Differentiated thyroid carcinomas are malignant tumors derived from thyroid follicular cells that retain, to varying degrees, structural and functional characteristics of normal thyroid tissue. The term differentiated indicates that the tumor cells preserve at least part of the follicular biological program, including thyroglobulin production, expression of the thyroid-stimulating hormone (TSH) receptor, the ability to take up iodine through the sodium iodide symporter (NIS), and complete or partial sensitivity to radioactive iodine. This preservation is not uniform: some neoplasms remain highly differentiated and indolent, whereas others become invasive, lose iodine uptake, metastasize, or progress toward more aggressive phenotypes.
This group mainly includes papillary thyroid carcinoma, follicular thyroid carcinoma, and oncocytic thyroid carcinoma. These tumors share a follicular origin but differ in morphology, genetics, diagnostic approach, patterns of spread, and clinical risk. Papillary carcinoma is defined primarily by its nuclear features and often spreads through lymphatic vessels; follicular carcinoma requires demonstration of capsular or vascular invasion and tends to spread hematogenously; oncocytic carcinoma is distinguished by mitochondrial accumulation, oncocytic cytology, and a variable risk of radioiodine-refractoriness.
Differentiated thyroid carcinoma is the most common form of malignant thyroid tumor and accounts for the predominant proportion of thyroid carcinomas. The increase in incidence observed over recent decades is largely attributable to the wider use of neck ultrasonography, the identification of small nodules, and the detection of subclinical carcinomas, whereas mortality has remained much lower than the rise in diagnoses. This epidemiological finding must not lead to underestimation: most patients have a favorable prognosis, but a minority develop locoregional recurrence, distant metastases, persistent disease, or loss of thyroid differentiation.
The modern classification of thyroid carcinomas derived from follicular cells is not limited to the microscopic appearance of the tumor but integrates architecture, nuclear cytology, invasion, grade, molecular profile, and clinical behavior. The concept of follicular origin indicates that the tumor arises from the epithelium responsible for thyroid hormone synthesis, although neoplastic progression may follow different pathways. A transformed follicular cell may acquire the nuclear phenotype of papillary carcinoma, form an invasive follicular neoplasm, become oncocytic through mitochondrial accumulation, or progressively lose differentiated features in high-grade forms.
Papillary carcinoma is the prototype of differentiated thyroid neoplasms that can often be diagnosed cytologically. Its cells display characteristic nuclear alterations, including enlargement, clearing, grooves, pseudoinclusions, and overlapping, which frequently allow a preoperative diagnosis by fine-needle aspiration. Papillary architecture may be evident, but it is not essential in every variant because the definition depends primarily on the nuclear profile. Its clinical behavior is dominated by frequent cervical lymphatic spread, multifocality, and a broad prognostic spectrum ranging from indolent microcarcinoma to aggressive variants.
Follicular carcinoma has a different diagnostic identity. The tumor cells form follicular structures and may appear cytologically similar to those of a follicular adenoma; malignancy is established only when capsular invasion and/or vascular invasion is demonstrated. Fine-needle aspiration can therefore identify a follicular neoplasm but cannot definitively confirm carcinoma in the absence of metastases or evident invasion. The central biological feature is angioinvasion, because entry into blood vessels explains the tendency toward hematogenous spread to the lungs and bones.
Oncocytic carcinoma, historically known as Hürthle cell carcinoma, is now regarded as a distinct category. It is composed predominantly of oncocytic cells rich in mitochondria, with granular eosinophilic cytoplasm, and requires demonstration of invasion or metastases to be classified as carcinoma. Oncocytic change alone does not indicate malignancy because oncocytic cells may also occur in thyroiditis, hyperplastic nodules, and adenomas. Oncocytic carcinoma is clinically relevant because it combines mitochondrial biology, potentially reduced iodine uptake, metastatic risk, and the need for follow-up tailored to the degree of invasion.
Thyroid differentiation is not a fixed attribute. A tumor may initially be well differentiated and subsequently acquire alterations that reduce the expression of thyroglobulin, the TSH receptor, NIS, thyroid peroxidase (TPO), and other thyroid-specific genes. When this occurs, the disease may become less responsive to radioactive iodine, more visible on fluorodeoxyglucose positron emission tomography (FDG-PET), and more difficult to control with thyroid-selective treatments. Loss of the follicular program is therefore the transition that links molecular biology, imaging, and prognosis.
Differentiated carcinomas constitute the great majority of malignant thyroid tumors. Papillary carcinoma is by far the most common, whereas follicular carcinoma and oncocytic carcinoma are less frequent but clinically important because they have a greater propensity for hematogenous spread than classic papillary carcinoma. Their frequency varies according to age, sex, geographic region, iodine intake, intensity of ultrasonographic screening, and histological criteria. The higher incidence among women is consistent, but prognostic risk increases with advanced age, large tumors, macroscopic invasion, distant metastases, and loss of differentiation.
Exposure to ionizing radiation, especially during childhood, is the most firmly established environmental etiological factor for differentiated thyroid carcinomas, with a particularly clear association with papillary carcinoma. Radiation causes DNA breaks, chromosomal rearrangements, and clonal selection in biologically active thyroid tissue. Risk depends on dose, age at exposure, latency period, and tissue susceptibility. A history of neck radiotherapy, environmental exposure, or nuclear accidents must therefore be investigated systematically when evaluating a suspicious nodule because it changes the pretest probability and the threshold for clinical concern.
Iodine intake influences the relative distribution of thyroid neoplasms. In areas with iodine deficiency and long-standing nodular goiter, follicular tumors have historically been more common, whereas papillary carcinoma predominates in iodine-sufficient populations. This relationship must not be interpreted as simple causality because tumor development depends on interactions among thyrotropic stimulation, nodular proliferation, somatic mutations, the microenvironment, and clonal selection. The association between iodine deficiency, goiter, and follicular neoplasms is nevertheless important for understanding why the same diagnostic category may have different distributions across populations.
A family history of nonmedullary thyroid carcinoma, certain genetic syndromes, thyroid nodularity, chronic autoimmune thyroiditis, obesity, and age may be associated with a higher probability of diagnosis, although they do not all have the same causal weight. Autoimmune thyroiditis can make the gland heterogeneous, lead to more frequent ultrasonographic assessments, and create interpretative difficulties, whereas the direct role of chronic inflammation in carcinogenesis remains complex. Family history must be assessed carefully when several relatives are affected, when the tumor develops at a young age, or when syndromic manifestations coexist. The clinical objective is to distinguish an associated factor from a demonstrated cause.
Overdiagnosis is a significant component of contemporary epidemiology. Extensive use of ultrasonography and nonthyroid imaging has increased the detection of small nodules and microcarcinomas that, in many cases, would not have caused symptoms during the patient’s lifetime. This phenomenon mainly concerns low-risk papillary carcinoma but influences the entire approach to thyroid nodules. Appropriate medical practice must identify aggressive tumors early while avoiding excessively intensive treatment of minimal and indolent neoplasms. The quality of management depends on risk stratification, not merely on the increased number of diagnoses.
The carcinogenesis of differentiated thyroid tumors results from activation of signaling pathways that regulate cellular proliferation, survival, differentiation, invasion, and metabolism. Two major molecular programs help explain their behavior: “BRAF-like” tumors, which are more typical of classic papillary carcinoma, and “RAS-like” tumors, which are more frequent among follicular neoplasms. This distinction does not replace histological diagnosis, but it explains why some tumors retain follicular architecture while others acquire a papillary phenotype, lymphatic spread, and a greater reduction in thyroid-specific genes. The mitogen-activated protein kinase pathway is a central node in this transformation.
In papillary carcinoma, the BRAF p.V600E mutation, rearranged during transfection (RET) rearrangements, neurotrophic tyrosine receptor kinase (NTRK) fusions, and other events activate proliferative signals that converge on RAF, mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK). This activation supports growth, survival, invasiveness, and remodeling of the microenvironment. When mitogen-activated protein kinase signaling is particularly intense, it may reduce the expression of NIS and other differentiation-related genes, contributing to loss of iodine uptake. BRAF-like biology therefore connects genotype, papillary morphology, aggressive variants, and the risk of radioiodine-refractoriness.
Follicular carcinoma often shows predominantly RAS-like alterations, including mutations in neuroblastoma RAS viral oncogene homolog (NRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS), paired box gene 8/peroxisome proliferator-activated receptor gamma fusion (PAX8::PPARG), and alterations of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. These tumors tend to retain follicular architecture and a relatively preserved differentiation program, although they may acquire capsular and vascular invasion. A RAS mutation alone does not establish malignancy because it may also occur in benign or borderline lesions, but it defines a biological context consistent with follicular neoplasms.
Oncocytic carcinoma involves distinctive mitochondrial and chromosomal alterations. Oncocytic cells accumulate mitochondria, often in association with mitochondrial DNA mutations and dysfunction of the respiratory chain, particularly complex I. Genomic studies have demonstrated widespread chromosomal losses, near-haploid states, and profiles that differ from those of classic papillary carcinomas. This pattern gives oncocytic carcinoma an independent biological identity and may contribute to reduced iodine uptake, greater metabolic avidity on FDG-PET, and a variable clinical course. Mitochondrial reprogramming is therefore part of the pathogenesis, not merely a cytoplasmic staining characteristic.
Clinically unfavorable progression is often associated with additional alterations. Mutations in the telomerase reverse transcriptase (TERT) promoter, tumor protein p53 (TP53) alterations, loss of tumor suppressor genes, increased chromosomal instability, tumor necrosis, and increased mitotic activity may accompany progression toward more aggressive forms. The coexistence of initiating drivers and progression-related alterations reduces dependence on the normal follicular program and increases the risk of invasion, metastases, and treatment resistance. The concept of dedifferentiation describes this progressive loss of clinically exploitable thyroid functions.
The most common presentation of differentiated carcinomas is the detection of a thyroid nodule, either palpable or identified by ultrasonography. Thyroid function is normal in most patients, and systemic symptoms are absent because the tumor does not produce hormones in clinically relevant quantities. Medical history should assess the duration and growth of the nodule, previous neck irradiation, family history, history of goiter or thyroiditis, dysphonia, dysphagia, dyspnea, local pain, lymphadenopathy, bone pain, persistent cough, and neurological symptoms. A normal TSH level does not exclude malignancy because endocrine function and oncological risk are separate dimensions.
Physical examination should follow an orderly sequence: inspection of the neck, palpation of the thyroid during swallowing, assessment of consistency, mobility, tenderness, fixation, tracheal deviation, and systematic examination of the central and lateral cervical lymph nodes. The voice should be assessed, and laryngoscopic evaluation should be considered in cases of dysphonia, previous neck surgery, or suspected invasion. A hard, fixed nodule, a cystic lateral neck mass, rapid growth, or vocal cord paralysis may indicate more advanced disease. Clinical findings must always be integrated with cervical ultrasonography because a normal palpation examination and clinically significant disease may coexist.
Presentation differs among the various entities. Papillary carcinoma may present with cervical lymph node metastases even when the primary tumor is small; follicular carcinoma may present as an apparently regular solitary nodule or with bone or lung metastases; oncocytic carcinoma may present as an indeterminate oncocytic lesion, an invasive mass, or systemic disease. These differences reflect their patterns of spread: lymphatic in papillary carcinoma and hematogenous in invasive follicular and oncocytic neoplasms. Clinical assessment must therefore evaluate not only the nodule but also the most plausible route of spread.
Most thyroid nodules are benign, and the objective is not to treat every nodular finding aggressively but to identify those with a sufficient probability of malignancy or clinically relevant anatomical features. Size, growth, ultrasonographic suspicion, TSH, history of radiation exposure, age, family history, and lymph nodes must be interpreted together. A small nodule adherent to the trachea or recurrent laryngeal nerve may be more clinically important than a larger intraparenchymal low-risk nodule; a lateral cervical lymph node metastasis or bone lesion changes the diagnostic priority. Initial assessment must convert suspicion into a graded clinical risk.
First-line diagnostic assessment includes TSH measurement, high-resolution thyroid and cervical ultrasonography, and ultrasound-guided fine-needle aspiration when indicated. TSH guides functional evaluation: when it is suppressed, scintigraphy may identify an autonomously functioning hyperactive nodule, which generally has a lower probability of malignancy than a nonfunctioning nodule. Ultrasonography describes composition, echogenicity, margins, shape, echogenic foci, capsule, relationships with adjacent structures, and lymph nodes. Fine-needle aspiration defines cytological risk according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Diagnosis arises from the integration of thyroid function, ultrasonographic morphology, and cytology.
Cytology has different diagnostic value depending on the tumor type. In papillary carcinoma, it may be diagnostic or highly suspicious because the nuclear alterations are visible in the aspirated sample. In follicular and oncocytic tumors, however, cytology may identify a follicular or oncocytic proliferation but cannot demonstrate the capsular or vascular invasion required to distinguish adenoma from carcinoma. This difference is crucial: a Bethesda result compatible with a follicular or oncocytic neoplasm indicates a level of risk and the need for a diagnostic and therapeutic surgical strategy, not automatic certainty of invasive carcinoma. The limitation of follicular cytology derives from the histological nature of the diagnosis itself.
Histological examination of the surgical specimen is the definitive reference standard when diagnosis requires assessment of the capsule, vessels, margins, and invasion. The pathology report should specify histological type, variant, size, multifocality, extrathyroidal extension, vascular invasion, margins, lymph nodes, metastases, necrosis, mitotic activity, and high-grade transformation when present. In papillary carcinoma, the report is particularly important for identifying variants, extension, and lymph node involvement; in follicular and oncocytic carcinoma, the number and extent of foci of vascular invasion are fundamental. Without these data, subsequent treatment cannot be appropriately tailored.
Molecular testing may be useful in indeterminate nodules and advanced disease, but it must not be interpreted outside the clinical context. In Bethesda III and IV nodules, validated molecular panels may modify the probability of malignancy and guide surveillance, lobectomy, or more extensive surgery. In metastatic, recurrent, radioiodine-refractory, or progressive tumors, molecular profiling is used to identify therapeutic targets, including RET fusions, NTRK fusions, BRAF mutations, and progression-related alterations. The value of a molecular test depends on its ability to change an actual clinical decision.
Second-line investigations are not necessary for every nodule. Computed tomography (CT), magnetic resonance imaging (MRI), scintigraphy, FDG-PET, and bone imaging should be used when there is suspected local invasion, complex lymph node involvement, retrosternal disease, distant metastases, elevated thyroglobulin, negative scintigraphy, or progressive disease. Contrast-enhanced CT may be essential for planning complex surgery, although the iodine load must be managed before any subsequent radioiodine treatment. Imaging selection should answer a specific question regarding anatomical extent, systemic risk, or treatment planning.
Staging of differentiated thyroid carcinomas must be interpreted at several levels. The American Joint Committee on Cancer (AJCC) system is primarily used to estimate the risk of disease-specific mortality, whereas clinical stratification systems such as that of the American Thyroid Association (ATA) are used to estimate the risk of persistence or recurrence and to guide treatment and follow-up. A purely anatomical classification is insufficient because two patients with similar disease extent may have different outcomes depending on histological type, vascular invasion, completeness of resection, iodine uptake, and response to treatment. The core of the assessment is the individual prognosis.
The main prognostic determinants are age, tumor size, macroscopic extrathyroidal extension, clinically significant lymph node involvement, distant metastases, aggressive histological variants, extensive vascular invasion, positive surgical margins, macroscopic residual disease, loss of iodine uptake, and radiological progression. In papillary carcinoma, the volume and location of lymph node metastases are particularly relevant; in follicular and oncocytic carcinoma, angioinvasion and hematogenous metastases are especially important. The same term differentiated may therefore describe diseases with markedly different levels of risk.
Risk is not defined permanently at the time of surgery. After surgery, possible radioactive iodine treatment, and the first follow-up assessments, the response to treatment substantially modifies the prognosis. An excellent response reduces residual risk and allows less intensive follow-up; an incomplete biochemical response requires interpretation of thyroglobulin and anti-thyroglobulin antibodies; an incomplete structural response indicates visible disease and requires specific clinical decisions. Dynamic risk stratification is one of the reasons modern follow-up is individualized rather than uniform.
The prognostic significance of metastases depends on their location and biology. Iodine-avid micronodular lung metastases, particularly in younger patients, may progress slowly and respond to radioactive iodine; bone metastases, non-iodine-avid lesions, FDG-avid disease, and rapidly progressive disease have a less favorable impact. The presence of metastases must not be interpreted only as a binary finding because disease volume, symptoms, growth rate, accessibility to local treatments, and radiometabolic sensitivity are also important. The most relevant parameter becomes clinically significant disease.
High-grade or poorly differentiated forms are biologically beyond classic differentiated carcinoma, but they may develop from follicular cell-derived neoplasms. Tumor necrosis, high mitotic activity, loss of differentiated architecture, reduced thyroglobulin expression, and increased FDG-PET avidity indicate a more aggressive trajectory. Recognition of this transition is essential because it reduces the effectiveness of the typical tools used for differentiated tumors, including radioactive iodine and TSH suppression. Loss of differentiation is therefore both a prognostic and therapeutic event.
Treatment of differentiated carcinomas must be proportionate to risk. In very small intrathyroidal tumors without suspicious lymph nodes and with a favorable location, active surveillance may be appropriate in selected cases, particularly for low-risk papillary microcarcinoma. In indeterminate follicular or oncocytic nodules, surgery often has both diagnostic and therapeutic value because it allows examination of the capsule and vessels. In invasive, metastatic, or high-risk tumors, treatment requires more extensive surgery, possible radioactive iodine, TSH suppression, and intensive follow-up. The key principle is therapeutic proportionality.
Surgery may consist of lobectomy or total thyroidectomy, with therapeutic lymph node dissection when necessary. Lobectomy may be sufficient for low-risk intrathyroidal tumors and for follicular or oncocytic neoplasms requiring an initial histological diagnosis. Total thyroidectomy is preferred when risk is higher, when disease is bilateral, when metastases are present, when radioiodine is planned, or when more sensitive biochemical follow-up is required. Lymph node dissection should be guided by documented disease, particularly in clinically suspicious compartments.
Radioactive iodine with iodine-131 is a selective tool, not an automatic treatment. It may be used to ablate thyroid remnants, treat suspected microscopic disease, manage iodine-avid metastases, or improve the interpretation of follow-up in selected patients. It is generally of limited value in completely resected very-low-risk tumors and is more appropriate in high-risk, metastatic, or iodine-avid disease. Oncocytic carcinoma and dedifferentiated forms may take up less iodine, whereas some differentiated lung metastases may respond well. The decision depends on iodine uptake, recurrence risk, disease burden, and anticipated toxicity.
Levothyroxine has a replacement function and, in selected patients, a TSH-suppressive function. Because TSH may stimulate residual differentiated thyroid cells, more intensive suppression may be justified in patients at high risk or with persistent disease. In low-risk patients with an excellent response, prolonged and marked suppression may cause more harm than benefit by increasing the risk of atrial fibrillation, tachycardia, osteopenia, osteoporosis, and fractures. The TSH target must therefore be individualized and revised over time.
Advanced disease requires a multidisciplinary approach. Resectable cervical lesions, bone metastases associated with mechanical risk, brain metastases, compressive masses, and painful lesions may require surgery, external-beam radiotherapy, ablation, embolization, or other local treatments. When disease is progressive, unresectable, and radioiodine-refractory, systemic options include antiangiogenic multikinase inhibitors and therapies directed against specific molecular targets. Systemic treatment should be initiated in the presence of documented progression, symptoms, anatomical risk, or a significant tumor burden because toxicity may be substantial.
Follow-up of differentiated carcinomas is based on clinical assessment, cervical ultrasonography, thyroglobulin, anti-thyroglobulin antibodies, TSH, and targeted imaging when indicated. After total thyroidectomy, thyroglobulin is a highly useful marker of residual thyroid tissue or tumor, provided that it is interpreted with a consistent method and together with antibody levels. After lobectomy, thyroglobulin is less specific because the remaining thyroid tissue physiologically produces the protein. The value of the marker depends on the surgical context, not on an isolated numerical result.
Anti-thyroglobulin antibodies may interfere with measurement and make thyroglobulin falsely low or unreliable. In such cases, the antibody trend may have indirect value: a progressive decline is generally reassuring, whereas persistence or an increase may suggest residual or recurrent disease, particularly when associated with suspicious ultrasonographic or imaging findings. The same laboratory and analytical method should be used whenever possible because methodological differences may lead to incorrect interpretations. Appropriate follow-up evaluates longitudinal trends, not isolated measurements.
Cervical ultrasonography is the main examination for locoregional surveillance, particularly in patients with papillary carcinoma and a risk of lymph node involvement. It should assess the thyroid bed, any residual tissue, the central compartment, and the lateral compartments. In high-risk follicular and oncocytic carcinomas, ultrasonography alone is insufficient because recurrence may be systemic; in these cases, chest CT, bone imaging, MRI, or FDG-PET become important according to thyroglobulin levels, symptoms, and histology. Surveillance should reflect the tumor’s pattern of spread.
Response to treatment is classified as excellent, indeterminate, biochemically incomplete, or structurally incomplete. An excellent response allows the intensity of follow-up and TSH suppression to be reduced; an indeterminate response requires observation and reassessment; an incomplete biochemical response requires a reasoned search for disease and monitoring of trends; an incomplete structural response requires local treatment, systemic treatment, or selective surveillance according to location and growth. The dynamic response prevents both overtreatment of patients who have been cured and underestimation of persistent disease.
The duration of follow-up must be individualized. Many low-risk patients with an excellent response can be monitored at progressively longer intervals, whereas patients with extensive angioinvasion, metastases, radioiodine-refractory disease, or an incomplete structural response require prolonged monitoring. Late recurrences are possible, particularly in invasive follicular and oncocytic tumors. The appropriate strategy maintains continuity without turning follow-up into excessive surveillance without clinical benefit.
The principal oncological complications are locoregional persistence, cervical recurrence, distant metastases, invasion of aerodigestive structures, and radioiodine-refractoriness. In papillary carcinoma, lymph node disease is often the predominant issue; in follicular and oncocytic carcinoma, lung and bone metastases related to vascular invasion are particularly important. Bone metastases may cause pain, pathological fractures, spinal cord compression, and functional impairment; lung metastases may remain clinically silent or progress to respiratory failure. The most relevant biological complication is structural progression.
Radioiodine-refractoriness is a major challenge in advanced disease. It may present as absent uptake, loss of uptake after previous treatments, progression despite uptake, or mixed disease containing both iodine-avid and non-iodine-avid lesions. When the tumor loses iodine uptake and becomes FDG-avid, this often indicates reduced differentiation and a less favorable prognosis. Not all refractory lesions require immediate treatment, but progressive, symptomatic, or threatening disease requires multidisciplinary evaluation. Resistance to radioactive iodine completely changes the relative importance of the available treatment options.
Surgical complications include hypoparathyroidism, hypocalcemia, recurrent laryngeal nerve injury, superior laryngeal nerve injury, cervical hematoma, infection, seroma, pathological scarring, and lymphatic leakage after lateral neck dissection. Risk increases with total thyroidectomy, reoperations, lymph node dissections, and locally invasive tumors. These complications justify a conservative approach in very-low-risk tumors and a more extensive approach only when the oncological benefit is concrete. Surgical morbidity is one of the main reasons initial risk stratification must be accurate.
Complications of radioactive iodine include sialadenitis, xerostomia, taste alterations, nausea, cervical pain, lacrimal dysfunction, bone marrow toxicity at high doses, temporary effects on fertility, and a small increase in the risk of second malignancies in selected settings. The treatment remains valuable when indicated but should not be used indiscriminately. In low-risk tumors, the benefit may be minimal, whereas in iodine-avid metastatic tumors it may be substantial. The decision requires assessment of the net benefit.
Chronic TSH suppression may cause iatrogenic subclinical thyrotoxicosis, atrial fibrillation, tachycardia, reduced bone mass, an increased risk of fractures, and worsening of pre-existing heart disease. Risk is higher in older adults, postmenopausal women, and patients with cardiovascular disease. In patients with persistent disease, significant suppression may be useful; in patients who have been cured, it should be progressively reduced. Levothyroxine management must follow the response to treatment rather than remain fixed according to the initial risk assessment.
The most frequent management challenge is achieving the correct balance between overtreatment and undertreatment. On one hand, indolent papillary microcarcinomas and low-risk follicular lesions may be subjected to extensive surgery, radioactive iodine, and follow-up-related anxiety without proportionate benefit. On the other hand, angioinvasive tumors, aggressive variants, metastatic disease, or loss of differentiation may be underestimated when assessment relies only on size or cytology. Appropriate management requires diagnostic precision, therapeutic proportionality, and dynamic reassessment.