Papillary thyroid carcinoma (PTC) is the most frequent thyroid cancer, accounting for 80% to 85% of all thyroid cancers.1 Papillary thyroid carcinoma has many histological variants, up to 50% of all PTCs.2 It includes several well-known subtypes, such as the follicular, tall cell, diffuse sclerosis, and solid variants.3 Furthermore, a single discrete focus of PTC arising within an otherwise benign encapsulated follicular nodule, which is classified as a PTC arising within a follicular adenoma (FA) (PTCFA), as supported by molecular alterations, is another subtype.4–6 However, PTCFA is a very unusual histologically defined subtype of PTC, accounting for less than 1% of all PTC cases reviewed over a 10-year period at 2 large academic medical institutions.4 There have been few pathological reports regarding PTCFA.4–6 Although it is clinically significant because it is a malignant entity, ultrasonographic features have not been described to date. Here, we report a rare case of PTCFA that was evaluated using ultrasonography (US), and a core biopsy was performed because of the possibility of follicular neoplasm. This case underwent a right hemithyroidectomy, and PTCFA was confirmed. Although PTCFA is a recognized histopathological entity, no US findings of this rare type have been published. This report describes this unusual entity and provides awareness of possible considerations when encountering a complex solid nodule during US examination.
A 26-year-old man underwent thyroid US for a known thyroid nodule in the right lobe. According to the patient, the thyroid nodule was first detected 3 years earlier at another hospital, and he had not experienced any discomfort associated with the nodule. Otherwise, he had no notable medical history.
On physical examination, no specific abnormality was detected, and there was no evidence of symptoms indicative of hypothyroidism or hyperthyroidism. Thyroid function tests, performed by radioimmunoassay, revealed a high thyroglobulin level (62.57 ng/mL; normal range, 0–35 ng/mL), TSH of 1.13 uIU/mL (normal range, 0.25–4.0 uIU/mL), FT4 of 1.44 ng/dL (normal range, 0.89–1.78 ng/dL), thyroglobulin antibodies of 0.01 U/mL (normal range, 0–0.3), and microsomal antibodies of 0.02 U/mL (normal range, 0–0.3). Ultrasound showed an oval solid nodule with heterogeneous echogenicity in the right lower pole of the thyroid gland (2.2 × 1.8 × 2.8 cm, 5.88 mL). Most of the nodule was isoechogenic, but there was a markedly hypoechoic focus (1.0 × 0.6 × 0.9 cm) within the nodule. It showed a hypoechoic rim around the nodule with suspicious focal disruption (Fig. 1, A and B). Color Doppler images revealed markedly increased vascularity in the hypoechoic area (Fig. 1C). There were no metastatic lymph nodes. A US-guided core biopsy was performed in the isoechoic area (Fig. 1D). The specimen showed several cores of a fibrous capsule and compact microfollicles with the colloid material. A follicular neoplasm was considered more likely than nodular hyperplasia.
The patient underwent a right hemithyroidectomy. Macroscopically, the cut surface of the right thyroid showed a 2 × 2-cm, well-circumscribed, encapsulated gray tan mass with a focal whitish solid area (Fig. 2A). Histologically, the nodule was composed of thyroid follicles and a thin fibrous capsule, which favored FA, and a focal area of irregular follicular architecture lined by tumor cells with enlarged nuclei, chromatin clearing, an irregular nuclear membrane, and rare nuclear grooves, consistent with a papillary carcinoma (Fig. 2B). Immunohistochemical staining for CK19 and galectin 3 demonstrated negative results in the FA and strong positivity in the papillary carcinoma area, supporting the diagnosis of a PTCFA (Fig. 2, C and D). The follow-up thyroglobulin level was normalized to a value of 2.96 ng/mL. The patient was discharged and received hormone therapy for TSH suppression. He had no evidence of recurrence or metastasis after 4 years.
Papillary thyroid carcinoma arising within a FA represents a clinically significant, rare, histologically defined subset of PTC in which an otherwise benign-appearing, circumscribed follicular nodule contains a single discrete focus of PTC. This presentation of PTC is very unusual, less than 1% of all PTCs.4 Unlike the nuclei within the surrounding benign-appearing adenomatous nodule of PTCFA cases, nuclei within the discrete focus exhibit unequivocal nuclear features of PTC. Some cases can be challenging, even in histological specimens, and may require special immunohistochemical stains, such as galectin-3, keratin 19, or HBME-1 for characterization. Although PTCFA is a clinically significant but rare histopathological entity, its ultrasonographic features have not been described previously. There have only been histopathological reports regarding PTCFA.4–6
In fine-needle aspiration (FNA) biopsy (FNAB), PTCFA is often interpreted as “atypia of undetermined significance/follicular lesion of undetermined significance” (AUS/FLUS).4 Even in a retrospective review of cytomorphological features, PTCFAs had no intranuclear pseudoinclusions and a papillary architecture in 85% to 88% of cases, making it difficult to recognize these tumors cytologically as “malignant” by FNAB. The category of AUS/FLUS encompasses a group of cases that are not definitively benign but lack the cytological features to warrant a diagnosis of “follicular neoplasm” or “suspicious for malignancy.” Papillary thyroid carcinoma arising within an FA will have variable admixtures of cells with features of both PTC and a benign thyroid nodule and may not fully meet the criteria for a cytological diagnosis of either entity. Fine-needle aspiration biopsy results for PTCFA are not definitively diagnosed cytologically as PTC in most cases.4 The recommended management for an initial AUS/FLUS interpretation is clinical correlation and a repeat FNAB at appropriate intervals in most cases.7–9 However, PTCFA is one subtype of PTC that requires more careful management, such as a lobectomy.
In this case, US showed a mixed echogenic solid nodule, in which the majority of the nodules revealed isoechogenicity, indicating a benign nodule, with only a small markedly hypoechogenic focus in the periphery. The markedly hypoechogenic focus and increased vascularity were compatible with PTC on pathology. The isoechoic portion with a peripheral rim was compatible with FA. This case raises the question of the interpretation of a mixed echogenic solid nodule on US. The echogenicity of the nodule was described as hyperechogenic, isoechogenic, or hypoechogenic, compared with the thyroid gland, or as markedly hypoechogenic, compared with the adjacent strap muscle on US. Generally, the echogenicity of the dominant solid components is used in the classification of mixed solid nodules. Ha et al10 reported that the majority of nodules showing a focal marked hypoechogenicity within an isoechoic nodule are benign, whereas 13.8% of those nodules are malignant. The malignant nodules include PTC, PTC within nodular hyperplasia, and PTC adhering to the surface of adjacent nodular hyperplasia. In their study, a peripheral location of a focal markedly hypoechogenic focus had a strong correlation with malignancy.10 Therefore, when a mixed solid nodule containing a focal marked hypoechogenicity is detected on US, its malignant potential should be considered according to the location of the hypoechogenicity.
Knowledge of PTCFA, a rare type of thyroid tumor, and the malignant potential of this unusual US feature is important when aspirating thyroid nodules. Fine-needle aspiration biopsy has been established as the screening method of choice in the initial evaluation of a thyroid nodule, and use of the recently proposed Bethesda System for Reporting Thyroid Cytopathology guidelines has helped to provide a more uniform classification system.9 One of the limitations of FNAB is that the reliability of the results depends on adequate sampling of the lesion. The diagnostic accuracy of thyroid FNAB is affected by nodule heterogeneity, as was demonstrated in a study evaluating false-negative cytological PTC specimens.11 Similarly, nodule heterogeneity and sampling are likely to play an important role in the detection of PTCFA cases, in which only a single focus of a larger benign-appearing nodule indicates PTCFA. One would predict that the size of the PTC within a benign nodule would influence the rate of a “malignant” diagnosis as a subset of PTCFA. It is possible that application of molecular markers could have a role in identifying PTCFA cases within FNAB.5–12 In cytology samples, the use of molecular markers to aid the general classification of AUS/FLUS cases has shown some success.12,13 In prospective studies that compared FNA with a core biopsy, the diagnostic yield with a core biopsy exceeded that with a FNA biopsy by approximately 10%.14 Although FNA is the initial evaluation modality chosen for thyroid nodules with high sensitivity, in some cases, it does not collect sufficient diagnostic material, even with repeated attempts. In comparison, a core biopsy provides a large core of tissue, which can be more helpful for making surgical decisions than FNA.15 Thus, during FNAB of mixed echogenic solid nodules, targeting of the hypoechogenic solid focus, alternative core biopsy, or additional molecular analyses should be considered. The most common surgical management will initially be a lobectomy, and clinical decision making will dictate which of these cases, based on nodule size and other patient risk factors, will require a complete thyroidectomy.
In conclusion, PTCFA represents a rare subset of PTC exhibiting overlap with a benign thyroid nodule and conventional PTC on US that corresponds to the histopathology. Papillary thyroid carcinoma arising within a FA should be considered in the diagnosis when a suspicious markedly hypoechogenic focus is seen in a mixed echogenic nodule, especially with a peripheral location, on thyroid US. Therefore, we recommend that FNA targeting the hypoechogenic focus or a core biopsy rather than FNA is needed for a mixed echogenic nodule, even if the suspicious features are only minor. Additional molecular analyses should be considered. Understanding unusual suspicious ultrasonographic findings could be helpful in detecting PTCFA and provide adequate management in place of follow-up US. Thus, further larger cohort studies are required to evaluate mixed echogenic indeterminate thyroid nodules properly.
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