June 2019 - Presented by Dr. Guofeng Gao (Mentored by Dr. Anthony Karnezis)


The tumor resembles these 3 entities (PTC, HTT and NIFTP) best by architectural, cytological and IHC features, and has nuclear features of PTC that were seen on the FNA.


The above case, because of the predominantly trabecular architecture and a markedly hyalinized stroma, resembles HTT (hyalinizing trabecular tumor). HTT is a rare distinct thyroid neoplasm of presumed follicular cell origin with characteristic histologic features of non-invasive and non-metastasising encapsulated thyroid tumors (trabecular growth pattern, prominent intertrabecular stromal hyalinization, abundant eosinophilic cytoplasm, abundant nuclear grooves and intranuclear cytoplasmic pseudoinclusions). The concept of HTT as a benign lesion originated from in 1987 Carney et al, which was adopted by the second edition of the WHO classification of thyroid tumors as “Hyalinizing trabecular adenoma” and later, due to some reports of rare cases showing malignant behavior (including metastases, vascular invasion or invasive growth pattern), was renamed to “hyalinizing trabecular tumor” in the recent WHO classification and placed in a separate category of tumors with low malignant potential. Very recently, HTT is proposed to rename as ‘‘GLIS-rearranged hyalinizing trabecular adenoma.’’, due a report demonstrating highly prevalent GLIS rearrangements (particularly PAX8–GLIS3) in HTT but not in PTC.

Grossly, HTT is usually a single, solid, well circumscribed, encapsulated or non-encapsulated lesion with homogeneous and delicately lobulated cut surfaces. Histologically, at low-power magnification, HTT displays typical trabecular architecture with prominent hyalinized stroma (inter-trabecular and/or intra-trabecular) that closely resembles amyloid. At medium-power magnification, the neoplastic cells are medium to large sized, columnar, polygonal or fusiform, and arranged in trabeculae supported by a delicate fibrovascular stroma. At high-power magnification, the neoplastic cells have abundant finely granular amphophilic, eosinophilic or clear cytoplasm, and nuclei showing irregular nuclear contours, prominent nuclear grooves and intranuclear cytoplasmic pseudoinclusions. Scant or absent calcifications/psammoma bodies may be observed. Immunohistochemically, besides its similarity to NIFTP, HTT tumor cells display a distinctive cell membrane and cytoplasmic positivity for Ki-67 (using clone MIB-1), which has been reported in nearly all cases of HTT when the reaction is performed at room temperature and utilized as a useful diagnostic tool. However, the tumor cells of this case only display rare weak nuclear staining of Ki67 and absence of cytoplasmic or cell membrane Ki-67 positivity (repeated and confirmed by consultation institution), which is unusual for this diagnosis, and HBME1 staining performed at consultant institution suggests PTC-like gene expression; therefore, this case is highly unlikely an HTT.


Papillary thyroid carcinoma (PTC) is the most common cancer of the thyroid, and its diagnosis is based the classic nuclear features of PTC: irregular nuclear contours, prominent nuclear grooves and intranuclear cytoplasmic pseudoinclusions. There are two most common subtypes of PTC: classic PTC and the follicular variant (FVPTC). The classic PTC diagnosis is based on the presence of papillary architecture, while the FVPTC diagnosis is based on follicular growth pattern. There are two major subtypes of FVPTC: infiltrative and encapsulated/well demarcated. When encapsulated FVPTC (EFVPTC) is invasive, it behaves like follicular carcinoma (pushing invasion into the thick tumor capsule and/or vascular invasion). It is the noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) that is renamed to Non-Invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP).

PTC is usually associated with good survival. However, some PTC variants (like tall cell variant) may behave more aggressively. BRAFV600E and/oror TERT promoter mutations are often found in aggressive variant of PTC. The solid/trabecular PTC variant also display worse behavior and has similar histologic features: solid, trabecular, or nested (insular) appearance, thus making it problematic to differentiate from this case because of its hyalinizing stroma and trabecular growth pattern. The polygonal to tall tumor cells with abundant eosinophilic cytoplasm of this case also focally resembles the tall cell variant of PTC. However, the solid/trabecular variant of PTC has all or nearly all of a solid, trabecular, or nested (insular) appearance. In contrast, the tumor of this case does not display all (100%) or nearly all solid, trabecular noninvasive growth pattern, and the trabecular pattern of this tumor with the tumor cells (polygonal, tall or columnar) perpendicular to the orientation of the trabeculae, is more characteristic of HTT rather than solid/trabecular PTC variant. Although the HBME1 staining performed at consultant institution suggests PTC-like gene expression, but its expression is weak and focal, not supporting PTC, either.


NIFTP (Non-Invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features) was recently renamed by a multidisciplinary team of thyroid pathologists, endocrinologists and an endocrine surgeon from "noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC)", due to multiple reports of the excellent prognosis of the encapsulated/well-delimited tumors of FVPTC without vascular and capsular invasion after complete resection, even when treated only with lobectomy. Thus, the nature of the lesion is altered, NIFTP is no longer classified as ‘carcinoma’, therefore, tumor staging (e.g., TNM/AJCC) is not necessary and not need to submit to guidelines for differentiated thyroid carcinoma. The change from EFVPTC to NIFTP is endorsed by the World Health Organization (WHO) in the 4th edition of the classification of endocrine tumors.

The diagnosis of NIFTP has these required essential features: encapsulated or circumscribed neoplasm from adjacent thyroid parenchyma, follicular growth pattern and nuclear features of PTC; no solid or trabecular growth, no papillae; no vascular or capsular invasion and no tumor necrosis or high mitotic activity. Therefore, the diagnosis of NIFTP can only be made after complete resection of the tumor and complete evaluation of the entire tumor capsule interface to exclude capsular invasion on the surgical excision specimen. Microscopically, at low-power magnification, there is obvious fibrous capsule (thick, thin, perhaps partial), or the tumor may be well circumscribed and clearly demarcated from adjacent thyroid tissue; and there is obviously follicular growth pattern (microfollicular, macrofollicular or normofollicular) with abundant colloid. At high-power magnification, the neoplastic cells display the nuclear features of classic PTC. No psammoma bodies observed. Recent molecular profiling of such tumors has demonstrated that they closely resemble follicular neoplasm of the thyroid (follicular adenoma or carcinoma), while infiltrative FVPTC is closely related to classic PTC. Molecular tests are helpful but not required for NIFTP diagnosis. However, NIFTP diagnosis can be excluded if BRAFV600E or TERT promoter mutations are identified in the tumor, as well as distant metastasis and morphological characteristics of any other PTC variant (like tall cell variant) or oncocytic lesion. The presence of nuclear features of PTC are shared among NIFTP, different variants of PTC and hyalinizing trabecular tumor of the thyroid (HTT), which sometimes make it difficult or impossible to distinguish NIFTP from different variants of PTC and HTT, particularly in fine needle aspiration materials. Although the above tumor is an encapsulated neoplasm with classic PTC nuclear features, its predominantly trabecular architecture and prominent hyalinized stroma preclude the diagnosis of NIFTP.

Technically the above tumor does not completely fit the diagnostic criteria for neither the 3 entities (PTC, HTT and NIFTP) and does not neatly correspond to an established entity; however, this tumor has some features of PTC, HTT and NIFTP: it’s encapsulated; it has very low Ki67 labeling; it has prominent HTT-like morphology; and it has PTC-like cytology and IHC. Taken together, these features suggest this tumor is a benign tumor with HTT morphology, PTC/HTT nuclear features, and PTC-like IHC. Therefore, the specific trabecular pattern of HTT, which is basically a benign/very low malignant potential tumor, suggests this tumor is NIFTP-like - encapsulated, PTC-like differentiation (i.e. HBME1), very low Ki67 – but with HTT-like architectural features.

A differential diagnosis histologically is medullary thyroid carcinoma (MTC), because of the circumscribed growth pattern, the markedly hyalinized inter-trabecular and intra-trabecular stroma amorphous material that can closely resemble amyloid, the variable nuclear expression of Ki-67 and the nuclear expression of TTF-1. However, the medium sized round or elongated tumor cells of MTC are negative for thyroglobulin expression and positive for neuroendocrine markers (chromogranin and synaptophysin) and calcitonin express, and the amyloid material in MTC is only weakly PAS-positive and is Congo red positive (exhibiting apple green birefringence when viewed under cross polarized light).

Another histologic differential diagnosis is paraganglioma, which is very rare in thyroid but can display strikingly similar morphology. However, its expression of chromogranin, synaptophysin and other neuroendocrine markers can help the differential diagnosis. IHC can easily help the differential diagnosis.

The poorly differentiated thyroid carcinoma (a solid aggressive variant of PTC), should be kept in the differential diagnoses, because it can have similar growth pattern but has high-grade histology features. Poorly differentiated thyroid carcinoma can coexist with other histological types of thyroid cancer, and its diagnostic features include carcinoma of follicular cell origin, over 50% solid/trabecular/insular growth of the tumor area, absence of PTC nuclear features, and dedifferentiated convoluted nuclear features, tumor necrosis or over 3 mitotic figures per 10 high‐power fields.


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