DOI 10.1515/cclm-2012-0610 Clin Chem Lab Med 2013; 51(7): 1477–1481
Luca Giovanella*, Frederik A. Verburg, Mauro Imperiali, Stefano Valabrega, Pierpaolo Trimboli and Luca Ceriani
Comparison of serum calcitonin and procalcitonin in detecting medullary thyroid carcinoma among patients with thyroid nodules Luca Ceriani: Department of Nuclear Medicine and Thyroid Centre, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Abstract Background: To prospectively evaluate the role of procalcitonin (PCT) in detecting or excluding medullary thyroid carcinoma (MTC) among patients with thyroid nodules and increased calcitonin (CT) levels. Methods: Fourteen of 1236 patients referred for thyroid nodules had increased serum CT > 10 pg/mL. A stimulation test with pentagastrin was done and both CT and PCT were measured after stimulation. All patients underwent thyroid ultrasound, fine-needle cytology and, if indicated, surgery with histological and immunohistochemical examination of the surgical specimens. Results: After follow-up, two MTCs were found. These two patients had basal CT > 100 pg/mL and detectable ( > 0.1 ng/mL) PCT, with 100% sensitivity. Pentagastrin stimulated CT achieved values above 100 pg/mL in two MTCs and in other two cases with no MTC outcome (50% PPV and 83% NPV). On the contrary, all patients with no MTC had both basal and stimulated undetectable PCT (100% PPV and 100% NPV). Conclusions: The addition of basal PCT measurement in patients with thyroid nodule(s) and increased CT may significantly improve accuracy of CT measurement without needing a PG stimulation test. Keywords: calcitonin; medullary thyroid carcinoma; procalcitonin; thyroid nodule. *Corresponding author: PD Dr med. Luca Giovanella, Department of Nuclear Medicine and Thyroid Centre, Oncology Institute of Southern Switzerland, Via Ospedale 12, 6500 Bellinzona, Switzerland, Phone: +41 91 8118672, Fax: +41 91 8118250, E-mail:
[email protected] Luca Giovanella and Mauro Imperiali: Department of Laboratory Medicine, Ente Ospedaliero Cantonale, Lugano, Switzerland Frederik A. Verburg: Department of Nuclear Medicine, RWTH Aachen University, Aachen, Germany Stefano Valabrega: Department of Surgical Science, Sapienza University, Ospedale S. Andrea, Rome, Italy Pierpaolo Trimboli: Section of Endocrinology and Diabetology, Ospedale Israelitico, Rome, Italy
Introduction Medullary thyroid carcinoma (MTC) is a malignant tumor originating from the thyroid C-cells and accounting for 1.4%–5% of all thyroid cancer types [1]. Serum calcitonin (CT) is the more sensitive marker for the diagnosis and follow-up of MTC [2, 3], and its use has been also supported in detecting occult MTC in patients with nodular goiter [4, 5]. However, elevated CT may be induced by several conditions such as small cell lung, breast and pancreatic cancers, neuroendocrine tumors, renal failure, sepsis, smoke or alcohol consumption, proton-pump inhibitor therapy. Moreover, non-medullary thyroid diseases, such as follicular cancers, goiter and autoimmune thyroid diseases could be associated with mild-moderate CT increase [6, 7]. Thus, CT value as a MTC diagnostic marker may be impaired by several circumstances. In all, thyroid nodules patients with increased CT value require more investigations. In this regard, CT stimulation by pentagastrin (PG) is a pivotal test. However, while both basal and stimulated CT levels > 100 pg/mL have a nearly absolute sensitivity [8, 9], false-positive results are not rare especially for mildly elevated basal CT. For these reasons, the routine CT testing in patients with thyroid nodules is still a matter for debate. The European Consensus by European Thyroid Association and Cancer Research Network recommends measuring CT in the initial evaluation of thyroid nodules [10]; the American Thyroid Association guidelines for thyroid nodules could not recommend either for or against the routine CT test due to unresolved issues of sensitivity, specificity, assay performance, cost-effectiveness, and PG unavailability in the USA [11, 12]. Considering these limitations, AACE/AME/ETA recently recommended CT only in subjects with familial history of MTC, in patients with MTC suspicious cytology, and in patients undergoing surgery for goiter to avoid an incomplete treatment when MTC is
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1478 Giovanella et al.: Role of PCT to detect MTC in patients with thyroid nodules histologically discovered [13]. Procalcitonin (PCT) is a CT precursor found at low serum concentrations in healthy individuals, which increases in systemic inflammation, infection and sepsis [14]. More recently, PCT has been preliminarily shown to be an accurate additional marker to CT in MTC diagnosis and follow-up, with the advantages of better in vitro stability and consistency of analytical methods [15, 16]. Additionally, no or only marginal increase of serum PCT was observed after PG infusion in patients with non-medullary diseases but increased basal serum CT. Currently, no prospective data on the addition of PCT measurement in patients with thyroid nodules and increased CT are available. The present study aimed to prospectively evaluate the role of routine PCT measurement in detecting MTC among patients with thyroid nodules, and to assess the potential improvement provided by adding PCT to increased basal CT.
AACE/AME/ETA guideline by echogenicity, echostructure, margins, presence of microcalcifications (defined as hyperechoic spots), shape, and vascular signal [13]. All cytological samples were evaluated by experienced thyroid cytopathologists and classified into five classes according to the SIAPEC/IAP guidelines: TIR 1, non-diagnostic; TIR 2, benign; TIR 3, follicular lesion; TIR 4, suspicious for malignancy; TIR 5, malignant [18]. Immunocytochemical stain was used, when appropriate. Patients with indeterminate (TIR 3), suspicious (TIR 4) or malignant (TIR 5) cytological outcome underwent surgery, while subjects with benign cytology were followed up for at least 24 months. Basal and/or stimulated CT levels > 100 pg/mL prompted to thyroidectomy with bilateral dissection of the central neck compartment. Surgical specimens were examined by microscopy with 0.5 cm serial sections and totally included in cassettes for histological and immunohistochemical examination, as suggested by the Blue Book on the Pathology and genetics of tumors of endocrine organs [19]. Germline mutations of the RET proto-oncogene were investigated in all patients with MTC or C-cell hyperplasia (CCH).
Results Materials and methods The Ethics Committee of the Ente Ospedaliero Cantonale (Bellinzona, Switzerland) approved this study and all subjects gave written informed consent prior to inclusion. The initial series included 1479 consecutive patients (785 females and 694 males, mean age 54 ± 19 years) referred to our centers between January 2008 and December 2010 with nodular thyroid disease. Exclusion criteria were pulmonary or pancreatic tumors, kidney failure, Graves’ disease, autonomously functioning thyroid nodules, autoimmune thyroid diseases, sepsis, alcohol abuse, smoking, or the use of proton-pump inhibitor therapy in the last month. Measurement of thyroid stimulating hormone (TSH), free-T4 (fT4), thyroid peroxidase autoantibodies (AbTPO) and CT were done on the IMMULITE® 2000 XPi platform (Siemens Healthcare Diagnostics, Erlangen, Germany). The CT assay is standardized against the 2nd International WHO calibrator 89/620 and was performed in strict adherence to the manufacturers’ instructions as stated in the package insert. The limit of detection (LoD) and the limit of quantification (LoQ) of CT assay were 2.00 and 5.00 pg/mL, respectively. PCT was measured on a Kryptor system (BRAHMS, Berlin, Germany) by a homogenous time-resolved amplified cryptate emission immunometric fluorescent assay. The assay has a functional sensitivity of 0.1 ng/mL. In patients with basal CT values > 10 pg/mL exclusion of interferences from heterophilic antibodies was performed by employing heterophilic antibody blocking tubes (Scantibodies Laboratory Inc. Santee, CA, USA) as previously described [17]. Patients with true high CT value underwent stimulation test by i.v. bolus injection of 0.5 μg/kg PG (Pentagastrin Injection BP, Cambridge Laboratories, Wallsend, UK) and serum samples were drawn after 2 and 5 min to measure stimulated CT and PCT. Patients with serum TSH below 0.1 mIU/L underwent 99mTcpertechnetate thyroid scintigraphy and patients with hot thyroid nodules or Graves’ disease were excluded from the present study. All patients underwent thyroid ultrasound (TUS) with a Acuson X150 instrument (Siemens Healthcare Diagnostics) featuring a linear 10–13 MHz transducer. Thyroid nodules were assessed according to
After exclusion of patients with pulmonary or pancreatic tumors (n = 2), kidney failure (n = 11), thyroid autonomy or Graves’ disease (n = 10), autoimmune thyroid diseases (n = 72), sepsis (n = 1), alcohol abuse (n = 19), smoking (n = 96), heterophile antibodies interferences (n = 1) or use of proton-pump inhibitor therapy in the last month (n = 31), 1236 patients (674 females and 562 males, mean age 53 ± 17 years) were included in the final series. Basal serum CT levels were > 10 ng/mL (from 12 to 347 pg/mL) in 14 (1.1%) patients. After clinical or histological follow-up, two patients had histologically proved MTC, one had CCH, and the remaining 11 subjects had nonmedullary thyroid cancers (n = 2) or benign diseases (n = 9) (Table 1). The RET proto-oncogene analysis was proposed to three medullary outcomes (two MTC and one CCH), and no mutation was found. On the one hand, basal CT > 100 pg/mL was found only in two MTC, while PG-stimulated CT > 100 pg/mL was recorded in two of the above-mentioned cases and in the other two cases (one CCH and one MNG). Mean values of basal and PG-stimulated CT in the non-medullary group were 18 ± 10 (ranging from 12 to 34) pg/mL and 65 ± 55 (from 33 to 150) pg/mL, respectively. On the other hand, basal PCT was elevated only in MTC, being undetectable in the CCH case as well as in non-medullary diseases. In addition, PG-stimulated PCT values of MTC patients increased with respect to the basal condition, being undetectable in the remaining 12 subjects. Thus, basal and PG-stimulated PCT achieved 100% accuracy (Table 2). Finally, a significant drop of serum CT was demonstrated in MTC patients after thyroidectomy.
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Giovanella et al.: Role of PCT to detect MTC in patients with thyroid nodules 1479
Table 1 Clinical and pathological data of 14 patients with increased basal CT. Age
Gender
b-CT
Medullary thyroid cancers 63 M 347 66 M 165 C-cell hyperplasia 43 M 31 Non-medullary thyroid diseases 37 F 12 44 M 22 51 F 19 75 M 31 34 F 17 56 M 34 31 M 28 47 M 31 59 F 21 60 F 19 41 M 14
s-CT
b-PCT
s-PCT
FNC (TIR)
Histo
Stage
1847 798
1.1 0.75
3.7 1.5
5 3
MTC MTC
pT1N1a pT1N0
114
< 0.1
< 0.1
2
CCH
39 55 47 59 33 150 51 64 43 57 40
< 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1
< 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1 < 0.1
2 2 5 2 2 2 2 2 3 3 2
PTC
8.5
