Preoperative neck ultrasound combined with pathological data can significantly impact the outcome of medullary thyroid carcinoma

Abstract

The diagnosis of medullary thyroid carcinoma (MTC) is challenging since the accuracy of ultrasound (US) and fine-needle aspiration cytology are suboptimal. As a result, MTC has a generally poor prognosis. The aim of this study was to analyze whether perioperative data can modify the risk of relapse in these patients. The institutional database of Turin Mauriziano Hospital was searched to extract records of MTCs diagnosed between 2000 and 2021. Kaplan-Meier curves and Cox and logistic regression analyses were performed, and the hazard ratio (HR) was calculated. Seventy-three MTC patients (median age 58 yr) were found. Disease-free survival was significantly different according to staging (HR: 9.12; p = 0.037), capsular status (HR: 5.49; p = 0.02), and neck US (HR: 9.19; p = 0.04). In the logistic regression analysis, CEA level (β: –0.01; p = 0.043), histological multifocality (OR: 7.4; p = 0.034), and metastatic lymph nodes at histology (β: –0.13; p = 0.006) were significantly associated with structural recurrence. Two logistic multivariate models best explained the variance in recurrence: 1) neck US presentation plus histological multifocality (AIC: 27; r²: 0.37; x²: 12.4; p = 0.002) and 2) number of neck metastases plus capsular invasion (AIC: 26; r²: 0.40; x²: 13.7; p = 0.001). Pathological data are associated with MTC prognosis. Preoperative neck US can significantly help to predict MTC outcome.

MEDULLARY THYROID CARCINOMA (MTC) is a malignant tumor first described in 1959 as having a solid nonfollicular histologic pattern, characterized by the presence of amyloid in the stroma and associated with a high incidence of lymph node metastases [1]. MTC is classified as a neuroendocrine tumor originating from neoplastic parafollicular C cells with the unique feature of producing calcitonin (Ctn). MTC represents approximately 5% of all thyroid cancers [2]. Approximately 25% of MTCs are caused by mutation of the RET proto-oncogene and are considered “familial.” When MTC coexists with tumors of the parathyroid gland and the medullary component of the adrenal glands (pheochromocytoma), it is termed multiple endocrine neoplasia type 2 (MEN2). The remaining 75% of MTCs are caused by somatic mutations that are present only in neoplastic cells and therefore are considered “sporadic” [3]. MTC most commonly presents as a solitary thyroid nodule in patients in the fourth to sixth decade of life [4]. Although our knowledge about MTC has significantly increased during the last 30 years, it is still a very aggressive tumor with a poor prognosis. In fact, patients with sporadic MTCs present neck lymph node metastases in at least 45% of cases and distant metastasis at diagnosis in at least 10% of cases; in addition, 70% of patients presenting with a palpable MTC already have evidence of cervical node metastases at surgery [5, 6]. These figures are attributed to the challenging diagnosis of MTC, as it exhibits heterogeneous ultrasound (US) or fine-needle aspiration (FNA) cytology patterns, and these methods have significant limitations [7]. Therefore, an early diagnosis and a tailored surgical treatment extended until the removal of all tumor burden are critical to obtain a good prognosis for patients; on the other hand, international guidelines report discordant recommendations concerning the diagnostic work-up and the surgical approaches for MTC.

The measurement of calcitonin (Ctn) has been shown to be the most reliable MTC diagnostic tool [8, 9], although routine testing for Ctn levels in patients with nodular goiter is not universally accepted because MTC is rare and the consequent cost-effectiveness is not uniformly favorable. International recommendations in this context are ambiguous: a consensus from the European Thyroid Association (ETA) in 2006 was in favor of routine Ctn testing during the initial nodule workup [10]; the 2015 American Thyroid Association (ATA) guidelines were neither in favor of nor against it [11]; and the 2010 ETA, American Association of Clinical Endocrinology (AACE), and Associazione Medici Endocrinologi (AME) all recommended Ctn measurement in specific patient settings [12]. Finally, regarding treatment, there are relevant differences between the guidelines concerning surgical approaches, and further evidence emerged from studies that are considered milestones in the literature of this disease [13].

Since surgical resection represents the only cure for these patients, the historical institutional experiences can be useful to disseminate good practices in MTC management and improve the diagnostic accuracy, surgical approaches, and outcome of patients.

The present study was undertaken to report the historical series of MTCs diagnosed at a single high-volume institution and analyze whether perioperative data (i.e., presurgical assessment, surgical approach, pathological staging) can modify the risk of relapse in these patients. Records of different diagnostic factors were detailed. MTC relapse over time during follow-up was analyzed according to baseline data.

Methods

Institutional thyroid nodule(s) patient management

Mauriziano Hospital is a high-volume primary care center in Turin. At this center, the departments of endocrinology, pathology, and surgery have traditionally extensive experience in the field of thyroid disease. The institutional Thyroid Center includes all the specialists involved in the management of thyroid patients. As a consequence, the historical institutional database includes highly detailed records about all patients managed and/or operated on. At Mauriziano Hospital, patients diagnosed with thyroid nodule(s) undergo thyroid function tests and Ctn measurement. According to Ctn levels, patients are managed as follows: patients with Ctn values above 100 pg/mL are usually referred to surgery after thyroid investigations (i.e., neck US, thyroid hormone measurement, FNA) are completed, and patients with Ctn between the upper reference and 100 pg/mL undergo further examinations (i.e., FNA, Ctn stimulation test, laboratory tests, imaging procedures). Patients with mild-to-moderate suspicion for MTC are generally managed according to other characteristics (i.e., Ctn value after stimulation, FNA report, goiter-related symptoms). In all cases, decision-making depends on careful multidisciplinary preoperative assessment. Thyroid and neck US is always performed before surgery by highly experienced endocrinologists. Lymph nodes presenting any of the following US features are considered suspicious: cystic content, peripheral hypervascularity, macrocalcifications, hyperechoic spots, lack of hyperechoic hilum, and longitudinal/anteroposterior diameter ratio <2. Any suspicious lymph node is evaluated via FNA, and if multiple suspicious lymph nodes in the same neck level are identified, FNA is performed on the largest lymph node. The surgical extent is based on the neck US results and serum Ctn values; the higher Ctn levels are, the more extended the surgical excision.

After initial surgery, MTC patients are referred for regular follow-up, including serum evaluation of thyroid hormones and MTC markers (i.e., Ctn and carcinoembryonic antigen (CEA)) and imaging procedures (neck US, computed tomography, magnetic resonance) when needed.

Data extraction

The institutional database was searched to extract records of MTC diagnosed by histology during the period from 2000 to 2021. Once the patient list was initially extracted, data recorded at diagnosis were collected. In addition to the demographic data, the following information was extracted: Ctn value, CEA value, neck US presentation (i.e., with or without suspicion for cervical metastases), cytological assessment (i.e., suspicious for or consistent with MTC, benign, indeterminate, not adequate), histological diagnosis with TNM staging, compartment-oriented surgery, and follow-up period.

Recurrence definition during follow-up

A disease-free status was defined as no evidence of disease (NED). Patients with high Ctn levels and localized metastases identified by cytology/histology and/or imaging were defined as having structural recurrence (sREC). Patients with persistently elevated Ctn levels without imaging positivity for metastases were defined as having biochemical recurrence (bREC). Structural disease-free survival (DFS) was calculated from the date of surgery to the date of the last follow-up examination in NED patients and from the date of surgery to the date of relapse diagnosis in sREC patients.

Statistical analysis

Numerical continuous variables are reported as medians and interquartile ranges (IQRs). Continuous variables were compared between two groups by the Mann-Whitney test. Categorical variables were compared between two groups by the chi-square test (χ² test). DFS was estimated by the Kaplan-Meier method with curves analyzed by the log-rank test. A Cox proportional hazards model was used in univariate and multivariate analyses to analyze the effect of predictors on cancer recurrence over time (expressed as the hazard ratio (HR)). Logistic regression analyses were performed considering sREC as the dependent variable (expressed as the odds ratio (OR)). Some variables were dichotomized to better evaluate their impact in terms of HR/OR. Continuous variables were evaluated by ROC curve analysis. Since pTNM staging could be significantly different over time, it was analyzed as a dichotomous variable (i.e., stages I–II vs. III–IV). Statistical significance was set at p < 0.05. Statistical tests were performed using “The Jamovi Project (2022)” - Jamovi (Version 2.3) [Computer Software], available at https://www.jamovi.org.

Results

Flow of patients and main data

During the study period, 73 MTCs were found in the institutional database, including 46 females and 27 males. The median age of the patients was 58 years (IQR 48–70). Sixty-four patients underwent FNA, and FNA was performed on MTCs in 60/64 cases. Among these, 43/60 (71.7%) FNA cytology results were consistent with MTC, 8/60 (13.3%) were suspicious for MTC, 5/60 (8.3%) were indeterminate FNA results, 2/60 (3.3%) were benign/not neoplastic specimens, and the remaining 2 samples were not adequate. Preoperative Ctn levels were available in 58 (79.5%) cases, with a median value of 497.5 pg/mL (IQR 116.9–1499.5). There were 44 (78.9%) cases with Ctn >100 pg/mL, 11 (18.9%) with Ctn between 20 and 100 pg/mL, and 3 (5.2%) with Ctn between 10 and 20 pg/mL. The measurement of Ctn in FNA fluids was performed in 6 cases, with high values in all samples. Data about surgery were available in 71 cases: 71/71 underwent total thyroidectomies; neck dissection of the central neck compartment alone was performed in 27 cases, central and unilateral latero-cervical compartments in 6 cases, and central and bilateral latero-cervical compartments in 31 cases (Table 1).

Table 1

Availability and median values of MTC patient main data

Parameter	Cases with available data	Median value (IQR)
Age (years)	73	58 (48–70)
Follow-up (months)	62	76 (36–120)
Ctn (pg/mL)	58	497.50 (116.90–1,499.50)
CEA (ng/mL)	29	19.89 (4.70–92.40)
Diameter (mm)	43	15 (9–24.50)
Lymph nodes removed	19	34 (14–42)

MTC, medullary thyroid cancer; IQR, interquartile range; Ctn, calcitonin; CEA, carcinoembryonic antigen.

Patients with US findings of neck lymph node metastases showed different Ctn and CEA values. No statistically significant differences were found for age or maximum diameter of the lesion (Table 2). The extent of surgery was different for Ctn, CEA and maximum diameter of the lesion but not for patient age (Table 3). Finally, the extent of the operation was different for the detection of suspected neck metastases on US (χ² test = 16.5; p < 0.001).

Table 2

Difference of the most relevant baseline parameters respect to the presence of US suspicion of neck metastases

Parameter	Mann-Whitney test	p
Age	307.0	0.762
Ctn	189.0	0.034
CEA	32.0	0.042
Major diameter	71.0	0.053

US, ultrasound; Ctn, calcitonin; CEA, carcinoembryonic antigen.

Table 3

Difference of the most relevant baseline parameters respect to surgery extension to laterocervical compartments.

Parameter	Mann-Whitney test	p
Age	484.0	0.188
Ctn	163.0	<0.001
CEA	25.0	<0.001
Major diameter	73.0	<0.001

Ctn, calcitonin; CEA, carcinoembryonic antigen.

Analysis of disease-free survival according to data at diagnosis

Among the patients followed up over time, 12 (18.8%) had sREC, 8 (12.5%) had bREC, and 44 (68.7%) had NED. As shown in Table 4, DFS was significantly different among staging, capsular status, and neck US results. Kaplan-Meier curves are illustrated in Figs. 1–3. Multivariate Cox regression did not improve univariate Cox regression models.

Table 4

Data of variables with significant HR.

Variable	Results	HR (95%CI)	p
High TNM stages (III–IV) vs. Low TNM stages (I–II)	24 High, 33 Low	9.12 (1.14–73.17)	0.037
Capsular invasion	6 +ve, 51 –ve	5.49 (1.31–23.04)	0.020
US suspicious for neck met	18 +ve, 36 –ve	9.19 (1.09–77.18)	0.041

HR, hazard ratio; US, ultrasound; +ve, positive; –ve, negative; Available data were following: 54 for neck US, 57 for capsular status, 57 for TNM staging.

Fig. 1

Kaplan Meier curves based on US neck presentation.

Blue line, patients with no US suspicion of neck metastases; red line, patients with presence of US suspicion of neck metastases.

Fig. 2

Kaplan Meier curves based on capsular invasion.

Blue line, patients with no thyroid capsular invasion at pathology report; red line, patients with thyroid capsular invasion at pathology report.

Fig. 3

Kaplan Meier curves Low stages vs. High stages.

Blue line, patients with pTNM Low stages; red line, patients with pTNM High stages.

Regression analyses

In the logistic univariate analysis, CEA level (β: –0.01; p = 0.043), neck US results (OR: 24.00; p = 0.005), multifocality on histology (OR: 7.4; p = 0.034), thyroid capsule invasion on histology (OR: 8.00; p = 0.028), number of lymph nodes positive on pathology report (β: –0.13; p = 0.006), and pathology staging (OR: 28.00; p = 0.003) were significantly associated with sREC.

In the multivariate regression analysis, there were two models that can be considered reliable to explain the variance of sREC. The first included neck US presentation and multifocality on histology (AIC: 27; r²: 0.37; x²: 12.4; p = 0.002). The second one included the number of neck metastases and thyroid capsular invasion (AIC: 26; r²: 0.40; x²: 13.7; p = 0.001).

Discussion

Medullary thyroid carcinoma is a very aggressive neuroendocrine tumor. Therefore, early diagnosis and surgical treatment extended until removal of all tumor burden are critical to obtain a good prognosis for patients. Despite this, to date, the international guidelines report discordant recommendations on this topic, particularly about the diagnostic work-up (i.e., serum Ctn measurement in patients with thyroid nodules) [9, 11, 12, 14, 15]. Furthermore, there are differences between the surgical approaches indicated by the guidelines [5] and the evidence obtained from studies considered milestones in the treatment of this disease [13]. Here, we retrospectively analyzed a historical series of MTCs diagnosed and treated at a single high-volume institution. The aim of this study was to evaluate which perioperative features can be considered modifiers of recurrence risk in MTC patients. The results showed which factors are correlated with prognosis and can be used for patient management. Therefore, these results can be useful for disseminating good practices and drafting future guidelines.

First, the present series is reliable since it derives from a long period of experience of a single institution where multidisciplinary management is an active part of curing thyroid patients. TNM staging of our series showed a significant effect on DFS, as expected; a higher stage indicates worse DFS with a dramatic decrease in the order of months. This intrinsically emphasizes that thyroidologists must diagnose MTC early before it spreads. In a similar way, Ctn measurement at the diagnosis of nodular goiter or during the early follow-up period plays a fundamental role, given the nonoptimal reliability of US features, the TIRADS system, and FNA cytology in MTC detection [7].

Second, we found that other MTC pathological data, such as invasion of the thyroid capsule, number of neck metastases, and cancer multifocality, appeared to be related to recurrence, independent of the FNA results and the maximum nodule diameter. These features seem to be related to the intrinsic aggressiveness of each MTC case that is attributable to the genetic mutation burden acquired by the neoplasm. Additionally, CEA levels were significantly associated with recurrence, but data on this factor were sparse.

Third, we found that neck US suspicious for metastases was significantly associated with prognosis with the highest HR. Having a positive preoperative neck US increased the risk of cancer relapse by more than 800%. Thus, we can affirm that those patients who underwent total thyroidectomy combined with neck dissection had a better prognosis than those who did not since surgery was determined by neck US. In fact, there were patients with good outcomes over time who underwent thyroidectomy alone since their presurgical neck US was negative. Even though these data are retrospective, they are of high interest for clinical practice. Close collaboration and communication between surgeons, pathologists, and endocrinologists before, during, and after surgery should be mandatory. In particular, endocrinologists are advised to perform a careful biochemical and US assessment of patients with nodular thyroid disease. The latter should include the measurement of serum Ctn level at diagnosis and serum CEA level to better refine the risk stratification and to share information with surgeons when necessary. Furthermore, these features could also be integrated with intraoperative assessments, including the desmoplastic stromal reaction near the primary tumor lesion, which, if absent, demonstrated high specificity for negative cervical lymphadenopathy (pN0) [16], thus allowing for less aggressive surgery in selected cases. However, pathologists should be aware that preoperative FNA may cause reactive fibrosis, which can be difficult to differentiate from stromal desmoplasia [17].

Both the diagnosis and postoperative follow-up of medullary thyroid carcinoma remain a matter of debate [7]. Hence, the management of these patients remains difficult. Ctn is recognized as the most accurate tool in the initial diagnosis of MTC [7]. However, there is no universal consensus to screen for MTC in all patients with thyroid nodules by routinely measuring Ctn. US is pivotal for discriminating suspicious from benign thyroid nodules, but its performance is suboptimal [18]. MTC is correctly detected on cytological specimens in just above 50% of cases [19]. Other imaging procedures, such as computed tomography, magnetic resonance, and PET, can be useful to identify patients with more aggressive cancer; however, no evidence-based data support the use of the latter imaging tools [7]. In addition, circulating markers other than Ctn and CEA have no superior performance. From this standpoint, the present study can add information useful to improve our clinical practice.

The limitations of this study are its retrospective design and the lack of information on some patients, which does not allow a complete analysis of all recruited cases. On the other hand, the real-world data of a high-volume primary care center and a relatively large series for MTC epidemiology constitute important strengths of this study found in few other studies in the literature.

In conclusion, the present study showed that MTC outcome is significantly influenced by pTNM staging and other pathological features. Furthermore, this study strongly indicates that preoperative neck US plays a main role and is essential to improving MTC prognosis. Preoperative multidisciplinary discussion must be considered in managing MTC patients.

Conflicts Declaration

Funding

No funding supported this study.

Conflict of interest

The authors declare no competing interests.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Data availability

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author contributions

Conceptualization, M.D. and P.T.; methodology, T.P. and P.T.; software, T.P.; validation, P.T., M.D. and F.R.; formal analysis, M.D., F.R., A.M., G.C., A.C., and L.D.; investigation, M.D., A.M., F.R., G.C., A.C., L.D., and T.P.; data curation, M.D., A.M., F.R., G.C., A.C., L.D., and T.P.; writing—original draft preparation, T.P.; writing—review and editing, M.D., T.P., and P.T.; visualization, M.D., F.R., A.M., G.C., A.C., L.D., and P.T.; supervision, P.T.; All authors have read and agreed to the published version of the manuscript.

References

• 1   Hazard  JB,  Hawk  WA,  Crile  G Jr (1959) Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. J Clin Endocrinol Metab 19: 152–161.
• 2   Fugazzola  L (2023) Medullary thyroid cancer—an update. Best Pract Res Clin Endocrinol Metab 37: 101655.
• 3   Cabanillas  ME,  McFadden  DG,  Durante  C (2016) Thyroid cancer. Lancet 388: 2783–2795.
• 4  (2021) SEER Cancer Statistics Review, 1975–2018. National Cancer Institute. Bethesda, MD, USA. https://seer.cancer.gov/csr/1975_2018/ accessed on April 18, 2023.
• 5   Wells  SA Jr,  Asa  SL,  Dralle  H,  Elisei  R,  Evans  DB, et al. (2015) Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25: 567–610.
• 6   Moley  JF (2010) Medullary thyroid carcinoma: management of lymph node metastases. J Natl Compr Canc Netw 8: 549–556.
• 7   Trimboli  P,  Mian  C,  Piccardo  A,  Treglia  G (2023) Diagnostic tests for medullary thyroid carcinoma: an umbrella review. Endocrine 81: 183–193.
• 8   Bugalho  MJ,  Santos  JR,  Sobrinho  L (2005) Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cytology as compared with serum calcitonin measurement. J Surg Oncol 91: 56–60.
• 9   Elisei  R,  Romei  C (2013) Calcitonin estimation in patients with nodular goiter and its significance for early detection of MTC: european comments to the guidelines of the American Thyroid Association. Thyroid Res 6 (Suppl 1): S2.
• 10   Pacini  F,  Schlumberger  M,  Dralle  H,  Elisei  R,  Smit  JW, et al. (2006) European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 154: 787–803.
• 11   Haugen  BR,  Alexander  EK,  Bible  KC,  Doherty  GM,  Mandel  SJ, et al. (2016) 2015 American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid cancer. Thyroid 26: 1–133.
• 12   Gharib  H,  Papini  E,  Paschke  R,  Duick  DS,  Valcavi  R, et al. (2010) American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. Endocr Pract 16: 468–475.
• 13   Machens  A,  Dralle  H (2010) Biomarker-based risk stratification for previously untreated medullary thyroid cancer. J Clin Endocrinol Metab 95: 2655–2663.
• 14   Schlumberger  M,  Bastholt  L,  Dralle  H,  Jarzab  B,  Pacini  F, et al. (2012) 2012 European thyroid association guidelines for metastatic medullary thyroid cancer. Eur Thyroid J 1: 5–14. Erratum in: Eur Thyroid J 1: 54.
• 15  American Thyroid Association Guidelines Task Force,  Kloos  RT,  Eng  C,  Evans  DB,  Francis  GL, et al. (2009) Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19: 565–612. Erratum in: Thyroid 19: 1295.
• 16   Scheuba  C,  Kaserer  K,  Kaczirek  K,  Asari  R,  Niederle  B (2006) Desmoplastic stromal reaction in medullary thyroid cancer-an intraoperative “marker” for lymph node metastases. World J Surg 30: 853–859.
• 17   Aubert  S,  Berdelou  A,  Gnemmi  V,  Behal  H,  Caiazzo  R, et al. (2018) Large sporadic thyroid medullary carcinomas: predictive factors for lymph node involvement. Virchows Arch 472: 461–468.
• 18   Ferrarazzo  G,  Camponovo  C,  Deandrea  M,  Piccardo  A,  Scappaticcio  L, et al. (2022) Suboptimal accuracy of ultrasound and ultrasound-based risk stratification systems in detecting medullary thyroid carcinoma should not be overlooked. Findings from a systematic review with meta-analysis. Clin Endocrinol (Oxf) 97: 532–540.
• 19   Trimboli  P,  Giannelli  J,  Marques  B,  Piccardo  A,  Crescenzi  A, et al. (2022) Head-to-head comparison of FNA cytology vs. calcitonin measurement in FNA washout fluids (FNA-CT) to diagnose medullary thyroid carcinoma. A systematic review and meta-analysis. Endocrine 75: 33–39.