Central Compartment Nodal Bulk: A Predictor of Permanent Postoperative Hypocalcaemia

Abstract

Central compartment clearance (CCC) for Papillary thyroid cancers (PTC) is one of the factors causing postoperative hypocalcaemia. We aimed to examine determinants of this major sequela. 41 patients treated for PTCs between 2014 and 2016 were studied. Surgical details, tumour and nodal characteristics, incidence of transient, temporary and permanent hypocalcaemia were noted. Central clearance was done bilaterally in 24 (58.5%) cases, ipsilaterally in 17 (41.6%). Central nodes were involved in 26 (63.4%) cases, unilaterally in 15 (36.6%), bilaterally in 11 (26.8%). Transient hypocalcaemia developed in 10 (24.4%) cases, temporary hypocalcaemia in 6 (14.6%) cases, and permanent hypocalcaemia in 2 (4.9%) cases. 17 (41%) patients were symptomatic. 9 (21.9%) patients received intravenous calcium. The only factor consistently associated with development of hypocalcaemia of all patterns, was the presence of matted central compartment nodes (p = 0.021). Matted nodes also related to a longer length of stay (p = 0.04) and requirement of intravenous calcium (p = 0.000). Extent of CCC, nodal yield, nodal positivity, perinodal extension, number of parathyroids identified, gender or pT size were not significantly associated. Symptomatic patients did not necessarily become permanently hypocalcaemic (p = 0.8). Patients requiring intravenous calcium were more likely to take oral calcium after discharge (p = 0.002). Postoperative hypocalcaemia is more likely in cases with bulky involved central nodes where extensive clearance is done. In routine CCC, even if done bilaterally, preservation of parathyroid function is possible. Permanent hypocalcaemia after CCC need not be taken as inevitable.

Introduction

The subject of central compartment clearance for differentiated thyroid cancers is a contentious one. This is especially true for cases without clinico-radiological evidence of involved nodes. The pros and cons of CCC have been discussed extensively [1–6]. Present guidelines are based upon literature on incidence of central nodal metastases, disease outcomes and morbidity data [1]. Long-term morbidity due to permanent hypocalcaemia with lifelong requirement of calcium is the one complication that all discussions are pivoted upon and one which all surgeons wish to prevent.

Parathyroid injury is one of the two major morbidities which may occur after CCC; the other being iatrogenic injury to recurrent laryngeal nerve (RLN). Parathyroid injury may be direct, following inadvertent or deliberate removal, or indirect following devascularisation or congestion. The number of glands disrupted and the severity of damage determine the degree and duration of hypocalcaemia. In literature, incidence of temporary or transient hypocalcaemia after CCC is 10–45% and that of permanent hypocalcaemia is 0–5% [6, 7]. Some of the known risk factors are presence of thyroid malignancy (vs goitre), technical issues such as ligation of central branches of the inferior thyroid artery, preservation of ≤ 2 parathyroid glands [8], female gender and low preoperative serum calcium [9]. Identification (as opposed to preservation) of a higher number of parathyroids may increase the probability of temporary (though not permanent) hypocalcaemia [10]. Larger disease volume and longer duration of surgery may predispose to parathyroid injury [11].

Factors favouring normocalcaemia are the preservation of≥ 2 parathyroid glands [12] and capsular dissection technique with ligation of capsular arterial branches, preserving a long segment of the end artery supplying the parathyroids and lesser dissection in the lateral and central compartments [8, 13]. Postoperative supplementation with calcium and vitamin D has been shown to prevent permanent hypoparathyroidism [14–16]. Autotransplantation has questionable benefit; most series show inadequate recovery of the transplanted glands [17].

We aimed to study the predictors of hypocalcaemia in a cohort of patients undergoing CCC; we added the variable of ‘nodal bulk’ – a greater nodal bulk being the presence of 3 or more nodes as a conglomerate (matted nodes) in the central compartment. Higher nodal bulk implies more tissue clearance causing disruption of parathyroid vasculature. We also divided early hypocalcaemia into transient and temporary categories in keeping with our system of patient triaging.

Patients and Methods

This was a retrospective analysis of cases treated between October 2013 and January 2016 in the Head Neck Unit of a State Cancer Hospital. Patients with papillary carcinoma thyroid (PTC) or its variants, undergoing surgery (total thyroidectomy with ipsilateral or bilateral CCC) with a follow-up of at least 1 year, were studied. Patients with micropapillary cancer and follicular or medullary cancer and those with second malignancies were excluded. Clinical details – age, gender, tumour and nodal characteristics – were documented. Findings of the ultrasonogram (or other radiology if done) and of the cytological examination were documented. Preoperative serum total calcium, serum albumin and thyroid function tests were noted. Surgery – total thyroidectomy or completion thyroidectomy – was done, as the case may be. The central compartment, between the common carotid artery and the midline and from the hyoid till the level of brachiocephalic artery, was cleared. Capsular dissection was done with ligation of only the capsular branches of the inferior and superior thyroid arteries. Parathyroids glands were identified and preserved with their vessel. A gland was auto-implanted in the sternomastoid muscle only in case of dislocation or complete devascularisation. The extent of CCC (unilateral or bilateral) and central nodal characteristics including multiplicity, bulk, fixity and adherence to the RLN was noted. The number of parathryoids identified and preserved was documented. Nodal bulk as seen by the presence of matted nodes in the central compartment was recorded. Histopathology details were noted (Table 1). Staging was as per AJCC-UICC 7th edition. Postoperatively, as per institutional practice, all patients received oral calcium and vitamin D for 15 days or till calcium levels were stable for 15 days with dose reduction. If serum calcium was less than 7 mg per dl, calcium gluconate was given intravenously. Symptoms and signs of hypocalcaemia, if any, were noted. Total serum calcium on postoperative day (POD)1 and or POD 2 and, subsequently if indicated, duration of calcium supplementation and length of hospital stay (LOS) were recorded. On follow-up visits, serum calcium levels and status of supplementation were documented.

Table 1.

Frequencies of some of the variables studied

VARIABLE	VALUE
AGE	<55yrs	38 (92.7%)
	>55yrs	3 (7.3%)
GENDER	Male	11 (26.8%)
	Female	30 (73.2%)
CCC EXTENT†	Ipsilateral	17 (41.5%)
	Bilateral	24 (58.5%)
pT STAGE	T1,T2	16 (39%)
	T3,T4	25 (61%)
OVERALL NODAL INVOLVEMENT‡	pN0	10 (24.4%)
	pN1a	5 (12.2%)
	pN1b	26 (63.4%)
CENTRAL NODAL INVOLVEMENT	Total	26/41 (63.4%)
	Unilateral	15/26 (58%)
	Bilateral	11/26 (42%)
NUMBER OF PARATHYROIDS PRESERVED	≥Four §	11 (26.8%)
	Three	25 (61%)
	Two	4 (9.7)
	One	1 (2.5%)
INCIDENCE OF HYPOCALCAEMIA	Transient Temporary Permanent	$\begin{array}{c}10\left(24.4\%\right)\\ 6\left(14.6\%\right)\\ 6\left(4.9\%\right)\end{array}\}18/41\left(43.9\%\right)$
	Normocalcaemic	23/41 (56.1%)
GROSS CENTRAL NODE EXTRA-NODAL SPREAD		9 /41 (22%)
NUMBER OF SYMPTOMATIC PATIENTS		10 /41 (24.4%)
NUMBER OF PATIENTS GIVEN INTRAVENOUS CALCIUM		9 /41 (22%)

† CCC central compartment clearance ‡ includes lateral and central compartments §, includes one case with 5 glands

Hypocalcaemia (serum total calcium < 7.5 mg/dl irrespective of symptoms) was termed ‘transient’ if it lasted below 14 days and did not prolong LOS. Additionally, the serum calcium should show a normalising trend within the duration of stay. Hypocalcaemia lasting between 14 days and 12 months was termed ‘temporary’. In addition, patients would not be critically calcium dependant. Hypocalcaemia persisting beyond 12 months was called ‘permanent’; the patient would also have to be dependent upon oral/intravenous supplementation and serum calcium monitoring.

For the statistical analysis, variables studied were (Table 1) age, gender, pT and pN stage, extent of CCC (unilateral or bilateral), presence of matted nodes, encirclement or involvement of the RLN and the number of parathyroid glands identified/preserved. Central nodal yield (number harvested), nodal positivity and microscopic extranodal extension (ENE) and extrathyroidal extension (ETE) were also analysed. These were examined against transient, temporary and permanent hypocalcaemia separately and collectively. Pearson’s chi-squared test was followed by a linear regression (enter method) to test the actual impact of these variables.

Results (Table 1)

41 patients with PTC aged between 18 and 75 years were studied. There were 11 males (26.8%) and 30 females (73.2%). Upfront total thyroidectomy was done in 37 (90.2%) cases; hemithyroidectomy followed by completion thyroidectomy was done in 4 (9.8%) cases. CCC was done in all – bilaterally in 24 (58.5%) cases and ipsilaterally in 17 (41.5%) patients.

16 patients (39%) had early cancers (T1/2); 25 (61%) patients had T3/4 cancers. 10 cases (24.4%) were pN0, 5 (12.2%) were pN1a, and 26 (63.4%) were pN1b. Central nodes were involved in 25 (61%) cases – 15 (36.6%) unilaterally and 10 (24.4%) bilaterally. Gross ENE seen as matted central nodes intraoperatively was noted in 9 of the 41 (22%) cases; in 4 of these, the RLN was encircled by nodal disease. The number of central nodes harvested varied from 0 to 25 on the right side and 0 to 14 on the left side, of which 0 to 22 nodes (right) and 0 to 13 nodes (left) were involved. Though we do not have information on the size of central nodal conglomerates, individual nodes measured up to 1.5 cm in maximum diameter.

In 10 of 41 (24%) cases, 4 parathyroids were identified and preserved; in 25 (61%) patients, 3 glands were identified and preserved, while in 4 (9.7%) cases, only 2 parathyroids could be identified. In 1 patient (2.5%) where unilateral CCC was done, only 1 parathyroid gland was identified; 1 patient (2.5%) had supernumerary parathyroids (5 in number).

Preoperative serum calcium and albumin levels were normal in all patients.

Transient hypocalcaemia developed in 10 of 41(24.4%) cases, temporary hypocalcaemia in 6 (14.6%) cases and permanent hypocalcaemia in 2 (4.9%) cases. Thus 18 of 41 (43.9%) cases had some form of hypocalcaemia, and 23 of 41(56.1%) cases were normocalcaemic.

17 of 41 patients (41%) were symptomatic for hypocalcaemia. Interestingly, 36% of patients with POD2 serum calcium > 7.5 mg per dl were symptomatic, whereas 45% patients with POD2 calcium levels below 7.5 mg per dl were asymptomatic. 35% of patients who were pN0 or unilaterally pN+ as compared to 60% of those who were bilaterally pN+ for central nodes were symptomatic.

Of the 9 cases with matted nodes, hypocalcaemia was seen in 6 (66%); of these, transient hypocalcaemia developed in 3(50%), temporary hypocalcaemia in 1 (17%) and permanent hypocalcaemia in 2 (33%) patients.

9 of 41 (21.9%) patients required intravenous calcium, 3 patients for a week or longer – all 3 had possessed matted central nodes. The LOS was increased by > 1 week in all 9 patients. 24% patients with involved central nodes had increased LOS due to hypocalcaemia.

Statistical Analysis (Table 2)

Table 2.

Univariate and multivariate analyses of factors associated with development of all patterns hypocalcaemia

S.no	Variable	Univariate analysis (p value)	Linear regression (1-tailed significance)
1	Age	0.33	0.8
2	Pt	0.23	0.4
3	Pn	0.26	0.4
4	Extrathyroidal extension	0.56	0.10
5	Central node clearance (uni- or bilateral)	0.06	0.18
6	Central nodal involvement laterality (unilateral or bilateral)	0.29	0.8
7	Central compartment pn+ or pn0	0.6	0.6
8	Number of central nodes harvested	0.23	0.77
9	Number of central nodes involved	0.83	0.61
10	Perinodal extension †	0.35	0.57
11	Number of parathyroids identified/preserved‡ (2 or more)	0.14	0.08
12	Recurrent nerve free /close to disease§	0.17	0.14
13	Gender (female)	0.406	0.4
14	Presence of matted central nodes	0.006	0.021

† Includes nodes of both central and lateral compartments ‡ Includes glands which were identified as well as preserved with or without an identifiable vascular pedicle §Includes cases where nodal disease was shaved off the recurrent nerve

The solitary factor significantly associated with postoperative hypocalcaemia was the presence of matted central nodes. Certain factors, bilateral CCC, engulfment of RLN, bilateral central nodal involvement and identification of fewer parathyroids, impacted development of hypocalcaemia but did not achieve significance in overall multivariate analysis.

Other Characteristics

Data on central nodal size and microscopic ENE was incomplete; therefore, their significance could not be ascertained. The number of nodes harvested and the number involved did not influence early or late calcium levels (p = 0.22 & 0.83). The number of nodes harvested had no association with number of parathyroids identified (p = 0.13). Incidentally, the more the nodes harvested, the greater was the probability of identifying pathologically positive nodes (p = 0.002).

Biochemistry and Symptomology

Although patients with a POD2 serum calcium < 7.5 mg per dl were more likely to be symptomatic, there was no statistical significance (p = 0.3). As expected, patients requiring intravenous calcium were more likely to be symptomatic (p = 0.04). The number of parathyroids identified/preserved had no correlation with symptom severity (p = 0.23). Symptomatic patients did not necessarily become permanently hypocalcaemic (p = 0.802).

Length of Stay

There was a nonsignificant trend towards a longer LOS after bilateral CCC (p = 0.113). There was no correlation between gender and LOS (p = 0.28) or duration of intravenous calcium (p = 0.53).

Permanent Hypocalcaemia

As seen in Table 3, the most notable factors were presence of matted nodes and nodal encirclement of RLN. The latter is a consequence of the former, and though it does not figure as a predictor in the multivariate analysis or of hypocalcaemia overall, this finding can be considered an indirect marker of central nodal bulk. As expected, LOS and the time taken to stabilise calcium are closely associated with permanent hypocalcaemia.

Table 3.

Some of the factors studied against permanent hypocalcaemia

S.no	Variable	Univariate analysis (p value)	Linear regression (1-tailed significance)
1	Matted nodes	0.006	0.008
2	Unilateral vs bilateral ccc	0.08	0.07
3	Unilateral vs bilateral central nodal involvement	0.47	0.28
4	Rln encircled by nodes	0.09	0.6
5	Time taken for calcium level stabilisation (> 2 weeks)	0.000	0.041
6	Requirement of intravenous calcium > 1 week	0.05	0.5
7	Increased length of stay> 2 weeks	0.003	0.046

Discussion

The indications for routine CCC are debated, with no consensus on routine prophylactic CCC or extent of therapeutic CCC. There is equivalent amount of literature favouring all patterns of intervention. Sufficient data shows better outcomes following CCC for all cases of DTC, with comparable morbidity in the hands of experienced surgeons [1, 18–23]. However, concerns about two sequelae of CCC – permanent hypoparathyroidism and RLN injury – prevent pursuance of a uniform policy of CCC. The extent of CCC differs between and within institutions, based on patient profile, surgeon expertise and institutional guidelines.

In this study, moving away from these contentions, we examined factors affecting serum calcium in patients who had undergone CCC. The aim was to scrutinise if permanent hypocalcaemia is implied after CCC or if the dread of this sequela may be overrated. The surgeons in this study perform a combined average of 50 thyroidectomies annually for malignant disease.

CCC protocol

It is our practice to clear central nodes in all cases of PTCs. The decision to do a unilateral or a bilateral CCC is based upon clinico-radiological as well as intra-operative findings. In case of preoperatively detected or suspected bilateral central nodes, in bilateral thyroid lobar disease and in patients with lateral nodal disease on both sides as seen intra-operatively, the practice is to do a bilateral CCC. In all others, a unilateral CCC is done. An inspection of the contralateral central compartment is done in all the latter cases to rule out gross central nodal disease.

Technique of Parathyroid Preservation

We follow the time-tested method of capsular dissection, as mentioned above. Identification of the glands is by location, colour, texture and presence of an exclusive vascular twig entering the gland. All effort is made to maintain the parathyroids in their bed with their individual vessel. In case of congestion, the capsule is incised to relieve stasis. We do not perform autotransplantation routinely.

The above method has evolved over the years and has been described in fine detail by many authors [24–27]. Although the approach is the same in prophylactic and therapeutic CCC, the presence of involved nodes makes glandular safeguarding challenging. We had several patients with matted central nodes adherent to a bulky thyroid tumour, requiring to be removed en masse. In these, performing an adequate CCC without violating the immediate space around the parathyroid presents technical difficulties.

Definition of Hypocalcaemia

Though the technical definition of hypocalcaemia varies [28, 29], we divided out patients at 7.5 mg per dl for several reasons. One, POD1 calcium > 7.5 mg/dl implies faster recovery with routine calcium supplementation – which all our patients received by default. Two, we wished to factor out haemodilution and other biochemical alterations leading to a decrease in measured serum calcium [29, 30]; especially in the absence of ionised calcium values. Another study has taken this cut off [31] for similar reasons; the authors also included the presence of symptoms in defining hypocalcaemia.

Timelines

Most authors [32, 33] define temporary hypocalcaemia as that occurring immediately after surgery and lasting up to 6 months [30, 32, 34] or in some descriptions up to 1 year [35, 36], and hypocalcaemia of any longer duration is termed permanent. We categorise cases into transient, temporary and permanent hypocalcaemia; this reflects our system of triaging patients into low, medium and high risk for long-term intervention. This also demarcates hypocalcaemia due to surgical stress or haemodilution (transient) from that occurring due to parathyroid stunning [29], oedema, transitory ischaemia or congestion [31] (temporary) and that due to permanent ischaemia, complete dislocation or inadvertent removal of parathyroids (permanent hypocalcaemia). The latter two can thus be further examined since they relate to disease biology, surgical technique and surgeons’ expertise.

Incidence of Hypocalcaemia

Most patients undergoing total thyroidectomy with bilateral CCC have been seen to have reduced serum calcium levels as compared to preoperative levels [6, 31]. The incidence of immediate postoperative hypocalcaemia in literature, with levels below the laboratory range of normal, is around 50% [31]. Temporary hypocalcaemia (till 6–12 months after surgery) following unilateral or bilateral CCC ranges between 5 and 60% (median 25%) [6, 31, 37]. Permanent hypocalcaemia ranges between 0.5 and 5% in most papers [6, 23, 34–37]. The incidence of hypocalcaemia in our study is comparable.

Predictors of Hypocalcaemia (Table 4)

Table 4.

Showing inconclusive/conflicting evidence for most factors relating to the development of hypocalcaemia – all associations are for transient/temporary hypocalcaemia

S no	Variable	References describing statistically significant association	References negating significant association
1	Age	41	36
2	Female gender	41	36
3	T size	8	32
4	Parathyroid identification	14	44
5	Number of parathyroids identified and or preserved	8	36,45,60
6	Parathyroid autotransplantation	42,46	47
7	Incidental parathyroidectomy	48	49
8	Central compartment clearance (ccc)	48,52	28,39
9	Surgeon expertise	51	28
10	Prolonged surgery (generally > 120 minutes)	42,43	53
11	Preoperative vitamin d levels	41	54

The factors found in numerous studies as impacting postoperative calcium levels, for thyroid surgery done for all indications [8, 10, 13, 20, 27, 31, 35, 37–50], are enlisted in Table 4. Intriguingly, data in support of and against each of these factors coexists. Thus, literature is divided on the importance of tumour size, female gender, age, clear identification of parathyroids, the number of parathyroids identified and/or preserved, autotransplantation, incidental parathyroidectomy, nodal yield and nodal involvement, surgeons’ experience, operative time and blood levels of vitamin D on postoperative calcium levels. Also, these determinants are associated, if at all, with short-term hypocalcaemia only.

Literature is more conclusive on factors causing or preventing permanent hypocalcaemia. Adherence to anatomic dissection has been described in historical papers as well as contemporary workers [9, 25, 26, 29] as being essential in preserving parathyroid function. The concepts of peripheral ligation of the superior and inferior thyroid artery branches and capsular dissection of the thyroid gland as anterior to the parathyroids as possible have been emphasised by authors over the years [9, 29, 51–53]. There is much importance given to minimal and gentle handling of tissues near the parathyroid, so as to keep the gland in its bed and to preserve the terminal arterial branches supplying it [51–55]. It is recommended that parathyroid venous congestion be relieved by making a linear incision on its capsule [52], while (only) complete devascularisation be followed by autotransplantation [16, 42, 43, 53–57]. Routine autotransplantation has been disrecommended [43, 56, 57].

Significance of Nodal Bulk

Specific literature linking bulk (matting) of central nodes to parathyroid damage and permanent hypocalcaemia could not be found, though a higher nodal yield is associated with hypoparathyroidism [27]. In our series, we found that not the number but nodal bulk or density was related to parathyroid dysfunction, to LOS and to need for intravenous calcium administration. The presence of involved but discrete nodes requiring sharp dissection to separate them from the RLN did not necessarily lead to hypocalcaemia. Though higher nodal bulk is a relatively subjective criterion, in our experience, it complements other subjective guides such as parathyroid gland discolouration and congestion in the effort to preserve parathyroids.

Critical Number of Parathyroids

The number of parathryoids required for normocalcaemia without supplementation is thought to be 2 [8, 57, 58] in most series. However, it is accepted [57, 59] that it is difficult to ascertain whether it is recovery of the identified/transplanted glands or possible ectopic parathyroids which eventually lead to normocalcaemia. In our opinion, at least 2 undisturbed parathyroids are ideal for preventing hypocalcaemia. Mild discolouration did not seem to lead to loss of function, though this is difficult to quantify.

Definition of Parathyroid Recovery

Serum parathormone levels ≥ 10 pg/ml, normal serum total and/or ionised calcium levels, absence of symptoms and cessation of medication or a combination of the above [36, 60] are known criteria defining normal parathyroid function. In the absence of the facility of assays of the parathormone and ionised calcium, we relied on measurement of total serum calcium combined with symptomology for assessing recovery.

Calcium Supplementation

Earlier thought was to stress-stimulate parathyroids by refraining from supplementation, in the absence of symptoms or low calcium levels [57]. The practice of routine calcium and vitamin D administration is now being accepted as a cost-effective method of parathyroid ‘splinting’ to hasten recovery [61, 62]. In our centre, we found this to be beneficial, and we supplement both calcium (calcium citrate maleate) and vitamin D (cholecalciferol) to all patients.

Drawbacks

This is a retrospective study with a limited number of patients, with inherent biases. We lacked the facility of performing parathyroid hormone and ionised calcium levels. We do not have data on the cases where we did parathyroid autotransplantation, though, as mentioned before, this was a small number. We have not included cases where there was incidental parathyroidectomy, and this too was seen in a few cases only. Since this study was done to study the phenomenon of hypocalcaemia alone, we have not incorporated recurrence data (though we have recorded no nodal recurrences within the limited follow-up period of 3 years).

Despite these limitations, this analysis has improved our ability to identify patients likely to require careful calcium monitoring and long-term supplementation. Consequently, we can prognosticate better and counsel patients accordingly.

Conclusions

Permanent hypocalcaemia after total thyroidectomy with central compartment clearance is more likely in cases with bulky involved central nodes where extensive clearance is done. In cases with smaller though involved central nodes or with large tumours where bilateral clearance is done, it is possible to preserve parathyroid vascularity and function by adhering to principles of anatomic dissection. The occurrence of hypocalcaemia need not be an inevitable event after central compartment clearance. Routine postoperative calcium and vitamin D supplementation appear to be beneficial in recovery of parathyroid function.