Introduction
Most patients with differentiated thyroid carcinoma undergo total thyroidectomy as part of definitive treatment. Neck dissection involving the lateral compartment (usually levels two to four, with or without level five) and central compartment (level six) is standard treatment for patients presenting with palpable or radiological evidence of metastatic lymphadenopathy.Reference Ito, Tomoda, Uruno, Takamura, Miya and Kobayashi1 However, the role of central compartment neck dissection for clinically staged node 0 disease is still unclear. The British Thyroid Association recommends that total thyroidectomy and central neck dissection be performed for patients who have papillary carcinoma and uninvolved nodes but who are deemed at high risk (i.e. male, aged more than 45 years, tumour larger than 4 cm in diameter, and extracapsular or extrathyroidal disease).2
The aim of combined total thyroidectomy and limited lymphadenectomy is to remove all macroscopic malignant cervical lymphadenopathy, while causing minimum associated co-morbidity.Reference Pacini, Schlumberger, Dralle, Elisei, Smit and Wiersinga3 Despite these guidelines, elective neck dissection (whether central compartment or lateral) remains controversial, due to the lack of clear data regarding its survival benefit and the complications associated with the procedure.Reference Henry, Gramatica, Denizot, Kvachenyuk, Puccini and Defechereux4
The principal additional morbidity risk arising from central neck dissection is hypocalcaemia (and perhaps increased risk of recurrent laryngeal nerve palsy).Reference Henry, Gramatica, Denizot, Kvachenyuk, Puccini and Defechereux4 Hypocalcaemia arising from hypoparathyroidism constitutes significant morbidity. In some patients, hypocalcaemia is difficult to control and requires frequent monitoring and treatment adjustment, often more so than for patients requiring thyroxine replacement. It should also be borne in mind that many of these patients are relatively young, and that the burden of lifelong hypocalcaemia management is therefore significant.
The aim of this study was to ascertain the risk of hypocalcaemia in a series of consecutive patients undergoing total thyroidectomy for differentiated thyroid cancer, in order to analyse principally the effect of central neck dissection. Our study cohort comprised consecutive patents referred to the Christie Hospital thyroid multi-disciplinary team, whose surgery had been performed in referring cancer network hospitals which formed part of this team. This afforded a representative group of patients operated upon by both ENT and endocrine surgeons within a number of different units.
Methods
A retrospective case note review was undertaken. The study included all patients referred to the thyroid oncology multi-disciplinary team at Christie Hospital having undergone total thyroidectomy with or without neck dissection between 2004 and 2006. Data collected comprised age, gender, pre-operative diagnosis, type of operation, histopathology (i.e. diagnosis and nodal status), presence of post-operative hypocalcaemia, and calcium replacement type and duration. Hypocalcaemia was defined as an adjusted calcium level of less than 2 mmol/l, which necessitated calcium or vitamin D analogue replacement.
Post-operative hypocalcaemia was classified into two groups: transient hypocalcaemia (resolving within two years of surgery) and permanent hypocalcaemia (persisting for more than two years after surgery).
The type of operation undertaken was determined from the surgical operative notes or the referral letter. It was assumed that all surgeons' operative notes were consistent with the standardised classification for neck dissection,Reference Robbins, Clayman, Levine, Medina, Sessions and Shaha5 whereby level six lies centrally, the superior border being the hyoid bone, the inferior border the suprasternal notch and the lateral borders the common carotid arteries.
Univariate analysis of variables, including the association between central neck dissection and hypocalcaemia, was carried out using categorical tables, performing Pearson's chi-square test, Fisher's exact test and the Mann–Whitney test as appropriate. Multivariate analysis was carried out using multiple regression. The Statistical Package for the Social Sciences version 16.0 software was used for analysis. All tests were two-tailed, and differences were considered significant at p < 0.05.
Results
A total of 127 patient case notes were reviewed. These patients had been referred to the Christie Hospital thyroid oncology multi-disciplinary team by 34 consultant surgeons, within the two cancer networks for which the Christie Hospital provides thyroid clinical oncology services. Overall, 39 patients (31 per cent) had transient hypocalcaemia and seven (6 per cent) had permanent hypocalcaemia. The most common relevant supplementation was calcium with or without vitamin D (e.g. Calcichew or Calcichew D3). As would be expected, those with transient hypocalcaemia were less likely to have been commenced on 1α-calcidol (2.6 per cent) than those with permanent hypocalcaemia (14.3 per cent).
No cases of vocal fold palsy could be identified from the Christie Hospital notes. However, as the surgical information was based on the operative record, histopathology report and referral letter, it could not be confirmed that all patients had undergone post-operative laryngoscopy, or how many patients had suffered voice problems post-operatively.
Table I demonstrates the patients' clinicopathological characteristics. Pathology categorised as miscellaneous comprised muco-epidermoid carcinoma (one case) and Hürthle cell carcinoma (three cases). Overall, 78 patients underwent total thyroidectomy without central neck dissection and 49 underwent total thyroidectomy with central neck dissection. A comparison between these two groups is shown in Table I. The groups were similar except that, unsurprisingly, all patients undergoing lateral neck dissection (generally levels two to five) also received central neck dissection (i.e. there were no lateral dissections in the total thyroidectomy only group). Also, more of the total thyroidectomy only group received a two-stage thyroidectomy (i.e. lobectomy then completion) rather than a primary total thyroidectomy (p = 0.03).
Table I Patient clinicopathological characteristics
TT = total thryoidectomy; L6 = level 6; ND = neck dissection; IQR = interquartile range; y = years; Ca = carcinoma; HC = hypocalcaemia
Histopathological examination identified the presence of metastatic nodes in the central compartment in 18 of the 35 patients undergoing total thyroidectomy plus central neck dissection without lateral neck dissection; and in 11 of the 14 patients who also underwent a lateral selective neck dissection (i.e. a total of 29/49).
The effect of having a central neck dissection was significant both in terms of transient and permanent hypocalcaemia. The incidence of transient hypocalcaemia in the total thyroidectomy only group and the total thyroidectomy with level six neck dissection group were 18 per cent (14/78) and 51 per cent (25/49), respectively (p < 0.001). The corresponding rates of permanent hypocalcaemia were 1 per cent (one of 77) and 12 per cent (six of 49), respectively (p < 0.01).
The effects of various other parameters on the incidence of transient and permanent hypocalcaemia are shown in Table II. There was a weak association between lateral neck dissection and permanent hypocalcaemia (p = 0.03), perhaps a reflection of the fact that this group always had level 6 neck dissection (Table I). Upon multivariate analysis, only central neck dissection was significantly associated with transient hypocalcaemia (p < 0.001). No parameters were significantly associated with permanent hypocalcaemia, although this may reflect the low number of cases of permanent hypocalcaemia.
Table II Comparison of patients with transient vs permanent hypocalcaemia
*Includes permanent cases. †No hypocalcaemia (HC) vs transient (trans) HC; ‡permanent (pers) HC vs trans HC. IQR = interquartile range; y = years; T = tumour
Discussion
These findings indicate that, in the collective experience of a representative group of surgeons in different hospitals, total thyroidectomy combined with central neck dissection for the treatment of differentiated thyroid cancer was more likely to result in transient (51 per cent) and permanent (12 per cent) hypocalcaemia, compared with total thyroidectomy alone. Our data were derived from an unselected, consecutive patient series involving surgery performed by both otolaryngology-head and neck surgeons and endocrine surgeons. Most similar studies have been based in single surgical units and have therefore possibly been prone to bias. Our study should constitute a more representative reflection of contemporary practice within the UK.
Whilst this study had the advantage of being multi-institutional, this also brought disadvantages. For example, when analysing histopathological reports, we found a great degree of variance in the reporting of parathyroid gland and tissue inclusion and the total number of lymph nodes found. Even when the latter information was included, the number of lymph nodes was dependent on histopathological tissue sectioning. Similarly, there was variation in the technique of central neck dissection. It was assumed that the operating surgeon defined central neck dissection as per the standardised definition.Reference Robbins, Clayman, Levine, Medina, Sessions and Shaha5 However, in practice central neck dissection could vary from sampling a few nodes to full dissection of tissue from right to left common carotid arteries and from hyoid to suprasternal notch. We were unable to analyse inter-surgeon variability because of the large number of surgeons and the small number of thyroidectomies per surgeon (an overall mean of approximately four per surgeon).
The criteria used to define hypocalcaemia in the literature vary widely.Reference Mehanna, Jain, Randeva, Watkinson and Shaha6 Our definition, i.e. adjusted calcium level of less than 2 mmol/l and calcium supplementation, has been used by many other studies.Reference Abboud, Sargi, Akkam and Sleilaty7–Reference Lindblom, Westerdahl and Bergenfelz10 The demarcation point between transient and permanent hypocalcaemia varies, but most agree that it should be at least one year post-operatively.Reference Mehanna, Jain, Randeva, Watkinson and Shaha6
Other authors have also reported the relationship between central neck dissection and hypocalcaemia, with similar results. Roh et al. Reference Roh, Park and Park11 reported that transient post-operative hypocalcaemia was higher in patients undergoing total thyroidectomy plus nodal dissection, compared with patients undergoing total thyroidectomy alone (30.5 vs 9.6 per cent, respectively; p = 0.001). Henry et al. Reference Henry, Gramatica, Denizot, Kvachenyuk, Puccini and Defechereux4 reported hypocalcaemia incidences of 14 and 4 per cent following total thyroidectomy with central neck dissection and total thyroidectomy alone, respectively.Reference Henry, Gramatica, Denizot, Kvachenyuk, Puccini and Defechereux4 Pereira et al. Reference Pereira, Jimeno, Miquel, Iglesias, Munne and Sancho12 reported a 60 per cent incidence of transient hypocalcaemia and a 5 per cent incidence of permanent hypocalcaemia following neck dissection.Reference Pereira, Jimeno, Miquel, Iglesias, Munne and Sancho12
The British Thyroid Association states that, following total thyroidectomy, 30 per cent of patients will require calcium supplementation with or without 1α-calcidol, but that, by three months, less than 10 per cent will continue to do so. There is no mention of increased hypocalcaemia as a result of central neck dissection.2
The occurrence of transient hypocalcaemia following total thyroidectomy and central neck dissection is a concern, not least because it usually presents late (typically the second post-operative day) and therefore results in prolonged patient hospitalisation.Reference Roh, Park and Park11 A recent study found that routine post-operative treatment of patients undergoing total thyroidectomy and central neck dissection with calcium and vitamin D reduced the risk of transient hypocalcaemia without causing parathyroid hormone inhibition.Reference Roh, Park and Park13 Taken together with our findings, this information supports the role of prophylactic treatment of all patients undergoing total thyroidectomy and central neck dissection with calcium and vitamin D. Such treatment should not only prevent hypocalcaemia but also reduce in-patient stay.
Permanent hypocalcaemia is a troublesome complication requiring lifelong medication and frequent blood test monitoring. It is not uncommon to find a fluctuating response to a stable therapeutic regime of calcium and vitamin D. This necessitates closer monitoring of calcium levels in patients receiving long-term treatment. The goals of therapy are to maintain a serum ionised calcium level within the normal range and to avoid hypercalciuria.Reference Litvak, Moldawer, Forbes and Henneman14 Studies have also found that long-term hypoparathyroidism may result in increased bone mineral density in the lumbar spine, the significance of which is not entirely clear.Reference Chan, Tiu, Choi, Choi, Kong and Shek15, Reference Laway, Goswami, Singh, Gupta and Seith16 Chronic hypocalcaemia due to poor compliance may be associated with cataract formation, ectopic calcification (of the basal ganglia), and, less commonly, parkinsonism and dementia. Thus, permanent hypocalcaemia is not a trivial complication.
Much controversy remains regarding the oncological advantage of elective central neck dissection in the treatment of differentiated thyroid carcinoma,Reference Mazzaferri, Doherty and Steward17 irrespective of the undoubted high incidence of pathologically detectable lymph node metastases in all levels of the neck.Reference Mazzaferri, Young, Oertel, Kemmerer and Page18
• Elective central compartment neck dissection is increasingly performed as part of surgical management of differentiated thyroid cancer
• There is no conclusive evidence of the oncological advantage of elective central neck dissection in differentiated thyroid cancer
• In this study, the incidence of transient and permanent hypocalcaemia following total thyroidectomy with central neck dissection was 51 and 12 per cent, respectively; that following total thyroidectomy alone was 18 and 1 per cent, respectively
• Systematic implementation of central neck dissection, in the absence of clinical nodal involvement or other high risk factors, should be avoided unless a survival benefit can be demonstrated, particularly in units administering post-operative radio-iodine to most patients
The British Thyroid Association recommends that total thyroidectomy and central neck dissection should be carried out in patients deemed to be at high risk.2 The revised (2009) American Thyroid Association guidelines recommend that ‘routine central-compartment (level VI) neck dissection should be considered for patients with papillary thyroid carcinoma and suspected Hürthle carcinoma’. This recommendation does go on to state that central neck dissection may be omitted if surgery is followed by radio-iodine therapy.Reference Cooper, Doherty, Haugen, Kloos, Lee and Mandel19 The European Thyroid Cancer Taskforce argue that central neck dissection is advantageous for staging of the disease, to guide subsequent treatment.Reference Pacini, Schlumberger, Dralle, Elisei, Smit and Wiersinga3 There seems to be a general and on-going trend towards increasing use of elective central neck dissection in the treatment of thyroid carcinoma.Reference Hartl and Travagli20
However, there is a significant difference between the UK and many parts of Europe, and certainly the US (and even more so Japan), in that, in the UK, most patients with differentiated thyroid cancer undergoing total thyroidectomy are also treated with post-operative radio-iodine.2 Hence, the need to stage metastatic disease to help determine the need for post-operative radio-iodine is not nearly so relevant.
Given the above controversies surrounding elective central neck dissection, our findings of increased transient and permanent hypocalcaemia after central neck dissection suggest that the systematic implementation of such dissection in the absence of pathological disease needs reassessment, particularly in the setting of post-operative radio-iodine therapy administered almost by default. Alternative approaches include simple intra-operative exploration of the central compartment to determine central neck dissection,Reference Pereira, Jimeno, Miquel, Iglesias, Munne and Sancho12 and ipsilateral central neck dissection only.Reference Lim, Choi, Yoon, Kim and Koo21
Conclusion
The collective experience of a representative group of UK thyroid surgeons is that total thyroidectomy combined with central neck dissection is more likely to result in transient (51 per cent) and permanent (12 per cent) hypocalcaemia (the latter requiring long-term medication and monitoring), compared with total thyroidectomy alone. Whilst most of our patients did have evidence of pathological lymphadenopathy, there remained no evidence of any survival benefit following central neck dissection. There appears to be an increasing prevalence of systematic implementation of central neck dissection in the absence of clinical nodal involvement or other high risk factors; however, this should be avoided unless a survival benefit can be demonstrated, particularly in units where post-operative radio-iodine therapy is administered to most patients. In patients who do undergo central neck dissection, consideration should be given to routine post-operative calcium and vitamin D supplementation.
