The diagnosis and management of small and indeterminate lymph nodes in papillary thyroid cancer: preoperatively and intraoperatively

Abstract

Although thyroid cancer is an indolent tumor with a favorable prognosis, lymph node metastasis (LNM) serves as a major concern for many patients. Because LNM is strongly correlated with recurrence, distant metastasis, and shortened survival, a precise and timely diagnosis and following appropriate management for LNM are necessary. However, significant challenges still exist in the diagnosis of small LNs (<1 cm in diameter), and their low volume makes it difficult to determine whether they are metastatic or benign. Therefore, the diagnostic technique for these small and indeterminate LNs (siLNs) has been one of the leading research subjects in recent years. The implementation of innovative technologies, such as contrast-enhanced ultrasonography, frozen section, and molecular detection, has brought great progress to the diagnosis of siLNs. Meanwhile, the strategies for managing siLNs in clinical practice have evolved considerably over the past several years, with several appropriate options recommended by guidelines. In this review, we aim to provide a systematic overview of the latest studies and potential evidence about effective approaches for detecting and evaluating siLNs. Furthermore, the following management modalities of siLNs in different situations are well discussed.

Keywords: diagnosis; lymph node metastasis; management; small and indeterminate lymph nodes; thyroid cancer.

Figure 1

Conventional ultrasound and contrast-enhanced ultrasound image characteristics of LNs. On conventional ultrasound, ultrasonic malignant manifestations generally includes hypo-echogenicity, absence of hilum, microcalcification, increased vascularity, cystic change and round shape. Thyroid imaging reporting and data system (TIRADS) scores each thyroid nodule and differentiate benign and malignant based on the presence of these signs. Among them, the calcification exhibits a relatively higher degree of malignant potential. In contrast-enhanced ultrasound, heterogeneous enhancement, nonenhancement, and centripetal perfusion are the main manifestations of malignant LNs, while homogeneous enhancement, ring enhancement, and centrifugal perfusion are the main manifestations of benign LNs.

Figure 2

Operational pattern of SLNB for detecting the siLNs of PTC patients. The sentinel lymph nodes are identified by injecting appropriate LN dyes. The colored LNs are extracted from the suspect compartment and sent to frozen section, while the uncolored LNs are temporarily retained. If the frozen pathology results are negative, it is feasible to dispense with further dissection and preserve the remaining portion of the LNs. If positive, whole-level LND is indicated, which may be accompanied by potential surgical complications (e.g., vocal cord paralysis induced by recurrent laryngeal nerve injury). siLNs, small and indeterminate lymph nodes; SLNB, sentinel lymph node biopsy; PTC, papillary thyroid cancer; LN, lymph node; LND, lymph node dissection.

Figure 3

Mechanistic diagram of potential detection techniques for siLNs. (A) Mannose was disulfide bonded with the near-infrared dye IR780 to form a Mannose-IR780 conjugate (MR780), which was further self-assembled into quenched fluorescence nanoprobes. The ligand Mannose exhibited specific affinity for the CD206 molecule, which is a highly expressed receptor on the TAM surface. When CD206 is selectively targeted, the disulfide bond is cleaved under the influence of the microenvironment (including GSH), thus achieving fluorescence molecular imaging of micrometastasis through interactions between specific dyes and molecules. (B) The ErNPs were modified by balixafortidea, a peptide antagonist of the chemokine receptor CXCR4, to assemble the fluorescence probe ErNPs@POL6326. The probes could be efficiently drained into LNs when given subcutaneously to infiltrating metastatic breast tumor cells via CXCR4-related endocytosis. A significant difference in fluorescence signals was observed between metastatic LNs and nonmetastatic LNs. TAM, M2 tumor-associated macrophage; GSH, glutathione; TC, thyroid cancer; PTC, papillary thyroid cancer.

Figure 4

FS-assisted surgical decision-making in the management of lateral cervical siLNs. If there were any siLNs in compartment IV, the patients were first subjected to single compartment dissection at level IV. The following removal scope was determined based on the results of FS analysis. If there was no metastasis, the current degree of lymphadenectomy was sufficient. If metastasis was proven, levels II-III or III dissection was suggested according to whether the patient underwent SND or SSND, respectively. FS, frozen section; siLNs, small and indeterminate lymph node; SND, selective neck dissection; SSND, superselective dissection.

Figure 5

A schematic diagram throughout the entire process of diagnosing and managing siLNs.