Large thyroid masses, particularly if rapidly growing, are often life-threatening events because of the mechanical compression and/or infiltration of the vital structures of the neck (1–3). The most common is anaplastic thyroid carcinoma (ATC), which often appears with hoarseness, cervical pain, dysphagia, dyspnea, and stridor (4, 5). Moreover, beyond local compression, ATC is characterized by high rates of distant metastases and rapidly fatal clinical outcomes (6), and most patients die within 6 months from the diagnosis (1, 7). Conversely, large thyroid masses other than ATC are not necessarily life threatening and can be successfully treated with specific therapies. A clear identification of the histology of these masses is essential to select the most appropriate therapeutic approach (8–10).

All ATC cases are defined as stage IV and primary tumor considered T4 by the American Joint Committee on Cancer (11). According to the American Thyroid Association (12), the therapeutic options include radical surgery, if possible, external radiotherapy, and/or chemotherapy, which should be combined to maximize the disease control (3, 13, 14).

Since ATC is highly aggressive, a rapid diagnosis and treatment should be mandatory. Moreover, since other thyroid masses can have similar clinical presentation, but different outcomes, differentiating ATC from thyroid lymphoma (TL), poorly differentiated thyroid cancer (PDTC), and thyroid gland metastases (TGM) could improve the therapeutic approach and survival (8).

Currently, fine needle aspiration cytology (FNAC) is the most common diagnostic procedure (3), but it has shown several limitations particularly in the identification of ATC or TL (15–17). Therefore, patients with a suspicion of ATC or TL frequently require a surgical conventional biopsy, with more time elapsed to achieve the correct diagnosis (18). Moreover, in the case of surgical conventional biopsy, particularly in ATC, the surgical wound does not quickly heal, thus leading to a further delay in beginning potential treatments.

Core needle biopsy (CNB) represents a minimally invasive, safe, and accurate procedure providing a histological sample, which retains not only its cytologic appearance but also the tissue architecture. CNB has been suggested as a complementary method to FNAC, mainly to overcome possible inconclusive diagnosis (19). Accordingly, FNAC can play an important diagnostic role in the initial evaluation of ATC, but CNB may be necessary for definitive diagnosis and to perform molecular analysis (3). To our knowledge, no studies comparing the sensitivity of FNAC and CNB, on the same patient, in the diagnostic accuracy for detecting the malignancy of large thyroid masses and discriminating the histology have been performed.

The aim of this prospective study was to compare the diagnostic performance of FNAC and CNB in a large series of patients, thus exploring the possibility that CNB could be the first and main diagnostic tool in the presence of a large and rapidly growing thyroid mass.

We prospectively collected the data of 95 consecutive patients with large thyroid masses admitted to either the Endocrine Unit or the Endocrine Surgery Unit of the University Hospital of Pisa between April 2014 and January 2020.

The study was conducted according to the guidelines of the Declaration of Helsinki, approved by the local Ethical Committee (CEAVNO, Comitato Etico Area Vasta Nord Ovest). For the policy of the University Hospital, all patients signed an informed consent both for the performance of invasive procedures and for the use of their data for scientific purposes.

At the time of enrollment, patients had a median age of 70 years (IQR = 58–79 years, range = 28–91 years), and 55 out of 95 (57.9%) were women ( Table 1 ).

Large thyroid masses, particularly if rapidly growing, represent a clinical challenge as they are often related to life-threatening events. In order to quickly reach a diagnosis and carry out appropriate treatments, several procedures have been proposed (3, 25). Surgical conventional biopsy achieves diagnosis in almost all cases, but it has several limitations. It may increase the morbidity and mortality, especially in the elderly, is time-consuming, is invasive, may cause tissue damage, and often requires hospital admission, general anesthesia, and potential transfer to the intensive care unit. Therefore, due to the surgical risk, this approach is not be suitable for all patients (26). Conversely, FNAC is usually the first type of biopsy chosen because it is more immediate, is performed without general anesthesia, and can allow the diagnosis of malignancy in >60% of ATC cases (27, 28). However, cytology, particularly in rare and high-grade malignant neoplasms, does not often give information about the histotype of the tumor, which is, indeed, necessary for the planning of further therapeutic procedures (29). Because of the presence of necrotic material and inflammatory cells in aspirates, we also had 20% of non-diagnostic cases, a higher prevalence when compared to the non-diagnostic FNAC commonly observed when thyroid nodules were submitted to the procedure in our center (30). This percentage of non-diagnostic cases could potentially be reduced by using cell block specimens on the FNA material. However, this is not a routine procedure, the rate of non-diagnostic results could be slightly reduced (31), and, although commonly applied in our center in lung and liver lesions, it is not performed on thyroid nodules.

Several types of neoplasia were diagnosed in our series. Indeed, beyond ATC and PDTC, the most frequently diagnosed neoplasia on CNB (36.8% and 28.4%, respectively), TL (13.7%), TGM (6.3%), and other rare neck cancers (12.6%), such as angiosarcoma, mesenchymal neoplasia, squamous cell carcinoma, and plasmacytoma, were also diagnosed. Similar results were reported by Choi et al. (32), who performed FNAC and CNB in a series of 52 thyroid nodules clinically suspicious for TGM. Unlike in our study, FNAC and CNB were not performed in all cases; nevertheless, their study demonstrated the higher sensitivity of CNB vs. FNAC in the diagnosis of TGM.

It was clearly demonstrated that 18.9% (18/95) of these masses, although localized in the thyroid, were indeed either metastases from other types of tumors or quite rare tumors. However, none of them was identified by FNAC, but were clearly recognized by CNB, which is a true biopsy and allows the pathologist to perform immunohistochemistry, which can better characterize the origin of the tumor (33).

The role of CNB compared to FNAC has already been explored in the diagnosis of thyroid nodules, particularly in cytologically indeterminate lesions. Na et al. (34) evaluated 161 patients with indeterminate cytology and confirmed the higher sensitivity of CNB compared to FNAC in detecting malignancy. However, in our experience, the CNB procedure required that the nodule dimension be ≥3 cm, thus representing a limitation in its routine application. The higher sensitivity of CNB compared to FNAC in detecting malignancy was also confirmed in other human tumors (35–38).

Regarding large neck masses, in particular ATC, Ha et al. (26) evaluated the diagnostic performance of FNAC and CNB in a series of patients with ATC or TL. However, FNAC was performed in 83.8% and CNB in only 32.2% of the study group. The authors obtained 100% and 90.9% positive predictive values for CNB and FNAC in diagnosing ATC, respectively. In our series, the positive predictive values for ATC diagnosis were 100% and 17.1% and for TL diagnosis were 92.3% and 61.5% for CNB and FNAC, respectively. Moreover, unlike in our study, their data were retrospectively collected, CNB was performed in only a minority of cases, and only in a few patients (8.1%) were CNB and FNAC simultaneously performed.

In our series, in the 24 cases submitted to surgery, the correlation between the CNB and histology results was very high since in only 12% of the cases was it slightly discordant. This could be, at least in part, due to the heterogeneity of the ATC, being either of pure anaplastic origin or deriving from the dedifferentiation of a preexisting PTC (3). In any case, this discordance did not play any role in the management of the patients. In the era of precision medicine, in which treatments are targeted against specific genes and mutations of the tumor, the ability to perform a rapid and correct histological diagnosis cannot be overlooked. Indeed, particularly in ATC cases, in which a definitive cure is unlikely with standard treatments, the molecular signature of the neoplasia could improve the outcome of patients harboring actionable mutations (i.e., BRAF V600E) (24, 39), as well as in a neoadjuvant setting (40). In our series, although the material obtained from CNB was optimal to perform molecular analysis in most cases (96.8%), it was performed in only 17.9%. This quite low frequency of analyzed cases is not unexpected since the knowledge about the impact of molecular analysis on the treatment of patients with ATC is quite recent (41). Molecular analysis could also be performed on cytological material (42); however, in several cases, cytology does not provide correct information on the histotype, limiting the choice of genetic profile to be analyzed. Conversely, when the histology is known, as in most cases of CNB, a specific molecular profile can be studied, being different not only according to different tumors (43) but also in the context of different thyroid tumors (44, 45). Accordingly, in metastatic malignancies for which the primary site is unknown, the key role of CNB compared to FNAC has been clearly demonstrated, both in clarifying the primary site of the tumor and in obtaining sufficient material to perform the molecular analysis (8, 46).

CNB is a safe and well-tolerated procedure associated with a low incidence of complications when performed in expert hands (47). However, several potential complications have been reported, such as hematoma, voice change, infection, edema, vasovagal reaction, hemoptysis, and dysphagia (34, 48, 49). In a large single-center study, in which CNB was performed on 6,687 thyroid nodules, very few major (0.06%) and minor (0.79%) complications were described (50). Also, in other studies, low rates of major complications, such as bleeding and tumor cell seeding, were observed (51).

These findings are in accordance with our experience, although in the different setting of large thyroid masses, we did not experience any complications related to the CNB procedure. However, to minimize complications, CNB should be performed by well-trained physicians, under real-time US guidance and with a good awareness of neck anatomy and potential complications (52).

To our knowledge, this is the first prospective study comparing the diagnostic performance of FNAC and CNB in a large series of rapidly growing thyroid masses. The main limitation of our study was that it was performed in a tertiary referral center for the treatment of thyroid cancer, therefore making our results not completely reproducible in routine clinical practice. However, it is recommended that these rare thyroid masses should be managed in referral centers able to perform these kinds of procedures. Conversely, the strengths of this study included the large number of patients enrolled; the use of neck US to identify the areas suitable for biopsy, avoiding the presence of tissue necrosis and inflammation; and the simultaneous use of both FNAC and CNB on the same patient, at the same time, from the same skin incision.

In conclusion, our study demonstrates that CNB is a safe procedure able to optimize the diagnostic times and to obtain an early histological diagnosis, which is fundamental to starting an early and specific treatment. Moreover, the CNB sample can also be immediately analyzed for its molecular profile, with the great advantage that, if a druggable mutation is revealed, a more specific and active drug can be immediately started. This evidence strongly supports the official introduction of CNB in routine clinical practice for the diagnosis of large and rapidly growing thyroid masses.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Comitato Etico Area Vasta Nord Ovest (CEAVNO). The patients/participants provided written informed consent to participate in this study.

AM, LDN, RE, and GM: conceptualization, methodology and data curation. LDN, AA, PP, CEA, and GM: surgical procedures. RC: imaging revision. LT, CU, and FB: cytological and histological analysis. AM and LDN: formal analysis. AM, LDN, AA, PP, CEA, EM, RE, and GM: investigation. AM, LDN, and RE: writing—original draft preparation. All authors: writing—review and editing. RE and GM: supervision. All authors contributed to the article and have read and approved the submitted version.

The work was supported by the Ministero dell’Istruzione, dell’Università e della Ricerca Italiano (MIUR, investigator grant 2017, project code PRIN 2017YTWKWH).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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