Fine-needle aspiration uses finer needles (21–27 gauges) than the large-bore needles of large-needle aspiration (14 gauge). Recently introduced CNB devices have a smaller bore (usually 18–21 gauge) and spring-activated needles (184445). Large-needle biopsy, performed without US guidance with a large-bore needle, is not recommended for thyroid nodules.

The proper CNB needle conditions for thyroid nodules are the following. First, the entire length of needle should not exceed 10 cm because the thyroid gland is a superficial organ. Second, needle thickness, especially inner diameter, determines the thickness of the specimen. However, there is still no evidence supporting the choice of needle gauge. Some studies report the use of 16–22-gauge needles (1821454647). Although the use of 18–21-gauge needles is universal for thyroid nodules, 18-gauge needles have been mainly used in Korea (1819484950). The thinner the needle, the less damage to normal tissue but the lower the amount of tissue obtained. CNB needles for thyroid nodules typically have the following characteristics: diameter, 18–21 gauge; needle length, 6–10 cm; excursion length, 1.1–2.0 cm. However, there is no evidence regarding the relationship between needle thickness, complication rate and diagnostic accuracy. Finally, the length of the stylet, namely, the penetration length, can be selected according to the size of nodule and is usually 1–2 cm.

Core needle biopsy needles are composed of two needles, the stylet and the cutting cannula (Fig. 1) (1844). The stylet or inner needle has an approximately 2-mm-long sharply sloped tip to penetrate tissue and a specimen notch for holding the sampled tissue. The cutting cannula or the outer blade is the outer component of the CNB needle and plays a role in cutting the tissue and placing it on the specimen notch. CNB needles are divided into two types according to the mechanism of action: automated and semi-automated. The automated needle is called a double-action needle because both inner and outer needles are spring-activated. This type of needle fires the stylet via a spring action that can more easily penetrate hard tissue. However, it may be more prone to adjacent tissue damage. The semi-automated needle is called a single-action needle because the spring activates just once: the stylet is manually introduced, followed by the spring-activated needle. The semi-automated needle enables a relatively safe procedure, despite the presence of a risky aspect because operators manually push the stylet into the tissue. There are various kinds of spring power. Although a device with a strong spring can better penetrate hard tissues such as calcifications or fibrosis, it has higher potential for injury of normal tissue or vessels. The amount of tissue obtained depends on the needle thickness and the length of the specimen notch (51).

The guiding needle or coaxial needle is a separate needle that provides assistance and easy intraneedle passage of the core needle to the target. It provides a clear path to work through when performing multiple biopsies in the same area and can improve accuracy and efficiency. However, the needle tract is greater because the size is larger than that of the corresponding biopsy needles.

Modern CNB devices, particularly 18–21-gauge, spring-activated, core needles, are recommended for the procedure.

Fasting is not recommended for CNB in standard conditions (31). Informed consent should be obtained from all patients after discussion with them of the purpose, procedure, possible complications, and need for CNB. The use of drugs, especially those that affect bleeding tendency, such as warfarin, heparin, aspirin, or clopidogrel bisulfate, should be checked. Interruption of such agents can reduce the risk of biopsy-related complications. Bleeding tendency is checked by communication with patients and a screening blood test for coagulation is usually unnecessary. Aspirin and clopidogrel bisulfate should be withdrawn for 7–10 days, warfarin for 3–5 days, and heparin for 4–6 hours before the procedure. After the procedure, aspirin and clopidogrel bisulfate can be started from the next day, warfarin that night, and heparin 2 hours later (52). However, anticoagulant withdrawal should be carefully discussed with the prescribing physician. Warfarin can be transiently changed to shorter-acting heparin (52).

Patients with bleeding tendency, such as those taking anticoagulation medications or with disorders affecting the coagulation cascade, should be thoroughly evaluated and any problems corrected before CNB.

Core needle biopsy should be performed by experienced operators under US guidance. Operators should determine the appropriate type of CNB needle and access route via preprocedural US evaluation, which is also important for improving safety and diagnostic accuracy (31). Although no standard technique for thyroid CNB has been established, the KSThR recommend the following techniques for effective and safe procedures.

Experience is one of the most important factors for CNB safety. Less-experienced operators may have difficulties in finding the needle tip under US, which can increase the possibility of complications. CNB procedures by less-experienced operators should be supervised by experienced operators.

During the US-guided procedure, there are two options for the guidance of CNB needles: a free-hand technique or a US probe-guiding device. Our society recommends a free-hand technique because it allows greater freedom, permitting the operators both to select the puncture point and to adjust the route during the procedure (51). Before the procedure, the nodule size, position, characteristics, and vascularity should be evaluated by gray-scale and color Doppler US. Vascular injury can be minimized by the use of color Doppler US guidance during the procedure. The operator should decide the CNB approach route using the information from the preprocedural US evaluation. Approximately four approach routes are available: transisthmic, lateral, longitudinal, and oblique. The most suitable approach has been suggested to be the transisthmic approach. It is recommended to choose a needle with a similar specimen notch length to nodule diameter to minimize the sampling of normal tissue (1822).

Patients lie down in a supine position with their neck fully extended. Local anesthesia with 1% lidocaine applied using a finer needle through the route is recommended. Figure 2 shows a CNB procedure on US. To pass through the skin and thyroid capsule, a snapping movement of the wrist is favored for effective rapid needle passage and to reduce pain.

Skin puncture can be effectively performed without skin incision by introducing the needle through the entry hole created by the needle or by direct skin puncture with a rapid snapping movement of the wrist with the core needle. The entire length of the CNB needle must be monitored during the procedure and the needle should remain parallel to the axis of the US probe during the procedure, which is mandatory for the optimal US guidance of CNB. A vertical approach of the needle should be avoided because the entire length of the needle cannot be visualized by US during the procedure. Complete vessel mapping along the approach route (from the skin to the nodule) via color Doppler US is crucial to avoid vessel injury and ensure a safe CNB procedure.

When using a double-action CNB needle, ensure that the entire length of the needle (including the needle tip) is visualized as a single plane before stylet firing, and the anticipated moving distance of the stylet should be exactly estimated before firing. The needle tip must be in a safe place, in most cases within the thyroid capsule, and there must be no large vessels within the imagined firing route. Once all of these aspects are checked and the operator is certain of the safety of the imagined route, the stylet can be fired followed by cutting cannula. When a successive method is used, the location of the specimen notch can be adjusted after stylet firing to select the most appropriate sampling site. For pathological interpretation, the three following components should be obtained: nodule tissue, nodule-parenchyma border (sometimes there is a visible capsule), and normal thyroid parenchyma (4651). While adjusting the specimen notch position, blood can rapidly fill the specimen notch if there is a hypervascular nodule. In this case, the CNB might not harvest any adequate tissue, only blood. Simultaneous or rapid firing of a cutting cannula can prevent this kind of blood filling. When a single-action needle is used, the stylet is manually advanced to the margin of the nodule or within the nodule. After adjustment of the location of the stylet and specimen notch, the cutting cannula is fired in the same fashion as for the double-action needle.

Nodules found in a dangerous location should be carefully evaluated. When the nodule is located near the thyroid capsule, placement of the stylet tip outside the capsule is very cautiously allowed because vascular injury and massive bleeding may occur when the specimen notch is located outside the thyroid capsule. In this situation, a single-action needle is safer because fine adjustment of the specimen notch position is possible. After confirmation that the specimen notch is within the thyroid capsule, cutting cannula firing can follow. CNB may also be technically difficult when there is a small nodule located in the deep posterior area of the thyroid gland. In this situation, first insert a stylet into the nodule by manually advancing the stylet and then elevate the nodule with the inserted stylet. The direction of firing would be changed after positioning the stylet to a safer lateral or oblique lateral direction and, then, the cutting cannula can be safely fired (Fig. 3).

Sometimes, thyroid nodules containing severe fibrosis and/or heavy calcification may be too hard to be penetrated by a CNB needle. To successfully obtain samples from such hard nodules, operators can try to stab the nodule with a needle tip to identify a weak point, use a double-action needle with spring power, and/or adjust the specimen notch direction. Sometimes, the nodule is so hard that the needle may be deflected and damage adjacent structures. Thus, before sampling hard nodules, careful evaluation of the surrounding structures is vital (363753).

Biopsy techniques using a guiding needle (coaxial needle) are useful for repeat CNB. In this technique, the biopsy needle is inserted through the lumen of the guiding needle, which has been placed from the skin to the near surface of the nodule. After local anesthesia to the entry point on the skin, the guiding needle is inserted and placed so that the tip is just in front of the near surface of the nodule. The stylet of the guiding needle is removed and the biopsy needle is inserted. The stylet is fired first, then the cutting cannula to obtain the biopsy sample. To obtain any additional samples, the biopsy needle is removed to harvest the tissue sample, leaving the guiding needle in place. Biopsy needle re-insertion and sample collection can be performed through the lumen of the remaining guiding needle. The use of guiding needles has the following advantages: 1) the tip of the guiding needle is sharper, so skin and thyroid capsule penetration is easier; 2) multiple sampling can be done easily via the single insertion of a guiding needle; 3) complications are minimized by reducing the number of repeat thyroid punctures; and 4) finer manipulation of the guiding needle allows the biopsy needle to avoid any critical structures near the nodule.

After biopsy, visual assessment of the tissue sample can help to determine if additional CNB is required (15182237). An important advantage of CNB over FNA is the possibility for visual assessment of the tissue obtained. To the naked eye, normal thyroid parenchyma is seen as blood-red soft tissue. Most cancers, especially when they are solid and fibrous, are seen as hard and whitish tissue. Calcifications are seen as milky whitish tissue.

Therefore, the adequacy of the CNB specimen can be determined via visual assessment. After visual assessment, the harvested tissue should be immediately fixed in formalin. One or two biopsy sampling is sufficient for the adequate histology diagnosis in most thyroid nodules. If the specimen size is too small or inadequate by visual assessment, additional biopsy should be considered. When a nodule has heterogeneous components on US, it is advised to sample tissue from multiple sites of the nodule to represent all areas of the nodule. When there is a complication, such as bleeding, additional sampling can be postponed. Manual compression should be performed immediately after the biopsy for 20 to 30 minutes.

(A) CNB should be performed by experienced operators under US guidance.

(B) Manual compression of the biopsy site should be performed immediately after the procedure for 20 to 30 minutes.

Although US-guided FNA has been established as an accurate diagnostic method for thyroid nodules, non-diagnostic results are a diagnostic limitation of FNA (554). Non-diagnostic FNA results show a broad range of malignancy rates. Because non-diagnostic aspirates are common causes of false-negative FNA results, the current guidelines recommend repeat FNA under US guidance, although approximately 9.9–47.8% will once again be non-diagnostic (58955). Surgery is recommended for solid nodules with repeated non-diagnostic results for diagnostic purposes (534).

The rates of non-diagnostic results of CNB vary from 1.1% to 7.2% (15181921224756575859). However, three studies reported a non-diagnostic result rate of more than 10% (13%, 23%, and 40.6%, respectively) (43560). Several current guidelines, such as those of the NCI, AACE/ACE/AME, and KSThR, suggest CNB for thyroid nodules with repeated non-diagnostic FNA results (313261). However, the guidelines do not recommend CNB as a first-line diagnostic tool. CNB has been suggested as an effective diagnostic tool for thyroid nodules with previous non-diagnostic results in FNA (1835). Four studies compared the effectiveness of CNB and repeat FNA for thyroid nodules with initially non-diagnostic FNA results (18355657). In these studies, CNB achieved lower non-diagnostic results than repeat FNA. Furthermore, CNB can reduce inconclusive results and unnecessary surgery (1518). One study showed that repeat FNA was the most significant factor for second non-diagnostic biopsy results, although non-diagnostic results of CNB were not related to cystic component, calcifications, or other US features (56). These results suggest that CNB can be used instead of repeat FNA as the subsequent diagnostic approach for thyroid nodules with initially non-diagnostic FNA results. The combination of repeat FNA and CNB has also been suggested, with this combination achieving significantly better results than FNA alone (35).

In recent systematic review and meta-analysis studies, CNB is suggested as an effective diagnostic tool to reduce inconclusive results in thyroid nodules with previously non-diagnostic FNA result (62636465). In these studies, CNB showed lower non-diagnostic or inconclusive results than repeat FNA.

Main causes of non-diagnostic results in CNB are a fibrotic nature of the thyroid nodule or a targeting error. Fibrosis of thyroid nodules is prominent in thyroid nodules with degeneration (37). Targeting errors are usually caused by inexperienced operators, small thyroid nodules, deep nodules, and heavily calcified nodules (1837). Pathological analysis of specimens obtained after a targeting error reveals the presence of normal thyroid tissue only, skeletal muscle, or adipose tissue (60).

Core needle biopsy can be used as an alternative to FNA for thyroid nodules with non-diagnostic cytology in previous FNA.

One of the limitations of FNA is atypia (follicular lesion) of undetermined significance, which has been reported in about 10–20% of FNA biopsies. The guidelines recommended repeat FNA for these nodules but repeat FNA also shows a non-diagnostic rate of 1–7% and a rate of repeated atypia (follicular lesion) of undetermined significance of 3.8–31.0% (101112). The malignancy risk of the atypia (follicular lesion) of undetermined significance category is 15–25% according to the Bethesda system (54). However, there has been a tendency to overuse the diagnosis of atypia (follicular lesion) of undetermined significance and the reported malignancy risk varies from the proposed rate, from 14% to 38% (6667). To improve the accurate detection of malignancy in these lesions, several solutions have been suggested, such as the use of CNB, BRAF mutations, gene expression classifiers, and a combination of US findings (18216869707172). There are no clear guidelines on the management of atypia (follicular lesion) of undetermined significance. AACE/ACE/AME guidelines do not recommend either in favor of or against the use of CNB in nodules with indeterminate cytology because of the limited evidence and the lack of established reporting systems (5). A recent CNB study showed that subcategory nodules of nuclear atypia had higher risk of malignancy, of becoming surgical candidates, of having malignant US findings, and of having malignant CNB readings than subcategory nodules of architectural atypia (69). Other studies suggested that CNB was helpful for subcategory nodules of nuclear atypia but not (or less helpful) for subcategory nodules of architectural atypia (394873). However, another study of 153 consecutive patients suggested that CNB might be more useful for management decisions than repeat FNA in both subcategory nodules of nuclear atypia and subcategory nodules of architectural atypia and has the potential to be a first-line alternative diagnostic tool in initially diagnosed atypia (follicular lesion) of undetermined significance (39).

The recently revised ATA management guidelines proposed that repeat FNA or molecular testing be used and that, if the results are inconclusive again, surgical excision be performed with consideration of clinical and US features and patient preferences (34). Application of immunohistochemical stains such as galectin-3, cytokeratin-19, Hector Battifora and mesothelioma 1 (HBME-1), and BRAF^V600E(VE1) to CNB specimens from thyroid nodules with prior indeterminate FNA reports has been tried (2572). It is unclear whether the addition of immunohistochemical stains would significantly improve diagnostic accuracy for all thyroid nodules. However, immunohistochemical stains seem to be effective for thyroid nodules with indeterminate CNB results (after initial atypia [follicular lesion] of undetermined significance in FNA) (2572).

Several recent studies have shown the usefulness of CNB for thyroid nodules with previous atypia (follicular lesion) of undetermined significance. In a retrospective study comparing three management tools (CNB, repeat FNA, and diagnostic surgery for previous atypia [follicular lesion] of undetermined significance in FNA), the CNB results were better (77.8% benign, 20.3% cancer, and 1.8% non-diagnostic) than those of repeat FNA (35.2% benign, 16.1% cancer, and 48.6% non-diagnostic) and comparable with those of diagnostic surgery (19). In a prospective study of concurrent CNB and FNA, the incidence of non-diagnostic or atypia (follicular lesion) of undetermined significance was lower in CNB (3.1% non-diagnostic and 23.6% atypia [follicular lesion] of undetermined significance) than in repeat FNA (9.3% non-diagnostic and 39.8% atypia [follicular lesion] of undetermined significance) (18).

Core needle biopsy may be used as an alternative to FNA for thyroid nodules with atypia (follicular lesion) of undetermined significance in previous FNA.

The preoperative diagnosis of follicular neoplasm in the thyroid gland is challenging because some thyroid nodules with Bethesda IV in FNA are non-neoplastic nodules such as nodular hyperplasia and chronic thyroiditis (50). In particular, FNA cannot distinguish follicular carcinoma from follicular adenoma because their differentiation is based on the histologic evaluation of surgical specimens. In nodules with Bethesda category IV, FNA obtains a retrospective neoplasm rate of 60–80% and malignancy rate of 20–40% (124974). CNB has been introduced as a complementary method for thyroid nodules because the large amount of specimen obtained can facilitate more detailed histologic evaluation and ancillary immunohistochemical staining (182324). Moreover, Nasrollah et al. (46) have suggested a new sampling technique that includes the capsule of the nodule and the surrounding extranodular parenchyma, as well as nodular tissue (75). This technique could allow follicular neoplasm and unencapsulated non-neoplastic nodules to be distinguished by identifying the presence of a fibrous capsule on histologic evaluation.

Core needle biopsy is not recommended by current guidelines for the differentiation of follicular adenoma and carcinoma (532). However, the differentiation of follicular neoplasm from nodular hyperplasia is also important for avoiding unnecessary surgery in clinical practice. The management strategy is surgery for follicular neoplasm, but the follow-up strategy more closely resembles that of nodular hyperplasia (5054). There have been few previous studies of the diagnostic value of CNB for follicular neoplasm of the thyroid gland (4950). Yoon et al. (50) reported that CNB was superior to FNA for the diagnosis of follicular neoplasms in terms of the false-positive neoplasm rate (4.7% vs. 30.8%), unnecessary surgery rate (3.7% vs. 26.2%), and malignancy rate (57.9% vs. 28.0%). The researchers believe that CNB can play a role in reducing unnecessary surgery and increasing diagnostic confidence for patients with follicular neoplasm. In contrast, Min et al. (49) determined that CNB was not superior to FNA in the prediction of malignancy (malignancy rate, 46% vs. 48%, p > 0.05). The role of CNB in the diagnosis of follicular neoplasm is still debatable. Therefore, a large prospective study is required to validate the diagnostic efficacy of CNB for follicular neoplasm.

(A) CNB has advantages to differentiate encapsulated follicular neoplasms from non-neoplastic nodule.

(B) CNB cannot differentiate follicular thyroid carcinoma from follicular adenoma.

Calcified nodules of the thyroid gland are frequently encountered and calcification has been reported to be an important factor related to FNA failure (3776). Restriction of free needle movement during FNA may hinder the collection of adequate and accurate cytological specimens from calcified nodules. CNB has a technical failure rate of 1.1% for the collection of tissue from dense calcified thyroid nodules and a non-diagnostic rate of 0.7–7.7% and could prevent unnecessary diagnostic surgery (363753). CNB obtains fewer inconclusive diagnoses than FNA and could minimize the need for diagnostic surgery in patients with calcified thyroid nodules (3653).

Core needle biopsy may be used as an alternative to FNA for calcified thyroid nodules.

The utility of CNB has commonly been highlighted for thyroid nodules with previous non-diagnostic results or atypia (follicular lesion) of undetermined significance in FNA. However, only three studies used CNB as the first-line approach for thyroid nodules. These studies enrolled 31, 369, and 632 thyroid nodules, respectively (475977). As a first-line diagnostic tool, CNB reported a high diagnostic accuracy (97.0–97.7%), low non-diagnostic rate (1.1–3.2%), low rate of false-negative results (0–3.9%), and low complication rate. In addition, Trimboli et al. (59) emphasized the high diagnostic accuracy of CNB compared with FNA (96.8% vs. 78.0%, p < 0.05). Zhang et al. (47) showed that CNB had a high rate of conclusive and accurate diagnosis in thyroid nodules with suspicious US findings. This study achieved a high rate of conclusive CNB results regardless of nodule size, vascularity, and US features. Therefore, CNB could reduce repeat biopsy, diagnostic surgery, and unnecessary follow-up (4777). Suh et al. (77) reported a role for CNB in initially detected thyroid nodules in a large cohort (n = 632). Based on subgroup analysis, they stressed that diagnostic performance was not significantly associated with nodule size and that there were no independent risk factors associated with inconclusive results.

Current evidence suggests that CNB may be considered an effective diagnostic tool for initially detected thyroid nodules, especially for thyroid nodules with suspicious US features (4759). Despite these excellent diagnostic performances, more evidence from large well-designed studies are necessary before CNB can be considered a first-line diagnostic tool because previous studies were performed in specific populations, such as in patients with thyroid nodules with suspicious US features, in single centers, and with retrospective designs. In conclusion, CNB may be used as a first-line diagnostic tool for initially detected thyroid nodules with suspicious US features. However, the evidence is still insufficient.

Core needle biopsy may achieve low rates of non-diagnostic and inconclusive results for initially detected thyroid nodules. However, the utility of CNB as a first-line diagnostic tool for these nodules is uncertain based on current evidence.

Application of CNB to thyroid nodules in children is rare due to the rarity of thyroid nodules in the pediatric population. In addition, most (67.3%) incidentally detected thyroid lesions in children are cysts (78). Only a single institute has reported its experience with CNB (60). This study showed that CNB had relatively high non-diagnostic (13%) and inconclusive (30%) rates. The sensitivity and specificity for malignancy were 88% and 85%, respectively. The results suggested that CNB is comparable to FNA in a similar patient population. CNB has an advantage over FNA in that it can reduce the misinterpretation of parathyroid lesions as follicular neoplasms of the thyroid and decrease the false-positive diagnosis of Hashimoto's thyroiditis that leads to unnecessary thyroidectomies.

Core needle biopsy has been reported to be useful for the specific diagnosis of some malignant thyroid lesions, especially lymphoma, anaplastic carcinoma, and medullary carcinoma (16264379). Both anaplastic thyroid cancer and thyroid lymphoma can be present as rapidly growing thyroid masses in elderly patients (80). Because these tumors have distinct therapeutic strategies and prognoses, they should be accurately differentiated from each other and from other types of thyroid cancers. In a single-center study of 104 patients with anaplastic thyroid cancer and thyroid lymphoma, CNB was suggested to reduce the rate of unnecessary diagnostic surgery by achieving higher diagnostic sensitivity and positive predictive values than FNA. In a large multicenter study of 191 patients with medullary carcinoma, CNB also achieved higher sensitivity and positive predictive values than FNA. Therefore, CNB could be a complementary diagnostic tool to optimize the surgical management of patients with clinically suspected medullary carcinoma (43).

Ultrasound–cytology discordance is a challenge in the management of thyroid nodules. The KSThR previously suggested repeat biopsy for US–cytology discordant nodules (30). Because the risk of malignancy is much higher (20.4–56.6%) for suspicious nodules than those with benign US features (< 3%), a mismatch between US and cytological findings results in a patient being subjected to repeat FNA or even diagnostic surgery (818283). However, benign thyroid nodules, which contain fibrotic and hemorrhagic tissue, can also show suspicious US features in nodules with degenerative changes after FNA/CNB, with intranodular bleeding, or after ethanol and radiofrequency ablation (84858687888990). Degenerative changes can replace the entire thyroid nodule or focal area of nodules (8485). CNB has an excellent diagnostic performance in the management of US–cytology discordant nodules and improves diagnostic confidence via the histologic information obtained from CNB specimens (848590).

Hyalinizing trabecular tumors pose a challenge to diagnosis due to frequent cytological diagnosis of papillary thyroid carcinoma after FNA (919293). Several studies suggested a role for CNB in this rare thyroid tumor (9194). In four cases reported by Choi et al. (91), CNB was a reliable approach to the proper diagnosis of all cases. When CNB does suggest hyalinizing trabecular tumor, an additional immunohistochemical stain such as Ki-67 and cytokeratin 19 can differentiate hyalinizing trabecular tumors from papillary thyroid carcinoma.

(A) CNB can be used as an alternative to FNA in patients with clinical and radiological features of uncommon malignancies (anaplastic carcinoma, lymphoma, or medullary carcinoma).

(B) CNB can be used as an alternative to FNA for thyroid nodules with US–cytology discordance in previous FNA.

In a meta-analysis by Suh et al. (95), both CNB and FNA showed high specificity (99% vs. 100%) for the diagnosis of thyroid malignancy. However, CNB demonstrated a significantly lower pooled proportion of non-diagnostic (5.5%, p < 0.001) and inconclusive (8.0%, p < 0.001) results than FNA (22.6% and 40.2%, respectively) and higher sensitivity (91% vs. 74%, p = 0.053). The area under the curve (0.99 vs. 0.94) was also higher in the CNB studies than in the FNA studies. In addition, the frequency of non-diagnostic CNB results was significantly higher for studies published before 2013 than for those published in 2013 or later (10.9% vs. 0.9%, p < 0.001). This difference was explained by the development of devices and technical advances during recent years.

False-positive results have not been reported in CNB results with Bethesda category 6 and have rarely been reported with Bethesda category 5 (224796). A recent large cohort study (97) of 676 surgically diagnosed cases reported a false-positive rate in malignant CNB diagnosis of 2%. The rate of false-negative results is generally low, ranging from 0 to 3.8% (4172021224577979899). In large cohort studies (each including more than 500 patients), the rates of false-negative results ranged from 1% to 3% (227797). The reasons for the false-negative cases were targeting error, large nodules with heterogeneous component, and cancers with severe calcification and/or fibrosis (18223637). Therefore, to minimize false-negative results from these thyroid nodules, sampling from at least two locations is required.

Regarding the diagnostic accuracy of thyroid malignancy, a meta-analysis by Suh et al. (95) compared the results of 12 CNB studies (2122454756575969859699100) with those of 6 FNA studies (224556575996). The specificities of both CNB and FNA were very high (both 99.5%) but the sensitivity was higher for CNB (74% [95% confidence interval, 67–81%] vs. 50% [95% confidence interval, 44–56%]).

The accurate interpretation of CNB requires good knowledge of both clinical and US findings, and this information should be provided to pathologists on the request form. The request form should include patient identifiers, gender, clinical details, US findings, the biopsy site, and the number of biopsy cores.

The optimal fixation of CNB specimens is paramount. Biopsy cores should be wrapped in saline- or fixative-moistened gauze or filter paper to prevent specimen loss and tissue folding and be placed in 10% neutral buffered formalin solution as soon as possible. The fixative volume should be at least 10 times that of the tissue specimen. The duration of tissue fixation should be between at least 6 and 72 hours at room temperature (117).

Core needle biopsy mostly provides a histological diagnosis to distinguish malignant from benign nodules but it sometimes cannot give a definite diagnosis. A categorical reporting system for CNB helps to ensure effective communication between pathologists and clinicians, with less likelihood of misinterpretation of pathologic results. Thus, the Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group (118) has developed a microscopic reporting system for thyroid CNB based on the six-level reporting categories of the Bethesda System for Reporting Thyroid Cytopathology (54).

The advantage of CNB over FNA is the easy ability to perform immunohistochemical or molecular testing using additional tissue sections of CNB paraffin blocks. A combination of immunohistochemical markers consisting of galectin-3, HBME-1, cytokeratin 19, or CD56 is commonly used for the diagnosis of papillary carcinoma (23121122). Panels including more than one immunostaining marker are more accurate than single markers (121). The BRAF^V600E mutation is the most commonly used molecular test and is highly specific for papillary carcinoma (23). Immunohistochemistry for calcitonin can confirm the diagnosis of medullary carcinoma. Immunohistochemistry is mandatory for the diagnosis of lymphoma and should be performed on any CNB specimen suspicious for lymphoma (48).