10 1089@thy 2019 0785 PDF

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© Mary Ann Liebert, Inc.

DOI: 10.1089/thy.2019.0785
1
Early diagnosis of medullary thyroid cancer: Are calcitonin
stimulation tests still indicated in the era of highly sensitive
This paper has been peer‐reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
calcitonin immunoassays?
Early diagnosis of medullary thyroid cancer: Are calcitonin stimulation tests still indicated in the era of highly sensitive calcitonin immunoassays? (DOI: 10.1089/thy.2019.0785)

Martin B. Niederle 1,2; Christian Scheuba 1, Philipp Riss 1, Andreas Selberherr 1, Oskar
Koperek 3, Bruno Niederle 1,4

1 Division of General Surgery, Department of Surgery,

Downloaded by GRIFFITH UNIVERSITY from www.liebertpub.com at 02/14/20. For personal use only.
2 Department of General Anesthesia, General Intensive Care and Pain Management,

3 Clinical Institute of Pathology,

4 former Chief of the “Endocrine Surgery” Section, Senior Clinical Investigator, Department
of Surgery,
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Medical University of Vienna, Waehringer Gürtel 18‐20, Vienna A‐1090, Austria

Corresponding author:
Martin B. Niederle, MD, PhD
Email: martin.niederle@meduniwien.ac.at

Keywords: Medullary thyroid cancer, Calcitonin, tumor marker, stimulation, diagnosis,
treatment

Acknowledgment:

The authors have no conflict of interest to declare.
This paper is not based on a previous communication to a society or a meeting.
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Abstract

Background
Measurements of both basal (b) calcitonin (CT) and calcium (Ca) ‐stimulated CT (Ca‐sCT)
levels are performed to identify medullary thyroid cancer (MTC) at an early stage when
used as part of the diagnostic workup of thyroid nodules (CT screening). Novel
immunochemiluminometric assays, which are highly sensitive and specific for monomeric
CT and avoid cross‐reactivity, have been introduced over the past decade. No
prospectively generated data have so far become available to answer the frequently raised
question as to whether Ca‐sCT in contrast to bCT alone is helpful and therefore still
indicated for the early detection of MTC.

Methods
Ca‐stimulation tests were performed in 149 consecutive patients with thyroid nodules and
elevated bCT. Regardless of Ca‐sCT levels, all patients had an operation applying a uniform
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surgical protocol, including thyroidectomy and systematic lymph node dissection. Recently
published sex‐specific cut‐off levels for the differentiation of MTC and other C‐cell
pathologies (C‐cell hyperplasia) were used to compare the diagnostic performance of bCT
or Ca‐sCT alone and in combination using receiver‐operating characteristic (ROC) analysis.
Additionally, CT cut‐off levels to predict lateral lymph node metastasis were evaluated for
bCT compared to Ca‐sCT. Follow‐up for all patients was documented and correlated with
initial CT levels.

Results
MTC was identified in 76 (50.1%) patients, in 21/76 (27.6%) with lymph node and in 4
(5.3%) with distant metastasis. Using predefined cut‐off levels, patients could effectively
be subdivided into a group above the cut‐off level with definitive diagnosis of MTC (100%)
and below (gray zone) with a significant overlap of C‐cell hyperplasia and MTC (all
classified as pT1a; males: 19/58 [37.5%], females: 7/41 [17.1%]). The areas under the ROC
curve (AUC) were excellent for the diagnosis of MTC in all tests. Determination of bCT
proved to be superior for both diagnosing MTC in males (AUC for bCT: 0.894; AUC for Ca‐
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sCT: 0.849) and females (bCT: 0.935; Ca‐sCT: 0.868) and also for diagnosing lymph node
metastasis in the lateral compartment (males: bCT: 0.925; Ca‐sCT: 0.810; females: bCT:
0.797; Ca‐sCT: 0.674). Combining both tests did not improve diagnostic accuracy. Using a
cut‐off level of > 85 pg/ml for females and > 100 pg/ml for males, the sensitivity for
diagnosing lateral neck lymph node metastasis was 100%. Below these cut‐off levels, no
patient showed persistent or recurrent disease (median follow‐up: 46 [± 27] months).

Conclusions
Predefined sex‐specific bCT cut‐off levels are helpful for the early detection of MTC and for
predicting lateral neck lymph node metastasis. Ca‐sCT did not improve preoperative
diagnostics. bCT levels > 43 pg/ml and > 100 pg/ml for males and of > 23 pg/ml and > 85
pg/ml for females are relevant for advising patients and planning the extent of surgery.

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Introduction

Calcitonin (CT) is the established preoperative tumor marker for medullary thyroid
carcinoma (MTC). In the case of thyroid nodules with elevated CT, a reasonable suspicion
of thyroid C‐cell malignancy is indicated. However, sporadic hypercalcitonemia is not
thyroid‐C‐cell‐derived in all patients and does not always warrant a therapeutic
intervention. The value of CT is influenced by analytical, physiological, pharmacological
and pathological factors in patients with and without thyroid abnormalities. Release of CT
in C‐cell disease can be stimulated by intravenous injection of stimulating agents, e.g.,
pentagastrin or calcium (1).
Stimulation tests are used to differentiate MTC from other rare conditions in which mainly
non‐thyroid diseases (e.g., hypergastrinemia, hypercalcemia, renal insufficiency,
neuroendocrine tumors) are responsible for the elevation of serum CT (2). A significant rise
of serum CT levels after stimulation is only expected in patients with MTC (3‐5).
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In the last decade, commercial assays for measuring CT have progressed to the newest
immunochemiluminometric assays which are highly sensitive and specific for monomeric
CT. The cross‐reactivity with other CT‐related peptides is largely but not completely
eliminated, thus improving sensitivity and specificity for diagnosing MTC. Therefore, these
“new” CT assays are recommended whenever CT screening is part of the workup of thyroid
nodules (6).
As shown in the literature, CT screening in patients with thyroid disease reduced the TNM
stages of sporadic MTC comparing the periods before and after the routine measurements
of serum CT (7) and biochemical cure rates improved (8).
Although routine serum CT screening in patients undergoing evaluation for thyroid
nodules appeared to be cost‐effective (comparable to the measurement of thyroid‐
stimulating hormone, colonoscopy and mammography screening) (9), there still is an
ongoing discussion concerning its practical value. While European guidelines recommend
this procedure, Anglo‐American guidelines are more restricted (6, 10).
Because expert opinions vary regarding the usefulness of routinely measuring serum CT
levels in patients with nodular goiters, the members of the American Task Force suggested
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that the individual physician should decide whether CT determinations are useful in the
particular clinical situation (6).

Ultrasensitive CT assays have mostly eliminated false‐negative rates of a basal CT (bCT)
measurement when diagnosing C‐cell disease. However, as higher bCT levels are
pathognomonic for advanced MTC, diagnostic uncertainty exists at lower bCT
concentrations (“gray zone”) during CT screening. To increase the sensitivity of bCT in
these cases, the application of CT stimulation tests has been recommended (10‐14).

This prospective study aimed, on the one hand, to verify and confirm recently defined sex‐
specific bCT and calcium (Ca)‐stimulated (Ca‐sCT) cut‐off levels for a more precise early
diagnosis of MTC (1) and to confirm independently acquired data from another study
group (13, 15).
To our knowledge, this is the first study to prospectively investigate whether Ca‐sCT
compared to bCT is still helpful in improving the diagnosis of MTC and to predict the
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presence of lymph node metastasis in the era of novel immunochemiluminometric CT
assays in patients with elevated bCT concentrations in general and, in particular, in those
with “borderline” elevated CT increase, as recommended (16).
To answer these questions, this study was designed to analyze patients with elevated CT
levels diagnosed within a CT screening program applying one single, prospective,
diagnostic, surgical and pathohistological protocol.

Patients and Methods
Prospective protocol
Austria is an iodine‐replete endemic goiter region (17, 18). In 1994, the routine
determination of CT concentrations (CT screening) was introduced into the workup of
nodular thyroid disease at the Medical University of Vienna (a tertiary care center)
regardless of thyroid function, ultrasound morphology and/or size of the thyroid nodule(s).
As compared to 1.1 cases of MTC per 1,000 patients with nodular thyroid diseases
diagnosed at the Medical University of Vienna before CT screening was initiated, 3.2 cases
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of MTC per 1,000 patients were identified when bCT was determined in all patients with
thyroid nodules (19).
As not all patients with thyroid nodules and mildly elevated bCT levels have MTC and are
candidates for thyroid surgery, only subjects with bCT levels ≥ 10 pg/ml underwent a CT
stimulation test using pentagastrin as stimulation agent, regardless of the patients´ sex or
the immunoassay available at that time (20) to more precisely predict MTC (21, 22).
However, pentagastrin, which was not available world‐wide, was definitively taken off the
European market by the end of 2015. Therefore, stimulation by Ca gluconate was initially
recommended and introduced into clinical routine without clear cut‐off CT levels.
As shown recently (1), Ca is able to replace pentagastrin to predict MTC with a similar
diagnostic power using newly defined sex‐specific cut‐off values.
Because patients with Ca‐sCT concentrations at least two‐fold higher than bCT levels or >
100 pg/ml have a substantial risk of MTC, patients were offered an operation if there was
no relevant comorbidity (20). In patients who fulfilled the criteria (20), a uniform surgical
(23, 24) and pathological (25) protocol, both parts of the standard operative procedure
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(SOP) to diagnose and treat MTC, was followed rigorously.
As part of the SOP, a standardized ultrasound of the neck was performed in all patients to
confirm thyroid nodules of various sizes and morphology. However, the findings were not
used for surgical decision‐making, as previous analyses revealed an unsatisfying sensitivity
of ultrasound to detect particularly microMTCs. In addition, the sensitivity for diagnosing
lymph node metastases was seen to be low, especially for micro‐metastasis (23, 26).

Fine needle aspiration biopsy (FNAB) or CT measurements in wash‐out fluid from fine
needle aspiration (27) were not performed in this series, as routine bCT measurements
have been documented to show a higher sensitivity to diagnose MTC compared with fine
needle aspiration cytology, especially in diagnosing small (≤ 10 mm), curable MTC (28).

Patients
In five years (2012‐2016), 149 consecutive patients visited one of the three outpatient
departments of Vienna General Hospital at the Medical University. These patients
presented with various thyroid nodular diseases detected by standardized ultrasound of
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the neck, with normal thyroid function tests and elevated basal bCT levels (confirmed at
least one time on repeat measurements), and had an operation after performing a Ca
stimulation test.

No patient who was a member of a known MTC family or who had undergone prior
surgery for MTC was included in the study.

All patients had normal or nearly normal kidney function (glomerular filtration rate ≥ 45
ml/min/1.73m2) and other causes modifying bCT levels (e.g., intake of proton‐pump
inhibitors) were excluded before applying the Ca stimulation test.

The Ethics Committee of the Medical University of Vienna approved the clinical standard
protocol including all diagnostic and therapeutic procedures in thyroid nodules, in the case
of elevated bCT concentrations further actions and the retrospective analysis of the
patients’ records (EK1506/2014). Informed consent to all diagnostic and surgical
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procedures was obtained from each patient, adhering to the Declaration of Helsinki. All
biochemical and morphological data were collected prospectively and were analyzed
retrospectively correlated to histological findings in the thyroid gland and lymph nodes
after applying the same standardized surgical protocol in all patients.

To increase the power of the analysis, the data included in the present study were pooled
with those obtained in a previous preliminary study following the same SOP (1).

Biochemical analysis
The CT concentrations were determined with an immunochemiluminescent assay (ICMA)
from Diagnostic Products Corporation (DPC, Los Angeles, CA, USA), running as a fully
automated test on a Siemens 2000 Immunoassay System (Siemens Health Care), as
previously described in detail (22). This ICMA has been used world‐wide in many
publications. Therefore, the results of this study are comparable to findings in other
studies using the same assay.

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Calcium‐stimulated calcitonin test
Blood samples for CT determination were drawn with an indwelling catheter before (0)
and 2, 3 and 5 minutes after a 30‐second infusion of 2.5 mg Ca per kg body weight (Ca
gluconate 10% [10 ml containing Ca gluconate 2.25 mmol = 90 mg Ca++; Calcium Braun
10%®, B. Braun Melsungen AG, Melsungen, Germany]), as recently described in detail (1).

Surgery
Total thyroidectomy and bilateral central neck lymph node microdissection (level 6) were
performed in all patients regardless of preoperative bCT and sCT levels (23).
During initial surgery, systematic microdissection of both lateral neck lymph node
compartments (levels 2 to 5) saving the internal jugular vein, all nerves and muscles
(“functional” dissection) (24, 29) was performed without transsternal mediastinal
dissection (compartment C4) as part of the surgical SOP in all patients.
No permanent complications (hypoparathyroidism, paralysis of the recurrent nerve) were
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documented in the study patients.

Pathologic examinations
As published previoulsy (25), the removed thyroid glands and all lymph node specimens
were submitted to pathologic examinations. The surgeon provided the pathologist with
the CT levels before starting histological examinations, thus serving to look more carefully
for C‐cell abnormalities (25).
C‐cell hyperplasia (CCH) was considered when at least one area with > 50 C‐cells per one
low power field (x 100) was found in both thyroid lobes.

CCH was morphologically classified as focal, diffuse, nodular (summarized as
“physiological”) or neoplastic CCH (30, 31).
MTC was diagnosed if a focal loss or reduplication of the basement membrane was
observed upon immunohistochemistry (32).
The tumors were classified in accordance with the Union for International Cancer Control
(UICC) 2010 (6, 33).
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Molecular genetic analysis
The presence of germline mutations was tested in all patients by screening exons 5, 8, 10,
11, 13, 14, 15 and 16 of the rearranged‐during‐transfection (RET) proto‐oncogene (34).
Corresponding to the study protocol, the first patient diagnosed with MTC in a family with
a germline mutation (“index patient”) was not excluded from further analysis.

Postoperative follow‐up
All patients were followed clinically and biochemically. bCT and Ca‐sCT levels were
determined at 6 weeks, 6 and 12 months and then bCT once a year following surgery. The
patients appeared to be cured when both bCT and Ca‐sCT levels remained below 10 pg/ml
12 months following surgery. Persistently high bCT and/or Ca‐sCT levels were referred to
as “persistent” disease. Elevated bCT levels 12 months after previous normalization were
defined as “recurrent” disease.

Statistical methods
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The sensitivity, specificity, positive predictive value and negative predictive value of the
bCT and Ca‐sCT cut‐off values to predict MTC were calculated. The cut‐off values to predict
lateral compartment lymph node metastasis were defined by receiver‐operating
characteristic (ROC) curves describing the area under the curve (AUC), confidence intervals
(CI), and P values for males and females.
Subsequently, the documented sex‐specific thresholds of bCT and Ca‐sCT levels were used
to evaluate whether bCT or Ca‐sCT alone or in combination may improve the prediction of
MTC and whether bCT or sCT may also predict positive lateral lymph nodes as the basis for
planning the extent of surgery.
All calculations were done with SPSS Statistics (Version 23.0, IBM Corp. Released 2015.
IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp.) version 23 for Windows and
Microsoft Excel 16 for Windows.
Results
Baseline characteristics
All relevant demographic details of the study are summarized in Table 1.
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In the study period, 149 patients (males: 79; females: 70) had an operation for elevated
bCT and Ca‐sCT levels.
MTC was diagnosed in 76/149 patients (males: 40/79 [50.6%]; females: 36/70 [51.4%]).
The tumors were classified as pT1a in 48/76 patients (63.2%), pT1b in 16/76 (21.1%), pT2
in 6/76 (7.9%) and pT3 in 6/76 (7.9%) patients. No patient was diagnosed with a pT4
tumor.
The median tumor size was 5 mm (1‐17 mm) in male patients and 9 mm (5‐15 mm) in
female patients. Bilateral tumors were found in 12 patients (15.8%) and tumors were
multifocal in one thyroid lobe in another 4 patients (5.3%).
Lymph node metastases were diagnosed in 21/79 (26.6%) patients (males: 12/40 [27.6%];
females: 9/36 [25%]). Four patients had pN1a (central compartment only) disease and 17
had pN1b disease (lateral compartment with/without central compartment). On average,
126 (interquartile range [IQR] 78‐147; absolute range: 8‐177) lymph nodes were dissected.
Among patients in whom lymph node metastasis were found, a median of 12 (IQR 2‐26;
absolute range: 1‐53) lymph nodes were affected. The metastatic lymph node ratio (ratio
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between the number of metastatic lymph nodes and number of total removed lymph
nodes) was 0.095.
At the time of diagnosis, distant metastases were documented radiologically (rM1) in 4/76
(5.3%) patients (males: 3/40 [57.5%]; females: 1/36 [2.8%]). Two patients had metastases
to the liver, one to the brain and another patient had multiple metastases to the lung, liver
and bones.

In patients without MTC (overall: 73/149 [48.9%] ‐ males: 39/79 [49.4%]; females: 34/70
[48.5%]), CCH was diagnosed after immunohistochemical work‐up.

CCH was classified as physiological in 37/73 patients (50.7%) and as neoplastic in 36/73
patients (49.3%), respectively.

Additional follicular cell‐derived thyroid cancer was found in 44/149 patients (29.5%).

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Histologically, and apart from nodules of various sizes, the pathologist described diffuse
parenchymal infiltrations by lymphocytes (by definition chronic lymphocytic thyroiditis) in
31/149 patients (20.8%; males: 13/79 [MTC: 4, CCH: 9]; females: 19/70 [MTC: 9; CCH: 10]).

Germline RET mutations were documented in 8/76 patients (10.5%) with MTC (males: 4/40
[10.0%]; females: 4/36 [11.1%]) and in 2/73 (11.1%) with CCH (males: 1/39 [2.6%];
females: 1/34 [2.9%])

Sex‐specific basal and calcium‐stimulated calcitonin values to predict medullary thyroid
cancer
As presented recently, cut‐off levels for male and female patients were different for
predicting MTC (Table 2).
Applying the predefined cut‐off levels (1) for males with bCT levels > 43 pg/ml or Ca‐sCT >
1500 pg/ml and for females with bCT levels > 23 pg/ml or Ca‐sCT > 780 pg/ml
the patients could effectively be subdivided into two groups: Whereas MTC was detected
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in 100% (group 2; MTC only; no false‐positive patients) of the patients with CT levels above
the sex‐specific cut‐offs, there was a relevant overlap of patients with MTC or with CCH
among those with bCT or Ca‐sCT levels below the cut‐offs (group 1; mildly elevated).
In group 1, all patients with MTC (males: n=19; females: n=7) were classified as pT1a (tumor
diameter ≤ 10 mm). Only one female but no male patient was diagnosed with a lymph node
metastasis in the central compartment. No lymph node metastases in the lateral
compartment or distant metastases were found within this group (Tables 3a and 3b).
In group 2 (Tables 3a and 3b), MTC was classified as pT1 in 38/50 (76%) patients, as pT2 in
6/50 (12.0%) and as pT3 in 6/50 (12.0%) patients. Lymph node metastasis (pN1a 3/50
[6.0%], pN1b 17/50 [34.0%]) were present in 20/50 (40.0%), (Table 4) and distant
metastasis in 4/50 (8.0%).

Comparing the value of basal calcitonin and calcium‐stimulated CT alone or in
combination for predicting medullary thyroid cancer
Overall, the potentials of both bCT and Ca‐sCT to predict the presence of MTC expressed
as AUC were excellent (35). However, in both male and female patients, determination of
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bCT alone showed a slightly better test performance than CT stimulated by Ca (males:
0.894 vs. 0.849; females: 0.935 vs. 0.868; see Table 2). Whereas in males, the sensitivity
was only 5% higher for bCT measurement (53% vs. 48%; specificity 100% for both), the
difference in sensitivity was higher for females (81% vs. 69%; specificity 100% for both).
Therefore, 7 more patients (males: 3; females: 4) were correctly classified (definitive MTC)
by using bCT compared to Ca‐sCT (see Tables 2a and 2b).
However, based on the observation that no patient with Ca‐sCT levels < 110 pg/ml was
diagnosed with MTC, MTC could be ruled out in 7 patients using this cut‐off (males: 1;
females: 6).
When combining the results of bCT and Ca‐sCT, the definitive diagnosis of MTC failed to be
improved: Only one male patient was diagnosed with definitive MTC using Ca‐sCT (> 1500
pg/ml) but had bCT levels lower than the cut‐off of 43 pg/ml. Hence, sensitivity improved
from 53% to 55% for the combination of bCT and Ca‐sCT in male patients only, it did not
change in female patients.

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Comparing the value of basal calcitonin or calcium‐stimulated calcitonin for the
prediction of lymph node metastasis
In both males and females, the AUC were higher for bCT levels than for Ca‐sCT levels in the
diagnosis of both pN1a and/or pN1b lymph node metastasis (see Table 2).
All male patients with lymph node metastases had bCT levels ≥ 100 pg/ml (Table 4;
sensitivity: 100%). The specificity for the diagnosis of any lymph node metastases (pN1a or
pN1b) was 82% and for the presence of lateral lymph node metastases (pN1b only) was
74% (Table 2).
In women, one patient was diagnosed with a single lymph node metastasis in the central
compartment (N1a) with a bCT level of 23 pg/ml. Therefore, the cut‐off of ≥ 23 pg/ml was
used to diagnose any lymph node metastases (pN1a or pN1b) and the specificity was only
22% with a sensitivity of 100%. However, all other women (n=8) with lymph node
metastases had bCT levels ≥ 85 pg/ml and metastasis in the lateral compartment (Tables 2
and 4; specificity: 57%).

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Follow‐up
By definition, surgery served to clinically and biochemically cure 31/39 males (79.5%; lost
to follow‐up: n=1) and 32/36 females (88.9%). Within the follow up period of 46 [±27]
months, clinically or biochemically recurrent disease was documented in none of the
initially cured patients. All patients in group 1 (mildly elevated) and all patients not
predicted to have lymph node metastasis in the lateral neck compartment were cured
(Table 4). Overall, persistent disease was documented in 9/76 patients (11.8%; all in group
2 and initially with positive lymph nodes). Three of 76 patients (3.9%) (males: 2; females: 1;
all with distant metastasis at the time of diagnosis) died 19, 35 and 65 months after
surgery of persistent MTC.
According to the TNM staging (Table 5) and by definition, all stage I (n = 51), stage II (n = 3)
and stage III (n = 6) patients and 2/12 stage IVA (16.7%) patients were cured by surgery.
Persistent disease was identified in 9/12 stage IVA (75%) and 2/4 stage IVC patients (50%).
One stage IVA and two stage IVC patients died of their disease.

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Discussion

There is an ongoing discussion with regard to the value of routine serum CT screening for
MTC in the preoperative workup of thyroid nodules. Since surgical treatment for even
small MTC must be more aggressive compared to other types of thyroid cancer, the
preoperatively definitive (early) diagnosis of MTC significantly influences management (7).
However, elevated bCT levels must always be questioned and reasons for non C‐cell‐
derived CT elevations or the rare cases of false‐positive results due to heterophilic
antibodies are to be excluded (2).
Especially in the absence of thyroid nodules on ultrasound (no indication per se to
determine CT), or if there is a discrepancy between the size of a thyroid nodule and bCT
level (a small nodule and an inadequately high bCT level), stimulation tests may help to
differentiate thyroid from non‐thyroid sources of CT production (3‐5).
Ectopic CT production by neuroendocrine tumors has to be taken into account,
characterized by no or a less than two‐fold increase in CT levels after stimulation. When
stimulation exceeds bCT by more than two‐fold, MTC is found exclusively (3).
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As it may occasionally be difficult to interpret and draw conclusions regarding reproducible
elevated CT levels, various authors (36, 37) have discussed that if cut‐off levels based on Ca
stimulation testing would become well validated, CT screening would likely become more
widely accepted in the diagnostic workup for thyroid nodules.
After excluding non‐C‐cell‐derived CT elevations (2), the recommendation for further
diagnosis or treatment of patients with elevated CT values is to be based on the CT assay
used, the given patient’s sex and the absolute CT levels.
Up to now, there are no globally accepted CT cut‐off levels to predict MTC, as different CT
assays are used in different laboratories. The normal range of bCT and Ca‐sCT levels may
vary from laboratory to laboratory and from assay to assay. Each institution has to define
its own bCT and Ca‐sCT cut‐off labels to discriminate CCH/intrathyroid micro‐MTC from
larger tumors that may be associated with lymph node metastases. For serial
measurements of CT, it is recommended to use the same laboratory with its established
reference ranges (37).
Without specifying the characteristics of the CT assay, concentrations between 60 and 100
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pg/ml have been assessed as highly suggestive/pathognomonic of MTC in recently
published guidelines (10).
Applying different assays makes it difficult to interpret published results, impossible to
compare data and cut‐off values, and hard to follow recommendations to guide surgery
(21). In one recently published paper (38), four different assays based on three assay types
were used for CT measurement. Costante et al. (39) applied only one single assay (Nichols
Advantage (ICMA)) but did not offer sex‐specific cut‐offs. Studies should be compared
which respect to both assay characteristics and well known sex differences in bCT levels,
which are physiologically higher in males than in females (24, 40).
The Nichols and Siemens DPC assay and recently, also the Siemens DPC and the Roche
Cobas assay have been demonstrated to show an almost perfect linear correlation (21, 22,
41), and CT levels from one assay can thus easily be converted to another. In this study,
one of the widely used, highly sensitive ICMA (DPC Siemens Immulite 2000) for CT was
applied. Clear sex‐specific cut‐off levels to prognosticate MTC preoperatively have recently
been published for this assay (1).
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Based on the greatest accuracy at the lowest possible bCT level, MTC was predicted in all
males with bCT levels > 43 pg/ml or Ca‐sCT > 1500 pg/ml and in all females with bCT levels
> 23 pg/ml or > 780 pg/ml after Ca stimulation (no false‐positive). In this CT screening
program, more females were assigned preoperatively to the patients’ group with highly
elevated bCT levels. MTC was thus correctly predicted in more females (41.4%) than males
(26.6%; trend; p=0.055; chi‐square) (1). This is in accordance with recently published data
by Chambon et al. (42).
Using the same diagnostic standards, Colombo et al. (15) and Mian et al. (13) (in a lower
number of more inhomogeneous patients and without a prospective treatment protocol)
showed that the best levels of bCT to separate normal and CCH cases from MTC patients
were > 18.7 pg/ml (15) and, more precisely, > 26 pg/ml (13) in females and above 68 pg/ml
(13, 15) in males. Furthermore, Ca‐sCT levels > 79 pg/ml (13) and, more precisely, > 184
pg/ml (15) in females and > 544 pg/ml (13) and, more precisely, > 1620 pg/ml (15) in males
were shown to yield the highest accuracy to distinguish normal and CCH cases from
patients with MTC. However, CCH and MTC could not be discriminated below the
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published cut‐off levels (patients with “mildy elevated” bCT levels) (13).

Patients with bCT levels above the presented cut‐offs (highly elevated bCT levels in the
Siemens Immulite assay) are likely to have MTC (no false‐positive patients in the study)
and therefore should be offered an operation.
The findings of routinely applied neck ultrasound were not incorporated in the surgical
decision‐making because of previous findings (23) that neck ultrasound revealed an overall
sensitivity of only 90% in detecting MTC with a mean tumor size of 20 mm and larger. As
shown recently, in the subgroup of patients with pT1a tumors, the sensitivity was even
lower (71%) (26).
In the present study, 63.2% of patients were diagnosed with pT1a tumors. Overall median
tumor size was 7mm (IQR 2‐16mm), for pT1a tumors only 3mm (IQR 1‐6mm). Without
determination of bCT levels most of these thyroid nodules and as a consequence MTC
would not have been treated because of their small size. Additionally, the majority of
tumors ≤10mm would not be indicated to have FNAB. Small nodules are difficult or
impossible to examine by FNAB. The evaluation of bCT was shown to be superior as
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compared to FNAB, especially in diagnosing small (≤ 10 mm), curable MTC (43‐47). Boi et
al. (27) were the first to recommend CT measurements in wash‐out fluids from fine needle
aspiration to improve the diagnosis in primary (and metastatic) MTC in the workup of
thyroid nodules and to prevent unnecessary surgery. However, even this modification of
fine needle aspiration evaluation may be inconclusive or hardly possible because of the
small tumor sizes (48).
Lastly, the sensitivity of ultrasound to diagnose lymph node metastasis was only 43%
overall and 6% and 56% in the central and lateral neck, respectively (26).
The Ca‐sCT compared to the bCT (or the combination of both) did not improve the
accuracy for detecting MTC in females in the current study. Only in one additional male
patient, MTC was predicted correctly by also considering the Ca‐sCT level in interpreting
the biochemical results.
As tumor volume correlates with bCT levels (49, 50), the extent of initial surgery should be
adapted to preoperative CT levels (51). In the present study, lymph node and distant
metastases were documented in 57.1% and 14.3% of male and in 27.9% and 3.4% of
Thyroid
female patients with highly elevated CT levels.
Knowledge of bCT levels in patients with thyroid nodules facilitates a tailored surgical
strategy. Besides total thyroidectomy and central neck lymph node dissection, the
indication for lateral neck dissection at initial surgery may be individualized. Based on the
current analysis, it is recommended only in male patients with bCT levels ≥ 100 pg/ml and
in females with bCT levels ≥ 85 pg/ml as an additional procedure during initial surgical
strategy, since in this group, lateral lymph node metastases were detected in 52.9% males
and 40.0% females.

In 41/70 (58.6%) females and 58/79 (73.4%) males, the bCT levels were documented
below the “high risk” cut‐off CT, that strongly suggest MTC. In these patients with mildly
elevated bCT levels, there was an indistinct overlap between CCH and microMTC (gray
zone) (1) and bCT levels did not seem sufficiently specific to assess the diagnosis of MTC.
This is why stimulation tests have been recommended in the literature (11, 12, 39, 52).
To our knowledge, the current study is the first analysis to prospectively investigate the
possible value of Ca stimulation tests in patients with “mildly elevated” bCT to better
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17
discriminate CCH and MTC. However, CT stimulation failed to improve diagnostic accuracy,
as within the gray zone, neither bCT nor Ca‐sCT levels (or the combination of both) were
able to discriminate between CCH and MTC in either sex.
The goal of surgical treatment is to perform thyroidectomy before MTC develops or while
it is still confined to the gland in an attempt to prevent persistence and recurrent disease
and to improve cure rates. Respecting the sex‐specific cut‐off levels, in patients with mildly
elevated bCT values (gray zone), the final histological examination of the thyroid gland and
the central lymph nodes revealed MTC in more males (19/59 [32.2%]) than in females
(7/41 [17.1%]). All MTC in males and females of this group were classified as pT1. While all
tumors in 19 males were staged pN0, central lymph node metastases (pN1a) were
documented in 1/7 females. However, total thyroidectomy and bilateral central neck
dissection served to cure all individuals biochemically.
Frank‐Raue et al. (53) recommended to re‐evaluate patients with lower bCT values in
intervals of 3 to 6 months and advise surgery in patients only with rising CT levels, which
may indicate MTC. However, there is limited clinical experience using this approach. There
Thyroid
is only one series of 171 patients who were followed for 2 to 4 years and in 170 of those
basal levels remained lower than 20 pg/ml (applying the ICMA assay by Nichols Advantage,
corresponding to 16 pg/ml with the ICMA CT assay by Diagnostic Products Corporation
[(22)]). Only one man experienced an increase (to 33 [26] pg/ml) after two years of follow‐
up. He underwent a stimulation test (with pentagastrin) with positive results and a peak
level of 317 (254) pg/ml. Surgery demonstrated the presence of CCH only (39).
Many patients are aware that CT is a sensitive tumor marker for MTC. Reproducible mildly
elevated bCT levels may be the first sign of MTC in those presenting with thyroid nodules ≤
10 mm. With regard to the psychological burden of this knowledge, keeping some patients
in persistent anxiety and uncertainty, many patients request for an operation even after
having been informed about the minor long‐term consequences of mildly elevated bCT.
Potential morbidity must be carefully discussed with the patients and be balanced against
unnecessary thyroid surgery and continuous follow‐up.
In experienced surgical teams, patients who decide for surgery may be treated early by
total thyroidectomy and bilateral central neck dissection, which is mandatory because
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18
micrometastasis may also be present in patients with mildly elevated bCT levels, as seen in
one female patient.
Nevertheless, a restricted indication for surgery may theoretically exist in women, as MTC
was found in less than 20% of the female patients. A more liberal indication for surgery
should be considered in men, as MTC was found on histology in at least 1/3 males.
The Ca stimulation test may only be helpful to subclassify patients with mildly elevated
bCT, who are definitively not candidates for surgery:
In a previous investigation (cited by many following studies), surgery was recommended in
all subjects with an abnormal CT response (to pentagastrin) above 100 pg/ml. This was
because peak CT levels exceeding 100 pg/ml were considered to be indicative of MTC and
MTC was definitively documented in many patients (20). Costante et al. (39) also reported
that stimulated CT values after pentagastrin infusion of above 100 pg/ml predicted MTC in
at least 40%. Performing a Ca stimulation test in this study, females and males with Ca‐sCT
levels ≤ 110 had various types of CCH on immunohistochemistry, but no MTC was found.
Therefore, one may conclude that these patients are not candidates for surgery.
Thyroid

In conclusion, neither Ca‐sCT alone nor the combination of bCT and Ca‐sCT as compared to
bCT help to further improve the diagnosis of MTC in patients with highly elevated CT levels
(above predefined cut‐offs) or to differentiate between patients with CCH and micro‐MTC
in those with only mildly elevated CT levels (below predefined cut‐offs).
Knowledge of bCT levels alone facilitates a “tailored” surgical strategy in the central and
lateral neck in patients with thyroid nodules. Total thyroidectomy and central neck
dissection are the treatments of choice for initial surgery, as lymph node metastases in the
central compartment can be found even at low (mildly elevated) CT levels.
Analyzing the prospectively acquired data based on a broadly applied, highly sensitive CT
assay (DPC Siemens Immulite 2000), the cut‐off bCT levels for lateral neck lymph node
metastasis were ≥ 100 pg/ml in males and ≥ 85 pg/ml in females. sCT was not superior in
predicting lymph node metastasis and therefore should not influence the extent of
surgery. According to these results, lateral neck dissection seems to be indicated in
patients with bCT levels above these cut‐offs as lymph node metastases in the lateral
compartment were found in 52.9% of males and 40.0% of females.
Page 19 of 35

19
After critically excluding the rare cases of other sources of CT elevation in the workup of
thyroid nodules, surgery is definitively indicated in patients with highly elevated bCT levels.
Surveillance with periodical bCT measurements seems justified in compliant patients with
only mildly elevated bCT levels. In anxious patients and in those who refuse biochemical
follow‐up, early total thyroidectomy and bilateral central neck dissection can be
considered.

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Page 20 of 35

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Table 1 Demographic, clinical and pathologic details of the study population
Male Female
Total n/n (%) 79/149 (53.02) 70/149 (46.97)

Age (years) 58 (51‐67*) 52 (40‐64*)
CCH
Isolated CCH n/n (%) 39/79 (49.4) 34/70(48.5)
Physiological
15/39 22/34
(diffuse or nodular)
Neoplastic 24/39 12/34

Age (years) 57 (49‐65*) 49 (40‐56*)
Additional follicular cell‐derived
12/39 (30.8) 8/34(23.5)
thyroid cancer n/n (%)
PTC 12/12 8/8
FTC 0 0/34
Thyroid
Chronic lymphocytic thyroiditis 9/39 (25.0) 10/34 (29.4)

Germline RET mutation 1/34
1/39
(detected after surgery; n/n) exon 13/codon 791:
exon 11/codon 649: n=1
n=1
MTC
MTC n/n (%) 40/79 (50.6) 36/70 (51.4)
pT1a 26/40 (65.0) 22/36 (61.1)
pT1b 7/40 (17.5) 9/36 (25.0)
pT2 3/40 (7.5) 3/36 (8.3)
pT3 4/40 (2.5) 2/36 (5.6)
pT4 0 0
5 (1‐17) 9 (5‐15)
Tumor diameter (mm)
(absolute range: 1‐87) (absolute range: 1‐50)
Age (years) 59 (52‐68*) 62 (46‐69*)
(absolute range: 30‐76) (absolute range: 25‐79)
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Multifocality n/n (%) 12/40 (30.0) 4/36 (11.1)
Bilateral n/n (%) 11/40 (27.5) 1/36 (2.8)
Concomitant CCH n/n (%) 32/40 (80.0) 15/36 (41.7)

Physiological
9/32 9/15
(diffuse or nodular)
Neoplastic 23/32 6/15
Additional follicular cell‐derived
12/40 (30.0) 12/36 (33.3)
thyroid cancer n/n (%)
PTC 12/12 11/12
FTC 0 1/12
Chronic thyroid inflammation 4/40 (10.0) 9/36 (25.0)
Germline RET mutation (detected 4/36 (11.1)
after surgery; n/n) 4/40 (10.0) exon 13 codon 768: n=
exon10/codon 618: n= 1 1
exon 13/codon 790: n=1 exon 15/codon 891:
Thyroid
exon 13/codon 791: n=1 n=2
exon 15/codon 891: n=1 exon 16/codon 918:
n=1
N1 n/n (%) 12/40 (30.0) 9/36 (25.0)
N1a 3/12 1/9
N1b 9/12 8/9
Dissected nodes (all) ‐ n 17 (5‐89) 43 (12‐98)
12 5
Positive nodes (N1) ‐ n (2‐26, absolute range: 1‐ (2‐8; absolute range: 1‐
53) 10)
126 98
Dissected nodes (N1) – n (78‐147; absolute range: (81‐104; absolute
8‐177) range: 2‐156)
MLNR 0.095 0.051
M1 – n/n 3/40 1/36
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liver n=2 brain n=1
liver+lung+bone n=1
* Percentile (25‐75)
CCH: C‐cell hyperplasia
MTC: Medullary thyroid cancer
PTC: Papillary thyroid cancer
FTC: Follicular thyroid cancer
Local tumor stage according to UICC 2010 [1, 26] – pT1a: ≤10 mm; pT1b: 11‐20 mm; pT2:
21‐40 mm; pT3 Tumor more than 4 cm in greatest dimension limited to the thyroid or
tumor of any size with minimal extrathyroid extension beyond the thyroid capsule; pT4:
Advanced or very advanced disease;
Thyroid
N1: Lymph node metastasis; N1a: Central lymph node metastasis; N1b: Lateral lymph node
metastasis
M1: Distant metastasis
Germline RET mutation: Germline mutation in the rearranged‐during‐transfection (RET)
proto‐oncogene
MLNR: Metastatic lymph node ratio = ratio between number of metastatic nodes and total
number of lymph nodes removed
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Table 2 Sex‐specific bCT and Ca‐sCT levels
CT Cut‐
Diagnosis
type of off AUC Sens. Spec. PPV NPV
predicted
evaluation pg/ml
Males
0.894
bCT > 43 53% 100% 100% 67%
(0.824‐0.964)
> 0.849
MTC Ca‐sCT 48% 100% 100% 65%
1500 (0.762‐0.937)
any N
> 43
bCT + Ca‐ 0.896
or > 55% 100% 100% 68%
sCT (0.826‐0.965)
1500
0.937
bCT ≥ 100 100% 82% 71% 100%
N1a or (0.866‐1.000)
Thyroid
N1b 0.801
Ca‐sCT ≥ 501 100% 29% 38% 100%
(0.642‐0.960)
0.925
bCT ≥ 100 100% 74% 53% 100%
(0.840‐1.000)
N1b only
0.810
Ca‐sCT ≥ 741 100% 26% 28% 100%
(0.651‐0.969)
Females
0.935
bCT > 23 81% 100% 100% 83%
(0.872‐0.998)
0.868
MTC Ca‐sCT > 780 69% 100% 100% 76%
(0.781‐0.954)
any N
> 23
bCT + Ca‐ 0.941
or > 81% 100% 100% 83%
sCT (0.884‐0.997)
780
N1a or 0.726
bCT ≥23 100% 22% 30% 100%
N1b (0.544‐0.909)
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0.613
Ca‐sCT ≥ 341 100% 19% 29% 100%
(0.403‐0.823)
0.797
bCT ≥ 85 100% 57% 40% 100%
(0.651‐0.943)
N1b only
0.674
Ca‐sCT ≥ 341 100% 18% 26% 100%
(0.474‐0.874)

CT: Calcitonin; bCT: Basal calcitonin level; Ca‐sCT: Calcium‐stimulated CT levels; MTC:
Medullary thyroid cancer; N: Lymph node; AUC: Area under the curve; Sens.: Sensitivity;
Spec.: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; N0: No
lymph node metastasis; N1a: Lymph node metastasis in the central neck along the
recurrent laryngeal nerves; N1b: Lymph node metastasis in the lateral neck
Area under the curve ‐ sensitivity – specificity, positive and negative value to predict MTC
(with/without lymph node metastasis) and lymph nodes metastasis in the lateral neck
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Table 3a C‐cell morphology, TNM classification and comparison of bCT and Ca sCT cut‐offs in male patients (n=79).
bCT Ca‐sCT pT pN1 rM1 ∑

and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
id cancer: Are calcitonin stimulation tests still indicated in the era of highly sensitive calcitonin immunoassays? (DOI: 10.1089/thy.2019.0785)
≤ 43 > 43 ≤ 1500 > 1500

1a 1b 2 3 4
pg/ml pg/ml pg/ml pg/ml
n n n n n n n n n n n n
Group 1 CCH 39 39~ 39
Mildly MTC 19 18 1 19 0 0 19
elevated
Thyroid
Group 2 7 7 3 4 12 3
MTC 0 21 3 18 (pN1: (pN1: (pN1: (pN1: (rM1: (pN1: 21
Highly 2) 4) 2; 4; 3) 3)

Thyroid

elevated
~ Patient with sCT < 110 pg/ml: n=1
bCT: Basal CT level; Ca‐sCT: Calcium‐stimulated CT level; Immulite (Siemens)
CCH: C‐cell hyperplasia; MTC: Medullary thyroid cancer; CT: Calcitonin in pg/ml;

1)
rM1:
2)
rM1:
T: primary tumor; N1: Lymph node metastasis; p: pathological; rM1: Distant metastasis (by radiological imaging);
***
32
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33
Table 3b C‐cell morphology, TNM classification and comparison of bCT and Ca sCT cut‐offs in female patients (n=70)
bCT Ca‐sCT pT pN1 rM1 ∑

≤ 23 > 23 ≤ 780 > 780

1a 1b 2 3 4
pg/ml pg/ml pg/ml pg/ml
n n n n n n n n n n n n
Group 1 CCH 34 0 34~ 0 34
7
Mildly MTC 7 0 7 0 (pN1: 1 0 7
elevated 1)
3
15 9 2 8 1
Group 2 (pN1:
Thyroid
(pN1: (pN1: (pN1: (rM1: (pN1:

Highly MTC 0 29 4 25 1; 29
2) 4) 1) 1) 1)
elevated rM1:

1)

Thyroid

~ Patients with sCT < 110 pg/ml: n=6
bCT: Basal CT level; Ca‐sCT: Calcium‐stimulated CT level; Immulite (Siemens)
CCH: C‐cell hyperplasia; MTC: Medullary thyroid cancer; CT: Calcitonin in pg/ml;
T: primary tumor; N1: Lymph node metastasis; p: pathological; rM1: Distant metastasis (by radiological imaging);
34
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35
Table 4 Lymph node metastasis in the lateral compartment (N1b) and bCT cut‐off values and follow‐up
MTC
Follow‐up*
bCT
∑ N0 N1a N1b Persisting Tumor‐related

(pg/ml) Disease‐free
disease death
n n n n n n n
Male
 43 19 19 0 0 18**
> 43 4 4
4 0 0
< 100
≥ 100 17 5 3 9 9 6 2
Female
≤ 23 7 6 1 0 7
> 23 9 9 0 0 9
Thyroid
< 85
≥ 85 20 12 0 8 16 3 1
*: Follow‐up (median follow‐up: 46 [±27] months); ** Lost to follow‐up: n=1
MTC: Medullary thyroid cancer; bCT: Basal calcitonin level; N0: No lymph node metastasis; N1a: Lymph node metastasis in the central neck
along the recurrent laryngeal nerves; N1b: Lymph node metastasis in the lateral neck

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Thyroid

Medullary thyroid microcarcinoma recommendations for treatment ‐ a single‐

Total n/n (%) 79/149 (53.02) 70/149 (46.97)

Neoplastic 24/39 12/34

Chronic lymphocytic thyroiditis 9/39 (25.0) 10/34 (29.4)

Concomitant CCH n/n (%) 32/40 (80.0) 15/36 (41.7)

bCT Ca‐sCT pT pN1 rM1 ∑

≤ 43 > 43 ≤ 1500 > 1500

Group 1 CCH 39 39~ 39

Mildly MTC 19 18 1 19 0 0 19

Highly 2) 4) 2; 4; 3) 3)

bCT Ca‐sCT pT pN1 rM1 ∑

≤ 23 > 23 ≤ 780 > 780

Group 1 CCH 34 0 34~ 0 34

(pN1: (pN1: (pN1: (rM1: (pN1:

∑ N0 N1a N1b Persisting Tumor‐related

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