Introduction
The National Comprehensive Cancer Network (‘NCCN’) guidelines recommend routine thyroid lobectomy on the side of a laryngeal cancer for advanced laryngeal cancer requiring total laryngectomy, and this is common practice.Reference Brennan, Meyers and Jafek1–3 Yet, thyroid gland invasion by laryngeal cancer is uncommon, with an overall pooled incidence of 10.7 per cent.Reference Kumar, Drinnan, Robinson, Meikle, Stafford and Welch4 In addition, hemithyroidectomy with total laryngectomy is associated with a 32–89 per cent risk of hypothyroidism, with a relative risk of 2.1–3.6.Reference Gürbüz, Açikalin, Tasar, Çakli, Yorulmaz and Erdinç2,Reference Léon, Gras, Pérez, Rodríguez, de Andrés and Orús5–Reference Mourad, Saman, Sawhney and Ducic10
Rendering a patient as hypothyroid may be problematic if follow up is unreliable, or if the ability to monitor and treat hypothyroidism is unavailable, as it is in much of the developing world.Reference Fualal and Ehrenkranz11 Therefore, thyroid-sparing laryngectomy has been advocated to reduce the need for thyroid hormone replacement, with ipsilateral lobectomy or total thyroidectomy reserved for: intra-operative suspicion of thyroid involvement, cancers with more than 10 mm of subglottic extension, subglottic cancers, tumour (T) stage T4 cancers extending through thyroid cartilage, and T4 pyriform sinus cancers.Reference Biel and Maisel12 By employing this policy, thyroid-sparing laryngectomy surgery may be performed without adversely affecting oncological control when carried out in selected patients with advanced laryngeal and hypopharyngeal carcinoma.Reference McGuire, Viljoen, Rocke, Fitzpatrick, Dalvie and Fagan13
Aims
The study aimed to determine whether preserving the whole thyroid, compared to a single lobe, does indeed significantly lower the incidence of hypothyroidism in the setting of total laryngectomy with or without adjuvant radiotherapy.
Materials and methods
We conducted a retrospective, cross-sectional study of all patients who underwent total laryngectomy or laryngopharyngectomy for laryngeal and hypopharyngeal squamous cell carcinoma from 2009 to 2019 at Groote Schuur Hospital in Cape Town, South Africa. Institutional ethics approval was obtained. Patients were excluded on the following grounds: undocumented intra-operative status of the thyroid gland; patient outcome unavailable; patients who did not complete at least six months’ follow up; or patients who were lost to follow up.
Patients were divided into either an euthyroid group or a hypothyroid group. The euthyroid group consisted of patients with normal thyroid-stimulating hormone (TSH) and normal free thyroxine (FT4) levels. The hypothyroid group included patients with subclinical hypothyroidism (increased TSH and normal FT4) and overt hypothyroidism (increased TSH and decreased FT4). The normal range of TSH was regarded as 0.27–4.20 mIU/l and the normal range of FT4 as 12.0–22.0 pmol/l. Patients already commenced on thyroid replacement therapy were included in the hypothyroid group.
The two groups were compared in terms of age, gender, cancer stage, whether the thyroid gland was spared or sacrificed during surgery, and whether they received post-operative radiotherapy.
The radiotherapy technique at our institution evolved over the time of the study. Before 2012, patients were treated using three-dimensional techniques, and the stoma was not routinely irradiated. Since 2012, three-dimensional conformal radiotherapy and intensity modulated radiotherapy have been employed. The current protocol advocates stomal irradiation in patients with positive surgical margins, subglottic extension, or positive level 4, 5 or 6 nodal metastases.
The Fisher's exact test was used to determine whether there was an association between two categorical variables. A p-value of less than 0.05 was taken as the level for significance.
Results
Eighty-four patients met the inclusion criteria for the study. The median age at surgery was 57 years (interquartile range, 51–65 years). The male to female ratio was 4.6:1. A summary of patients’ characteristics is presented in Table 1.
Demographics of euthyroid and hypothyroid groups
Forty-six patients (54.8 per cent) were euthyroid and 38 (45.2 per cent) were hypothyroid. Age and local tumour extension (T stage) were not significant risk factors for developing hypothyroidism. Of patients who underwent thyroid-sparing total laryngectomy, 36.4 per cent (20 out of 55) were hypothyroid, compared to 62.1 per cent (18 out of 29) of patients who underwent hemithyroidectomy (p = 0.037).
Adjuvant radiotherapy was a significant risk factor for developing hypothyroidism: 58.9 per cent of patients (33 out of 56) who underwent adjuvant radiotherapy became hypothyroid, compared to 17.9 per cent (5 out of 28) who received no adjuvant radiotherapy (p = 0.001).
In patients who underwent thyroid-sparing total laryngectomy without adjuvant radiotherapy, 9.1 per cent (2 out of 22) had hypothyroidism, compared to 50 per cent (3 out of 6) who underwent hemithyroidectomy and no adjuvant radiotherapy (p = 0.05).
In the thyroid-sparing with adjuvant radiotherapy group, 54.5 per cent of patients (18 out of 33) were hypothyroid; in the hemithyroidectomy with adjuvant radiotherapy group, 65.2 per cent (15 out of 23) were hypothyroid (p = 0.582).
Discussion
The principal reasons for performing thyroid lobectomy as part of a total laryngectomy are to obtain clear surgical resection margins should there be direct tumour extension to the thyroid gland, and to clear occult paratracheal cervical metastases with subglottic and hypopharyngeal carcinomas.Reference Ogura14–Reference Harrison16 The potential oncological benefits of thyroid lobectomy should, however, be weighed against the morbidity of iatrogenic hypothyroidism.
Thyroid preservation is appropriate when intra-operative inspection of the larynx shows no extralaryngeal extension or when paratracheal nodal metastases are not a concern. It may be performed without adversely affecting oncological control when carried out in selected patients with advanced laryngeal and hypopharyngeal carcinoma.Reference McGuire, Viljoen, Rocke, Fitzpatrick, Dalvie and Fagan13 Intra-operative suspicion of thyroid involvement, cancers with more than 10 mm of subglottic extension, subglottic cancers, T4 cancers extending through thyroid cartilage, and T4 pyriform sinus cancers warrant ipsilateral lobectomy or total thyroidectomy.Reference Biel and Maisel12
Medical therapy for hypothyroidism is relatively inexpensive and is readily available in developed countries (a year's worth of generic levothyroxine costs the equivalent of USD $8.00). However, many patients in developing countries cannot afford or access treatment or monitoring of thyroid function. Current management of thyroid disease in the developing world is comparable to that received by a patient in North America or Western Europe 50 years ago.Reference Fualal and Ehrenkranz11 Hypothyroidism goes undetected unless patients are frequently screened for two years after surgery, and untreated hypothyroidism may contribute to poor wound healing and cause depression.Reference Buisset, Leclerc, Lefebvre, Stern, Ton-Van and Gosselin8,Reference Biel and Maisel12,Reference Cannon17,Reference Murken and Duvall18 It would therefore be beneficial to spare the thyroid gland to prevent this morbidity and to decrease the burden of disease on the already strained healthcare systems in developing countries.
Age and gender
The incidence of hypothyroidism in the normal population is 0.4 per cent per year in women and 0.06 per cent per year in men; the expected prevalence of clinical hypothyroidism is 1–2 per cent.Reference Vanderpump and Tunbridge19,Reference Vanderpump, Tunbridge, French, Appleton, Bates and Clark20
Several epidemiological studies confirm the occurrence of changes in thyroid hormone levels with ageing. Thyroid-stimulating hormone does not vary with age among males, but increases markedly among females after the age of 45 years.Reference Tunbridge, Evered, Hall, Appleton, Brewis and Clark21 The prevalence of thyroid deficiency in an unselected population of elderly subjects older than 60 years is 4.4 per cent.Reference Sawin, Castelli, Hershman, McNamara and Bacharach22
A correlation was found for mean age peak between those who developed hypothyroidism (60 years) versus euthyroid patients (50 years) following hemithyroidectomy with total laryngectomy.Reference Negm, Mosleh, Fathy and Awad23 An increased incidence of hypothyroidism with advanced age following hemithyroidectomy for primary thyroid pathology has also been reported.Reference Said, Chiu and Haigh24 Despite this, there was no significant difference between the age groups in our cohort (p = 0.229).
A single TSH measurement that is just below or above the reference limits may be a transient deviation in approximately 50 per cent of older patients. Therefore, treatment decisions should wait, if clinically possible, until repeat determinations are made over time.Reference Tabatabaie and Surks25
According to some studies on head and neck carcinoma patients, hypothyroidism appears more frequently in women.Reference Gal, Gal, Klotch and Cantor26–Reference Vrabec and Heffron28 This is possibly related to the increased prevalence of thyroid disorders in females. Other studies did not establish a similar link.Reference León, Quer, Burgués, Abelló, Vega and de Andrés29,Reference Tell, Lundell, Nilsson, Sjödin, Lewin and Lewensohn30 Our cohort showed no difference in thyroid function between males and females (p = 0.778).
Surgery
The pooled risk of hypothyroidism after a hemithyroidectomy for primary thyroid pathology is 22 per cent.Reference Verloop, Smit, Louwerens, Dekkers, Kievit and Schoones31 In patients with laryngeal cancer who undergo hemithyroidectomy with total laryngectomy, this rises to 32 per cent, and 89 per cent with adjunctive post-operative radiotherapy.Reference Gürbüz, Açikalin, Tasar, Çakli, Yorulmaz and Erdinç2,Reference Palmer, Gaggar and Shaw7–Reference Mourad, Saman, Sawhney and Ducic10
There was a significant difference in hypothyroidism rates in our cohort of patients who received thyroid-sparing surgery compared to those who had a hemithyroidectomy (p = 0.037). The incidence of hypothyroidism was 36.4 per cent among patients who had thyroid-sparing total laryngectomy, compared to 62.1 per cent in patients who had a hemithyroidectomy.
Similarly, in the cohort of patients who did not receive adjuvant radiotherapy, the incidence of hypothyroidism was significantly lower in the thyroid-sparing group (9.1 per cent) compared to the hemithyroidectomy group (50 per cent). Our results are supported by the findings of a study by Léon et al.Reference Léon, Gras, Pérez, Rodríguez, de Andrés and Orús5
Radiotherapy
The effects of radiotherapy on the thyroid gland have been studied extensively. The most notable study comprised a large series of patients treated for Hodgkin's lymphoma with radiotherapy that included the thyroid gland. The incidence of hypothyroidism was 30.6 per cent.Reference Hancock, Cox and McDougall32
Primary radiotherapy in the absence of thyroid surgery for head and neck cancers may result in a 23–53 per cent prevalence of subclinical hypothyroidism and an 11–33 per cent prevalence of clinical hypothyroidism.Reference Diaz, Jaboin, Morales-Paliza, Koehler, Phillips and Stinson33–Reference Boomsma, Bijl and Langendijk38
The incidence of hypothyroidism following adjuvant radiotherapy in our study was 58.9 per cent, which is comparable to reports in the literature.Reference Léon, Gras, Pérez, Rodríguez, de Andrés and Orús5 In the cohort of patients who received adjuvant radiotherapy, 54.5 per cent of patients who had thyroid-sparing surgery developed hypothyroidism, compared to 65.2 per cent of patients who had a hemithyroidectomy. These results showed no significant difference (p = 0.582).
Possible aetiological factors to explain the correlation between radiotherapy and hypothyroidism include injury to the endothelium of nutrient vessels and damage to the vasculature. These changes result in secondary degeneration of the follicular epithelium and decreased thyroid function.Reference Rubin and Casarett39
Preservation of as much of the thyroid gland as possible during a total laryngectomy is important to prevent radiotherapy-induced hypothyroidism.Reference Kojima, Tsukahara, Motohashi and Okada40 The possibility of injury to thyroid feeding vessels during neck dissection should also be considered and avoided, as this incurs a high risk for hypothyroidism following radiotherapy for head and neck cancer. Other risk factors include a high radiation dose, elapsed time since therapy and not shielding the midline.Reference Grande41
Cancer stage
Advanced stages of laryngopharyngeal cancer may be associated with an increased risk for hypothyroidism. This may be a result of the increased likelihood of these patients undergoing thyroid-sacrificing total laryngectomy because of direct extension of the tumour to the thyroid gland or the necessity to resect level 6 nodes. These patients are also more likely to require adjuvant radiotherapy because of close surgical margins, nodal metastases or perineural invasion. In our study, 32.3 per cent of patients with pathologically staged T3 cancer developed hypothyroidism, compared to 55.8 per cent of patients with pathologically staged T4 cancer. This difference was, however, not significant (p = 0.125).
• Thyroid lobectomy is recommended with total laryngectomy for laryngeal cancer, but is associated with a 32–89 per cent risk of hypothyroidism
• Many patients in developing countries cannot afford or access treatment or monitoring of thyroid function
• Sparing the thyroid gland does not need to compromise oncological control
• There was a significant difference in hypothyroidism rates for thyroid-sparing surgery versus hemithyroidectomy patients
• The incidence of hypothyroidism following adjuvant radiotherapy was 58.9 per cent, comparable to the literature
• Thyroid-sparing laryngectomy reduces the risk of hypothyroidism and should be considered in selected patients
Limitations
Most of the patients did not have baseline TSH assessments prior to surgery and radiation. Furthermore, the time schedule during follow up for thyroid function tests was not consistent, and the tests were not taken at specific, pre-determined time points.
Conclusion
This study, with a level of evidence of 4, found that thyroid-sparing laryngectomy reduces the risk of hypothyroidism. It should therefore be considered in selected patients without extralaryngeal cancer extension or when paratracheal nodal metastases are not a significant concern.
Competing interests
None declared
