts are already being made to develop and validate novel nomogram prediction models for determining the patients who are at high risk of distant metastasis after curative treatment.^{Reference Lu, Chiu, Lan, Peng, Tseng and Hsin8,Reference Liu, Wang, Wu, Zhang and Peng20} Similarly, cellular ratios, such as neutrophil-to-lymphocyte ratio, and molecular markers, such as loss of E-cadherin, have also been explored for their ability to predict the risk of developing distant metastasis after treatment of head and neck SCC. ^{Reference Zanoni, Valero, McGill, Montero, Shah and Wong25,Reference Rodrigo, Martínez, Allonca, Alonso-Durán, Suárez and Astudillo26}

Based on similar lines, if a reliable model could be extended to predict distant metastasis at the time of presentation of head and neck SCC, oncologists could get assistance in choosing the appropriate investigation in each case. For instance, a plain radiograph of the chest could suffice in model-predicted, low-risk cases for distant metastasis, with restriction of ¹⁸F-FDG-PET/CT only to high-risk cases or to those cases with suspicious nodules on a plain radiograph. Such models also could aid multidisciplinary tumour boards in the prognostication of the patients as well as in choosing appropriate therapeutic approaches.

Our study reiterates that distant metastasis is the most critical prognostic factor in head and neck SCC. The results of this study show that survival in head and neck SCC patients with distant metastasis is independent of the site and size of the primary tumour and the status of regional metastasis. However, a recent study, based on an extensive population-based database, with 1240 patients of head and neck SCC who had distant metastasis at presentation, has reported some of the above-mentioned factors as independent prognosticators of overall survival.^{Reference Zhu, Zhang, Luo, Shen and Zhu27} This disparity could be explained by the small sample size and retrospective nature of our study, with missing data on the follow-up in several of our patients, suggesting the need for further large and prospective studies in this regard. Also, although recently approved checkpoint inhibitors and cisplatin-based regimens are known to prolong the survival in metastatic head and neck SCC, we could not analyse the survival in our cohort by factoring the therapeutic regimen offered to our patients, because there was dearth in the relevant data regarding their utility, which mitigated further statistical analysis.^{Reference Devaraja28} Nevertheless, the poor utilisation of immunotherapeutic regimens in low- and medium-income countries has been documented by a recent study from another tertiary care centre.^{Reference Patil, Muthuluri, Choudhary, Parekh, Abraham and Noronha29} On the other hand, there has been increasing acceptance of curative intent therapy for oligometastatic disease of head and neck SCC, in appropriately selected clinical contexts, which also could not have been evaluated in our cohort.^{Reference Bahig, Huang and O'Sullivan30,Reference de Bree, Senft, Coca-Pelaz, Kowalski, Lopez and Mendenhall31}

Lastly, there are a few limitations in the existing guidelines that are used for differentiating the connected tumours from second primary tumours.^{Reference Devaraja32–Reference Geurts, Nederlof, van den Brekel, van't Veer, de Jong and Hart34} These diagnostic dilemma are particularly critical for separating a metachronous second primary tumour from a local recurrence.^{Reference Devaraja32} However, these guidelines are also applicable for differentiating a distant metastasis from a concurrent second primary at a distant site, such as lung or liver, and thus, one cannot rule out a slight overestimation of the distant metastasis rates in this study.^{Reference Leong, Koch, Reed, Eisele, Sidransky and Jin33,Reference Geurts, Nederlof, van den Brekel, van't Veer, de Jong and Hart34}