Follicular thyroid carcinoma (FTC) is an uncommon well-differentiated malignant tumor accounting for 10% of all thyroid malignancies (1,2). It has been reported to be more common in African American populations than in Asians or Caucasians, with a female predominance (3). Insular thyroid carcinoma (ITC) is another thyroid malignancy that is even rarer, poorly differentiated and accounts for only 0.1 to 6.2% of all thyroid malignancies (4). Although ITC is rare, it represents the main cause of mortality from non-anaplastic follicular cell-derived thyroid cancer, and 20% of patients with ITC present with distant metastasis at the time of diagnosis (5). The observation of ITC arising within the background of FTC is an exceedingly unique occurrence (6).

The present study reports a case of ITC arising within the background of FTC, with a brief review of the literature.

The ITC is a rare and highly aggressive thyroid malignancy that is morphologically and biologically considered an intermediate between fully differentiated and undifferentiated/anaplastic thyroid carcinomas (7). In 1984, Carcangiu et al (8) described ITC for the first time as a poorly differentiated carcinoma. It is termed as insular as it is composed of well-defined nests. However, this pattern may be less prominent, and tubercular or solid patterns are recognized and co-exist (9).

The tumor has frequently been misdiagnosed and often grouped with solid or moderately differentiated tumors, and it has sometimes been mistaken for anaplastic carcinoma (10). In comparison to patients solely with FTC, patients with ITC are older, more often male, have larger tumor sizes, are more likely to experience metastasis, are less likely to have a negative resection margin, and have a significantly lower survival rate (11). Patients with ITC usually complain of the presence of a rapidly growing neck swelling in association with dyspnea, dysphagia and voice hoarseness (12). The case described in the present study was a 52-year-old female with a hard neck mass and normal vocal cords, with no other associated symptoms.

Histologically, ITC is characterized by small uniform carcinoma cells, small follicles containing thyroglobulin and necrotic foci, with a prospect of a peritheliomatous structure formation (10). The aforementioned characteristics were also observed in the histopathological analysis of the case described herein. Necrosis is another obvious finding, with both capsular and vascular invasion (13). However, Harach and Franssila (14) concluded in their study that even though ITC has thyroglobulin secretion, among 5 cases, 2 cases were negative for thyroglobulin. The molecular processes behind the unique insular structure found in thyroid tumors pose a challenge, impeding the comprehension of the factors contributing to their aggressive nature. Recently, research has turned to molecular analysis techniques, such as polymerase chain reaction-single-strand conformation polymorphism analysis, in hopes of unraveling these mechanisms. These efforts have revealed a spectrum of mutations associated with ITC (15). Notably, genetic alterations affecting genes, such as the RAS family (N-ras gene) and p53 gene have been documented (16). Additionally, in poorly differentiated thyroid carcinoma, TERT promoter mutations are frequently observed. Despite this, mutually exclusive mutations in BRAF and RAS remain the prevailing driver mutations in poorly differentiated thyroid carcinoma (17,18). Due to limited resources, genetic tests were not conducted for the case reported in the present study. Almost all stages of FTC are treated with total or near-total thyroidectomy, iodine ablation and thyroid hormone suppression therapy (19). Similarly, aggressive management is recommended for patients with ITC, and the most appropriate treatment is total thyroidectomy followed by radioiodine therapy and close follow-up. These were also performed for the patient described herein. According to the study by Pezzi et al (11), the primary treatment for almost all patients with ITC was surgery undertaken in ~98% of cases, while this number was 95% in FTC cases. A total thyroidectomy was performed for the majority of patients with ITC (79.6%), with a positive margin being found in 32.7% of the resected ITC cases (11). A re-operation for these cases is usually associated with the risk of nerve injury and post-operative hypocalcemia (20).

The ITC is highly aggressive with a high rate of recurrence and distant metastasis, ranging from 36 to 92% (10). The prognosis of patients with FTC is dependent on several factors, such as post-operative residual gross, age, local or distant metastasis, size of the tumor and the pathologic category (21). Even though the effect of ITC on the biological behavior of masses with follicular origin remains unknown (22), studies in the genuine literature (23) still demonstrate that the presence of ITC in fully differentiated FTC is associated with distant metastasis (7,24). Moreover, it has been reported that patients who have tumors with a minor insular component are not evidenced to have a poor prognosis (7).

In conclusion, poorly differentiated ITC emerging from the background of FTC is a very rare incidence that is more aggressive than any other thyroid tumor, and it is usually associated with distant metastasis. The management of choice for these cases is direct total thyroidectomy, followed by radioiodine therapy.