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• Leboulleux S, Bournaud C, Chougnet CN, et al. Thyroidectomy without radioiodine in patients with low-risk thyroid cancer: 5 years of follow-up of the prospective randomised ESTIMABL2 trial. Lancet Diabetes Endocrinol, 2025;13(1):38-46; doi: 10.1016/S2213-8587(24)00276-6. PMID: 39586309.
• Background:
  • Radioiodine (RAI) has historically been used as an adjuvant therapy after total thyroidectomy for differentiated thyroid cancer (DTC) to ablate remnant thyroid tissue and reduce recurrence risk
  • However, for low-risk DTC, characterized by:
    • Tumors ≤ 2 cm without extrathyroidal extension or lymph node or distant metastases:
      • The benefit of routine RAI remains uncertain
  • Recent guidelines, including those from the American Thyroid Association (ATA):
    • Suggest that RAI may be safely omitted in select low-risk cases:
      • But prospective data confirming this approach have been limited
• Methods:
  • This was a multicenter, prospective, randomized, phase 3 study designed to assess whether omitting RAI affects oncologic outcomes in patients with low-risk DTC
  • Eligible patients were 18 to 75 years old, had undergone total thyroidectomy, and had pT1a-pT2N0 / NxM0 disease with no aggressive histologic features
  • Participants were randomly assigned (1:1) to either thyroidectomy alone (no RAI) or thyroidectomy followed by low-dose RAI (1.1 GBq, approximately 30 mCi)
  • Both groups received thyroid stimulating hormone (TSH) suppression therapy according to guidelines
  • The primary outcome was disease-free survival (DFS) at 5 years:
    • Assessed by determination of a structural disease event based on serial neck ultrasonography, a biochemical event based on thyroglobulin (Tg) and Tg antibody monitoring, or a functional event based on posttherapeutic RAI whole-body scanning (WBS)
  • Diagnostic WBS during surveillance was not performed, since it is not considered standard for low-risk DTC
  • Secondary outcomes included recurrence rate, quality of life (QoL), and adverse effects related to RAI
  • Statistical analysis was conducted using an intention-to-treat (ITT) approach, with Kaplan–Meier estimates for DFS and Cox proportional-hazards models for recurrence risk
  • This study aimed to provide high-level evidence guiding de-escalation strategies in low-risk DTC management
• Results:
  • The study included 730 patients with low-risk DTC who were randomly assigned to thyroidectomy alone (n = 365) or thyroidectomy followed by low-dose RAI therapy (1.1 GBq, n = 365)
  • Among 698 patients evaluable at 5 years, the proportions without an event were 93.2% in the no-RAI group and 94.8% in the RAI group, a difference of –1.6% (90% CI, –4.5 to 1.4)
  • Event occurrences were structural or functional abnormalities (n = 11: five in the RAI group and six in the no RAI group) and biologic abnormalities (n = 31; 13 in the RAI group and 18 in the no-RAI group)
  • After randomization and initial treatment (RAI or not), 11 patients in each group underwent a subsequent treatment consisting of additional surgery and / or RAI (¹³¹I) therapy
  • Postoperative serum thyroglobulin level of > 1 ng/ml measured during TSH suppression, patient age between 55 and 60 years, follicular histology, and larger tumor size were predictive of an event
  • The recurrence rate remained low and comparable between groups
  • No significant differences were observed in overall survival, and there were no cases of distant metastases in either group
  • Patients in the no-RAI group reported better QoL scores, with lower rates of fatigue, salivary gland dysfunction, and dry mouth, consistent with prior reports on RAI-related adverse effects
• Conclusions:
  • These findings support a de-escalation strategy in the postoperative management of low-risk DTC, reinforcing that thyroidectomy alone is sufficient in appropriately selected patients
  • This trial provides high-level evidence to guide modern risk-adapted treatment strategies and aligns with evolving guidelines recommending a more conservative approach while maintaining oncologic outcomes and improving QoL scores
• De-escalation trends for low-risk DTC have been suggested and even recommended in guidelines for many years; however, these recommendations lacked the backing of data from sufficiently large randomized controlled trials, which was the aim of this study
• The group published their initial 3-year findings in the New England Journal of Medicine in 2022, showing noninferiority at 3 years of surveillance alone after initial surgical treatment in over 700 randomly assigned patients
• Numerous retrospective studies and systematic reviews have also pointed to the safety of omitting radioiodine ablation for low-risk DTC
• The strengths of the study include its prospective, randomized, multicenter design, which reduces selection bias and enhances the reliability of the data
• The study also had clinically relevant, comprehensive, and patient-centered end points, including its primary end point of disease-free survival, and secondary outcomes, including recurrence rates and, importantly, quality of life
• The inclusion of patients from several centers and adherence to ATA low-risk criteria make the study findings more generalizable and directly applicable in clinical practice
• The study does have several shortcomings:
  • It focuses strictly on low-risk DTC, excluding intermediate-risk patients, thus limiting the ability to extrapolate findings to patients with larger tumors or minimal lymph node involvement
  • Additionally, the study included only T1Nx or T1N0 tumors, which were overwhelmingly of papillary histology, with only 3% follicular and 1% oncocytic, making it difficult to confidently apply the findings to these other thyroid cancer types
  • In our current era, it is also unfortunate that the authors do not report molecular profiles for the tumors that recurred and those that did not
  • Lastly, despite 5 years being a reasonable time frame for follow-up, given the indolent nature of DTC, it is possible that a longer follow-up (10 to 20 years) is needed to confirm sustained low recurrence rates
  • I found most astonishing was to see that patients enrolled in this study routinely underwent total thyroidectomy for T1 disease and that many of these patients also underwent central and even lateral neck dissections for clinically N0 disease
• It is important to have rigorous studies to prove the safety and efficacy of our treatment paradigms
• This study supports reducing overtreatment of low-risk thyroid cancer without compromising patient outcomes and shows improvement in patients’ quality of life with treatment de-escalation
• Key points of the study
  • Omitting RAI does not compromise oncologic outcomes:
    • At 5-years, disease-free survival and recurrence rates were not significantly different between those who received RAI and those who did not
  • Patients in the non-RAI group reported better quality-of-life scores with less fatigue and fewer salivary gland complications
• The ESTIMABL2 trial findings validate de-escalation strategies and align with dynamic risk assessment to identify individualized treatment considering risk-adapted management
• References:
  • Schlumberger M, Leboulleux S, Catargi B, et al. Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results of a randomised, phase 3, equivalence trial. Lancet Diabetes Endocrinol 2018;6(8):618-626.
  • Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26:1-133.
  • Lamartina L, Durante C, Filetti S, Cooper DS. Low-risk differentiated thyroid cancer and radioiodine remnant ablation: a systematic review of the literature. J Clin Endocrinol Metab 2015;100(5):1748-1761.
  • Leboulleux S, Bournaud C, Chougnet CN, et al. Thyroidectomy without radioiodine in patients with low-risk thyroid cancer: 5 years of follow-up of the prospective randomised ESTIMABL2 trial. Lancet Diabetes Endocrinol 2025;13(1):38-46.

• The adult transgender population in the US is estimated to be 0.6% of the population:
  • At least 1.4 million people
• Cross sex hormonal therapy:
  • Is androgen based for people transitioning female to male:
    • This results in decreased breast glandular tissue
    • The pathological histology of the breast tissue:
      • Is similar to a postmenopausal cis female
    • If the breast tissue remains intact, there is the same risk of benign and malignant disease as natal females
• “Top surgery” is:
  • Bilateral subcutaneous mastectomies
  • Chest contouring
  • Repositioning of the nipple areolar complex
• Guidelines for imaging prior to top surgery:
  • Generally follow established guidelines for cis gendered females
• The American Society of Plastic Surgeons recommends:
  • Pre-operative screening:
    • Based on age and risk factors per these existing guidelines
  • For high-risk patients:
    • This may include mammography and MRI
  • For average risk patients under the age of 40:
    • There are no defined guidelines, and this is left to surgeon discretion
• The risk of breast cancer following top surgery:
  • Has been shown to decrease risk when compared to natal female risk or when no top surgery is done
• For Female to Male  (F to M) patients who have not had top surgery:
  • Their risk is based on gender genotype and is same as cis gender women
• The goal of top surgery is chest contouring:
  • Thus, there is residual breast tissue over a standard nipple sparing mastectomy done for risk reduction or oncological purposes
• Top surgery does decrease breast cancer risk:
  • Studies have shown this risk is similar to natal males
  • Because there is likely residual breast tissue, it is imperative that physicians counsel patients about risk and self-awareness
• Testosterone therapy:
  • While theorized to undergo aromatization to estrogen and thus cause increased risk:
    • Has not been shown in this population to increase overall risk of development of breast cancer
• Cross sex hormone therapy:
  • Does not appear to alter breast cancer risk
• Currently screening guidelines from the American College of Radiology state:
  • That for transgender men who have not had top surgery, or had breast reduction only:
    • Guidelines for cisgender females should be followed:
      • Imaging is “not usually appropriate” in transmasculine patients of any age or risk if they had bilateral mastectomies (top surgery):
        • It is important to note that there are no longitudinal studies evaluating the efficacy of screening in this population
• References:
  • Hayward J. Updates in Transgender Breast Imaging. Seminars in Ultrasound  CT and MRI. Published online November 2022. doi:https://doi.org/10.1053/j.sult.2022.10.002
  • Choosing Wisely: An Initiative of the ABIM Foundation. http://www.choosingwisely.org. Accessed September 27, 2023. https://www.choosingwisely.org/wp-content/uploads/2015/02/ASPS-choosing-wisely-list.pdf
  • Meggetto O, Peirson L, Yakubu M, et al. Breast cancer risk and breast screening for trans people: an integration of 3 systematic reviews. CMAJ Open. 2019;7(3):E598-E609. doi:https://doi.org/10.9778/cmajo.20180028
    Gooren LJ, van Trotsenburg MAA, Giltay EJ, van Diest PJ. Breast cancer development in transsexual subjects receiving cross-sex hormone treatment. The journal of sexual medicine. 2013;10(12):3129-3134. doi:https://doi.org/10.1111/jsm.12319
  • Brown A, Lourenco AP, Niell BL, et al. ACR Appropriateness Criteria® Transgender Breast Cancer Screening. Journal of the American College of Radiology. 2021;18(11):S502-S515. doi:https://doi.org/10.1016/j.jacr.2021.09.005
  • Pivo S, Montes J, Schwartz S, et al. Breast Cancer Risk Assessment and Screening in Transgender Patients. Clinical Breast Cancer. 2017;17(5):e225-e227. doi:https://doi.org/10.1016/j.clbc.2016.08.003

👉An emerging quality indicator for breast cancer care is timeliness of care delivery and efficiency, which is a concern for patients as well as for clinicians.

👉Several recent studies have suggested detrimental effects of long delays between breast cancer diagnosis and starting adjuvant therapy.

👉The American College of Surgeons Commission on Cancer has defined receipt of systemic chemotherapy within 120 days of diagnosis of hormone receptor-negative cancer as a quality metric for patients younger than 70 years.

👉The goals of this analysis of data from the National Cancer Database were to examine the effect of surgical treatment type on time to adjuvant chemotherapy and the effect of treatment delay on survival among patients with stage I to III breast cancer treated with both surgery and adjuvant chemotherapy from 2010 to 2014.

👉A delay in starting adjuvant chemotherapy after surgery for breast cancer can adversely affect survival, say US researchers, who found that the type of surgery performed plays a significant role in that delay.

👉In particular, the team found that for women who underwent reconstruction after mastectomy, there was more likely to be a delay before starting adjuvant chemotherapy that was longer than the 120 days currently recommended.

👉This, crucially, could have an effect on survival, they warn, because a delay from diagnosis to chemotherapy of more than 120 days was associated with a 29% reduction in overall survival.

👉The research was published online in the Annals of Surgical Oncology on July 22.

👉Overall, the results were encouraging, in that 89.5% of women who are recommended chemotherapy postoperatively do get it within 120 days of their diagnosis, but there is still room for improvement – Dr. Arrangoiz

👉The authors of the study recommended that hospitals examine whether they can reduce the interval from breast cancer diagnosis to surgical procedure.

👉The delay, could be a result of poor access to care, longer wait times for a second opinion, and the coordination between surgeons needed to organize immediate breast reconstruction.

👉The authors point out not only that timeliness in the delivery of cancer care is a concern for patients and physicians on a subjective level but also that there is “a growing body of data” to suggest it affects outcomes.

👉Although previous studies were inconclusive or found no correlation between the timing of breast cancer care and overall survival, more recent studies have shown that long delays have detrimental effects.

👉This led to a recommendation by the American College of Surgeons’ Commission on Cancer to include the administration of systemic chemotherapy within 120 days of diagnosis as a quality metric for the treatment of some women with breast cancer.

• Transgender males over the age of 40:
  • Whom have not undergone top surgery (chest masculinization surgery):
    • Should be screened similarly to cisgender females and in accordance with current screening guidelines
• There is data to suggest that transgender men who have taken testosterone:
  • May have a decrease in breast cancer incidence:
    • However, the effects of exogenous testosterone on breast cancer risk are less clear, overall
• In transgender males who have not undergone top surgery and are determined to have a lifetime risk of greater than 20%:
  • Current recommendations mirror those for cisgender females:
    • With recommendation to undergo annual breast MRI as an adjunct to annal screening mammography
• References:
  • Irwing MS. Testosterone therapy for transgender men. Lancet Diabetes Endocrinol. 2017; 5(4): 301-311.
  • Gooren LJ. Et al. Breast cancer development in transsexual subjects receiving cross-sex hormone treatment. J Sex Med. 2013; 10 (12): 3129-3134.
  • Brown et al. ACR Appropriateness Criteria Transgender Breast Cancer Screening. JACR. 2021; 18 (11): S502-S515.
  • National Comprehensive Cancer Network (NCCN). Breast Cancer Screening and Diagnosis. V2.2023. BSCR-2. https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf

• The second most common type of thyroid cancer is:
  • Follicular thyroid carcinoma (FTC)
• Fundamentally all follicular carcinomas are:
  • RAS-like tumors
• There profile is different from classic PTC because:
  • They do not have BRAF mutations:
    • Most of them have RAS and RAS-like mutations
• Yoo S.K et al, from Korea showed that the genetic profile of follicular carcinomas:
  • Is very similar to follicular adenomas because they are related tumors
  • Most FTC originate from a FA and eventually break through the capsule and become carcinomas
• In encapsulated follicular variant of PTC:
  • Their molecular profile is much closer to a FA and FTC than to classic PTC
• Infiltrative follicular variant of PTC:
  • Has a molecular profile that is more like classic PTC than FTC
• The biologic difference between follicular pattern RAS-like tumors and classic PTC:
  • Is the infiltrative growth pattern (Figure)
  • The difference between these tumors:
    • Is not only phenotypically based on gross pattern, but also based on biological and clinical differences;
      • Because follicular pattern RAS-like tumors:
        • Retain avidity to radioactive iodine
      • BRAF-like tumors (classic PTC and infiltrative follicular variant of PTC):
        • Have the classic features of PTC
        • They are infiltrative
        • They spread to lymph nodes first and later to distant sites
        • They lose the expression of genes associated with thyroid differentiation
      • RAS-like tumors (FA, FTC, NIFTP, and invasive encapsulated follicular variant of PTC):
        • May or may not have nuclear features of PTC
        • They are encapsulated
        • They spread to distant sites (rarely to lymph nodes)
        • They retain expression of genes associated with thyroid differentiation

• The trans-genomic classification of thyroid cancer, particularly papillary thyroid carcinoma (PTC):
  • Has significant clinical implications, as it enables personalized diagnosis, prognosis, and treatment strategies
• Recent studies have identified molecular subtypes of PTC based on genomic and transcriptomic profiling:
  • Which provide insights into tumor behavior and therapeutic responses
• Key Molecular Subtypes
  • Immune-Enriched Subtype (Subtype 2):
    • High immune infiltration and overexpression of immune checkpoints
    • Potential candidates for immunotherapy.
  • BRAF-Enriched Subtype (Subtype 4):
    • Associated with aggressive features like:
      • Extrathyroidal extension
      • Advanced TNM stages
  • Enriched in MAPK and PI3K / AKT signaling pathways:
    • Suggesting targeted therapy options
  • Stromal Subtype (Subtype 3):
    • High stromal content with distinct microenvironmental features
  • CNV-Enriched Subtype (Subtype 6):
    • Characterized by copy number variations with unique genetic drivers
• Clinical Implications:
  • Prognostic Value:
    • Molecular subtypes correlate with survival outcomes
    • Type 3 subtypes (high-risk):
      • Show poorer progression-free survival compared to Type 1 (low-risk)
  • Therapeutic Guidance:
    • Subtypes like the Immune-Enriched or Ras-like Type 1:
      • May benefit from immunotherapy or radioactive iodine (RAI) therapy, respectively
    • BRAF-mutant subtypes:
      • May require targeted tyrosine kinase inhibitors due to RAI resistance
  • Preoperative Decision-Making:
    • Genomic classifiers applied to fine needle aspirates can help stratify patients for active surveillance or surgery
  • Tailored Treatments:
    • Understanding subtype-specific pathways enables the development of novel therapies, such as EZH2 inhibitors for aggressive subtypes
• This classification system bridges the gap between molecular biology and clinical practice, paving the way for precision medicine in thyroid cancer management

• Differentiated thyroid cancer (DTC):
  • Which includes papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and oncocytic thyroid carcinoma (OTC):
    • Is characterized by specific molecular alterations that affect key signaling pathways:
      • The mitogen‑activated protein kinase (MAPK) pathway
      • Phosphatidylinositol 3 – kinase – protein kinase B (PI3K-AKT) pathway 
• Key Genetic Alterations:
  • Papillary Thyroid Carcinoma (PTC):
    • BRAF Mutations:
      • Found in 45% to 75% (29% to 83%) of PTCs, particularly the BRAF V600E mutation (62% if the cases):
        • Which activates the MAPK pathway:
      • It is associated with aggressive features like extrathyroidal extension and advanced stage
    • RET / PTC Rearrangements:
      • Present in 10% to 20% (2.5% to 73%) of PTCs
      • These fusions also activate the MAPK pathway
    • RAS Mutations:
      • Occur in ~10% to 15% of PTCs:
        • Often in follicular-variant PTC
    • TERT Promoter Mutations:
      • Found in advanced cases
      • They are often co-mutated with BRAF V600E:
        • Indicating worse prognosis
  • Follicular Thyroid Carcinoma (FTC):
    • RAS Mutations:
      • Predominantly found (~30% to 50%)
      • Driving tumorigenesis via the MAPK and PI3K / AKT pathways
    • PAX8 / PPARγ Rearrangements:
      • Seen in ~30%
      • These are unique to FTC and are mutually exclusive with RAS mutations
  • Other Mutations Across DTC:
    • NTRK 1/3 Fusions:
      • Rare (~1% to 3%) but significant in some PTCs
    • PI3K / AKT Pathway Alterations:
      • Common in advanced or dedifferentiated cases
• Molecular Subtypes of PTC:
  • Recent studies have identified four molecular subtypes based on transcriptomic and genomic profiling:
    • Immune-Enriched Subtype (Subtype 2):
      • Characterized by:
        • High immune infiltration
        • Overexpression of immune checkpoints
    • BRAF-Enriched Subtype (Subtype 4):
      • Associated with:
        • BRAF mutations
        • Advanced TNM stage
        • Aggressive behavior
    • Stromal Subtype (Subtype 3):
      • Features high stromal content and distinct gene expression
    • CNV-Enriched Subtype (Subtype 6):
      • Defined by somatic copy number variations
• Pathway Dysregulation:
  • MAPK Pathway:
    • Activated by:
      • BRAF, RAS (intracellular signal
        transducers)
      • RET /PTC and NTRK 1/3 mutations (cell-membrane receptor tyrosine kinases:
        • Leading to increased tumor proliferation
  • PI3K / AKT Pathway:
    • Frequently altered in FTC and advanced DTC:
      • Contributing to tumor growth and survival
  • TSHR cAMP Pathway:
    • Altered in FTC through mutations like:
      • TSHR or GNAS
• Prognostic Implications:
  • Co-occurrence of BRAF V600E and TERT promoter mutations significantly worsens outcomes
  • Molecular profiling aids in risk stratification, guiding treatment decisions such as targeted therapies
• Therapeutic Implications:
  • Targetable alterations include:
    • BRAF inhibitors for BRAF-mutant tumors
    • RET inhibitors for RET fusion-positive cancers
    • Immune checkpoint inhibitors for immune-enriched subtypes
  • Molecular understanding of DTC provides a foundation for personalized treatment approaches and improved prognostication

• The COMET (Comparing an Operation to Monitoring, with or without Endocrine Therapy) trial:
  • A randomized clinical trial, investigated whether active monitoring is non-inferior to standard treatment (surgery with or without radiation) for low-risk DCIS (ductal carcinoma in situ):
    • Finding that active monitoring is a viable option
• Study Purpose:
  • The COMET trial aimed to determine if active monitoring, which involves close surveillance with surgery only if DCIS progresses to invasive cancer:
    • Is as effective as the standard treatment of surgery (lumpectomy or mastectomy) with or without radiation and / or hormone therapy for women with low-risk DCIS
• Study Design:
  • The COMET trial was a randomized controlled trial, meaning participants were randomly assigned to:
    • Either active monitoring or guideline-concordant care (surgery with or without radiation)
• Eligibility:
  • The study included women aged 40 and older with low-risk DCIS:
    • Defined as grade 1 or 2, hormone receptor-positive, HER2-negative, with no signs of invasive cancer, and the diagnosis confirmed by at least two pathologists
• Key Findings:
  • After 24 months of follow-up:
    • The two-year cumulative rate of invasive ipsilateral breast cancer was 5.9% in the guideline-concordant care arm and 4.2% in the active monitoring arm:
      • The difference met the threshold for noninferiority:
        • Meaning that neither treatment was deemed inferior to the other
• Implications:
  • The results suggest that active monitoring is a valid alternative to surgery for women with low-risk DCIS, potentially reducing overtreatment and improving quality of life
• Patient-Reported Outcomes:
  • The study also found that overall health-related quality of life remained stable from baseline to 2 years and did not differ significantly between the two treatment arms
• Funding:
  • The COMET study was funded by the Patient-Centered Outcomes Research Institute (PCORI), the Breast Cancer Research Foundation (BCRF), and other organizations
• Study Location:
  • The study was conducted across multiple sites in the United States

• Clinically, the term ‘goiter’ relates to an enlarged thyroid gland:
  • A finding that is associated with various neoplastic and non-neoplastic disorders
• Goiter often presents as:
  • A nodular and rarely as a diffuse process
• Most agree that the terms ‘colloid nodules,’ ‘multinodular goiter,’ ‘adenomatous goiter’ and ‘multinodular hyperplasia’:
  • Often used by pathologists are not reflective of the underlying pathology besides the mere confirmation of clinical findings
  • Molecular analyses of individual nodules
    in such cases have revealed that a good proportion of goitrous nodules is:
    • Monoclonal and represents neoplastic
      proliferations:
      • Making it impossible to distinguish between non-neoplastic and benign neoplastic follicular neoplasms i.e. adenomas on the basis of morphology alone (Mete & Asa 2012)
  • In addition, most of the adenomatous nodules
    encountered in patients with DICER1, PTEN and PTEN-like syndromes (Harrer et al. 1998a,b, Derwahl & Studer 2002):
    • Also represent multiple follicular adenomas (Wasserman et al. 2018, Cameselle-Teijeiro et al. 2021):
      • Therefore, an umbrella term of ‘follicular nodular disease’ (FND):
        • Has been proposed in the latest WHO classification, to avoid the above-mentioned issues (Baloch et al. 2022)
• In the 2017 WHO classification scheme of thyroid
  neoplasms:
  • Follicular adenoma was the only entity
    included in the benign follicular cell-derived tumors:
    • However, in the fifth edition, ‘follicular adenoma with papillary architecture’ (previously termed as papillary adenomatous / hyperplastic nodule) is also included in the benign neoplasm category
  • Follicular adenoma with papillary architecture:
    • Is a well-demarcated and non-invasive, often encapsulated tumor with intra-follicular centripetal papillary growth, and the lesional cells lack nuclear features of papillary thyroid carcinoma (PTC) (Mete & Asa 2012, Baloch et al. 2022)
    • These tumors are often associated with autonomous hyperfunction:
      • May therefore appear as hot or warm nodules on radionuclide thyroid scan (Mete & Asa 2012)
    • Molecular analyses have shown that these are driven by:
      • TSHR, GNAS or EZH1 mutations and alterations that activate the protein kinase
        A (PKA) pathway (Parma et al. 1993, Gozu et al. 2010)
    • These tumors may also occur in the setting of McCune–Albright and Carney complex syndromes:
      • Both are PKA pathway-related conditions driven by GNAS and PRKAR1A mutations, respectively (Kamilaris et al. 2019, Nosé et al. 2022)
    • Moreover, non-functional follicular adenomas with papillary architecture:
      • Can harbor DICER1 mutations, and a subset of these have been reported in association with DICER1 syndrome (Wasserman et al. 2018, Cameselle-Teijeiro et al. 2021, Juhlin et al. 2021):
        • Thus, the association between thyroid function and related tumor syndromes
          makes the distinction between these tumors clinically significant
    • Furthermore, a diagnosis of oncocytic
      follicular adenoma:
      • Requires >75% of tumor cells to exhibit oncocytic features (Baloch et al. 2022)
      • Overall, oncocytic thyroid tumors represent a distinct entity of thyroid neoplasms, supported by specific genetic aberrations
        including:
        • Mitochondrial DNA mutations and increased copy number alterations (Gopal et al. 2018, Doerfler et al.
          2021, McFadden & Sadow 2021)

• As mentioned previously follicular tumors:
  • Develop through a multistep process where they can be identified via cytopathology at different stages in their development
• These does not occur in BRAF-like tumors:
  • Where they develop from the early stages as microcarcinomas
• The problem is that in clinical practice we want the tumors to be classified in a binary distribution (benign or malignant):
  • Which is very difficult because of the multistep process of their development
• Noninvasive follicular thyroid neoplasm with papillary nuclear features (NIFTP):
  • Has partially resolved this problem (NIFTP would be a seen in the later stages of this multistep process)
• The diagnostic features of NIFTP include:
  • Follicular architecture
  • Nuclear features of PTC
  • Formation of a capsule with lack of invasion
• This entity was previously known as
  encapsulated follicular variant of papillary carcinoma
• The histologic criteria of NIFTP are depicted in
  Table.

• NIFTP should be viewed as a borderline malignant tumor (equivalent to carcinoma in situ):
  • If no invasion is identified on the final pathology:
    • The risk of recurrence is very low:
      • Less than 1%
• This lesion still requires surgical resection by a minimalistic approach usually is sufficient (thyroid lobectomy)
• The molecular characteristics of NIFTP include:
  • RAS and RAS-like mutations:
    • BRAF V600E and TERT mutations:
      • Should not be identified in this lesion
• NIFTP is considered a precursor lesion for:
  • Invasive encapsulated follicular variant of PTC (EFVPTC)
• The introduction of NIFTP did not resolve the uncertainty in the pathological diagnosis of PTC:
  • A study from four different institutions (Memorial Sloan Kettering Cancer Center
    – MSKCC, Moffit Cancer Center – MCC, Cedar Sinai Medical Center in Los Angeles – CSMC, Mount Sinai Health System in New York – MSHS) with RAS-positive thyroid nodules by Marcardis et al:
    • Identified a wide variation in the prevalence of NIFTP in resected indeterminate thyroid nodules across several institutions:
      • Ranging from 5% to 46%
    • At MSKCC:
      • The most common overall and non-malignant diagnosis in RAS-mutated
        nodules was:
        • NIFTP
    • This was significantly greater than the NIFTP rate at the other three institutions:
      • Where the most common overall and benign diagnosis was follicular adenoma / nodular hyperplasia
    • Significant variations in the rates NIFTP (5% to 13%) and follicular adenoma / nodular
      hyperplasia (63% to 85%) in the other three institutions (MCC, CSMC, MSHS) also occurred
    • This reflects the same issue that some thyroid nodules may be identified at stages in their development where the nuclear features
      of PTC are clearly absent, some at stages where the nuclear features are clearly present, while others can be
      identified at different stages in the development of the nuclear features of PTC (in some of these stages the nuclear features of PTC are not fully expressed):
      • Depending on where the pathologist draws the line in this continuum more or less thyroid nodules, will be called cancers or NIFTP, leading to the difficulty in making a
        diagnosis (Figure)