The case report is often criticised for its heterogeneity, uncontrolled design and risk of bias. However, in rare cases where no higher-level evidence is available, case reports have proven to be a great resource for clinicians. Systematic review and meta-analysis of case reports has been performed in the literature to study uncontrolled and rare events such as emergency treatment for aortic dissectionReference Murad, Rizvi, Malgor, Carey, Alkatib and Erwin18 and, more recently, cardiac events after Covid-19 vaccines.Reference Fazlollahi, Zahmatyar, Noori, Nejadghaderi, Sullman and Shekarriz-Foumani19 The evidence inferred from these studies has proven useful in clinical decision making. In this study, we employed the same design to investigate the characteristics of head and neck SCC spontaneous regressions.

Incidences of head and neck squamous cell carcinoma spontaneous regression

Historic reviews have put the rate of spontaneous regression at between 1 in 80 000 and 1 in 100 000.Reference Jessy1 Reports of certain types of malignancies regressing are more common than for others, with 1 in 4003 in metastatic melanoma and up to 1 in 100 in metastatic clear cell renal carcinoma.Reference Buchler, Fiser, Benesova, Jirickova and Votrubova20 Other common forms of malignancies that have a higher spontaneous regression rate include leukaemia and lung cancer.Reference Radha and Lopus21 In contrast, only eight cases of head and neck SCC spontaneous regression were identified in this study. A possible explanation is that head and neck cancers have a lower incidence than the above cancers worldwide.Reference Sung, Ferlay, Siegel, Laversanne, Soerjomataram and Jemal22

Reports of spontaneous regressions of all malignancies have surged in recent years. A review performed in 2005 estimated 10 reports per year from 1987 to 2003, while a recent study revealed 89 cases were published in 2021 alone.Reference Hobohm23,Reference Žarković, Jaganjac, Žarković, Gęgotek and Skrzydlewska24 This can be explained by the shift towards evidence-based research in modern medicine, which has made clinicians aware of the importance of biomedical research and encouraged more peer-reviewed publications. Accordingly, a 9 per cent yearly increase in published scientific papers was observed over the past decade.Reference Landhuis25 This is consistent with our findings, where 7 out of 8 of the case reports of head and neck SCC spontaneous regression were published within the past 10 years.

Case characteristics: are subsets of head and neck squamous cell carcinoma more likely to regress than other subsets?

Epidemiological studies showed males are more likely to develop head and neck SCC in a ratio of 2:1 to 15:1, depending on the site of disease.Reference Mehanna, Paleri, West and Nutting26 The majority of the patients are also over 50 years old.Reference Gormley, Creaney, Schache, Ingarfield and Conway27 This is in keeping with our findings, where patients had a median age of 66 years and 6 out of 8 cases were males, reflecting that demographics are unlikely to be a factor in head and neck SCC spontaneous regression.

Head and neck SCC can present with a wide range of symptoms depending on the site of primary disease. Cancers arising from the larynx will usually present with hoarseness or stridor acutely, whereas cancers of the pharynx and oral cavity can present with dysphagia and/or oral ulcerations. Among the cases in this study, patients all presented with expected symptoms with respect to the function of the primary site of tumour. This shows that head and neck SCC which go on to regress spontaneously can often have a typical presentation.

Spontaneous regression has been documented to occur in both early and late stages of malignancies.Reference Papac28 Logically, an early-stage tumour should be more likely to regress. However, in some tumours, such as neuroblastoma, advanced stages of disease are known for their tendency to undergo spontaneous regression.Reference Brodeur29 A subset of late-stage neuroblastoma (stage 4S) has a low telomerase activity, and telomere shortening has been suggested to be an explanation for spontaneous regression in this subset of patients.Reference Hiyama, Hiyama, Yokoyama, Matsuura, Piatyszek and Shay30 This trend was not observed in any current studies in head and neck cancers. Amongst the head and neck SCCs that had been formally staged in this study, two were T1, three were T3 and one was T4, therefore our findings did not confirm that stage of head and neck SCC at diagnosis was associated with spontaneous regression.

Currently, HPV testing is performed for all new oropharyngeal cancers in the UK and USA as per the relevant guidelines.Reference Craig, Anderson, Schache, Moran, Graham and Currie31,Reference Lewis, Beadle, Bishop, Chernock, Colasacco and Lacchetti32 Routine testing for other head and neck cancer sites is not recommended. In our study, p16 immunohistochemistry was performed in two of four oropharyngeal SCCs and in two of four laryngeal SCCs. Only one spontaneously regressed laryngeal cancer was found to be HPV p16-positive. In cervical intraepithelial neoplasia, where HPV is known to be a risk factor, lesions associated with HPV16 are less likely to resolve spontaneously.Reference Trimble, Piantadosi, Gravitt, Ronnett, Pizer and Elko33 Whether the same is true in the head and neck requires larger-scale studies, and perhaps premalignant dysplastic lesions could be investigated as they have a spontaneous regression rate as high as 20 per cent.Reference Rastogi, Puri, Mishra, Arora, Kaur and Yadav34

The latest American Joint Committee on Cancer (eighth edition) guideline recommends that for metastatic p16-positive SCC in the upper jugular lymph nodes with unknown primary, staging of the disease should be on the assumption that the primary is in the oropharynx.Reference Lydiatt, Patel, O'Sullivan, Brandwein, Ridge and Migliacci35 While this represents a population of microscopic tumours not detectable by direct endoscopic visualisation or radiological imaging, some of these primary cancers could have spontaneously regressed after nodal spread. This sequence of events was observed in case 7, where the primary oral cavity SCC had spontaneously regressed but a level II node was revealed to be positive for SCC on neck dissection. The incidence of spontaneous regression is likely to be higher if a proportion of unknown primary cases was in fact spontaneously regressed head and neck SCC.

On the other hand, there are reports of head and neck SCC where only the nodal disease had spontaneously regressed.Reference Kurita, Hirano, Ebihara, Takushima, Harii and Fujino36,Reference Seo, Rooper, Seiwert and Fakhry37 In these cases, the primary tumour was still present when the cervical node metastasis had disappeared without substantial treatment. Interestingly, only the regressed lymph node had been biopsied prior to surgical resection; the primary tumours at the roof of the tongue and the inferior pole of the left tonsil in the two cases were diagnosed radiologically. This is in concordance with the current thinking that biopsy-related microtrauma to the tumour could incite an immune-modulated response.

Mechanism of spontaneous regression

Numerous mechanisms of spontaneous regression, such as epigenetics, hormonal changes and loss of telomerase activity, have been studied.Reference Bodey38 In the current literature, however, the prevailing view is that regression is modulated by a host immune response against the tumour.Reference Papac28 How this immune response is triggered remains a research area of great interest and some proposed mechanisms were demonstrated in our review.

• Eight individual patients from seven countries were reported to have a spontaneously regressed head and neck squamous cell carcinoma

• The sites of the primary were at the larynx and oral cavity, in various stages from T1 to T4, and only one case was p16 HPV positive

• Biopsy-related trauma and micro-disruption of tumour could induce an antitumour immune response, leading to spontaneous regression, and one case had a documented prolonged febrile illness as a precursor event

• Regional induced hyperthermia therapy could have a role in the treatment of head and neck cancers

• Spontaneous regression in head and neck SCC is rare but likely to be under-reported

• A better understanding of how the host immune system can instigate an antitumour response will shed light on developments of novel treatment modalities

Biopsy micro-trauma

Ablation of the primary tumour can induce regression in a distant tumour, which is termed an abscopal effect. The antitumour immune response in these cases is mediated by the upregulation of heat-shock proteins, neoantigens and cytotoxic T cells.Reference Ngwa, Irabor, Schoenfeld, Hesser, Demaria and Formenti39 This mechanism is thought to be shared by micro-disruption of a tumour in biopsies as well.Reference Lopez-Pastorini, Plönes, Brockmann, Ludwig, Beckers and Stoelben40 Operative trauma has been shown to be associated with subsequent regression of the tumour in large case series.Reference Cole41,Reference Challis and Stam42 However, these reviews were published in the last century and are largely outdated. It is difficult to determine if there is an association between spontaneous regressions and biopsy-related trauma. This is because in modern practice, suspicious lesions would almost always be biopsied in the first instance as part of the diagnostic work up. Similarly, in our review, all cases of head and neck SCC spontaneous regressions were preceded by biopsies and, in one case, partial resection of the tumour.

We should expect a much higher incidence of spontaneous regression if biopsy trauma could indeed trigger an antitumour immune response. Nowadays, treatments are always commenced expeditiously on a positive cancer diagnosis. Tumours which otherwise could have spontaneously regressed are promptly treated and the subsequent regression of disease will be attributed to the oncological treatments. In fact, six of eight cases in our review had either refused, delayed or been deemed unfit for treatment, thus allowing interval time for spontaneous regression to take place.

Febrile illness and hyperthermia

Cases of spontaneous regression are often preceded by a febrile illness.Reference Cann, Van Netten and Van Netten43 Sustained hyperthermia has been shown to inhibit tumour cell proliferation in in vitro studies.Reference Curley, Palalon, Sanders and Koshkina44 Cytotoxicity modulated by various compartments of the immune system such as CD8+ T cells, natural killer cells and MHC class ligands are all enhanced when heated at 39.5 to 45°C.Reference Gao, Zheng, Ren, Tang and Liang45 In fact, induced hyperthermia has been used as an adjunct therapy in a wide range of cancers.Reference Wust, Hildebrandt, Sreenivasa, Rau, Gellermann and Riess46 In our review, only case 3 had a documented prolonged febrile illness as a precursor event. Case 6 reported an episode of influenza but there was no mentioning of fever. Case 8 received two doses of AstraZeneca Covid-19 vaccinations, of which fever is a common side effect. Retrospectively, it is difficult to determine if these patients had any true febrile illnesses prior to tumour regression. Nonetheless, hyperthermia therapy has been adopted as standard treatment protocol in a number of centres internationally.Reference Chia, Ho, Tan, Chua and Tuan47 Randomised controlled trials have demonstrated that regional therapeutic hyperthermia, as an adjunct to chemoradiotherapy in the treatment of head and neck cancers, is associated with a higher complete response rate and longer disease-free survival.Reference Kang, Liu, Qin, Wei and Wang48,Reference Ren, Ju, Wu, Song, Ma and Ge49

Micro-organism and oral cavity microbiome

The role of micro-organisms in cancer therapy was first explored with Coley's toxin, where injection of heat-killed micro-organisms was used for the treatment of sarcomas. Modern treatment of urinary bladder cancer involves injection of Mycobacterium bovis directly into the bladder. The reason for the therapeutic effect is thought to be an increased expression of interleukins, interferons and tumour necrosis factors.Reference Kucerova and Cervinkova50 In our review, only one patient hospitalised with peritonitis had a definitive bacterial infection preceding regression of tumour. He also had a prolonged swinging fever, which in itself could have triggered an antitumour response, as discussed. How the microbiome exerts its effect on the head and neck tumour microenvironment is unclear, but it has emerged as an active research area in recent studies.Reference Hayes, Ahn, Fan, Peters, Ma and Yang51