Procalcitonin as an Alternative Tumor Marker of Medullary Thyroid Carcinoma

Abstract

Context

Calcitonin (CT) measurement is pivotal in the management of medullary thyroid carcinoma (MTC), but several pitfalls can affect its reliability. Procalcitonin (ProCT) has been reported as a promising alternative MTC tumor marker.

Objective

This study aimed to determine the ProCT diagnostic accuracy in prediction and treatment monitoring of MTC.

Methods

Electronic databases were searched for observational studies published until May 2021 without language or time restrictions. Studies comparing ProCT and calcitonin accuracy were included. After removing duplicates and exclusion of not-eligible articles, relevant articles were screened independently by 2 reviewers. Eleven studies (4.5% of the identified studies) met the selection criteria. Two reviewers independently extracted data and assessed data quality and validity through QUADAS-2.

Results

A meta-analysis was performed on 11 sufficiently clinically and statistically homogeneous studies (n = 5817 patients, 335 MTC patients). Hierarchical summary receiver operating characteristics and bivariate methods were applied. Serum ProCT was found to be a highly accurate test for MTC diagnosis and monitoring. The pooled sensitivity, specificity, positive and negative likelihood ratios, area under the curve, and positive and negative predictive values for ProCT were 0.90 (95% CI: 0.71-0.97), 1.00 (95% CI: 0.85-1.00), 288 (95% CI: 5.6-14 929.3), 0.10 (95% CI: 0.03-0.33), 0.97 (95% CI: 0.95-0.98), 99%, and 2%, respectively.

Conclusions

The high accuracy, compounded with favorable analytical characteristics, give ProCT great potential to replace calcitonin as a new standard of care in the management of MTC.

medullary thyroid carcinoma, calcitonin, procalcitonin, meta-analysis

Calcitonin (CT) is the standard biochemical tumor marker for medullary thyroid carcinoma (MTC) diagnosis and follow-up (1). Nonetheless, several problems continue to influence CT measurement and its clinical reliability. First, CT is unstable in serum at room temperature and needs to be kept cool on ice during the entire process chain (2). Second, despite the use of the single calibrator WHO 89/620, significant variations in CT concentrations have been observed using different assays (3). Third, significant higher CT concentrations occur in healthy males compared to females, reflecting differences in C-cell distribution in males and females (4,5). Fourth, unspecific increases in serum CT concentrations might be observed in other neuroendocrine tumors, certain leukemias, systemic mastocytosis, small cell carcinoma of the lung, breast or pancreatic cancer, renal failure, and hyperparathyroidism as well as in patients taking proton pump inhibitor therapy and smokers (6-8). Finally, a concentration-dependent and biphasic half-life (~15 and ~40 min at physiological concentrations; ~3 and ~30 h at elevated concentrations) complicates CT use for monitoring the success of treatment interventions (9). All in all, careful standardized handling of serum samples, accurately defined assay-specific and gender-specific reference ranges, and a good knowledge of nonspecific causes of CT increase and CT disappearance kinetics are required to avoid misdiagnosis (2,5,9). Procalcitonin (ProCT) measurement has been suggested as an alternative MTC tumor marker to overcome these CT-related problems (10). ProCT is encoded by the CT gene and produced by the thyroid C cells and MTC tumor cells. It is a very stable protein and serum samples do not need to be kept cool on ice (11). Notably, ProCT features a concentration-independent in vivo half-life of 20 to 24 h (12) and is largely unaffected by diseases and therapies causing aspecific CT increases (13). Indeed, ProCT is also produced and secreted in response to inflammatory stimuli and plays an important role in the clinical diagnosis and prognosis of sepsis (14). These roles have to be considered when using ProCT as a tumor marker for MTC, but in the absence of infection, ProCT is almost exclusively secreted by C cells (15). Last but not least, intellectual property for commercial ProCT assays is licensed out by a single company, and therefore commercially available assays are highly comparable (16). A number of studies were published on the use of ProCT as a reliable alternative tumor marker in MTC, including 2 systematic reviews published in 2015 and 2016 (17,18). Since then, new primary studies on large patients series have been published. Our present study provides a meta-analysis of updated literature to obtain more robust evidence on ProCT performance in the assessment of MTC. Specifically, we aimed to address 2 clinical questions:

1. Are serum levels of ProCT predictive of MTC in patients carrying thyroid nodules (ie, prediction)?

2. Are postoperative serum levels of ProCT indicative of response to treatments in patients with MTC (ie, treatment monitoring)?

Materials and Methods

Protocols and Registration

The meta-analysis was performed according to the Synthesizing Evidence from Diagnostic Accuracy Tests (SEDATE) guideline on reporting a diagnostic test accuracy meta-analysis (19) and an update Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline (20). The methodology was registered in the PROSPERO (International Prospective Register of Systematic Review) database under the registration number CRD42021253278.

Eligibility Criteria

All original peer-reviewed research publications were considered. Eligible studies were selected according to the following criteria: (i) study design (prospective or retrospective); (ii) index test (ProCT serum levels); (iii) reference standard (CT measurement); (iv) type of data required for extraction (sensibility and specificity); (v) studies involving patients with confirmed progressive MTC, based on clinical, imaging, or histological evidence of persisting or recurrent disease or continuous elevation of serum CT; patients with confirmed MTC, deemed disease free (ie, remitting) by clinical assessment, imaging, and serum CT determinations; patients with non-MTC neuroendocrine tumor; patients with benign thyroid disease or nontoxic nodular goiter; and patients with suspected MTC. Review articles, systematic reviews with or without meta-analysis, case studies, and preclinical studies were excluded.

Information Sources and Search Strategy

The components of the PICOS (patient, intervention, comparison, and outcomes) question were as follows: patients with MTC (patients); ProCT measurement (intervention); CT measurement (comparison); the diagnosis of MTC through CT test (outcome); and retrospective or prospective studies (study design). A systematic search was carried out on PubMed, Embase, Web of Science, and Scopus from February to May 2021 without time and language restrictions. The literature search strategy was based on the following keywords: (thyroid neoplasm OR medullary thyroid OR MTC) AND (calcitonin OR calcitonin gene-related peptide) AND (procalcitonin OR PROCT OR ProCT OR procalcitonin). Outcome was not included in the search keywords given the nature of the field of diagnostic test accuracy (21). Additionally, hand searches were performed to identify articles other than those found in the electronic databases. A further hand search of the citation lists of the included studies was performed. Grey literature was searched using the Open Grey database (www.opengrey.eu) applied the previous search strategy. The first (title/abstract screening) and second (full-text assessment) steps of the search process were performed by 2 independent reviewers (L.G. and M.L.G.), and any disagreement was discussed until a decision was made by consensus.

Study Selection

The complete list of articles obtained through the systematic search was screened to remove duplicates and exclude ineligible articles. The potentially relevant articles to answer the research question were screened by reading titles and abstracts. The eligible studies were independently selected by 2 reviewers (L.G. and G.P.). Full texts of the remaining potentially relevant articles (ie, those that met the inclusion and exclusion criteria) were retrieved. The final eligibility of each study was assessed, and the reasons for exclusion were recorded. The definitive article selection was independently done by 2 authors (L.G. and F.D.). When there was disagreement, a third experienced reviewer (L.C.) was consulted to achieve a consensus.

Data Extraction

Two reviewers (L.G. and L.C.) independently extracted the data from the full texts of the studies that fulfilled the inclusion criteria. Disagreements were resolved through team discussions. No numerical information was extracted from the figures reported in the study publications.

Data extraction was organized in tables that included the following information:

• (1) Study characteristics: first author, year, country, study design

• (2) Sample size, true positive (TP), true negative (TN), false positive (FP), and false negative (FN)

• (3) Patients’ characteristics: pre- or postoperative patients

• (4) Index test: ProCT threshold and assay

• (5) Reference standard: CT threshold

If results were reported as sensitivity and specificity, main values were calculated through the following formulas:

1. TP = Se × P

2. FP = (S–P) – TN

3. TN = Sp × (S–P)

4. FN = P–TN

where Se = sensitivity, Sp = specificity, S = number of all subjects, and P = number of patients with confirmed MTC.

We used the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool to assess the quality of the included studies regarding biases affecting their applicability in 4 domains: patient selection, index test, reference standard, and flow and timing. Two authors evaluated each item. The index test was defined as the measurement of ProCT in serum. The presence of various assay for this test has to be addressed. The histological observation was considered as the reference standard (gold standard). The outcome was defined through clinical, imaging, or histological evidence of MTC through elevation of serum CT.

Statistical Analysis

The hierarchical summary receiver operating characteristics (HSROC) and bivariate methods are the most appropriate methodological approaches to considering heterogeneity between and within studies, respectively (22-24). Therefore, we performed a meta-analysis using hierarchical logistic regression to determine summary estimates of the sensitivity, specificity, diagnostic odds ratio, and likelihood ratios by bivariate random effects. The HSROC curve was adopted to model the parameters for the ROC curves and to take into account a possible threshold effect. The threshold effect was detected by Spearman’s correlation coefficient (21). Publication bias (bias across studies) was assessed by the Deeks’ funnel plot asymmetry test, where Ps lower than 0.1 indicated publication bias (25).The primary endpoints were the sensitivity and specificity. Predefined secondary endpoints were positive predicted value [PPV = TP/(TP + FP)], negative predicted value [NPV = TN/(TN + FN)], positive likelihood ratio [L+ = sensitivity/(1 − specificity)], negative likelihood ratio [L− = (1 = sensitivity)/specificity], and diagnostic odd ratio (DOR) = (TP/FN)/(FP/TN). Sensitivity analyses were performed by excluding studies that were considered outliers and by restricting the meta-analysis to subgroups (19). Subgroup analyses for the primary endpoint were predefined: assay for ProCT measurement [time-resolved amplified cryptate emission immunofluorometric assay (TRACE) vs other assays], threshold for ProCT (>0.15 ng/mL vs ≤0.15 ng/mL), and patients characteristics (pre- or postoperative patients). A meta-regression analysis was conducted for heterogeneity using the following predefined study-level covariates: (i) assay for ProCT measurement (TRACE vs other assays) and (ii) threshold for ProCT (>0.15 ng/mL vs ≤0.15 ng/mL). Meta-analysis was performed using STATA, version 17 (StataCorp., College Station, TX, USA) with metandi, metandiplot, and midas commands.

Results

Study Selection and Characteristics

The literature search identified 242 studies. As shown in Figure 1, 11 studies met the inclusion and exclusion criteria and were included in the meta-analysis (10,26-35). The included studies had a total of 5817 patients. Five studies were retrospective (10,26,33-35), and 6 studies were prospective (27-32). The details of the included studies are reported in Table 1. The methodological quality, assessed through QUADAS-2, was acceptable [Supplemental Figure 1 (36)]. The Deeks’ funnel plot asymmetry test [Supplemental Figure S2 (36)] suggested no significant evidence for publication bias (P = 0.44). Threshold effect was not observed as proved by Spearman’s correlation coefficient between sensitivity and specificity (rho = 0.1500).

Table 1.

Characteristics of the included studies (n = 11)

Study no.	Study	Country	Study design	ProCT threshold	CT threshold	Patients	TP	FP	FN	TN	ProCT assay
1	Algeciras-Schimnich et al (10)	United States	Retrospective	>0.15 ng/mL	>16 pg/mL in males and >8 pg/mL in females	590	83	26	8	473	TRACE (Kryptor®, BRAHMS, D)
2	Walter et al (28)	Switzerland	Prospective	>0.15 ng/mL	>20 pg/mL	111	67	40	2	2	CLIA (ProCa-S, BRAHMS, D)
3	Azevedo et al (26)	Portugal	Retrospective	>0.5 ng/mL	NR	52	12	0	24	16	TRACE (Kryptor®, BRAHMS, D)
4	Giovanella et al (27)	Switzerland	Prospective	>0.15 ng/mL	16 ng/mL for males, 8.0 ng/mL for females	168	1	0	0	167	TRACE (Kryptor®, BRAHMS, D)
5	Kaczka et al (29)	Poland	Prospective	>0.1 ng/mL	5.5 pg/mL for women, 18.9 for men	40	6	4	0	30	CLIA (Liaison®, DiaSORIN, I)
6	Giovanella et al (30)	Switzerland	Prospective	>0.1 ng/mL	10 pg/mL	1236	2	0	0	1234	TRACE (Kryptor®, BRAHMS, D)
7	Lim et al (31)	France	Prospective	>0.1 ng/mL	>15 pg/mL (children: 6 months-3 years), >10 pg/mL (females > 3 years), >20 pg/mL (males > 3 years)	476	38	82	6	350	TRACE (Kryptor®, BRAHMS, D)
8	Trimboli et al (33)	Switzerland	Retrospective	>0.20 ng/mL	12 ng/mL	55	11	1	1	42	TRACE (Kryptor®, BRAHMS, D)
9	Giovanella et al (32)	Switzerland	Prospective	>0.1 ng/mL	7.7 ng/L for males and 5.5 ng/L per females	2705	7	2	0	2696	TRACE (Kryptor®, BRAHMS, D)
10	Giovanella et al (34)	Switzerland	Retrospective	>0.20 ng/mL	3.1 pmol/L	226	16	0	0	210	ECLIA (Elecsys®, ROCHE, CH)
11	Kratzsch et al (35)	Germany	Retrospective	>0.06 ng/mL (1) >0.07 ng/mL (2) >0.07 ng/mL (3)	1 pg/mL	158	93	0	14	51	ECLIA, (Elecsys®, ROCHE, CH) (1) CLIA (CLIA PCT, PES, D) (2) CLIA (Architect®, Abbot, D) (3)

Abbreviations: CLIA, chemiluminescence immunoassay; CT, calcitonin; ECLIA, electrochemiluminescence immunoassay; FN, false negative; FP, false positive; ProCT, procalcitonin; TN, true negative; TP, true positive; TRACE, time-resolved amplified cryptate emission immunomefluorometric assay.

Figure 1.

PRISMA flow chart Source: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372(71). doi: 10.1136/bmj.n71

Meta-analysis

Our meta-analysis included 11 studies with a total of 5817 patients with nodular thyroid disease; 336 patients had a MTC. The prevalence of MTC ranged between 0.16% (30) and 60.36% (28). Regarding all included studies (n = 11), the summary estimates of sensitivity and specificity for the threshold between 0.06 and 0.50 ng/mL was 0.90 (95% CI: 0.71-0.97) and 1.00 (95% CI: 0.85-1.00), respectively (Fig. 2); the pooled estimates of L + and L− were 288 (95% CI: 5.6-14 929.3) and 0.10 (95% CI: 0.03-0.33), respectively. Fagan’s nomogram for posttest probabilities is reported in Supplemental Figure 3 (36). HSROC for all included studies is reported in Figure 3 and shows an area under the curve (AUC) equal to 0.97 (95% CI: 0.95-0.98). Azevedo et al (26) and Walter et al (28) were identified as outliers (Fig. 3). In the sensitivity analysis, exploring possible reasons of between-studies heterogeneity, after omitting the already mentioned outliers (26,28), the summary estimates remained without significant changes (n studies = 9, n patients = 5654, MTC prevalence = 4.6%) except for a slight decrease of AUC [AUC = 0.90 (95% CI: 0.87-0.93)]. The pooled sensitivity and specificity for the threshold between 0.06 and 0.50 ng/mL are 0.90 (95% CI: 0.85-0.93) and 1.00 (95% CI: 0.96-1.00), respectively [Supplemental Figure 4 (36)]; the pooled estimates of L+ and L− were 260.0 (95% CI: 20.5-3306.4) and 0.10 (95% CI: 0.07-0.15), respectively. Fagan’s nomogram for posttest probabilities and HSROC curve are reported in Supplemental Figures 5 and 6 (36), respectively. Omitting studies (26,29,33) with small samples (n studies = 8, n patients = 5611, MTC prevalence = 4.5%) showed no significant influence on the summary estimates of sensitivity and specificity for the threshold between 0.06 and 0.50 ng/mL [sensitivity = 0.91 (95% CI: 0.86-0.94); specificity = 1.00 (95% CI: 0.83-1.00)] [Supplemental Figure 7 (36)], and for the pooled estimates of L+ and L− [L+ = 443.6 (95% CI: 4.6-42 874.7); L− = 0.09 (95% CI: 0.06-0.14)], respectively. Fagan’s nomogram for posttest probabilities and HSROC curve are reported in Supplemental Figures 8 and 9 (36), respectively.

Figure 2.

Coupled forest plot reporting sensitivity and specificity for all included studies (n = 11, patients = 5817, reference-positive units = 391, reference negative units = 5426) with a ProCT threshold between 0.06 and 0.50 ng/mL. Pooled sensitivity = 0.90 (95% CI 0.71-0.97); pooled specificity 1.00 (95% CI 0.85-1.00); pooled positive likelihood ratio = 288.1 (95% CI: 5.6-14 929.3); negative pooled likelihood ratio = 0.10 (95% CI:0.03-0.33)

Figure 3.

Hierarchical summary receiver operating characteristics plot for all included studies (n = 11). Studies 2 (28) and 3 (26) are outliers. Area under the curve = 0.97 (95% CI: 0.95-0.98). Confidence and prediction contour are presented (red and grey lines).

In subgroup analyses, sensitivity and specificity in the subgroup (n studies = 6, n patients = 1201, MTC prevalence = 15.8%) with a threshold higher than 0.15 ng/mL of proCT measurement were 0.86 (95% CI: 0.64-0.96) and 1.00 (95% CI: 0.45-1.00) respectively [Supplemental Figure 10 (36)]; the pooled estimates of L+ and L− were 791.3 (95% CI: 0.8-766 017.4) and 0.14 (95% CI: 0.05-0.41), respectively. Fagan’s nomogram for posttest probabilities and HSROC curve are reported in Supplemental Figures 11 and 12 (36), respectively. From HSROC an increasing of the AUC emerged [AUC = 0.95 (95% CI: 0.93-0.97)] in comparison with the previous sensitive analysis. Sensitivity and specificity in the subgroup composed by studies with only postoperative patients (n studies = 4, n patients = 364, MTC prevalence = 48.6%) were 0.93 (95% CI: 0.85-0.97) and 0.91 (95% CI: 0.20-1.00), respectively (Fig. 4); the pooled estimates of L+ and L− were 10.8 (95% CI: 0.3-337.4) and 0.08 (95% CI: 0.04-0.15), respectively. Fagan’s nomogram for posttest probabilities and HSROC curve are reported in Supplemental Figures 13 and 14 (36), respectively. The meta-regression analysis showed that the covariate assay (TRACE vs other assays) is significantly influencing the sensitivity as well as the specificity, while the threshold (>0.15 ng/mL vs other thresholds) is significantly influencing the specificity [Supplemental Figure 15; Supplemental Table 1 (36)]. A subgroup analysis was performed for the 2 testing methods. Seven studies (n = 5282 patients) reported TRACE, which had the highest pooled DOR [2122 (95% CI: 107-41 951)] and the lowest heterogeneity of the testing assays (I² = 88%). Four studies (n = 535) used other assays [DOR 1917 (95% CI: 1-3 367 580, I² = 98%) [Supplemental Table 2 (36)].

Figure 4.

Coupled forest plot reporting sensitivity and specificity for the subgroup of studies postoperative procalcitonin (n = 4). Pooled sensitivity = 0.93 (95% CI: 0.85-0.97); pooled specificity 0.91 (95% CI 0.20-1.00); positive pooled likelihood ratio = 10.8 (95% CI: 0.4-328.8); pooled negative likelihood ratio = 0.08 (95% CI: 0.04-0.15).

Discussion

CT is the pivotal marker for diagnosing MTC in patients who are routinely screened for MTC or are suspected to have MTC as well as for monitoring those patients who have already been diagnosed with MTC. Nonetheless, the problem of cutoff values of basal CT to recommend thyroidectomy may generate a considerable amount of unnecessary surgeries when estimating the set point of CT too low. In facts, while almost 100% of patients with preoperative basal CT values > 100 pg/mL had MTC, only 5% of patients with CT values between 10 and 20 pg/mL had MTC (1-3). In a recent systematic review and meta-analysis on 17 studies involving 74 407 patients Vardarli et al (37) not only confirmed high sensitivity and specificity of basal CT in detecting MTC in patients with thyroid nodules but also demonstrated that the CT threshold is an independent influencing factor and suggested patients monitoring (wait and see) in referral centers to avoid overtreatment. Furthermore, CT assays have some intrinsic limitations that affect their reliability especially concerning the preanalytical phase and interassays comparability. As a number of studies were published on the use of ProCT as a reliable alternative tumor marker in MTC our meta-analysis aimed to determine whether ProCT serum levels are predictive of MTC in previously untreated patients (prediction), and whether changes in ProCT serum levels after surgery are indicative of response to treatment (treatment monitoring). Overall, as the main result of our study, sensitivity, specificity, and DOR of ProCT were consistently high across included studies for both prediction and treatment monitoring providing robust evidence demonstrating the comparable performance of serum ProCT and CT in diagnosing and monitoring MTC. A number of potential sources of between-study heterogeneity and uncertainty in the meta-analysis should be considered.

First, the serum CT level influences the workup to establish the diagnosis of MTC, and, in turn, the clinical performance of CT is biased toward 100% sensitivity. For instance, slightly increased CT levels (in the presence of undetectable ProCT not measured at that time) would have prompted clinical workup for MTC. Vice versa, CT values within reference range (in the presence of increased ProCT not measured at that time) would have not required further controls. Then, the best performance an alternative marker can show is equal to that of CT, and consequently, ProCT cannot achieve superiority over the current CT standard (35).

Second, the cutoff values chosen to represent the discriminatory power of ProCT in the different studies may have resulted in varying numbers of patients with progressing or remitting MTC confounding the predictive power of the marker. However, while subgroup analysis demonstrated a slight accuracy reduction, ProCT continued to keep a very high clinical value. This is well in line with previously published data demonstrating a 98% to 100% negative predictive value of ProCT for spuriously increased (ie, false positive) CT levels in nomedullary thyroid diseases (13,17,26,31,38). Recently, Giovanella et al evaluated 226 patients with confirmed progressing MTC (n = 16), remitting MTC (n = 23), benign thyroid diseases (n = 125), and non-MTC thyroid malignancies (n = 62). Both CT and ProCT were highly sensitive and specific MTC markers, but in the few cases with false-positive CT results (4 multinodular goiter, 1 Graves’ disease,) a negative ProCT measurement correctly excluded MTC. Moreover, no false-positive ProCT/true-negative CT results were observed (34). In addition, while serum CT increases after stimulation with pentagastrin and calcium gluconate with overlapping results in healthy subjects and patients with either MTC and non-MTC thyroid diseases, no or marginal influence on the release of ProCT was observed in healthy subjects and patients with non-MTC thyroid diseases implying a superior specificity of ProCT assays compared to basal and stimulated CT measurements (13,39),

Third, the use of different ProCT immunoassays and different ProCT thresholds in considered studies may have resulted in varying numbers of patients with progressing or remitting MTC, respectively. Indeed, in contrast to the limited comparability of all the different CT assays, an excellent agreement was recently demonstrated between 3 ProCT immunoassays in a series of 158 MTC patients (ie, 90%-99% at 0.1 ng/mL) (35). Notably, 2 of the 3 assays are from the same supplier (BRAHMS), and the third assay had been harmonized to the BRAHMS family. Data from Lippi et al, who showed that 10 fully automated commercial PCT assays deliver acceptable correlations in 176 routine lithium-heparin plasma samples, suggest that other PCT assays may be also appropriate for the purpose (16). Accordingly, changing in the assay methods has a slight impact of sensitivity, specificity, and DOR in our meta-regression analysis. Kratzsch et al (35) followed 158 operated MTC patients over 17 ± 9.1 years. Overall, 51 patients were cured (ie, CT < 1 pg/mL), 55 had minimal residual disease (ie, detectable CT with negative imaging), and 52 had a metastatic disease (ie, detectable CT with demonstrated structural disease). Serum ProCT, measured with 3 different assays, was fully detectable in all patients with metastatic disease (median levels 30.1, 14.5, and 16.1 ng/mL, respectively).

ProCT was detectable in the majority of 55 patients with minimal residual disease, defined by detectable CT and negative imaging, suggesting that the secretion of CT and ProCT is largely in parallel for this clinical situation. Finally, ProCT was undetectable in all cured patients with assay 1 [limit of quantification (LoQ): 0.06 ng/mL), 23 with assay 2 (LoQ: 0.01 ng/mL), and 13 with assay 3 (LoQ: 0.01 ng/mL). However, all cured patients had ProCT values below the 97.5th percentile of healthy adults established for different assays (about 0.05 ng/mL). Notably, while serum CT levels are higher in male than female requiring gender-specific thresholds, significant differences in ProCT levels are not reported in literature between male and females. On the other hand, healthy subjects mostly have undetectable ProCT levels (ie, <LoQ), which greatly reduce the likelihood of showing significant differences.

Fourth, the studies could have been used different patients’ selection criteria. This was particularly notable for the study of Lim et al, which enrolled patients based on high serum CT levels (31). However, outlier tests proved negative, and CIs for the results with and without this study overlapped.

Finally, a potential reservation against replacing the time-tested CT monitoring standard for MTC may be expected due to the opposition of medical community against introducing a new diagnostic standard in clinical practice. Additionally, ProCT is approved by the Food and Drug Administration as an infectious marker of lower respiratory tract infection. Given the rarity of MTC and for reasons of cost, the device manufacturer(s) may continue favoring off-label use of ProCT of MTC, instead of collecting and submitting medical device documentation to get ProCT approved for detection and monitoring of MTC. That considered, it seems reasonable to first adopt ProCT as a complementary marker in patients with thyroid nodules and positive CT testing (ie, rule-out test) and MTC patients with unclear postoperative serial CT measurement patterns. Basing on our own clinical experience this strategy will show advantages of this novel MTC biomarker, prompting thyroidologists to consider and support its adoption as a standard biomarker in MTC management. Last but not least, prospective head-to-head studies should be designed in patients with thyroid nodules using histology or fine-needle aspiration with cytopathology and CT immunohistochemistry and/or CT measurement on fine-needle washout as reference standards.

Conclusions

Our meta-analysis robustly demonstrates the clinical utility of ProCT for the diagnosis and monitoring of MTC: this finding, compounded with the better preanalytical and analytical characteristics, gives it great potential to replace CT as a new standard of care in the management of MTC.

Additional Information

Disclosure Summary: The authors report no conflicts of interest in this work.

Data Availability

Some or all data sets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.