Hypercalcitoninemia and Thyroid Nodules: When Cytology (Still) Matters Luca Giovanella, M.D.,1* Gioacchino Giugliano, M.D.,2 Fausto A. Maffini, M.D.,3 Fausto Chiesa, M.D.,2 and Massimo Bongiovanni, M.D.4

Medullary thyroid carcinoma (MTC) can assume various cytomorphological and architectural forms, mimicking other thyroid and extra-thyroid tumors and rendering the cytological and histological diagnosis challenging. Consequently, measurement of calcitonin (CT) levels is generally considered to be more accurate than cytology in diagnosing MTC. Here, we report on a patient with a multinodular goiter and significantly elevated basal CT levels; based on cytology examination and CT immunocytostains, neither MTC nor C-cell hyperplasia was detected upon final histopathological examination. CT testing has a high false-positive rate and low positive predictive value for detecting clinically relevant MTC. Judicious integration of cytological examination with immunocytochemical stains (when needed) may be useful for selecting the most appropriate therapy and avoiding overtreatment (i.e., central neck lymph node dissection in the present case). This case demonstrates that cytological examination with ancillary techniques is still valuable in patients with thyroid nodules and suspicious MTC. Diagn. Cytopathol. 2014;00:000–000. VC 2014 Wiley Periodicals, Inc. Key Words: medullary thyroid carcinoma; calcitonin; fineneedle aspiration cytology

Calcitonin (CT) is an important tool for the diagnosis, postoperative management, and follow-up of medullary 1 Department of Nuclear Medicine and Thyroid Centre, Oncology Institute of Southern Switzerland, CH-6500, Bellinzona, Switzerland 2 Department of Head and Neck Surgery, European Institute of Oncology, I-20100 Milano, Italy 3 Department of Pathology, European Institute of Oncology, I-20100 Milano, Italy 4 Institute of Pathology, CH-6600, Locarno, Switzerland *Correspondence to: PD Dr. med. Luca Giovanella, Department of Nuclear Medicine and Thyroid Centre, Oncology Institute of Southern Switzerland, Via Ospedale 12 CH-6500 Bellinzona, Switzerland. E-mail: [email protected] Received 14 September 2013; Revised 26 September 2013; Accepted 9 January 2014 DOI: 10.1002/dc.23102 Published online 00 Month 2014 in Wiley Online Library (


thyroid carcinoma (MTC). However, the utility of routine CT screening of patients with thyroid nodules has long been debated. The American Thyroid Association management guidelines for patients with thyroid nodules does not “recommend either for or against the routine measurement of serum calcitonin” due to unresolved issues of sensitivity, specificity, assay performance, costeffectiveness, and lack of pentagastrin (PG) availability in the United States.1 In contrast, the European Thyroid Association and Cancer Research Network developed a European consensus report on the management of differentiated thyroid carcinoma, including the use of CT screening in patients with thyroid nodules. These guidelines included the use of CT measurements in the initial diagnostic evaluation of thyroid nodules.2 Basal serum CT levels of 100 pg/mL prompt thyroidectomy.1–3 Calcium gluconate infusion has recently been proposed as an effective alternative to PG for stimulating CT secretion.4 Classically, MTC can be diagnosed by thyroid fine-needle aspiration cytology (FNAC), which has proved to be a rapid, cost-effective, safe, and reliable method to investigate thyroid nodules. Unfortunately, MTC is considered to be a great “mimicker” because the tumor can assume various cellular and architectural forms, resembling other thyroid and extra-thyroid tumors. Moreover, several variants have been described, rendering the cytological and histological diagnosis challenging.5–10 The key to cytologically diagnose MTC (in nonclassical situations) is to remember that this thyroid neoplasm may present unusual features and to apply ancillary techniques, either on the direct smear or on a cell block preparation (if available). Diagnostic Cytopathology, Vol. 00, No 00


Diagnostic Cytopathology DOI 10.1002/dc


Fig. 1. The smear of the first nodule was predominantly composed of erythrocytes and microfollicles forming trabecular structures in an imperceptible background of colloid (smear, Papanicolaou, 2003). [Color figure can be viewed in the online issue, which is available at]

Fig. 2. At higher magnification, the scattered microfollicles had follicular cells with regular nuclear contours, dark chromatin (sometimes with a micronucleolus), and no nuclear atypia (smear, Papanicolaou, 6303). [Color figure can be viewed in the online issue, which is available at]

MTCs immunocytochemically express CT and carcinoembryonic antigen (CEA) and are negative for thyroglobulin (Tg). In the present study, we report on a patient referred to our center with multinodular thyroid disease and a very high basal CT level. The FNAC results and immunocytochemical stains are reported and compared to the final results after surgical pathology examination including immunohistochemical CT stains.

Siemens Diagnostics, Erlangen, Germany) and was significantly elevated at 259.8 pg/mL. Others factors that cause elevated CT levels (including pulmonary or pancreatic tumors, kidney failure, thyroid antibody positivity, sepsis, alcohol consumption, smoking, or the use of proton-pump inhibitor therapy) were excluded. Interference from heterophilic antibodies was also excluded by employing heterophilic blocking tubes as previously described.12 USguided FNAC was then performed on both nodules as previously described. The contents of the needles were expelled onto glass slides and smeared with a second slide to spread the fluid across the surface. The slides were fixed in 95% ethanol, Papanicolaou (PAP)-stained, and read by a board-certified cytopathologist. In our center, FNAC specimens are categorized into five classes according to the SIAPEC/IAP guidelines: category (TIR) 1 for nondiagnostic cases; TIR 2 for benign cases; TIR 3 for follicular lesion cases; TIR 4 for suspicious for malignancy cases; and TIR 5 for malignant cases.13 The FNAC specimen from the first nodule consisted of follicular cell aggregates predominantly in microfollicular arrays (Figs. 1 and 2). In the second nodule, aggregates of follicular cells with complete oncocytic metaplasia and slight nuclear enlargement were detected. However, typical nuclear features of MTC (namely, “salt and pepper” chromatin) were not observed in either nodule. Due to the clinical observation of elevated serum CT levels and the periodic polymorphous appearance of MTC, we also utilized an immunocytochemical panel comprising CT, CEA, and Tg on selected smears of the nodules. Unstained smears were used for immunocytochemistry, and the following antibodies were applied: anti-CT (DAKO, polyclonal, 1:20), anti-CEA (DAKO, clone

Clinical Case A 42-year-old woman had an asymptomatic thyroid enlargement. Her past medical history and family history were unremarkable regarding endocrinological or thyroid disease. An enlarged thyroid gland with multiple nodules was found upon routine clinical examination by her family doctor. The thyrotropin (TSH) level was normal (1.5 mUI/L), and thyroperoxidase antibodies (TPOAb) were negative. The basal serum CT level was significantly elevated at 323.3 pg/mL (reference range

Hypercalcitoninemia and thyroid nodules: when cytology (still) matters.

Medullary thyroid carcinoma (MTC) can assume various cytomorphological and architectural forms, mimicking other thyroid and extra-thyroid tumors and r...
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