Written by Dr Eoin F. Cleere 1 , Professor James Paul O’Neill 2,3
Core Surgical Trainee, Royal College of Surgeons in Ireland, Dublin , Ireland
Department of Otolaryngology, Head and Neck surgery, Beaumont Hospital, Dublin, Ireland
Royal College of Surgeons in Ireland, Dublin, Ireland
1.The head and neck cancer care pathway
A 41 year old man presents to your clinic with a large swelling in his right neck. He is also complaining of some right ear pain, he has been feeling fatigued for the past month and has lost weight although he says he has not been eating much due to some reported pain on swallowing. He is a not a smoker and rarely drinks alcohol. What is your differential diagnosis? Are you concerned about any particular diagnosis?
History and examination
An extensive differential diagnosis exists for patients presenting with a new neck lump. This includes a variety of infective, inflammatory and congenital causes as well as neoplastic disease. In the above scenario history and clinical examination are critical in order to accurately narrow this differential diagnosis. In particular red flag features of head and neck cancer (HNC) must be sought in the history and these include: dysphagia, odynophagia, hoarseness, loosening of teeth or dentures no longer fitting, new neck lump, otalgia, persistent nasal obstruction (particularly unilateral), recurrent, frequent nose bleeds as well as constitutional symptoms of malignancy such as weight loss and fatigue. As your patient has some of these features (new neck lump, otalgia, odynophagia, weight loss and fatigue) you decide a referral to a head and neck clinic is warranted.
He presents to the head and neck surgical clinic where he is examined. Thorough, systematic head and neck examination includes evaluation of the 7 oral cavity subsites, the oropharynx, palpation of all 6 levels within the neck and finally flexible nasal endoscopy to examine the nasal cavity, nasopharynx, base of tongue and vallecula, hypopharynx and larynx including assessment of vocal cord mobility. Worrying features on examination would include non-healing ulcers, an irregular mass in the upper aerodigestive tract or a firm, fixed neck lump. In our patient an irregular looking ulcer overlying his right tonsil is detected and a 4 x 3cm fixed lump is present suspicious for a metastatic lymph node inferior to the angle of his right mandible.
Workup and staging
While this is all suspicious for a tonsillar squamous cell carcinoma (SCC) this patient now requires a biopsy for diagnostic confirmation. Biopsy of any obvious neck lumps may be under taken in the head and neck clinic via fine needle-aspiration cytology while less obvious lumps may need to be biopsied under ultrasound guidance. Assessment of any suspicious area in the upper aerodigestive tract (aside from the oral cavity) will typically necessitate panendoscopy of the upper aerodigestive tract under general anaesthetic. Your patient has an office based fine needle-aspiration cytology of his neck mass and biopsy of his tonsil performed under general anaesthetic. As suspected both results come back positive for an SCC. As the primary site of disease appears to be the right tonsil (within the oropharynx) the pathologist decides to check the ‘p16 status’.
He comes back to the head and neck clinic for the news he has a cancer and he is told he will need to undergo staging. For him this includes cross sectional CT scanning of his neck with contrast to assess his primary tumour and any associated locoregional lymphadenopathy as well as a PET scan to look for metastatic disease. He then needs an MRI to better asses the soft tissue extent of the primary disease.
Subsequently his name is put forward for the weekly head and neck multidisciplinary meeting (MDM) at the nearest HNC tertiary referral centre. Here his case is discussed by other members of the head and neck cancer service such as the radiation oncologist, oncologist, pathologist, radiologist and the head and neck surgeon. The patient is keen to pursue any treatment options available whether it be surgery, chemotherapy, radiotherapy or even a combination of these modalities. Everyone agrees his performance status is good owing to his young age, lack of comorbidities and general health and as such he should be fit for any treatment required. The pathologist has good news, his oropharyngeal SCC is p16+ conveying lower risk human papillomavirus (HPV) associated oropharyngeal disease. His imaging is discussed and he is staged according to the American Joint Committee on Cancer (AJCC) staging guidelines (8th edition) which helps to determine his management plan. The radiologist details just the one cystic 4 cm lymph node that was detected clinically and the primary tumour is approximately 3 cm confined to the right tonsil. No metastatic disease is evident making his disease T2N1M0 – stage I HPV positive oropharyngeal cancer. Considerations for the MDM members prior to deciding a treatment strategy include: tumour location, HPV status, the extent of disease, his performance status and preference to pursue curative treatment. An additional consideration in head and neck cancer care is the functional morbidity associated with any proposed treatment. Key functions such as phonation, swallowing, smell, hearing, the ability to breathe and appearance may all be impacted by treatment of HNC. In some case while surgery may be potentially curative, the necessary functional and aesthetic morbidity to achieve the desired R0 resection render this option not favourable. Additionally, complex reconstructive surgery may be necessary following major HNC surgical resection. In order to avoid the often necessary functional morbidity associated with surgery, radiotherapy with or without concurrent radio-sensitising platinum based chemotherapy is now often the treatment of choice contemporary HNC care. It is now known that in many HNCs chemoradiotherapy based options may provide similar oncologic outcomes to surgical resection. Putting all of this information together it is agreed by the MDM that our patient should undergo concurrent chemoradiotherapy under the care of the radiation oncologist and medical oncologist.
2. Background and epidemiology
HNC comprises of a heterogenous group of diseases affecting several anatomical subsites including: the nasopharynx, oropharynx, hypopharynx, larynx, oral cavity, salivary glands, nasal cavity and paranasal sinuses. Over 90% of HNCs are SCCs with other pathology such as adenocarcinomas, sarcomas and mucosal melanomas encountered infrequently. The critical risk factors for HNC remain smoking and heavy alcohol use. Other associations with HNC include male sex, HPV infection, increasing patient age and socioeconomic depravation.
In 2018, HNC was estimated as the seventh most common cancer worldwide with approximately 890,000 newly diagnosed cases as well as contributing to over 450,000 deaths. The latest National Cancer Registry Ireland (NCRI) report demonstrated that within Ireland 643 patients were diagnosed with HNC and 238 patients died secondary to HNC in 2014. While the incidence of many HNCs has decreased over the last 20 years owing to changes in smoking and alcohol usage within the general population, the incidence of HPV associated oropharyngeal cancer has steadily increased. Population based data from the United States demonstrated a 2.5% year on year increased incidence of HPV associated oropharyngeal cancer between 2002 and 2012.
Staging of HNC is subsite specific and is according to the most recent AJCC Cancer Staging Guidelines (8th edition – 2018) which now reflects the prognostic importance of extra nodal extension into the staging of regional lymph nodes. More than 60% of HNC patients present with either stage III/IV disease and as such the prognosis for many with HNC remains poor (estimated approximately 50% 5 year overall survival).
3. Oropharyngeal cancer
Oropharyngeal SCC includes cancers affecting the tonsils, the oropharyngeal wall, the posterior one-third of the tongue and the soft palate. Our understanding and management of oropharyngeal SCC has undergone a revolution in the last 10 – 15 years. This is a result of head and neck specialists understanding the importance of HPV as a oncogenic driver for some oropharyngeal SCCs as well as recognition of the prognostic importance of HPV in oropharyngeal SCC. This revolution has led to a dichotomy in oropharyngeal SCC management into HPV positive oropharyngeal cancer and HPV negative oropharyngeal SCC. As such contemporary management of oropharyngeal SCC necessitates a determination of HPV status. This is based on either detection of HPV DNA within tumour samples or else via p16 positivity (a surrogate marker of HPV).
HPV is a group of over 200 sexually transmitted viruses. Twelve strains of HPV are recognised as oncogenic (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) by the International Agency for Research on Cancer with HPV 16 the strain most frequently associated with carcinogenesis. As well as oropharyngeal SCC, HPV is implicated in the development of cervical cancer, vulva, vagina, penis and anus. HPV associated carcinogenesis occurs through HPV’s production of E6 and E7 oncogenes within infected cells which inhibit the tumour suppressor genes Rb and p53.
HPV positive oropharyngeal SCC has a tendency to occur in younger male patients and conversely to what was initially thought, it in fact does have an association with smoking and excess alcohol use, although not as strong as other HNCs. In both HPV positive and HPV negative local, early stage disease, either surgical resection or definitive radiotherapy may be potentially curable. Locally advanced disease on the other hand is typically treated by radiotherapy with concurrent platinum based chemotherapy.
Evidence in the last 10 – 15 years has demonstrated that the prognosis of HPV positive disease is far superior to that of HPV negative disease. The first major evidenced to support this was the Radiation Therapy Oncology Group (RTOG) 0129 trial which demonstrated this considerable survival advantage for advanced HPV positive oropharyngeal SCC versus advanced HPV negative oropharyngeal SCC at 8 years (70.9% vs. 30.2%, p < 0.001). With this prognostic benefit in mind the ICON-S study in 2016 analysed over 1900 patients with oropharyngeal SCC. Based on their data they proposed a modification to the old AJCC 7th edition staging guidelines for oropharyngeal SCC by including HPV positivity into the staging algorithm. Their recommendations were subsequently incorporated into the updated AJCC 8th edition staging guidelines for oropharyngeal SCC such that HPV positive and HPV negative disease are now subject to separate TNM staging.
Given the favourable prognosis associated with HPV positive oropharyngeal SCC, treatment morbidity and post treatment quality of life are of major concern. As a result there has been considerable focus within the literature on “De-escalation” strategies for patients with locally advanced HPV positive disease. Early-phase studies have trialled selectively reducing the radiation dose or volume (e.g. the E1308 trial and the OPTIMA trial) with promising results. The De-ESCALaTE HPV randomized control trail compared concurrent cetuximab with radiotherapy versus cisplatin with radiotherapy in an attempt to reduce cisplatin related toxicity. However, the investigators found that cetuximab offered no benefit in reducing treatment morbidity and instead was associated with reduced disease control and therefore recommended that radiotherapy with concurrent cisplatin should remain standard of care. Some patient series utilizing upfront transoral robotic surgery (ECOG-ACRIN E3311) or transoral laser microsurgical resection in locoregionally advanced disease have demonstrated potential for improved functional results with satisfactory survival outcomes in HPV positive disease.
The incidence of oropharyngeal SCC has drastically increased over the last number of years. Similar to other countries worldwide, the NCRI has estimated a 3.7% year on year increase in the incidence of oropharyngeal SCC within Ireland between 1994 – 2014. This is due to an almost epidemic-like increase in the incidence of HPV associated oropharyngeal SCC, thought to be in large part due to increasing HPV infectivity among the general population. Oral sex is the main risk factor for HPV infection. HPV vaccination against the major oncogenic strains of HPV prior to the onset of sexual activity is an effective strategy in preventing the development of HPV associated cancers. To this end the HPV vaccine was first introduced in Ireland for teenage girls in 2010 to prevent cervical cancer. Recognition that HPV vaccination is an effective preventative strategy for other HPV associated cancers like oropharyngeal SCC led to the HPV vaccine also being offered to adolescent males in Ireland from September 2019. As a result of worldwide introduction of HPV vaccination the incidence of HPV positive oropharyngeal SCC is likely to decrease in the future, although this decrease is not expected for 30 – 40 years.
4. Oral cavity cancer
Oral SCC is the most common HNC accounting for just over one-third of cases. Oral SCC may arise in any of the seven oral cavity anatomical subsites. These are: the lips, the upper and lower gingivae, the buccal mucosa, the retromolar trigone, hard palate, anterior two-thirds of the tongue (the most common subsite) and the floor of mouth. Oral SCCs may also arise under dentures and false teeth and therefore it is important to remove these prior to examination.
Surgical resection remains the primary definitive treatment strategy for oral SCCs. Depending on tumour staging at diagnosis this may range from a small local resection to complex ablative resections necessitating flap reconstruction with associated neck dissection. Additional treatment modalities such as radiotherapy or chemotherapy are typically reserved for adjuvant therapy in advanced disease, poor surgical candidates or as treatment of distant metastatic disease. Oral SCCs have a high propensity for spread to locoregional lymph nodes (30 – 40% of patients); the single greatest prognostic marker for HNCs as it is known to decrease overall survival by 50%. Thus, neck dissection is often a critical part of surgical resection in oral SCCs in order to provide important prognostic information to guide adjuvant therapy as well as to remove locoregional disease. Neck dissection is an invasive procedure that involves systematically removing all lymph nodes and associated fibrofatty tissue in a number of defined levels within the neck, with or without the associated ipsilateral sternocleidomastoid, internal jugular vein or accessory nerve. Evidently this procedure is associated with high morbidity and this risk of morbidity is justified in patients with advanced T3 or T4 disease (in whom the risk of nodal disease is greater) as well as those with clinically positive locoregional lymph nodes preoperatively to minimise disease burden. However, there has been debate among head and neck surgeons regarding the best strategy to manage T1 or T2 tumours with a preoperative clinically node negative neck. Some propose elective neck dissection in all cases owing to the propensity of oral SCCs to spread to local lymph nodes and the benefit of the important prognostic information provided by this procedure. Others argue that the approximately 10-15% risk of nodal disease in the T1 or T2 clinically node negative neck does not justify neck dissection and its associated morbidity. Therefore, there has been considerable focus within the literature to define the optimal management of patients with T1/T2 tumours without clinically detectable neck lymph nodes preoperatively. Some have proposed sentinel lymph node biopsy as an alternative to neck dissection in this setting although its role is still under investigation in an ongoing phase II/III trial (NCT04333537).
One such advance in this argument has been the establishment of tumour depth of invasion (DOI) as a negative prognostic indicator in oral SCC. DOI differs from tumour thickness in that it is measured as the deepest point of invasion of the tumour relative to the adjacent basement membrane thus only measuring the infiltrative aspect of the tumour. Recognition of DOI as a negative prognostic marker is due to data suggesting that a DOI >4mm is associated with spread to locoregional lymph nodes as well as a reduced overall survival. The importance of tumour DOI is now reflected in the updated T category for oral SCC in the 8th edition AJCC Staging Guidelines such that: a DOI >5mm may upstage a tumour from T1 to T2 while a DOI >10mm may upstage a tumour to T3 independent of size. Additionally, the importance of DOI is now recognised by major treatment guidelines. For example the latest National Comprehensive Cancer Network (NCCN) guidelines now recommend elective neck dissection for T1 or T2 tumours with DOI >4mm although the discrepancy in the AJCC cut-off of 5mm and the NCCN cut-off of 4mm must be highlighted.
5. Laryngeal cancer
The larynx (or voice box) represents the anatomical inlet to the trachea. It therefore plays a key role in phonation, breathing and preventing aspiration of food and liquids – functions that may be implicated in both presentation and treatment of this disease. Laryngeal cancer is the second most common HNC, representing almost one-third of all HNC cases and may affect any of the three anatomical subsites of the larynx. These are defined relative to the glottis (or vocal cords) as: the supraglottis (above the glottis), glottis and subglottis (below the glottis). This differentiation is important as the affected subsite has implications in the presentation, patterns of spread and of disease.
Glottic and supraglottic SCCs account for over 95% of laryngeal cancers. Glottic tumours tend to display a favourable prognosis. This is in large part due to their anatomical origin at the vocal cords where there is a sparse lymphatic supply. Therefore lymphatic spread is rare unless tumour extension beyond the glottis occurs. The 5 year overall survival in glottic tumours is above 70% (greater than 80% in disease localized to the larynx). In contrast, the hallmark of supraglottic disease is lymphatic spread (which occurs in about 55% of supraglottic tumours) owing to a rich lymphatic supply. Therefore the 5 year overall survival in patients with supraglottic disease is below 50% (greater than 60% if localized to the larynx at presentation).
The treatment of laryngeal cancer as with all HNC is dependent on the TNM staging. Localized low stage disease can be treated effectively with minimally invasive resection or definitive radiotherapy. Historically, the management of locally advanced disease was total laryngectomy – a life-saving yet highly morbid procedure with significant alterations in a patients ability to speak and swallow as well as necessitating a permanent tracheostoma. This paradigm has undergone a shift since publication of the landmark Veterans Association (VA) Larynx and RTOG 91-11 trials. These studies demonstrated comparable survival outcomes in locally advanced laryngeal cancer with either total laryngectomy or concurrent chemoradiotherapy. Crucially, chemoradiotherapy allows for laryngeal preservation in about two-thirds of patients with locally advanced disease. Owing to the ability of chemoradiotherapy to preserve the larynx in the majority of cases this is the initial primary treatment strategy for many of these cases in contemporary practice. However, an exception to this remains T4a disease. Repeated analysis demonstrate a survival benefit for patients with T4a disease undergoing upfront surgical resection in comparison to concurrent chemoradiotherapy. This is reflected in the 2017 American Society of Clinical Oncology (ASCO) guidelines on the use larynx preserving therapy in laryngeal cancer which propose upfront total laryngectomy for patients with T4a disease.
6. Advances in recurrent or metastatic HNC
Almost two-thirds of patients with HNC will either present with metastatic disease or develop a recurrence following initial treatment. These patients have a poor overall survival of less than 1 year. Where feasible locoregional recurrence is treated with either radiation or ‘salvage’ surgery. Unfortunately, this is not possible for many with recurrent or metastatic disease. Prior to 2019, the standard of care was defined by the EXTREME trial which demonstrated a benefit with the addition of Cetuximab to the previous chemotherapy regimen (platinum agent pus 5-fluorouracil) for patients with recurrent or metastatic HNC. The EXTREME regimen increased overall survival from 7 months to 10 months in this population. Given the poor prognosis of recurrent or metastatic HNC considerable efforts have been made to define novel treatment strategies for these patients. One advance to this end has been the recognition that immune system modulators may cause solid tumours to regress. This knowledge has led to the discovery and FDA/EMA approval of the programmed death 1 (PD-1) inhibitors Pembrolizumab and Nivolumab for metastatic or recurrent HNC based on the phase 3 KEYNOTE-048 and CheckMate-141 trials respectively. However, it must be stated that as many as 85% of patients may not confer any benefit from PD-1 inhibitors and as such patient selection remains an issue. This benefit may be predicted by expression of Programmed Death Ligand 1 (PDL-1). The utility of PDL-1 as a biomarker in predicting response to PD-1 inhibitors was demonstrated by trials such as the KEYNOTE-012 and KEYNOTE-055.
Since its approval Pembrolizumab has rapidly gained wide acceptance in the field of head and neck oncology. This is apparent from all the updated major HNC guidelines. The NCCN as well as the combined 2020 European Head and Neck Society / European Society for Medical Oncology / European Society Radiation Oncology (EHNS-ESMO-ESTRO) guidelines now recommend either Pembrolizumab plus cisplatin with 5-fluorouracil (in all cases) or Pembrolizumab monotherapy (in tumours with a PDL-1 expression) as first line therapy in recurrent or metastatic HNC.
7. Cutaneous SCCs of the head and neck
Cutaneous SCC (cSCC) is the second most common nonmelanoma skin cancer and one of the most common cancers diagnosed worldwide. The most common location of cSCC is in the head and neck region and as such these tumours are frequently treated by head and neck surgeons. Risk factors for cSCC include fair skin, sun exposure, previous irradiation and immunosuppression. While cSCC is one of the most common tumours worldwide the exact incidence is difficult to speculate owing to many cSCCs being reported under the umbrella term of non-melanoma skin cancer. In the vast majority of patients diagnosed with cSCC the prognosis is good and they may be treated by excision. However, some patients with cSCC display a propensity to developing local recurrence, disseminated metastatic disease and even dying as a result of their disease. Understanding the factors that predispose patients to an unfavourable prognosis is of critical importance. With this in mind the NCCN has defined 3 risk categories for cSCC and defined separate treatment pathways for these patients based on their risk status. These a classified as Low Risk, High Risk and Very High Risk depending on tumour factors (e.g size, site, degree of differentiation or perineural involvement) and patient factors (e.g immunosuppression). By definition all cSCC in the head and neck region irrespective of tumour or patient features are at minimum High Risk of local recurrence, metastatic disease or death from disease and become Very High Risk if >4cm, poorly differentiated, desmoplastic, invading >6mm or into subcutaneous fat or if vascular or lymphatic invasion is present. It is important to note that the risk status of a cSCC is independent of the tumour AJCC staging, although there are overlaps between features that define High Risk tumours and increased AJCC staging.
Treatment of local disease in cSCC is through either resection (wide local excision or Mohs microsurgery) or else radiotherapy in candidates not suitable for surgery. Operable locoregionally advanced disease in the head and neck may require additional procedures such as neck dissection or parotidectomy. Inoperable locoregional or metastatic disease is managed with chemoradiotherapy. Obtaining a clear margin at initial resection is critical to achieve a good treatment outcome. Patients with a positive margin at first resection have demonstrated a 10 fold increased risk of local recurrence and a 4 fold increased risk of dying secondary to disease. The recommended size of margin at excision varies by tumour risk category. The NCCN recommends a surgical excision margin of 4 – 6mm in Low Risk cSCC. The guidance for High Risk and Very High Risk cSCC is less clear with surgical excision and a ‘wider margin’ proposed. The British Association of Dermatologists (BAD) cSCC guidelines provide more clarity with regards this issue, proposing peripheral margins of at least 4mm for Low Risk, 6mm for High Risk and 10mm for Very High Risk cases. They also propose that in all dimensions at minimum a 1mm clear margin should be sought, including the deep margin (i.e. the margin at the base of the excision), and that a positive margin or margin <1mm increases patients from a Low Risk or High Risk category to a High Risk or Very High Risk category. In order to obtain a clear deep margin the BAD propose at minimum that cSCCs of the head should be excised down to the galea and in other areas the deep excision margin should include muscle, bone or underlying structures as appropriate.
In head and neck cSCCs adequate excision of the deep margin remains a challenge with over 90% of incomplete cSCC excisions in the head and neck as a result of deep margin tumour involvement. The difficulty in achieving adequate deep margin clearance is due to the critical neurovascular structures in close proximity to cSCCs of the head and neck. For example scalp cSCCS may invade the skull and obtaining a satisfactory deep margin in these instances may require excision of dura or even the patient’s brain. Other cases overlying and invading the temporal bone will necessitate wide local excision, parotidectomy and lateral temporal bone resection. This challenge in achieving adequate deep margin clearance given the anatomical constraints in the head and neck region in part explains why cSCCs in the head and neck are considered High Risk by the NCCN.
8. Thyroid cancer
While not strictly falling under the umbrella of HNC, specialists dealing with HNC frequently also treat thyroid cancer. Thyroid cancer largely refers to 4 distinct histological subtypes: papillary thyroid cancer, follicular thyroid cancer (collectively termed ‘differentiated thyroid cancer’ (DTC)), medullary thyroid cancer and anaplastic thyroid cancer. DTC accounts for well over 95% of cases. Risk factors for thyroid cancer differ from the typical HNC risk factors and these include: female sex, previous ionizing radiation, increased access to healthcare and family history. DTC has an excellent prognosis with long-term survival in well over 90% of patients following curative surgical resection. Patients with adverse features such as a large tumour (>4cm) or a tumour with extrathyroidal extension may undergo postoperative Radioactive Iodine (RAI) adjuvant therapy
Over the last half century the incidence of thyroid nodules and thyroid cancer has risen astronomically with some referring to it as an epidemic. Despite this, the observed mortality due to thyroid cancer worldwide has remained persistently low overall. This has led to the recognition that this thyroid cancer ‘epidemic’ is not in fact an epidemic of disease, but rather an epidemic of overdiagnosis of small, low-risk mainly papillary tumours due to increased availability of crosssectional imaging. This epidemic of over-diagnosis led to a huge number of patients undergoing unnecessary thyroid surgery for what is largely a non-lethal disease. Thyroid surgery is not without risk, with life-altering and potentially life-threatening complications such as recurrent laryngeal nerve injury, permanent hypocalcaemia and neck hematoma. Thus, there has been considerable focus on strategies to confront this epidemic of overdiagnosis and over-treatment. This has been reflected by the latest American Thyroid Association (ATA) guidelines which now propose that thyroid nodules <1cm should not be biopsied. Additionally, they recognized active surveillance as a reasonable strategy for low risk papillary thyroid cancer based on data from two Japanese cohorts which demonstrated no deaths among patients undergoing active surveillance with papillary microcarcinomas. It must be noted that active surveillance has yet to gain widespread acceptance.
However, the majority of detected thyroid nodules are benign and therefore considerable effort has been made to define a robust, accurate and efficient work-up for these patients in order to accurately diagnose or exclude malignant disease. The current paradigm is that patients with a detected thyroid nodule firstly undergo an ultrasound examination of their thyroid gland. Subsequently nodules that appear suspicious on ultrasound then undergo fine-needle cytology. This is scored cytologically according to classifications such as the Thy or Bethesda. One major limitation of these classifications is that a proportion of nodules will score an intermediate cytological score where the nodule is most likely but not definitively benign. This present paradigm poses a challenge as to definitively rule a cancer in or out for these indeterminate nodules, patients must undergo a diagnostic hemithyroidectomy. Since ultimately 70-80% of these indeterminate nodule are ultimately benign, this exposes a great number of patients to unnecessary surgical risk. As such there has been considerable effort to define a more accurate classification for these nodules with strategies such as genetic profiling, radiomic analysis and even serial imaging with fine needle cytology being trialled although no definitive consensus has yet been reached.
References available on request
For anyone looking for further information on head and neck cancer care we would recommend this excellent overview from the Lancet: https://doi.org/10.1016/ S0140- 6736(21)01550-6