Ultrasonography (US) is a standard tool used to evaluate thyroid nodules at follow-up assessments. These nodules may remain stable or may show changes in size at follow-up (12). Thyroid nodules that have decreased in size are usually benign and have various names, such as degenerating nodules (DNs) (34), collapsing benign cystic nodules (5), mummified thyroid syndrome (67), and vanishing tumors (89). Among these, DNs have been mainly described as benign thyroid nodules (34567101112); however, they are also related to malignant thyroid cancer (913), which can be induced spontaneously or after fine-needle aspiration (FNA) or core-needle biopsy (CNB) (345678910111213).

DNs may sometimes show suspicious US features, which may cause confusion to many doctors despite a reduction in their size. DNs that show a size reduction on follow-up US are identified as benign rather than malignant; however, these nodules may occasionally appear without any previous US findings. Furthermore, DNs frequently show suspicious US features and even FNA may reveal variable cytological results, such as benign findings, atypia of undetermined significance (14), or nondiagnostic results (1516). In such cases with US-cytology discordance (i.e., cytologically benign nodules with suspicious US features), the false-negative rate of FNA is nonnegligible (1718). The incidence of US-cytology discordant nodules is 2.8–19.7% (19), and guidelines recommend repeated US-guided FNA in such cases (202122). One of the main causes of US-cytology discordant nodules is DNs.

The histological findings for DNs show a decrease in or absence of follicular cells and secondary reactive or degenerative changes such as hemorrhage, degeneration, infarction, fibrosis, vascular thrombosis/proliferation, stromal cell proliferation, and squamous metaplasia (10). These changes include worrisome histological features such as cytologic atypia, architectural atypia, and necrosis, which often lead to issues in the cytological interpretation of FNA specimens.

These US-cytology discordant nodules may lead to unnecessary repeated biopsies or diagnostic surgical procedures. Therefore, in this review, we will discuss the mechanism and US-pathology correlations of DNs to improve their differential diagnosis and management strategies.

Studies on the natural history of benign thyroid nodules have shown that cystic or predominantly cystic nodules are more likely to decrease in size than solid nodules (123). In cystic or predominantly cystic thyroid nodules, the cystic portion can be spontaneously absorbed, desiccated, or crumpled over time. In solid nodules, iatrogenic injury by FNA/CNB can cause venous thrombosis and/or internal bleeding, which are mechanisms that potentially lead to nodule degeneration (7101124). Intranodular hemorrhage (spontaneous or FNA-induced hemorrhage) compressing peripheral nodule tissues is believed to be one of the initial mechanisms of DN development (Fig. 1). Hemorrhage usually occurs in thyroid nodules and may be associated with their rich blood supply. The prevalence of hemorrhage within thyroid nodules after biopsy is reportedly between 26.5% and 93.3% (102526), whereas even in patients who do not undergo FNA, the hemorrhage rate is still as high as 33.3% (10). An impaired blood supply due to venous thrombosis and hematoma regression may explain the further shrinkage and infarction that occurs later in the degradation process (7101124).

The considerable variation in the histological changes in DNs makes diagnosis difficult. Surgical specimens of DNs are divided into an acute stage and a chronic stage based on the interval between FNA and surgical excision of the lesion (11). LiVolsi and Merino (11) stressed the importance of histological changes in surgical specimens by proposing the “Worrisome Histologic Alterations Following Fine-Needle Aspiration of the Thyroid” (WHAFFT) syndrome. Symptoms of WHAFFT syndrome include acute changes such as hemorrhage, granulation tissue, mitosis, granulomas, capsular distortion (pseudoinvasion), and infarction and chronic changes such as fibrosis, metaplasia, infarction, cyst formation, papillary degeneration, papillary endothelial proliferation, and calcification (11). Hemorrhage and granulated tissues are the main histological changes observed within 3 weeks after FNA, which is the so-called acute stage. The chronic stage typically begins one month after FNA, during which fibrosis and capsule distortion are the dominant changes (1011).

Biopsy specimens show different gross features in FNA and CNB according to the degeneration stage. In the early stage, hemorrhage appears as a reddish toothpaste-like muddy material on FNA and CNB (Fig. 2). Cytopathological characteristics include numerous degenerated red blood cells, few hemosiderin-laden macrophages, and a few equivocal microcalcifications. In the second stage of hemorrhage regression, CNB specimens show a brown bread-like material containing diffuse stromal fibrosis with chronic inflammation and histiocyte deposition (Fig. 3). Whitish hard material can be seen on the CNB specimen until the chronic stage, at which dense stromal fibrosis with/without calcifications can be observed (Fig. 4). These cases usually show no histological evidence of malignancy, which is key to diagnosing DNs as benign lesions; however, atypical cells occasionally develop, resulting in atypia of undetermined significance on cytopathological assessments. Importantly, in the chronic stage, nondiagnostic results with FNA specimens are common because these specimens contain few follicular cells, and the consistency of DNs becomes harder due to fibrosis.

Most DNs are benign, but they frequently show suspicious US features. An understanding of the mechanism, US findings, pathological findings, and serial changes in DNs can minimize unnecessary procedures for patients. Some US features, including ovoid-to-round shape, ill-defined borders, low-echoic halo, inner isoechoic rim, and posterior shadowing, may help diagnose DNs. Follow-up US should be recommended first in cases showing nodule shrinkage and changes in echotexture and echogenicity on serial US images. For patients whose history is unavailable or whose nodules remain highly suspicious, biopsy should also be recommended. FNA may be the first choice, but DNs tend to present benign results, atypia of undetermined significance, or nondiagnostic results in FNA because of the histological nature of scarce follicular cells and hard fibrosis. Given the above conditions, it would be more useful to perform CNB instead of repeat FNA to avoid unnecessary diagnostic surgery.