Pathologic basis of the sonographic differences between thyroid cancer and noninvasive follicular thyroid neoplasm with papillary-like nuclear features

Abstract

Ultrasonography is pivotal in triage thyroid biopsy in the era after the identification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This pictorial essay illustrates the pathologic basis of the sonographic features that distinguish NIFTP from thyroid cancers. In this study, we present the correlations of ultrasonography to ×1 histopathology to assess shape and margin characteristics. Markedly hypoechoic nodules correlate to microfollicular/solid nodules, while isoechoic/hyperechoic thyroid nodules correlate to normofollicular/macrofollicular nodules. The ultrasound findings of NIFTP and minimally invasive encapsulated thyroid cancers are similar. Both are well-circumscribed, oval-to-round nodules with regular margins. Blurred or microlobulated margins indicate infiltrating tumors, while lobulated margins are characteristic of expansile tumors. Overtly invasive encapsulated tumors are characterized by oval-to-round nodules with irregular or lobulated margins. The ultrasound findings for infiltrative thyroid cancers show at least one of the following malignant features: marked hypoechoicity, taller-than-wide shape, microcalcifications, and blurred or microlobulated margins.

Keywords: Follicular variant of papillary thyroid carcinoma; Noninvasive follicular thyroid neoplasm with papillary-like nuclear features; Thyroid biopsy; Thyroid fine needle aspiration cytology; Thyroid histopathology; Thyroid neoplasms; Thyroid ultrasound.

Fig. 1.. Microfollicular noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (A-C) versus encapsulated macrofollicular Hürthle cell carcinoma with microscopic capsular invasion (D-F).

A-C. The top case is from a 49-year-old woman with a 1.5-cm right upper thyroid nodule. A. Ultrasonography shows a well-circumscribed, oval-to-round, markedly hypoechoic nodule (inset, Papanicolaou, ×600; microfollicles with mixed normal and papillary-like oval and clear nuclei aspirated). Fine needle aspiration (FNA): cannot exclude follicular variant of papillary thyroid carcinoma (Bethesda V/VI). B. Hemithyroidectomy shows an oval-round blue nodule with a thick capsule (H&E, ×1). The thick capsule was invisible on ultrasonography, because the echogenicity of the capsule and the tumor were both markedly hypoechoic. Notice that the black outlines of the cells in the insets disappear in the black background. C. The blue nodule was composed of microfollicles (left) and the cells had grooved, oval papillary-like nuclei with mild chromatin clearing (right). No evidence for invasion on thorough sampling and no increased mitotic figures or necrosis were present, so the final diagnosis was NIFTP (left, H&E, ×100; right, H&E, ×400). D-F. The bottom case is from a 62-year-old woman with a 1.4-cm right middle thyroid nodule. D. Ultrasonography shows a well-circumscribed, oval-to-round, hypoechoic nodule outlined by a markedly hypoechoic rim (inset, Papanicolaou, ×600; Hürthle cells with abundant granular cytoplasm containing non-papillary nuclei [round, granular chromatin, prominent nucleoli] along with abundant thin colloid aspirated). FNA: Hürthle cell nodule (Bethesda III/VI). E. Histopathology shows a pink oval-to-round nodule with multifocal microscopic capsular invasion (arrow points to one) undetectable by ultrasound (H&E, ×1). F. Colloid-filled macrofollicular nodule (left) composed of Hürthle cells with abundant granular cytoplasm with non-papillary nuclei (round with prominent nucleoli) (right); the final diagnosis was minimally invasive Hürthle cell carcinoma (left, H&E, ×100; right, H&E, ×400).

Fig. 2.. Normofollicular noninvasive follicular thyroid neoplasm with papillary-like nuclear features (A-C) versus poorly differentiated thyroid carcinoma (D-F).

A-C. The top case is from a 68-year-old woman with a 2.7-cm right lobe thyroid nodule. A. Ultrasonography shows an oval, isoechoic, homogeneous nodule with regular margins and hypoechoic rim (inset, Papanicolaou, ×600; oval clear nuclei with grooves [arrows] aspirated). Fine needle aspiration (FNA): suspicious for follicular variant of papillary thyroid carcinoma (Bethesda V/VI). B. Hemithyroidectomy shows an encapsulated, oval, pink nodule and the capsule correlated to the hypoechoic rim on ultrasonography (H&E, ×1). C. The nodule was pink because it was composed of normal-sized follicles filled with pink colloid. Notice the thin capsule at left upper corner. The papillary-like nuclei were oval, grooved, and clear (left, H&E, ×100; right, H&E, ×400). D-F. The bottom case is from a 63-year-old woman with a 1.7-cm left lobe thyroid nodule. D. Ultrasonography shows a markedly hypoechoic nodule with lobulated margins and coarse rim calcification (blue arrow) (top inset, the markedly hypoechoic nodule had a taller-than-wide shape on transverse view; bottom inset, Papanicolaou, ×600; aspirated cells with small round nuclei). FNA: suspicious for thyroid carcinoma (Bethesda V/VI). E. Histopathology shows an encapsulated blue nodule with expansile growth forming lobulated margins. The blue arrow points to coarse calcifications along a thick capsule. The black arrows point to capsular invasions (H&E, ×1). F. The nodule was blue due to the high nuclear density from the solid tumor nests. Similar to on FNA, the tumor has small, round nuclei (H&E, ×400).

Fig. 3.. Macrofollicular noninvasive follicular thyroid neoplasm with papillary-like nuclear features with cysts (A-D) versus minimally invasive follicular thyroid carcinoma with sharp demarcated microfollicular and macrofollicular components (E-H).

A-D. The top case was from a 37-year-old woman with a 3-cm right lobe thyroid nodule. A. An oval, isoechoic nodule was outlined by a thin hypoechoic rim on ultrasonography. The composition of the nodule was ~85% solid and ~15% cysts. Color Doppler ultrasonography shows mainly peripheral vascularity. Abundant thin colloid and sheets of epithelium with oval grooved papillary-like nuclei (inset, Papanicolaou, ×600) were aspirated. Fine needle aspiration (FNA): suspicious for macro-follicular variant of papillary thyroid carcinoma (Bethesda V/VI). B. Hemithyroidectomy shows a circumscribed solid cystic pink nodule with similar intensity of pinkness as the surrounding thyroid, correlating to the isoechoic nodule with a thin rim on ultrasonography (H&E, ×1). C. The macrofollicular nodule had a thin capsule (arrow) (H&E, ×20). D. The papillary-like nuclei along the colloid lake were elongated, grooved, and clear (H&E, ×400). E-H. The bottom case was from a 38-year-old woman with a 4.5-cm hypervascular nodule replacing the left lobe. E. A well-circumscribed hyperechoic nodule with hypoechoic rim contained sharply demarcated hypoechoic regions (inset, Papanicolaou, ×600; microfollicles with small, round, and dark nuclei aspirated from the hypoechoic region). FNA: follicular neoplasm (Bethesda IV/VI). F. Hemithyroidectomy shows a blue-pink two-toned nodule with a thick capsule (H&E, ×1). G. Sharply demarcated microfollicular region was present (H&E, ×20) (Inset, ×20; a single focus of capsular invasion was found in 12 sections on microscopic examination). H. Both the macrofollicular region (left) and microfollicular region (right) had small, round, and granular non-papillary nuclei (H&E, ×400).

Fig. 4.. Normofollicular noninvasive follicular thyroid neoplasm with papillary-like nuclear features (A-D) versus microfollicular follicular thyroid carcinoma with overt capsular invasions (E-H).

A-D. The case is from a 56-year-old man with a 1.6-cm right lower thyroid nodule. A. A round, isoechoic nodule is outlined by a hypoechoic rim on ultrasonography. Enlarged, oval, grooved, papillary-like nuclei (inset, Papanicolaou, ×600), along with 90% normal nuclei were present in the aspirate. Fine needle aspiration (FNA): cannot exclude follicular variant of papillary thyroid carcinoma (Bethesda V/VI). B. Hemithyroidectomy shows an encapsulated blue nodule with minute pink dots and lines. Neither capsular nor vascular invasions were found on thorough sampling and examination (H&E, ×1). C. The nodule was composed of mixed large and small follicles (H&E, ×40). D. The papillary-like nuclei were enlarged, oval, and grooved. The chromatin was dark, but powdery (H&E, ×400). E-H. The case bottom case is from a 27-year-old woman with a 3.3-cm right mid-lower nodule. E. An oval, homogeneous hypoechoic nodule with irregular borders is outlined by a hypoechoic rim on ultrasonography (inset, Papanicolaou, ×600; microfollicles with small, round, and granular non-papillary nuclei were aspirated). FNA: suspicious for thyroid carcinoma (Bethesda V/VI). F. The cut surface shows a bulging fleshy tan encapsulated (arrow) tumor with irregular margins. G. Thick capsule with overt capsular invasions and four microscopic angioinvasions (inset, ×100) were present (H&E, ×20). H. Microfollicular tumor with small, round, and granular non-papillary nuclei was present (H&E, ×400).

Fig. 5.. Mixed microfollicular versus normofollicular noninvasive follicular thyroid neoplasm with papillary-like nuclear features (A-D) and infiltrative follicular variant of papillary thyroid carcinoma (FVPTC) with irregular borders and microcalcifications (E-H).

A-D. The top case is from a 37-year-old woman with a 1.5-cm right mid-lower thyroid nodule. A. Oval, solid, hypoechoic (top third) and isoechoic (bottom two-thirds) nodule, outlined by a hypoechoic rim that was visible only along the isoechoic region was found on ultrasonography (inset, Papanicolaou, ×600; microfollicles with enlarged, oval, papillary-like nuclei aspirated). Fine needle aspiration (FNA): suspicious for FVPTC (Bethesda V/VI). B. Hemithyroidectomy shows a thinly encapsulated blue nodule with minute pink dots and lines. No invasion was found on microscopic examination (H&E, ×1). C. The nodule had both microfollicular (left) and normofollicular areas (right) (H&E, ×100). D. The papillary-like nuclei with clear oval nuclei were present in both the microfollicular (left) and normofollicular (right) regions (H&E, ×400). E-H. The bottom case is from a 25-year-old woman with a 0.8-cm right middle thyroid nodule. E. A markedly hypoechoic nodule with microcalcifications, echogenic center, and microlobulated margins was found on ultrasonography. Specks of calcifications and microfollicles with enlarged, oval, papillary-like nuclei with powdery chromatin were aspirated (insets, Papanicolaou, ×600). FNA: FVPTC (Bethesda VI/VI). F. Histopathology shows a blue nodule with a pink center and fussy margins (H&E, ×1). G. Tumor microfollicles infiltrated into surrounding pink colloid-containing normal thyroid. The arrow points to the residual calcifications surrounded by 3 holes, from microcalcifications that popped out during sectioning of the paraffin block (H&E, ×40). H. The pink center of the nodule is due to a fibrotic reaction to the infiltrating microfollicles (left); the blue region of the nodule had high nuclear density due to back-to-back microfollicles with enlarged, oval, papillary-like nuclei with powdery chromatin (right) (H&E, ×400).