Medullary thyroid cancer: epidemiological pattern and factors contributing to recurrence and metastasis

Abstract

Introduction

Medullary thyroid carcinoma (MTC) is a neuroendocrine thyroid carcinoma with parafollicular C cell differentiation. It can occur in either sporadic or hereditary form. Surgery is still the only curative treatment. The efficacy of chemotherapy and radiotherapy is poor.

Methods

This was a retrospective study of 31 patients treated surgically for MTC in our oncology centre at Mansoura University between January 2008 and February 2019.

Results

The mean age at diagnosis was 39.9 years. The median pathological size was 4cm. Multifocal disease was found in 12 patients and extrathyroid extension in 3 cases. Twenty patients were pathologically node positive. The median number of positive lymph nodes was four. Seven cases were metastatic at diagnosis. Local recurrence occurred in six individuals while distant recurrence occurred only in one. The median time from surgery to local recurrence was 12 months. The estimated mean disease free survival was 56.5 months. Disease free survival was significantly related to age, metastasis and side of nodal spread.

Conclusions

In our study cohort, the disease occurred predominantly in women and younger patients. Age, distant metastasis and nodal spread were the most significant prognostic factors. This study has also demonstrated that prognosis is not only affected by nodal involvement but also by side of involvement. The role of hemithyroidectomy in node negative unifocal disease with a small tumour size warrants further investigation.

Introduction

Medullary thyroid carcinoma (MTC) is the third most common subtype of thyroid carcinoma and it carries the second worst prognosis after anaplastic thyroid cancer. It is a neuroendocrine thyroid carcinoma with parafollicular C cell differentiation.^1–4

Macroscopically, the tumour is well circumscribed and non-capsulated. It has a firm consistency and a chalky white or red colour. Microscopically, MTC shows nests, sheets or trabeculae of cells with round, polygonal or spindle morphology, separated by fibrovascular stroma with characteristic amyloid deposition. The cells have round or oval nuclei with coarse chromatin as well as finely granular cytoplasm. Immunohistochemical staining shows positivity for calcitonin in most cases. Chromogranin A, synaptophysin and calcitonin gene related peptide are mostly positive as well.^2,5–9

Patients with MTC should undergo proper initial evaluation. Thorough history taking and physical examination must be performed. Details of symptoms of hyperparathyroidism, pheochromocytoma and carcinoid syndrome should be elicited, and a thorough family history should be obtained.

Neck ultrasonography is performed to evaluate the thyroid gland and cervical lymph nodes. MTC exhibits ultrasonographic features that are similar to other thyroid malignancies (eg calcifications, hypoechogenicity, spiculated margins and internal vascularity). However, in MTC cases, nodules tend to be larger and more cystic in nature with a more homogeneous solid component. The calcifications may be coarser than in papillary carcinomas. MTC appears cold on iodine imaging because it does not concentrate iodine. The role of fluorodeoxyglucose positron emission tomography is debatable. Neck and chest computed tomography (CT) as well as abdominal triphasic CT or magnetic resonance imaging should be performed in patients with nodal metastasis or elevated serum calcitonin (>400pg/ml). Biochemical evaluation involves serum calcitonin, carcinoembryonic antigen, calcium and urine or plasma metanephrine to exclude other components of MEN type 2 syndrome.^{1,4,9,10–14}

Methods

This was a retrospective study. The institutional registry at the oncology centre at Mansoura University was searched for medullary thyroid cancer patients who underwent surgical intervention between January 2008 and February 2019. Patients unfit for operative treatment were excluded. The objectives of the study were assessment of disease epidemiology, pattern of recurrence and metastasis. The primary outcome measure was disease free survival while the secondary outcome measures were development of recurrence and associated metastasis.

The data were analysed using SPSS^® version 22 (IBM, New York, US). Survival analysis was performed using Kaplan–Meier curves and significance was determined by employing the logrank test. A p-value of <0.05 was considered statistically significant.

Results

Thirty-one patients were operated on during the study period. Two-thirds of these (61.3%) were female. The mean age at diagnosis was 39.9 years. Three cases had a family history of MTC. All of the patients underwent total thyroidectomy and 25 underwent selective bilateral neck dissection (II, III, IV, Va, VI).

The median hospital stay was four days. The median pathological size was 4cm. Multifocal disease was found in 12 while extrathyroid extension was detected in 3 cases. The median number of lymph nodes retrieved was 24 and the median number of positive nodes was 4. Twenty patients were pathologically node positive (ipsilateral in 15 of these cases). Seven cases were metastatic at diagnosis. Adjuvant chemotherapy was used for seven patients while adjuvant radiotherapy was employed for nine. There was local recurrence in three cases and one individual developed distant recurrence. In addition, another three metastatic patients with complete local control encountered local failure. The median time from surgery to local recurrence was 12 months (Table 1).

Table 1.

Basic patient demographics and treatment data

Parameter	Data
Sex	12 male (38.7%), 19 female (61.3%)
Mean age at diagnosis	39.9 years (SD: 12.96 years)
Family history of MTC	3 (9.7%)
Neck dissection	25 SND (80.6%), 1 MBND (3.2%), 5 no lymphadenectomy (16.1%)
Median length of hospital stay	4 days (range: 1–13 days)
Median pathological size	4cm (range: 1–7cm)
Tumour site	13 right, 10 left, 7 both
Tumour focality	17 unifocal, 14 multifocal
Extrathyroid extension	3 (9.7%)
Median number of retrieved nodes	24 (range: 5–56)
Node positive patients	20 (64.5%)
Median number of positive nodes	4 (range: 0–32)
Side of positive nodes	15 ipsilateral, 5 contra/bilateral
Site of positive nodes	7 lateral, 13 lateral and central
Metastasis	7 (22.6%)
Stage	1 stage I, 6 stage II, 1 stage III, 20 stage IV
Adjuvant chemotherapy	7 (22.6%)
Adjuvant radiotherapy	9 (29.0%)
Recurrence	3 local, 1 distal
Progression	6 local, 1 distal
Median time to recurrence	12 months (range: 3–50 months)

MBND = modified bilateral neck dissection; MTC = medullary thyroid carcinoma; SD = standard deviation; SND = selective neck dissection

There was no incidental discovery of contralateral tumour foci. All of the patients had normal thyroid function. The postoperative course was uneventful in 30 cases. Only one individual developed haematoma with internal jugular vein thrombosis following surgery. There was no documented in-hospital mortality.

Disease free survival

The estimated mean disease free survival was 56.5 months. Disease free survival was significantly related to age, metastasis and side of nodal spread (Table 2, Fig 1).

Table 2.

Factors affecting disease free survival (DFS)

Parameter	Estimated mean DFS	p-value
Sex	Male: 32.4 months Female: 56.6 months	0.96
Age	≤40 years: 81.4 months >40 years: 21.0 months	0.001
Tumour focality	Unifocal: 65.6 months Multifocal: 29 months	0.34
Node side	Ipsilateral: 67.9 months Contra/bilateral: 2.4 months	0.001
Node site	Lateral: 45.2 months Lateral and central: 48.0 months	0.73
Nodal spread	No: 30.7 months Yes: 49.9 months	0.24
Metastasis	No: 73.0 months Yes: 0 months	0.00

Figure 1.

Kaplan–Meier curves showing disease free survival of medullary thyroid cancer patients by age group and distribution of node positive disease

Recurrence

True recurrence (defined by reappearance of medullary cancer either locally or at distant sites after clinical cure) was encountered in only four cases. However, none of the studied variables correlated significantly with recurrence.

Metastasis

Metastasis was found in seven patients; in six of these, it was present at the time of primary diagnosis and treatment. Factors that correlated significantly with metastasis included age >40 years, which carried a 12-fold increased risk, and presence of contralateral/bilateral nodal spread, with a risk that was 26 times higher. Those who developed metastasis were 35 times more likely than other patients to receive adjuvant chemotherapy (Table 3). Three individuals had single site metastasis (bony, hepatic and suprarenal metastasis) and four had metastasis at multiple sites (bone, lung, axillary node, suprarenal and liver).

Table 3.

Comparison between patients who developed distant metastasis and those who remained without remote disease

	Non-metastatic	Metastatic	Odds ratio	p-value
Sex			0.8	1.0
Male	9	3
Female	15	4
Age			12	0.028
≤40 years	16	1
>40 years	8	6
Tumour site			3.7	0.30
One lobe	20	4
Two lobes	4	3
Tumour focality			1.1	1.0
Unifocal	13	4
Multifocal	9	3
Extrathyroid extension			2	1.0
Absent	8	2
Present	2	1
Side of positive nodes			26	0.014
Ipsilateral	13	2
Contra/bilateral	1	4
Site of positive nodes			1.1	1.0
Lateral	5	2
Lateral and central	9	4
T stage			–	0.18
1	3	3
2	8	2
3	9	1
N stage			4.2	0.37
0	10	1
1	14	6
Median number of positive nodes	3	12	–	0.14
Median lymph node ratio	0.15	0.58	–	0.17
Adjuvant chemotherapy			35	0.004
No	14	1
Yes	2	5
Adjuvant radiotherapy			0.9	1.0
No	9	3
Yes	7	2

Discussion

MTC is a unique form of neuroendocrine thyroid carcinoma, which arises from parafollicular C cells. C cells account for 1% of thyroid cells and are responsible for calcitonin production. MTC makes up 3–5% of thyroid carcinoma cases. It usually presents with a thyroid nodule, in the upper to middle third of the right or left lobes. Distant metastasis usually spreads to the lung, brain or liver and it has a profound negative impact on survival.

The disease can occur either in sporadic or hereditary form (20–30%)¹⁵ as a part of MEN type 2 syndrome as well as non-MEN familial MTC. Nearly all patients with hereditary MTC have RET proto-oncogene mutation, which is also observed in up to 50% of sporadic cases.^2,16 Sporadic MTC with no RET mutation may show HRAS, KRAS or, rarely, NRAS mutations. MTC neither concentrates radioactive iodine, nor is it suppressed by levothyroxine treatment.^{1,2,9,14,15–20}

Sporadic MTC generally affects patients aged 40–60 years.^7,14 In our study, the mean age at diagnosis for the total cohort was 39.9 years. It tends to arise as a unilateral solitary tumour while hereditary MTC usually occurs in a bilateral multicentric pattern. Unifocal disease existed in just over half of our patients (n=17, 54.8%) and the disease was limited to one lobe (even if multifocal) in three-quarters (n=24, 77.4%).

Surgery is the main treatment for MTC and it can be cured if no residue is left behind. All patients with MTC should undergo total thyroidectomy and at least prophylactic central neck dissection, which offers a better cure rate than thyroidectomy alone, as well as better biochemical control. If the central nodes are involved and in cases with bulky tumours, the patient should also undergo prophylactic lateral neck dissection. Therapeutic lateral neck dissection is indicated if there is clinical or radiological lateral compartment involvement. Postoperative radiotherapy is indicated if there is residual gross neck disease. Vandetanib and cabozantinib are the preferred treatment for non-resectable local recurrence or metastatic disease. The efficacy of chemotherapy and radiotherapy is poor.^{1,5,9,12,16,18,21–25}

Usually, 70% of patients with clinically detectable MTC have cervical lymph node involvement while the incidence of distant metastasis is nearly 10%.¹⁴ In our study, 64.5% of patients had positive nodes and 22.6% had metastasis. For cases in which ultrasonography showed disease confined to a single lobe, no pathological carcinoma foci were found in the other lobe. This suggests that hemithyroidectomy may be a feasible option in a certain group of patients.

Age, sex, local invasion, angioinvasion, nodal and distant metastasis, postoperative calcitonin and completeness of surgical resection are the most significant prognostic factors for MTC.^{7,14,17–19,26} In our study cohort, not only the presence of nodal deposits but also the side of involvement was of prognostic importance. It was evident that deposits in contralateral lymph nodes indicate a worse prognosis despite there being no difference in staging category using the eighth edition of the American Joint Committee on Cancer staging system.²⁷ In our series, those aged >40 years had significantly lower disease free survival.

The incidence of skip lateral cervical nodal metastasis in the absence of central node involvement is 10%, being 25% for upper pole tumours.¹⁴ Another interesting finding among our patients was that there were no cases of central node metastasis in the absence of lateral neck disease.

It is acknowledged that this study has limitations. These include the small number of patients and the study cohort being confined to only surgical candidates. Furthermore, it was a retrospective study and there was no routine preoperative calcitonin measurement.

Conclusions

MTC is a rare but unique form of thyroid cancer, with a distinct origin and a specific treatment strategy. In our population, it occurred predominantly in women and younger patients (mean age: 39 years). Age, distant metastasis and nodal spread are the most significant prognostic factors for MTC. This study has also demonstrated that prognosis is not only affected by presence nodal involvement but also by side of involvement. The role of hemithyroidectomy as sufficient surgical treatment for node negative unifocal disease with a small tumour size warrants further investigation.