INTRODUCTION

Differentiated thyroid carcinomas (DTC) represent one of the most common types of thyroid cancer and are generally associated with favorable outcomes and an excellent prognosis [1-4]. However, a subset of these tumors acquires histologically highgrade features linked to significantly poorer outcomes. These cases have long been inconsistently classified, frequently overlapping with poorly differentiated thyroid carcinoma (PDTC) or being misdiagnosed as anaplastic thyroid carcinoma (ATC). Poor differentiation and high-grade features have emerged as independent prognostic indicators of adverse outcomes in a subset of thyroid carcinomas situated between well-differentiated and anaplastic types [5-7]. After decades of research and clinical refinement, the World Health Organization (WHO) in 2022 introduced these criteria into a newly designated group within the thyroid carcinoma classification, representing tumors with intermediate prognoses [8-10]. This group encompasses PDTC and a newly defined subtype, high-grade differentiated thyroid carcinoma (HGDTC) [6,11,12].

The concept of this aggressive form of follicular cell-derived thyroid carcinoma was first introduced in the early 1980s by Sakamoto et al. [13] and Carcangiu et al. [14], based on its distinctive solid, trabecular, or insular (STI) growth patterns. Two decades later, in 2004, this subset was classified as PDTC in the WHO Classification of Tumors of Endocrine Organs [15]. Shortly thereafter, in 2006, Hiltzik et al. [16] documented a new set of high-grade features, including necrosis and a mitotic count of ≥5 mitoses per 2 mm². In 2007, the Turin criteria for PDTC were established through international collaboration to reduce diagnostic bias. According to these criteria, PDTC is characterized by STI architecture; absence of papillary thyroid carcinoma (PTC)-like nuclei; and the presence of one or more of the following: convoluted nuclei, mitotic count ≥3 per 10 high-power fields, and/or tumor necrosis [17]. Subsequent studies underscored the clinical importance of these high-grade features in otherwise well-differentiated settings, showing an intermediate prognosis similar to PDTC and clear clinical relevance [18-20].

As outlined in the latest WHO Classification of Endocrine and Neuroendocrine Tumors (2022), HGDTC and PDTC are now recognized as distinct entities within the broader category of high-grade follicular cell-derived non-anaplastic thyroid carcinomas. HGDTC is defined by a mitotic count ≥5 per 2 mm² and/or unequivocal tumor necrosis while maintaining the architectural and cytologic characteristics of DTC, including PTC, invasive encapsulated follicular variant of PTC, follicular thyroid carcinoma (FTC), and oncocytic carcinoma of the thyroid (OCA) [12,21]. The diagnostic spectrum of HGDTC is presented in Table 1 [22]. An overview of HGDTC is illustrated in Fig. 1, summarizing essential perspectives for pathologists, surgeons, clinicians/oncologists, and patients.

Both PDTC and HGDTC share overlapping attributes, including aggressive clinical behavior and increased risks of advanced disease and distant metastasis [12,18,19]. Clinically, HGDTC demonstrates intermediate aggressiveness, more adverse than well-differentiated DTC but more favorable than ATC. Nonetheless, biologic heterogeneity driven by invasive phenotype and molecular alterations highlights the importance of a precise, reproducible diagnostic framework to optimize patient care.

This review elaborates on the histopathologic, clinical, and molecular characteristics of HGDTC, emphasizing features critical to its recognition. It also addresses the limitations of current diagnostic criteria and provides a comprehensive discussion of HGDTC and its defining attributes.

DIAGNOSTIC CHALLENGES

Preoperative diagnostic challenges

The accurate preoperative diagnosis of HGDTC remains difficult because it cannot be reliably determined based solely on cytologic features. Fine-needle aspiration (FNA) and even core-needle biopsy (CNB) often fail to capture diagnostic clues due to tumor heterogeneity and sampling limitations. High-grade areas are frequently focal within an otherwise well-differentiated tumor, and biopsies may target only low-grade regions, resulting in underdiagnosis or misclassification [23,24].

Cytologically, most HGDTCs fall within Bethesda categories III–VI but rarely display unequivocal high-grade morphology [23,25]. In a multi-institutional study by Torous et al. [23], only about one-quarter of confirmed HGDTCs showed overt cytologic atypia, increased anisonucleosis, mitotic figures, or necrosis. Degenerative or infarct-like changes can mimic necrosis, further complicating interpretation. Consequently, the sensitivity of cytology for detecting HGDTC is low, and architectural assessment after surgical excision remains essential for definitive classification. In a Swedish cohort study [25], only 29% of surgically confirmed PDTC/HGDTC cases were diagnosed as malignant on FNA, while 50% were classified as atypia of undetermined significance/follicular lesion of undetermined significance or as follicular neoplasm (indeterminate). Small proportions were reported as benign or non-diagnostic, underscoring the difficulty of cytologic recognition even when high-grade disease is present.

Both FNA and CNB provide limited architectural context and may not demonstrate the STI growth patterns required to identify PDTC or distinguish it from HGDTC. Reliable grading therefore necessitates histologic correlation with the entire tumor [21,26].

Molecular or immunohistochemical adjuncts can assist in recognition, particularly through the identification of high-risk molecular profiles such as telomerase reverse transcriptase (TERT) promoter mutations co-occurring with BRAF^V600E or RAS mutations, or by an elevated Ki-67 labeling index (Fig. 2). However, the absence of these features does not exclude HGDTC, and such alterations are not unique to HGDTC—they may also appear in well-differentiated DTC, PDTC, or ATC [27,28]. Thus, preoperative biopsy findings that suggest mitotic activity, necrosis, high Ki-67 index, or the coexistence of high-risk mutations should raise clinical suspicion. Nevertheless, a definitive diagnosis typically requires complete surgical resection for comprehensive histologic evaluation.

Histologic pitfalls

Under-recognition of necrosis

Tumor necrosis is a critical diagnostic and prognostic feature of HGDTC and is consistently associated with adverse outcomes across multiple studies [7,29,30]. It has been described under several terms, including fresh necrosis [16], comedo-type necrosis [21], and true necrosis [31]. Its distribution is heterogeneous, ranging from focal [16,31] and spotty [32] to extensive [16,20,21]. Recent cohorts comprising 164 HGDTC [20] and 18 high-grade PTC, diffuse sclerosing subtype (HGPTC-DS) [33] cases further indicate that focal [20] and comedo-type necrosis [33] are the most frequently observed patterns. Importantly, necrosis carries clinical significance even when focal, as studies show that its extent does not alter prognostic impact [5,34]. Reflecting this, the 2022 WHO classification identifies unequivocal necrosis—regardless of its extent—as a defining feature of HGDTC.

This criterion is particularly relevant in HGPTC-DS, where low mitotic activity may render necrosis the sole qualifying high-grade feature [33]. In one reclassification study, necrosis was identified in 97.6% of 41 HGDTC/PDTC cases, whereas a mitotic count ≥5 per 2 mm² was present in only 36.6% [31]. Although both features are associated with poor outcomes in univariate analyses [29,30], necrosis has demonstrated independent prognostic significance in multivariate models [7,29,35]. These findings emphasize the need for accurate recognition of necrosis in evaluating HGDTC.

However, recognizing true necrosis can be challenging. It may be underdiagnosed in tumors with otherwise differentiated morphology or misinterpreted as ischemic change due to vascular compromise or as a procedural artifact from cautery or FNA (Fig. 3). True tumor necrosis is defined by sharply demarcated areas showing cell membrane rupture, cytoplasmic degeneration, and karyorrhectic nuclear debris with ghost cell outlines, features consistent with neoplastic cell death [21,31,36]. In contrast, ischemic or artifact-related necrosis tends to be irregular and is often accompanied by hemorrhage, granulation tissue, hyalinization, or calcification [21]. Careful distinction between these patterns is therefore essential to avoid diagnostic underestimation.

Misclassification with HGDTC and PDTC

HGDTC and the previously established entity PDTC represent aggressive follicular cell-derived thyroid carcinomas with outcomes intermediate between well-DTC and ATC [37]. By definition, PDTC is diagnosed according to the Turin criteria, which require a STI growth pattern in combination with high-grade features such as necrosis, increased mitotic activity, or convoluted nuclei. In contrast, HGDTC retains the differentiated architectural patterns of follicular-derived carcinomas while exhibiting high-grade features. Although 10-year disease-specific survival (DSS) has been reported to fall as low as 50% in both entities, several studies have shown that disease-free survival and distant metastasis-free survival rates are generally higher in HGDTC compared with PDTC [11,20]. For both tumors, total thyroidectomy remains the standard initial treatment, and neck dissection is typically performed only when clinically or radiographically abnormal lymph nodes are identified [24].

Due to the overlapping morphological features and diagnostic criteria, differentiating between HGDTC and PDTC remains challenging for both pathologists and clinicians. Two key features that help avoid misclassification are nuclear atypia and tumor growth pattern. In HGDTC, nuclear atypia generally resembles that of its differentiated counterpart (PTC or FTC), whereas PDTC more frequently displays a monotonous appearance with less prominent nuclear features, known as convoluted nuclei (Figs. 4, 5) [11]. Furthermore, HGDTC typically retains the architectural characteristics of differentiated carcinoma and lacks the STI arrangement that defines PDTC (Figs. 4, 5). The STI growth pattern has been associated with poor prognosis in earlier studies [37] and can be recognized histologically by sheet-like arrangements of tumor cells (solid), elongated cords with a ribbon- or fence-like appearance (trabecular), or well-defined nests surrounded by fibrovascular stroma (insular) [21]. Although the inclusion of growth pattern in PDTC diagnosis has been debated, the WHO criteria define PDTC as an invasive follicular cell-derived carcinoma that exhibits an STI pattern, even if only focal, lacks PTC-type nuclear features, and shows at least one of the following: convoluted nuclei, mitotic activity ≥3 per 2 mm², or tumor necrosis [16,38]. Accordingly, the requirement for STI architecture in an invasive tumor distinguishes PDTC from HGDTC.

Misclassification with HGDTC/PDTC and ATC

Misclassification between HGDTC and ATC can occur, particularly in high-grade PTC with extensive tumor necrosis or dedifferentiated foci, such as squamoid or solid areas that can mimic squamous carcinoma [33]. Although uncommon, squamous differentiation in PTC has been documented and is often associated with tumor progression, molecular evolution, and poor outcomes [39,40]. However, it is essential not to mistake HGDTC for ATC at presentation, as the two entities differ markedly in both prognosis and management. While aggressive, HGDTC generally has an intermediate clinical course and remains responsive to multimodal therapy, including surgery, external-beam radiotherapy, and chemotherapy [11,20]. In contrast, ATC is among the most lethal human malignancies, with a median survival of only 3–10 months despite intensive multimodal treatment [41-43].

Careful evaluation of growth pattern and nuclear morphology, supplemented by immunohistochemistry, is critical to avoid this diagnostic pitfall. Retained papillary-type nuclear features in HGPTC-DS support a diagnosis of HGDTC, whereas ATC typically exhibits overt pleomorphism and lacks the nuclear features of PTC (Fig. 6) [33]. Immunohistochemistry further aids differentiation: HGDTC usually demonstrates diffuse and strong expression of thyroid lineage markers such as paired box gene (PAX8) and thyroid transcription factor-1 (TTF-1), with variable thyroglobulin staining, whereas ATC often loses expression of these markers, particularly thyroglobulin [33,44,45]. Additionally, squamoid areas in HGDTC may show only focal p40 positivity, in contrast to the diffuse staining pattern typically observed in squamous ATC [45].

Limited mitotic assessment

Elevated mitotic activity is a key diagnostic criterion that helps distinguish HGDTC from other thyroid carcinoma subtypes. A high mitotic count in HGDTC is associated with worse clinical outcomes and a greater risk of recurrence and metastasis [46]. Accurate assessment of mitotic activity in thyroid carcinoma requires careful evaluation limited to viable tumor regions, excluding stromal areas, inflammatory foci, and prior FNA sites. Historically, mitotic counts have been reported as the number of mitoses per high-power field, though this approach is subject to substantial variation in field size among microscopes, even at the same ×400 magnification. The adoption of digital pathology platforms has further introduced variability, increasing the potential for measurement error. To standardize reporting, the WHO now recommends using international (International System of Units [SI]) units, expressing mitotic activity as mitoses per mm², and explicitly documenting the percentage of positive tumor cells quantified in the hotspot across whole-slide images [47].

Although mitotic count has long served as a straightforward measure of proliferative activity, additional biomarkers have proven more practical and reliable, particularly in endocrine neoplasms and digital pathology contexts [48]. Ki-67 expression, which marks cells actively engaged in the proliferative cycle, has emerged as a highly sensitive indicator of cellular proliferation [49]. While mitotic activity generally correlates with Ki-67 labeling, this association is strongest in endocrine and neuroendocrine tumors with low to moderate proliferative rates (Ki-67 index <30%) [48]. Nonetheless, accurate quantification of both mitotic count and Ki-67 index remains affected by variables such as hotspot selection, field size, and threshold definition, regardless of whether manual or artificial intelligence (AI)-assisted techniques are used (Fig. 7).

Phosphorylated histone H3 (PHH3) has been used as a mitotic marker since the early 1990s [50]. Because its expression peaks almost exclusively during the M phase, it serves as a robust indicator of mitotic activity. Incorporating PHH3 immunostaining into the diagnostic panel adds significant value by helping pathologists distinguish true mitotic figures from mimickers such as degenerating or pyknotic cells, thereby improving the precision of mitotic detection (Fig. 7) [48].

Microcarcinoma with high mitotic activity

According to the 2022 WHO criteria, any DTC can be classified as high-grade when either necrosis or a mitotic count of ≥5 mitoses per 2 mm² is present. However, special caution is warranted when applying these criteria to papillary thyroid microcarcinomas (PTMC).

PTMC, defined as PTC measuring <1 cm, is generally regarded as a low-risk tumor with an excellent prognosis [51,52]. Its rising incidence over recent decades has primarily resulted from enhanced diagnostic practices, raising concerns about overdiagnosis and overtreatment [53]. In the absence of adverse features, PTMC typically follows an indolent course, and active surveillance has emerged as a safe alternative to immediate surgery [51]. A recent meta-analysis found that only a small proportion of patients experienced disease progression, with 5-year tumor enlargement >3 mm and new nodal metastasis occurring in 5.3% and 1.6% of cases, respectively [54].

A subset of PTMCs may present with nodal metastasis, which confers a higher risk of disease recurrence [55,56]. Predictors of nodal involvement include angioinvasion, extrathyroidal extension (ETE), the tall-cell subtype, and tumor size >6 mm [57]. Occasionally, PTMCs may display focal elevated mitotic activity or tumor necrosis [58]. Although these high-grade features are sometimes seen in microcarcinomas harboring the BRAF^V600E mutation, only tumor necrosis has shown a statistically significant association with this aggressive alteration [58]. For this reason, most experts caution against automatically upgrading PTMC to high-grade PTC based on mitotic count alone. Instead, pathologists are advised to (1) document the mitotic count in the pathology report; (2) evaluate for corroborating high-risk features such as gross ETE, tumor necrosis, or high-risk molecular alterations (e.g., BRAF^V600E and/or TERT promoter mutation); and (3) avoid overcalling HGDTC in PTMC unless these additional adverse findings are present. This conservative approach minimizes overtreatment while ensuring that genuinely aggressive biology is appropriately recognized.

Special scenario: high-grade diffuse sclerosing PTC

A recent study by Ghossein et al. [33] represents the most extensive clinicopathologic characterization to date of HGPTC-DS, a rare and aggressive neoplasm defined by diffuse sclerosing PTC (PTC-DS) features combined with high-grade characteristics, namely tumor necrosis and/or increased mitotic activity. Although PTC-DS itself is an uncommon but aggressive variant of PTC, the addition of high-grade features further worsens clinical outcomes. Among 18 analyzed cases, mitotic activity was generally low (median 1 mitosis per 2 mm²); however, tumor necrosis was uniformly present. Compared with conventional PTC-DS, HGPTC-DS exhibited more aggressive clinicopathologic features, including higher rates of positive surgical margins (61% vs. 12%), advanced pT3b/pT4 stage disease, gross ETE, larger nodal metastases (median size 2.2 cm vs. 1.3 cm), and a greater nodal burden (median 26 nodes vs. 14 nodes). These characteristics translated into poorer outcomes, with significantly reduced 10-year recurrence-free survival (36% vs. 63%) and regional recurrence-free survival (36% vs. 69%). Nevertheless, overall survival remained relatively favorable (90%), reflecting an intermediate prognosis between PTC and ATC. These findings underscore the importance of distinguishing HGPTC-DS from conventional PTC-DS and ATC. At the molecular level, HGPTC-DS closely parallels PTC-DS, with frequent RET fusions (56%), occasional ALK receptor tyrosine kinase (ALK) fusions (22%), and infrequent BRAF^V600E mutations (11%). These results indicate that, although HGPTC-DS shares oncogenic drivers with PTC-DS, it diverges in clinical behavior due to its high-grade histopathologic features [33].

Diagnostic dilemmas in FTC with high-grade features: PDTC vs. HGFTC

Differentiating between PDTC and high-grade FTC (HGFTC) within the FTC spectrum is particularly challenging. Both entities share overlapping histologic characteristics but differ in diagnostic criteria, prognostic implications, and molecular associations.

PDTC is defined by the Turin criteria: (1) the presence of a STI growth pattern; (2) absence of conventional PTC-type nuclear features; and (3) at least one of the following: convoluted nuclei, mitotic count ≥3 per 2 mm², or tumor necrosis. In contrast, HGFTC retains the cytoarchitectural hallmarks of FTC but qualifies as ‘high-grade’ solely based on a mitotic count ≥5 per 2 mm² and/or unequivocal tumor necrosis.

An important diagnostic dilemma arises because growth architecture does not always correlate with proliferative activity. For instance, an FTC with an STI pattern (meeting Turin architecture) but with low mitotic activity and no necrosis does not satisfy PDTC criteria (Fig. 8). Conversely, an FTC with purely follicular growth yet demonstrating a mitotic count ≥5 per 2 mm² and/or necrosis qualifies as HGFTC. The most challenging scenario occurs when STI and follicular growth patterns coexist within the same FTC (Fig. 8). If the STI component lacks highgrade features while the follicular areas display mitoses or necrosis, the diagnosis should favor HGFTC, as the defining highgrade features are confined to the differentiated component. Conversely, if high-grade features are restricted to the STI areas, the diagnosis fulfills PDTC by Turin criteria.

The greatest diagnostic uncertainty arises when both STI and follicular components exhibit high-grade features. In such cases, the pathologist must balance whether the tumor should be classified as PDTC (emphasizing Turin architecture) or HGFTC (emphasizing high-grade cytology in differentiated areas). Current evidence offers no definitive consensus; thus, careful documentation of the distribution of growth patterns and high-grade features is recommended to guide clinical management.

These considerations underscore that proliferative markers, rather than the architectural pattern alone, determine high-grade status in HGFTC.

PROGNOSTIC ASSESSMENT

Survival outcomes

HGDTCs are associated with significantly worse outcomes than well-differentiated DTCs, a difference consistently attributed to their more aggressive clinicopathologic behavior [7]. Cohort analyses of HGDTC cases show a progressive decline in DSS over time, with pooled data indicating a 5-year DSS of approximately 76.0% [28]. In the series analyzed by Schipor et al. [28], HGDTC demonstrated metastatic disease in 23.2% of cases, cervical lymph node involvement in 42.2%, and ETE in 61.4%. Another institutional cohort found that HGDTCs were more likely than non-HGDTCs to present with larger tumor size, vascular invasion, gross ETE, distant metastasis at diagnosis, and higher stage and American Thyroid Association (ATA) risk classification [7]. These consistently identified high-risk features serve as reliable prognostic indicators, underscoring the need for vigilant postoperative surveillance and, when appropriate, more aggressive therapeutic strategies.

An unresolved question: how much do mitoses vs. necrosis ‘weigh’ in prognosis?

Although both increased mitotic activity and tumor necrosis define high-grade differentiation in thyroid carcinoma, their relative prognostic impact remains debated. Some studies suggest that tumor necrosis exerts a stronger adverse effect than mitotic count alone, reflecting a more biologically aggressive phenotype and correlating with distant metastasis and disease-specific mortality. In contrast, while mitotic activity is an objective and reproducible metric, its prognostic value appears variable—particularly in the absence of necrosis. In multivariate analyses of large cohorts, extensive necrosis and lack of encapsulation have emerged as independent predictors of poor survival, whereas a mitotic count ≥5 per 2 mm² retained limited independent value once necrosis was accounted for [11,20]. Nonetheless, mitotic activity remains clinically meaningful, as it identifies a subset of tumors with elevated proliferative potential even when necrosis is absent. Consequently, the current WHO framework continues to regard both features as equivalent diagnostic criteria for high-grade classification, while acknowledging that necrosis may confer a stronger adverse prognostic influence.

Impact on invasion phenotype

HGDTC represents a heterogeneous entity encompassing multiple subtypes with variable biological behavior. Under the WHO classification, the defining criterion for HGDTC is the presence of high-grade histologic features within an otherwise differentiated carcinoma. However, invasiveness remains a prerequisite for malignancy. A follicular adenoma that demonstrates high-grade features but lacks capsular or vascular invasion should not be diagnosed as HGDTC.

Both angioinvasion and infiltrative growth have long been recognized as hallmarks of aggressive clinical outcomes in DTC [59,60]. These features are integral to distinguishing follicular-patterned carcinomas from indolent entities such as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) [61]. In a retrospective cohort of 252 patients with HGDTC, tumors were stratified into five subgroups based on the degree of angioinvasion and infiltration [26]. Notably, despite harboring high-grade histologic features, the encapsulated noninvasive and minimally invasive subtypes (limited to capsular invasion) displayed an indolent course, with no cases of metastasis at presentation and a 100% 5-year DSS. Similarly, Rivera et al. [32] reported that noninvasive encapsulated HGDTCs did not recur over a median follow-up of 11.9 years, even when extensive tumor necrosis was present. In contrast, encapsulated angioinvasive tumors with focal and extensive vascular invasion demonstrated reduced 5-year DSS rates of 90.4% and 88.1%, respectively. The unencapsulated infiltrative subtype exhibited the most aggressive behavior, with nodal metastasis in 55% of cases, distant metastasis at diagnosis in 25%, and a 5-year DSS of 68% [26].

At the molecular level, HGDTC is similarly diverse, encompassing both BRAF- and RAS-driven tumors that reflect its derivation from PTC, invasive encapsulated follicular variant of PTC, FTC, or OCA [62]. Earlier studies emphasized that most HGDTCs arise from BRAF-mutated PTC [19,40]. More recent evidence, however, has revealed that distinct clinicopathologic subgroups of HGDTC harbor different molecular profiles: infiltrative tumors are typically BRAF-like, whereas encapsulated angioinvasive and minimally invasive tumors are RAS-like, and noninvasive cases often contain dicer 1, ribonuclease III (DICER1) mutations [26,32]. During tumor dedifferentiation, additional genetic alterations—most notably TERT promoter and TP53 mutations—are frequently acquired and contribute to disease progression [63].

Despite these distinctions within HGDTC, experts advise against retaining a diagnosis of NIFTP when high-grade features such as tumor necrosis or elevated mitotic activity are present [64]. Even in an encapsulated, noninvasive lesion, the presence of such features signifies a biological shift away from the indolent behavior typical of NIFTP, thereby justifying reclassification as HGDTC.

Clinical prognosticators

Several clinical characteristics, including patient age, sex, and specific molecular alterations, have been shown to significantly influence the prognosis of HGDTC. HGDTC exhibits a slight female predominance, with a mean age at diagnosis ranging from 45 to 54.8 years [28,46]. Older age (≥55 years) and male sex are associated with poorer DSS outcomes in HGDTC [7,18,46]. This pattern parallels the progression observed in PDTC, HGDTC, and ATC, which often arise through dedifferentiation of pre-existing DTCs. Advancing age promotes the accumulation of sequential molecular alterations accompanied by corresponding histopathologic and clinical changes, leading to high-risk features and an intermediate prognosis in HGDTC [28,65].

Molecular analysis has become an essential tool in prognostication. In HGDTC, the most frequent driver mutations involve BRAF (29.0%) and RAS (31.7%), followed by alterations in TERT (46.6%), TP53 (10.4%), and PTEN (10.0%) [19,20,28]. These genetic changes play pivotal roles in driving disease progression, enhancing metastatic potential, and contributing to unfavorable clinical outcomes [7,20,28,66]. Of particular importance, the coexistence of BRAF and TERT promoter mutations—often termed the ‘genetic duet’—is strongly associated with disease aggressiveness, distant metastasis, and elevated mortality risk in HGDTC [7,20,28,66-69].

The TERT promoter mutation represents the most common secondary alteration, typically detected in a clonal pattern, and is strongly linked to disease progression, particularly in advanced thyroid tumors such as HGDTC and PDTC. Meanwhile, TP53 mutations occur almost exclusively in high-grade thyroid tumors, being identified in 10%–35% of PDTCs and up to 80% of ATCs [67,70]. Their coexistence correlates with worse outcomes, including higher rates of distant metastasis and earlier development of radioiodine refractoriness [71]. Integrating these molecular findings with cytologic features may provide valuable preoperative insight for predicting disease progression to HGDTC and could inform individualized management strategies [23,28,67].

MOLECULAR LANDSCAPE

High-grade transformation in DTC results from the accumulation of early oncogenic drivers and subsequent progression-associated genetic events. Large-scale genomic studies, including The Cancer Genome Atlas (TCGA), have identified oncogenic drivers in over 96% of PTCs, with BRAF^V600E being the most prevalent (60%), followed by RAS mutations, predominantly NRAS (8.5%) and RET gene fusions (6.3%) [72,73]. Less common alterations include mutations in Harvey rat sarcoma viral oncogene homolog (HRAS), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), eukaryotic translation initiation factor 1A X-linked (EIF1AX), phosphatase and tensin homolog (PTEN), TP53, protein phosphatase, Mg²⁺/Mn²⁺ dependent 1D (PPM1D), checkpoint kinase 2 (CHEK2), and AT-rich interaction domain 1B (ARID1B), along with rare gene fusions involving BRAF, peroxisome proliferator activated receptor gamma (PPARG), neurotrophic receptor tyrosine kinase 1 (NTRK1), neurotrophic receptor tyrosine kinase 3 (NTRK3), ALK, and THADA armadillo repeat containing (THADA) [73]. These alterations correlate with distinct histologic subtypes and tumor behaviors [72].

Molecular subtyping based on gene expression profiling has categorized PTCs into BRAF-like and RAS-like groups [72,74]. The latter subtype is generally associated with less aggressive clinical behavior and is enriched for follicular architecture and mutations in genes such as EIF1AX, DICER1, PTEN, isocitrate dehydrogenase (NADP(+)) 1(IDH1), SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1), and speckle type BTB/POZ protein (SPOP), as well as PPARG and THADA fusions [73,74]. In contrast, BRAF^V600E–driven tumors are most frequently seen in classic and tall-cell variants of PTC, characterized by infiltrative growth and a strong tendency for lymph node metastasis [75], whereas RAS-driven tumors are more often linked to follicular-patterned carcinomas and angioinvasive behavior [73]. In FTC, the predominant driver mutations occur in NRAS, HRAS, and KRAS, followed by alterations in DICER1, enhancer of zeste 1 polycomb repressive complex 2 subunit (EZH1), EIF1AX, PTEN, IDH1, and SPOP, as well as PPARG gene fusions [73,74]. In OCA, the most common molecular alterations involve mitochondrial DNA mutations, followed by changes in RAS genes, death domain associated protein (DAXX), EIF1AX, Rho GTPase activating protein 35 (ARHGAP35), APC regulator of Wnt signaling pathway (APC), FAT atypical cadherin 1 (FAT1), and cyclin dependent kinase inhibitor 1A (CDKN1A) [73,76].

A recent systematic analysis of HGDTC demonstrated comparable frequencies of BRAF and RAS driver mutations—approximately 29% and 32%, respectively [20,26,28]. As previously discussed, BRAF^V600E mutations predominantly drive the infiltrative subtype of high-grade follicular-patterned carcinoma, whereas NRAS mutations are more common in encapsulated angioinvasive and minimally invasive variants [26]. In contrast, encapsulated noninvasive tumors most frequently harbor DICER1 mutations as their principal genetic alteration [26]. These findings highlight the molecular heterogeneity and diverse origins of HGDTC.

Transformation from well-differentiated DTC to HGDTC or PDTC represents a multistep evolutionary process in which tumor clones acquire additional genetic and epigenetic alterations that impair differentiation and promote aggressive biological behavior. These alterations involve several key oncogenic pathways and functional gene groups, including activation of the TERT promoter, inactivation of tumor suppressor genes (TP53, PTEN, RB transcriptional corepressor 1 [RB1]), aberrations in the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway, and dysregulation of cell-cycle regulators such as cyclin dependent kinase inhibitor 2A (DKN2A), cyclin dependent kinase inhibitor 2B (CDKN2B), and cyclin E1 (CCNE1). Moreover, genes involved in chromatin remodeling and histone modification—particularly components of the switch/sucrose-non-fermentable (SWI/SNF) nucleosome remodeling complex—are increasingly implicated in this process [67,73,77].

Among these events, TERT promoter mutations are the most common progression-associated alteration, present in nearly 50% of HGDTCs. Other recurrent changes include mutations in TP53, PTEN, and EIF1AX, each occurring in approximately 10% of cases [20,26,28]. Although phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations are relatively uncommon (around 3%), their functional impact is considerable due to the central role of the PI3K/AKT pathway in promoting dedifferentiation and tumor progression [28]. The relatively low frequency of PIK3CA mutations in HGDTCs may partly explain their lower lethality compared with ATCs, which exhibit a higher mutational burden and pronounced genomic instability [28].

Furthermore, although the molecular landscape of HGDTC is predominantly characterized by early driver mutations and progression-associated alterations, one study has reported the presence of actionable kinase fusions in a subset of HGDTCs, particularly within the HGPTC-DS [33]. In this cohort, RET fusions were identified in five cases and striatin (STRN)::ALK fusions in two cases [33]. Actionable kinase fusions refer to genetic rearrangements involving tyrosine kinase genes that result in constitutive activation of downstream signaling pathways, such as the mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR cascades [78]. These alterations are clinically significant because they may be targeted with specific inhibitors, offering potential therapeutic options beyond conventional treatment. In the broader context of PTC, particularly those lacking BRAF^V600E mutations, various kinase gene rearrangements—most notably involving RET, NTRK1/3, and ALK—have been reported. RET rearrangements are found in approximately 30% of pediatric and 9% of adult PTCs [79], while NTRK1/3 fusions occur in roughly 16% and 6%, respectively [80]. ALK rearrangements are rare but occur more frequently in radiation-exposed patients [81,82]. Additionally, these fusions have also been detected in other aggressive thyroid cancer subtypes, with kinase fusions identified in approximately 10%– 14% of PDTC and 3%–5% of ATC [83].

These observations emphasize the growing importance of comprehensive molecular profiling in thyroid cancer, not only for refining histopathologic classification and prognostication but also for identifying patients who may benefit from targeted therapies.

TREATMENT STRATEGIES

The mainstay of treatment for thyroid carcinoma is surgical therapy combined with radiation and systemic therapy, depending on tumor behavior and risk stratification [84,85]. While most DTCs have a good prognosis with surgery alone, PDTC and HGDTC often require a more meticulous and multidisciplinary approach, as distant metastases are commonly present both at early and late stages of disease presentation [6,28,31,86]. These factors influence the extent of surgical intervention and the use of additional adjuvant therapies, such as radiation and systemic treatment. Because the classification of HGDTC is relatively new, treatment-related data remain limited. However, a combination of therapeutic modalities may yield improved outcomes, with some reports suggesting a 5-year survival rate approaching 89%. Current recommendations are derived from prior clinical experience and recent case studies and are tailored individually based on clinical, cytologic, histologic, and molecular findings [87,88].

Treatment strategies for HGDTC per the 2025 ATA guidelines

HGDTC is encompassed within the ATA’s ‘unfavorable histopathologic subtypes’ of follicular cell-derived non-anaplastic thyroid carcinomas, and management follows the high-risk DTC paradigm [84]. Accurate histologic subtyping should be reported explicitly, including identification of ‘high-grade follicular cell-derived non-ATC.’

Initial therapy is surgical. Preoperative diagnosis of HGDTC is uncommon; therefore, the extent of initial surgery is determined according to the principles applied for DTC. When lobectomy is performed and the postoperative histopathologic examination establishes the diagnosis of HGDTC, completion thyroidectomy is generally recommended because the estimated risk of structural recurrence exceeds 30%, corresponding to the high-risk category of ATA recurrence-risk stratification [84].

Postoperative radioactive iodine (RAI) is routinely recommended for ATA high-risk DTC [84]. When RAI is selected for high-risk patients without known distant metastases, the typical administered activity is 3.7–5.55 GBq (100–150 mCi). In patients with distant metastases at diagnosis, RAI after total thyroidectomy is also recommended, with an administered activity of 3.7–7.4 GBq (100–200 mCi) or dosimetry-guided therapy when feasible to optimize therapeutic benefit while minimizing toxicity. For higher activities, especially those exceeding 7.4 GBq (200 mCi), individualized dosimetry is recommended to reduce the risk of adverse effects.

For patients with rising thyroglobulin (or interfering thyroglobulin antibodies [TgAb]) and little or no structural disease on neck ultrasound, ¹⁸F-fluorodeoxyglucose (FDG)–positron emission tomography/computed tomography (PET/CT) can aid in localizing disease. FDG avidity is frequently observed in aggressive histologic subtypes and tends to increase with tumor burden. Stimulation with thyroid-stimulating hormone seldom improves detection and may instead increase the rate of false-positive findings.

Once radioiodine-refractory (RAIR) disease is confirmed, additional empiric RAI therapy is not recommended. Management should instead focus on local control when feasible, including treatment of iodine-avid bone metastases, and initiation of systemic therapy. Before starting systemic therapy for progressive RAIR disease, tissue-based biomarker testing is advised to identify actionable oncogenic drivers. When such drivers are detected, targeted therapy is preferred as first-line treatment: RET fusion- positive tumors should receive a RET inhibitor (e.g., selpercatinib or pralsetinib); NTRK fusion-positive tumors should receive a tropomyosin receptor kinase (TRK) inhibitor (e.g., larotrectinib or entrectinib); and ALK fusion-positive tumors should receive an ALK inhibitor. For patients lacking an actionable driver, or after progression on a driver-directed agent, multikinase inhibitor (MKI) therapy with lenvatinib or sorafenib is recommended. Cabozantinib should be considered as a second-line option following MKI failure or intolerance.

In selected patients with BRAF- or RAS-mutated RAIR disease, redifferentiation through MAPK pathway inhibition can restore iodine avidity and enable effective RAI therapy. Prospective data, including from the Redifferentiation Phase II Trial With Trametinib and Dabrafenib Followed by Radioactive Iodine Administration for Metastatic Radioactive Iodine Refractory Differentiated Thyroid Cancer Patients With a BRAF^V600E Mutation (MERAIODE trial), have demonstrated objective responses following short-course dabrafenib/trametinib (for BRAF-mutant tumors) or trametinib (for RAS-mutant tumors) therapy, followed by RAI administration. At present, the guideline primarily recommends redifferentiation therapy for BRAF-or RAS-mutant tumors [84].

Surgical management

Thorough preoperative evaluation is essential for all thyroid nodules to determine tumor type and disease extent. HGDTC may arise from various types of DTC, including encapsulated and non-encapsulated forms, as well as invasive or infiltrative tumors with or without ETE. Thus, the optimal surgical strategy must be tailored to the biological behavior of each tumor subtype.

A systematic review of HGDTC reported average rates of metastasis at presentation, lymph node involvement, and ETE of 23.81%, 42.23%, and 61.44%, respectively [28]. Therefore, extended total thyroidectomy is often recommended as the initial treatment. Any gross lesions should be resected to achieve complete tumor clearance, as recommended by the ATA. Locoregional involvement may necessitate additional procedures, such as esophageal or unilateral nerve resection, to preserve the central compartment of the neck and prevent life-threatening complications including airway obstruction or hemorrhage [84,86]. Furthermore, surgical intervention may be useful as a palliative measure in cases where the tumor involves the esophagus, trachea, larynx, or recurrent laryngeal nerve [88].

Nodal dissection in HGDTC or PDTC is indicated when biopsy-proven metastases are present and should ideally be performed concurrently with thyroidectomy. The current recommended approach is selective nodal dissection, which preserves adjacent structures such as the sternocleidomastoid muscle, spinal accessory nerve, and internal jugular vein. Although prophylactic neck dissection may be beneficial in undifferentiated carcinoma, no formal recommendation currently exists for high-grade follicular cell-derived thyroid carcinoma [89]. Distant metastases are managed according to their location. The most common sites include the lungs, bones, and mediastinum, though several cases have also reported brain involvement. Bone metastases may be treated by direct surgical resection, which allows accurate staging and informs further management strategies, whereas lung and brain metastases may benefit from adjuvant stereotactic radiosurgery or systemic therapy [28,90,91].

Although rare, encapsulated tumors in HGDTC and PDTC, particularly in the absence of vascular invasion, are generally associated with an excellent prognosis. Surgical management often consists of lobectomy or total thyroidectomy alone, occasionally followed by RAI therapy. Nevertheless, this scenario often presents a dilemma regarding the optimal extent of treatment and the potential risk of inadequate long-term follow-up. Importantly, retrospective studies indicate that a risk of distant metastasis and mortality persists even in encapsulated cases. Therefore, strict postoperative surveillance is warranted [20,32].

Radioiodine therapy

RAI remains a cornerstone in the management of DTC, particularly the papillary and follicular subtypes, due to their inherent ability to concentrate iodine. This selective uptake enables targeted ablation of residual thyroid tissue and metastatic deposits, thereby improving disease control and long-term survival. Its therapeutic efficacy depends on the maintenance of thyroid-specific differentiation features that preserve iodine avidity [86,92,93]. However, RAI therapy is often ineffective in aggressive carcinomas such as PDTC and HGDTC, as BRAF and RAS mutations promote poor differentiation and high-grade features that reduce iodine uptake, resulting in RAIR disease [86,94]. BRAF-mutated thyroid carcinoma demonstrates aberrant MAPK pathway activation, driving dedifferentiation and RAIR through impaired iodide uptake and defective organification. Central to this process is the dysfunction of the sodium/iodide symporter (NIS), a key mediator of active iodide transport in thyroid follicular cells, whose loss leads to diminished thyroid-specific function and the establishment of RAIR [94]. The ATA recommends high-dose ¹³¹I (100–200 mCi) for aggressive thyroid carcinoma without distant metastasis [84].

In a cohort study of 138 post-thyroidectomy patients, Caldeira et al. [46] reported 12 RAIR cases—substantially higher than the annual incidence of 4–5 per million [93]. RAIR is associated with poor prognosis, particularly when distant metastases are present, where 10-year survival drops below 10%. RAI uptake scanning is therefore critical for guiding individualized management [93,94].

RAIR may be identified at the time of initial RAI therapy or later during follow-up, based on absent uptake on diagnostic or post-therapy scans, structural progression within 1–16 months, failure to achieve remission, or high uptake on ¹⁸FDG-PET imaging [93,94]. In metastatic or recurrent RAIR disease, regular laboratory and imaging surveillance is recommended, with local therapies (surgery or external-beam radiotherapy) considered before systemic treatment. While resensitization strategies have shown benefit in DTC [95], evidence in HGFTC remains limited. Once DTC progresses to a RAIR state, management shifts toward systemic therapy options such as MKIs or targeted agents. This shift reflects the loss of iodine avidity, rendering additional RAI therapy ineffective. Systemic therapy for RAIR, as recommended by the ATA, includes tyrosine kinase inhibitors (TKIs), though long-term adherence and tolerability remain major clinical challenges [84,94].

Multimodal integration

Surgery remains the primary treatment for HGDTC, followed by close surveillance to monitor disease progression. RAIR is common, often necessitating individualized management strategies and careful consideration before initiating systemic therapy. Whenever possible, local modalities should precede TKIs to minimize long-term disease burden, medication dependence, and adverse effects [84,86].

For oligo-progressive disease (two to five lesions in one to two organs), the ATA recommends focal treatment, which can improve progression-free survival and overall survival while delaying the need for systemic therapy. Local options include surgery, stereotactic body radiotherapy (SBRT), external beam radiotherapy (EBRT), thermoablation (radiofrequency, laser, cryoablation, microwave), and percutaneous ethanol injection. Surgical resection is preferred for solid metastases (e.g., lung, brain, bone), while EBRT or SBRT is indicated for tumors >4 cm, ETE, lymph node involvement, or incomplete resection [84,86]. Dudzinski et al. [96] demonstrated that SBRT provides excellent local control with low toxicity, although overall survival (P=0.003) and progression-free survival (P=0.007) remain poorer in HGDTC than in DTC.

Close monitoring of clinical signs, biochemical markers, and structural disease persistence after initial surgery with or without RAI is essential. Recurrence may be detected clinically through symptoms or physical examination, biochemically by abnormal serum thyroglobulin levels, and radiologically using ultrasound or axial imaging (CT or magnetic resonance imaging [MRI] with contrast) [97]. Because most HGDTCs are initially managed with total thyroidectomy, serum thyroglobulin measurement 12 weeks post-surgery may aid in evaluating therapeutic response and detecting recurrence [84]. However, no specific guideline currently defines the optimal frequency or duration of postoperative biochemical monitoring in HGDTC. Moreover, these tumors may secrete less thyroglobulin due to dedifferentiation, limiting its reliability for follow-up [86]. Imaging, therefore, plays a crucial role, particularly for common metastatic sites, with ultrasound and CT/MRI with contrast recommended [97]. When lymph node recurrence is suspected, FNA biopsy can be valuable. Additionally, whole-body RAI scans or ¹⁸F-FDG-PET/CT in cases of RAIR can assist in detecting recurrent disease and assessing treatment response following systemic or local therapy for invasive tumors [84].

PRACTICAL RECOMMENDATIONS

In practical thyroid pathology, it is strongly recommended that pathology reports consistently document key histopathologic parameters relevant to HGDTC, including the invasion phenotype, mitotic count per 2 mm², presence of tumor necrosis, status of ETE, vascular invasion, and Ki-67 index. These features are essential for accurate risk stratification and prognostication in thyroid carcinoma. The invasion phenotype, encompassing both the type and extent of invasion, has a well-established association with metastatic potential and clinical outcome [98]. Similarly, ETE and vascular invasion are recognized predictors of aggressive disease and recurrence risk [99]. The Ki-67 index, reflecting proliferative activity, provides additional prognostic information beyond the mitotic count and has been validated as a valuable adjunct in assessing tumor biology [100]. Incorporating these parameters into routine reporting ensures comprehensive evaluation and facilitates evidence-based clinical management. From a diagnostic standpoint, pathology reports should not only describe morphologic characteristics but also integrate molecular findings when applicable. Given that HGDTC and HGPTC-DS exhibit distinct molecular profiles—informative for both biological understanding and therapeutic implications—molecular reflex testing is recommended in all such cases.

Multidisciplinary tumor board discussion is crucial in the management of high-grade tumors, which often exhibit aggressive clinical behavior and resistance to conventional therapy. Early involvement of a tumor board—including pathologists, endocrinologists, surgeons, oncologists, radiologists, and molecular specialists—enables integrated evaluation of histopathologic, molecular, and imaging data, ensuring accurate staging and prognostic assessment. In particular, for tumors demonstrating infiltrative growth or harboring fusion-positive status, case discussion at initial presentation is strongly advised to optimize surgical planning, guide adjuvant treatment decisions, and evaluate eligibility for targeted therapies (e.g., RET or ALK inhibitors), which are most effective when introduced early in the disease course.

FUTURE DIRECTIONS

As HGDTC has only recently been incorporated into the spectrum of thyroid neoplasms, the current WHO classification does not yet fully capture its morphologic and molecular diversity. Future studies are essential to address these gaps, enabling a more precise and nuanced framework that will improve diagnostic accuracy and guide tailored therapeutic strategies. Prospective investigations are warranted to stratify HGDTC by invasion phenotype to refine adjuvant therapy guidelines. Differentiating encapsulated noninvasive or minimally invasive tumors, encapsulated angioinvasive tumors, and infiltrative tumors may provide clinically meaningful insights, as these phenotypes are associated with distinct molecular backgrounds and prognostic behaviors. Infiltrative HGDTCs are typically BRAFlike, whereas encapsulated and angioinvasive tumors are more often RAS-like, and noninvasive cases frequently harbor DICER1 mutations [26]. Recognition of these molecular–morphologic correlations underscores the need for phenotype-driven risk stratification, which may ultimately inform surgical planning, adjuvant therapy selection, and surveillance strategies.

Another important challenge lies in standardizing the definition of necrosis included in the diagnostic criteria for HGDTC. At present, expert opinions differ regarding which types of necrosis should qualify for inclusion, leading to inconsistencies in classification and interobserver variability. Establishing a uniform consensus on the morphologic spectrum of necrosis relevant to HGDTC will be essential to improve diagnostic reproducibility, enable meaningful cross-study comparison, and ensure reliable prognostic stratification. Similarly, assessment of mitotic activity in HGDTC requires greater standardization. Current rigid criteria would benefit from clearer guidance on technical parameters, such as hotspot identification and optimal methodologies for mitotic counting. The implementation of digital pathology tools for mitotic quantification may provide a more objective and reproducible approach, reducing interobserver variation and improving diagnostic consistency across institutions.

Given the poor prognosis associated with HGDTC, clinical trials exploring targeted therapies for RET fusion- and ALK fusion-positive tumors are crucial to improving patient outcomes and expanding the therapeutic landscape.

CONCLUSIONS

HGDTC requires a meticulous diagnostic approach that integrates histopathologic features, invasion patterns, and molecular data to guide prognosis and therapeutic decision-making. Recognizing necrosis-only high-grade presentations, accurately subtyping by invasion phenotype, and incorporating reflex molecular profiling are pivotal to optimizing patient management. For clinicians, adopting a proactive, genotype-informed strategy is essential to effectively manage this heterogeneous but increasingly targetable subset of thyroid carcinomas.

Article information

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

This work was supported by the Commercialization Promotion Agency for R&D Outcomes (COMPA) grant funded by the Korea government (Ministry of Science and ICT) (2710086164).

Fig. 1.

Schematic summary of the clinicopathologic concept of high-grade differentiated thyroid carcinoma (HGDTC) within the tumor category of high-grade follicular cell-derived non-anaplastic thyroid carcinoma, which comprises two subtypes: poorly differentiated thyroid carcinoma (PDTC) and HGDTC. For pathologists, diagnosis requires identifying ≥5 mitoses per 2 mm² and/or tumor necrosis in a carcinoma that retains differentiated morphology, while specifying the lineage: follicular thyroid carcinoma (FTC), papillary thyroid carcinoma (PTC), invasive encapsulated follicular variant of PTC, or oncocytic carcinoma of the thyroid (OCA). Surgeons adhere to the management principles of differentiated thyroid carcinoma (DTC), recommending completion thyroidectomy if HGDTC is confirmed after lobectomy. Clinicians and oncologists treat HGDTC as high-risk DTC according to the American Thyroid Association (ATA) guidelines, incorporating radioactive iodine (RAI) and targeted therapies when appropriate. For patients, HGDTC represents a more aggressive yet treatable form of thyroid cancer that requires comprehensive therapy and close multidisciplinary follow-up. IEFVPTC, invasive encapsulated follicular variant of papillary thyroid carcinoma; FDG-PET, fluorodeoxyglucose positron emission tomography.

Fig. 2.

High-grade differentiated thyroid carcinoma (HGDTC) diagnosed on core-needle biopsy. (A) Ultrasonography shows a 4.6-cm thyroid nodule with a well-defined margin, mixed internal echogenicity, and a focal cystic component. (B) Low-power view of the core biopsy reveals a follicular-patterned tumor morphologically distinct from adjacent normal thyroid tissue (hematoxylin and eosin [H&E] stain, digital zoom 2×). (C) High-power view demonstrates absence of papillary nuclear features and frequent mitoses (arrow); 5 mitoses per 2 mm² were identified in the specimen (H&E stain, digital zoom 80×). (D) Ki-67 immunostaining shows a labeling index of 8%, supporting high proliferative activity consistent with high-grade morphology (immunohistochemical stain, digital zoom 40×).

Fig. 3.

Examples distinguishing true tumor necrosis from ischemic or degenerative changes. (A) Ischemic change accompanied by hemorrhage (hematoxylin and eosin [H&E] stain, digital zoom 20×). (B) Atrophic change in the left half of a follicular-patterned tumor, representing degenerative alteration rather than true necrosis (H&E stain, digital zoom 20×). (C) True comedo-type necrosis in a high-grade follicular thyroid carcinoma, showing ghost cell outlines and karyorrhectic debris (H&E stain, digital zoom 40×). (D) Comedo-type necrosis in a high-grade papillary thyroid carcinoma, representing genuine tumor necrosis (H&E stain, digital zoom 40×). Panels (A) and (B) depict changes that should not be misinterpreted as necrosis, whereas (C) and (D) illustrate definitive examples of tumor necrosis.

Fig. 4.

Examples of poorly differentiated thyroid carcinoma (PDTC) and high-grade differentiated thyroid carcinoma (HGDTC). (A) Lowpower view of PDTC showing a solid–trabecular–insular growth pattern hemorrhage (hematoxylin and eosin [H&E] stain, digital zoom 5×). (B) High-power view showing tumor necrosis and frequent mitoses (arrow) in tumor cells lacking nuclear features of papillary carcinoma, confirming PDTC hemorrhage (H&E stain, digital zoom 40×). (C) Low-power view of a follicular thyroid carcinoma showing preserved follicular architecture with vascular invasion beyond the capsule (H&E stain, digital zoom 2×). (D) High-power view of the same lesion as (C) demonstrates frequent mitoses (arrows) within the follicular cells, supporting a diagnosis of high-grade encapsulated angioinvasive follicular carcinoma (HGDTC) (H&E stain, digital zoom 60×).

Fig. 5.

Examples of high-grade papillary thyroid carcinomas (PTC). (A) High-grade hobnail PTC demonstrating tumor necrosis (N) (hematoxylin and eosin [H&E] stain, digital zoom 20×). (B) High-grade tall-cell PTC showing frequent mitotic figures (arrow) (H&E stain, digital zoom 40×).

Fig. 6.

Dedifferentiation from high-grade papillary thyroid carcinoma (PTC) to anaplastic thyroid carcinoma (ATC). (A) Transition from high-grade PTC (left), retaining papillary-type nuclear features, to anaplastic carcinoma (right) showing loss of differentiation and marked pleomorphism (hematoxylin and eosin [H&E] stain, digital zoom 10×). (B) High-power view of the ATC component, characterized by severe nuclear pleomorphism, prominent nucleoli, and numerous mitotic figures (H&E stain, digital zoom 40×). Even a focal anaplastic component should be documented in the pathology report.

Fig. 7.

Assessment of proliferative activity using Ki-67 and phosphorylated histone H3 (PHH3) in high-grade follicular thyroid carcinoma (FTC). (A) The high-grade FTC shows a microfollicular, highly cellular area with increased mitotic activity (hematoxylin and eosin [H&E] stain, digital zoom 5×). (B) The corresponding area exhibits a high Ki-67 labeling index on immunostaining (immunohistochemical stain, digital zoom 5×). (C) Artificial intelligence (AI)-assisted image analysis was used for accurate Ki-67 quantification, yielding a value of 12% (immunohistochemical stain, digital zoom 40×). (D) PHH3 immunostaining highlights mitotic figures (arrows), confirming regions of active proliferation (immunohistochemical stain, digital zoom 40×).

Fig. 8.

Diagnostic challenge in follicular carcinoma showing both follicular and solid/trabecular patterns. (A) Within the same tumor, the left side shows a well-differentiated follicular pattern, whereas the right side exhibits a poorly differentiated solid/trabecular pattern (hematoxylin and eosin [H&E] stain, digital zoom 2×). (B) High-power view demonstrating follicular architecture in the upper portion and trabecular arrangement in the lower portion (H&E stain, digital zoom 10×). (C) Ki-67 immunostaining shows a higher labeling index in the follicularpatterned area than in the trabecular area, indicating greater proliferative activity in the differentiated component (immunohistochemical stain, digital zoom 10×). If the trabecular component showed high Ki-67 labeling and frequent mitoses, the diagnosis would favor poorly differentiated thyroid carcinoma. However, in this case, the follicular component demonstrates higher proliferative activity, supporting a diagnosis of high-grade follicular thyroid carcinoma (HGFTC). (D) Lymph node metastasis composed exclusively of follicular-patterned tumor further supports classification as HGFTC. This case illustrates that when differentiated and poorly differentiated patterns coexist, diagnostic emphasis should be placed on the region showing the highest proliferative activity (H&E stain, digital zoom 10×).

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