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Pathology of Oropharyngeal Squamous Cell Carcinoma (OPSCC)

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Two Distinct Disease Entities:
    • OPSCC is now classified as two biologically and prognostically distinct diseases:
      • Based on high-risk HPV status: 
        • HPV-associated (p16-positive) and HPV-independent (p16-negative) carcinoma:
          • A division formalized in the WHO classification and the AJCC 8th edition staging system
    • HPV-associated tumors:
      • Carry a markedly better prognosis:
        • With 8-year overall survival of 70.9% versus 30.2% for HPV-negative disease in RTOG 0129:
          • HR 0.30; 95% CI 0.21–0.42
  • Histopathology:
    • HPV-Associated (
    • ) OPSCC:
      • These tumors arise from the specialized reticulated epithelium lining the tonsillar crypts rather than the surface mucosa
      • Characteristic features include:
        • Nonkeratinizing growth:
          • Lobules and sheets of immature basaloid cells with high nuclear-to-cytoplasmic ratios and hyperchromatic nuclei; absent or minimal keratinization
        • Basaloid cytology:
          • Resembling deep crypt epithelium, with lobular / endophytic growth and smooth pushing borders
        • Permeating tumor-infiltrating lymphocytes:
          • Within and around tumor nests
        • Absence of surface dysplasia:
          • Dysplasia is confined to crypts
        • Cystic nodal metastases:
          • Which can mimic branchial cleft cysts
      • In a 4-year prospective study of 435 OPSCCs:
        • Strictly defined nonkeratinizing morphology had a 99.1% positive predictive value for p16 positivity and 100% PPV for HR-HPV mRNA positivity
        • A “nonkeratinizing with maturation” (hybrid) intermediate pattern is p16-positive in ~92% of cases
    • HPV-Independent (Keratinizing) OPSCC:
      • These resemble conventional keratinizing SCC of the upper aerodigestive tract:
        • With keratin pearl formation
        • Individual cell keratinization
        • Intercellular bridges
        • Progressive squamous maturation
        • Origin from dysplastic surface epithelium
      • Molecularly they are characterized by high rates of:
        • TP53 mutation
        • CCND1 (cyclin D1) copy-number gains
        • 9p21 / CDKN2A loss
  • A Note on Grading:
    • Although HPV-associated tumors appear “poorly differentiated” by conventional criteria:
      • They paradoxically carry the best prognosis:
        • Westra has argued they may be best viewed as well-differentiated given their resemblance to native crypt epithelium
    • Both the 2018 CAP guideline and its 2025 update recommend against providing traditional grade / differentiation status for HPV-associated OPSCC:
      • Instead recommend reporting the WHO histologic subtype
    • Conventional grading (G1 to G4) still applies to HPV-independent OPSCC
    • Certain morphologic features retain prognostic value even within p16-positive disease:
      • Tumor cell anaplasia (nuclei ≥ 5 lymphocyte diameters) and multinucleation:
        • Independently predicted worse disease-specific survival (HR 9.9 and 11.9, respectively), and “non-classic” HPV-positive morphology was associated with poorer 5-year survival (58.4% vs 83.9%)
      • Keratinization:
        • Independently predicts worse survival
The 2025 CAP update enumerates the recognized morphologic subtypes.
  • Histologic Variants:
    • Basaloid SCC:
      • Is a mixed entity resolvable by HPV status:
        • HPV-positive:
          • Younger patients
          • p16+ / p53−
          • Prognosis – favorable
        • HPV-negative:
          • Older patients
          • Tobacco / alcohol-related
          • p53 overexpression
          • Biology – aggressive
    • Lymphoepithelial-like carcinoma:
      • Requires mandatory dual HPV and EBV testing:
        • As it closely mimics metastatic nasopharyngeal carcinoma
  • HPV / p16 Testing:
    • Who to Test:
      • All patients with newly diagnosed OPSCC should undergo HR-HPV testing, regardless of histologic subtype:
        • A strong CAP recommendation, endorsed by ASCO and listed as required in NCCN workup
      • Testing may be performed on the:
        • Primary tumor, a nodal metastasis, or FNA of a cervical node
      • Routine testing is not recommended for:
        • Nonsquamous oropharyngeal or non-oropharyngeal head and neck carcinomas (except sinonasal)
      • p16 IHC — the First-Line Test:
        • p16 immunohistochemistry is the recommended primary test:
          • Positivity requires:
            •  ≥ 70% nuclear AND cytoplasmic expression with at least moderate-to-strong intensity:
              • Typically in a confluent / block-like pattern
        • The E6H4 clone is most widely used and validated
        • With these criteria:
          • Sensitivity for transcriptionally active HR-HPV approaches 100% with specificity of ~ 85% to 95% in the oropharynx
        • Cases with 50% to 70% staining are equivocal and warrant HPV-specific testing
        • p16 and HPV may be used interchangeably only within the oropharynx
      • HPV-Specific (Direct) Testing:
        • The 2025 CAP update expanded indications for confirmatory HPV-specific testing beyond p16 IHC:
  • HPV-specific testing should be performed in:
    • Low-prevalence geographic regions
    • Equivocal p16 staining
    • Discrepancy between p16 and morphology (e.g., p16+ but keratinizing)
    • Large multisite tumors
    • Non-tonsillar / non-base-of-tongue subsites
    • Clinical trials
    • SCC of unknown primary
  • Discordant Results:
    • p16+ / HPV− discordance occurs in ~ 4% to 20% of cases:
      • In the multinational HNCIG-EPIC-OPC analysis (n=7,654):
        • Discordant patients had intermediate prognosis:
          • Significantly worse than double-positive and better than double-negative: 

Initial Thyroid Surgery for Thyroid Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Surgery is the initial treatment for most thyroid cancers and is often curative for those with low-risk disease
  • Historically, the majority of cancers measuring greater than 1 cm were recommended for total thyroidectomy:
    • To facilitate surveillance, allow for radioiodine therapy, and reduce the likelihood of recurrence
  • Newer data, however, has cast doubt on the necessity of removal of the entire gland:
    • The recent trend to the use of less radioiodine therapy has obviated the need to perform total thyroidectomy in many patients with low-risk thyroid cancer
    • Further strengthening the argument for less extensive surgery is the recognition that the risk of complications with total thyroidectomy is double that seen in lobectomy, regardless of the surgeon’s experience level
    • Most importantly, multiple retrospective studies have revealed that outcomes are equivalent in patients with low-risk disease treated with lobectomy compared with total thyroidectomy when controlled for tumor size and extent of disease
  • Those tumors measuring 4 cm or with preoperative evidence of nodal involvement or ETE, regardless of size:
    • Should proceed with total thyroidectomy
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Indications for Radioactive Iodine Therapy in Thyroid Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • There are three main indications for postoperative iodine-131 (131I) use:
    • To treat any known (or unknown) residual disease
    • To reduce the risk of recurrence
    • To destroy remaining noncancerous thyroid cells:
      • This last indication:
        • Called remnant ablation, improves the sensitivity of serum Tg and may also be used as a staging tool to identify previously undiagnosed tumors
  • The use of RAI therapy is a contentious issue with conflicting findings regarding recurrence and survival benefit:
    • Largely stemming from the lack of prospective, randomized, and controlled trials
  • The patients for whom RAI may be beneficial can be clarified based on the initial risk stratification of the individual tumor (Table) and the postoperative disease status
RAI, radioactive iodine, ATA, American Thyroid Association, TNM, The Tumor, Node, and Metastases scoring system, ETE, extrathyroidal extension, ENE, extranodal extension.
Modified from 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):1–133.
  • Studies have consistently shown that patients with American Thyroid Association (ATA) low-risk tumors measuring 1 cm lacking nodal and distant metastases:
    • Do not benefit from RAI therapy, and its use is not recommended
  • Additionally, low-risk tumors measuring 1 to 4 cm lacking local or distant metastases with complete tumor resection and no tumor invasion into the locoregional tissues or structures:
    • Do not derive mortality benefit from adjuvant RAI therapy:
      • As such, RAI therapy should not be routinely used in this group unless there is an aggressive histology or evidence of vascular invasion
  • In contrast, RAI does appear to be beneficial in terms of mortality and disease-free survival for those patients with a high-risk tumor:
    • Its use is routinely recommended in the postoperative management of these patients
  • For the remaining patients, including those with intermediate risk for recurrence:
    • There is conflicting data regarding the benefits of therapy:
      • Use of RAI in this cohort of patients should be considered on a case-by-case basis
#Arrangoiz #Surgeon #Doctor #CancerSurgeon #ThyroidSurgeon #ParathyroidSurgeon #HeadandNeckSurgeon #SurgicalOncologist #MountSinaiMedicalCenter #MSMC #Miami #Mexico #ThyroidCancer

American Thyroid Association Response to Therapy Classification in Thyroid Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Excellent Response to Therapy:
    • Patients with no biochemical (unstimulated serum thyroglobulin (Tg) < 0.2 or stimulated Tg < 1.0 ng/mL) or radiographic evidence of disease are classified as having an excellent response to therapy
    • Patients with an initial low to intermediate risk of recurrence who meet these criteria:
      • Are recommended to have serum Tg monitored every 12 to 24 months
    • Patients with initially high-risk disease:
      • Should continue to have a serum Tg measurement at least every 6 to 12 months
  • Biochemical Incomplete Response to Therapy:
    • Patients who have undergone total thyroidectomy and remnant ablation and have an unstimulated serum Tg > 1 ng/mL or a stimulated Tg > 10 ng/mL or a rising thyroglobulin antibody (TgAb) titer with negative imaging:
      • Are classified as having a biochemical incomplete response to therapy
    • Such patients should undergo imaging with sonography of the neck:
      • If the disease is unable to be located:
        • Cross-sectional imaging of the neck and chest should be performed
    • Serum Tg should be followed at least every 6 to 12 months.
  • Structural Incomplete Response to Therapy:
    • Those patients with structurally or functionally (on diagnostic whole-body scan [DxWBS] or 18(FDG-PET) evident disease are classified as:
      • Having a structural incomplete response to therapy
    • Unfortunately, the majority of patients in this category will have persistent disease in spite of additional treatments
    • Disease-specific death rates are high in this group:
      • 11% with locoregional metastases
      • 50% with distant metastases
  • Indeterminate Response to Therapy:
    • Patients with biochemical or structural findings that cannot be confidently classified as either excellent response or persistent disease:
      • Are deemed as having an indeterminate response to therapy
    • Such patients may be carefully followed with biochemical testing and serial imaging to better delineate which category is ultimately appropriate
    • It is estimated that up to 20% of these patients will eventually develop conclusive evidence of disease requiring additional therapy
#Arrangoiz #Doctor #Surgeon #ThyroidSurgeon #ParathyroidSurgeon #HeadandNeckSurgeon #CancerSurgeon #MountSinaiMedicalCenter #MSMC #Miami #Mexico #ThyroidCancer

Breast Cancer Chest Wall Recurrence Management

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • A postmastectomy chest wall recurrence:
    • Carries a high risk of concurrent or subsequent distant disease:
      • So the first steps are:
        • Tissue confirmation with receptor reassessment (ER / PR and HER2) and systemic staging to establish whether the recurrence is truly isolated:
          • Which determines whether curative-intent multimodality therapy versus palliative systemic therapy is appropriate
  • High risk of concurrent systemic disease:
    • Staging First:
      • In the ACOSOG / Alliance AFT-01 study of stage II to III patients:
        • Synchronous distant metastases were present in 27% overall at the time of locoregional recurrence:
          • 30% specifically for postmastectomy chest wall recurrence
          • 35% for nodal
          • 15% for in-breast
      • A separate cohort found distant metastases in:
        • ~32% of patients at diagnosis of locoregional recurrence
    • This justifies obtaining systemic staging and receptor status before committing to local therapy
  • NCCN staging modalities — confirmed with nuance:
    • NCCN workup for recurrent disease (BINV-18) includes:
      • History / physical
      • CBC, comprehensive metabolic panel with LFTs and alkaline phosphatase
      • Imaging:
        • Chest diagnostic CT ± contrast
        • Abdomen ± pelvis CT with contrast or MRI
        • Bone scan or sodium fluoride PET / CT (category 2B):
          • With FDG-PET/CT “useful in certain circumstances” (and FES-PET/CT considered for ER-positive / lobular disease)
        • Brain and spine MRI are reserved for relevant symptoms
        • So PET/CT is positioned as an option in select circumstances rather than fully interchangeable with CT + bone scan
      • Critically, NCCN also mandates biopsy of the recurrence with re-evaluation of ER / PR and HER2:
        • Because receptor status can discordantly change between primary and recurrence
  • Surgical excision to negative margins + comprehensive chest wall / nodal RT — confirmed:
    • For an isolated chest wall recurrence after mastectomy, NCCN (BINV-19) recommends:
      • Consider appropriate systemic therapy to best response if indicated, then surgical resection if feasible + consider surgical axillary staging + post-mastectomy RT (radiation-naïve patients), or repeat RT if feasible and indicated in previously irradiated patients
    • Corroborating data:
      • The DEGRO guideline calls:
        • Complete (R0) resection followed by chest wall RT with strongly advised regional nodal irradiation the standard, using 50 to 50.4 Gy ± 10 Gy boost
    • A retrospective series of isolated chest wall recurrences found chest wall plus RNI significantly improved progression-free and overall survival versus chest wall RT alone:
      • Supporting comprehensive nodal coverage
  • Multidisciplinary management — confirmed:
    • NCCN explicitly emphasizes that a multidisciplinary approach is especially important in recurrence to consider all treatment options
    • Involvement of a plastic / reconstructive surgeon is appropriate when full-thickness chest wall resection and reconstruction are needed
  • CALOR trial — confirmed, with updated final numbers:
    • The final analysis (median 9-year follow-up, 162 patients):
      • Confirmed a significant chemotherapy benefit for ER-negative isolated locoregional recurrence (DFS HR 0.29, 95% CI 0.13–0.67; 10-year DFS 70% vs 34%) but no benefit for ER-positive recurrence (HR 1.07, 95% CI 0.57–2.00; 10-year DFS 50% vs 59%; P-interaction = 0.013)
      • The overall survival interaction was not significant (P = 0.53)
      • This refined the earlier 2014 Lancet Oncology report:
        • Which had shown an overall DFS benefit (HR 0.59) driven by the ER-negative subgroup
  • Systemic therapy:
    • Is tailored to receptor status of the recurrence, not just chemotherapy
    • All hormone receptor-positive recurrences:
      • Should receive endocrine therapy:
        • Which is standard of care and improves disease-free survival:
          • SAKK 23/82 established tamoxifen’s role
      • HER2-positive recurrences:
        • Should receive HER2-targeted therapy
        • Chemotherapy is the component that CALOR showed benefits specifically ER-negative disease:
          • Emerging data qualify the “no chemo for ER-positive” message
    • A 2025 multi-institutional retrospective cohort of 958 patients with HR-positive / HER2-negative locoregional recurrence:
      • Found adjuvant chemotherapy associated with better invasive DFS (HR 0.70), particularly for non-IBTR recurrences and recurrences during adjuvant endocrine therapy:
        • Though with a worse trend in overall survival and the caveats of retrospective design
    • Genomic assays (e.g., Oncotype DX) are being explored to identify HR-positive patients who can safely omit chemotherapy
    • The POLAR trial is evaluating palbociclib in HR-positive recurrences
    • These do not overturn CALOR but reflect evolving practice
  • Reirradiation is now a more established option for previously irradiated patients:
    • Modern techniques (IMRT, proton therapy, brachytherapy, hyperthermia, ± radiosensitizers):
      • Achieve local control of ~ 60% to 75% with acceptable toxicity, with the decision factoring in prior dose, interval since prior RT, and cumulative normal-tissue toxicity
  • NCCN cautions the same:
    • Truly unresectable or widespread systemic disease shifts management to palliative systemic therapy per the metastatic algorithms (BINV-21 onward) rather than curative local therapy
  • References:
    • NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, Version 6.2026

Thyroid Nodules

Rodrigo Arrangoiz MS, MD, FACS, FSSO

What Are Thyroid Nodules?

Thyroid nodules are very common in the general population.

🔹 With modern high-resolution ultrasound, thyroid nodules are detected in up to 50–60% of adults

🔹 More than 90% are benign

🔹 Most people have no symptoms and feel completely well

👉 The key is not panic — it’s proper evaluation.

🔍 How should thyroid nodules be evaluated?

The most important first step is a high-resolution thyroid ultrasound, which allows us to:

Accurately measure and characterize nodules Assess features associated with cancer risk Use validated risk-stratification systems (ATA / TI-RADS) Decide whether a biopsy is actually necessary

🧪 A key fact for patients

Only 5–10% of thyroid nodules are cancer.

When thyroid cancer is detected early, cure rates are excellent.

👨‍⚕️ Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

Having a thyroid nodule is common.

Having it evaluated correctly by an experienced team makes all the difference.

📚 References

Haugen BR et al. ATA Guidelines for Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid Durante C et al. Long-term surveillance of benign thyroid nodules. JAMA Gharib H et al. Fine-needle aspiration biopsy of thyroid nodules. Endocrine Practice

Active Surveillance for Recurrent Thyroid Cancer: Right or Wrong?

Rodrigo Arrangoiz MS, MD, FACS, FSSO

The modern evidence suggests that active surveillance (AS) is appropriate for carefully selected patients with low-volume, stable recurrent differentiated thyroid cancer (DTC), but progressive or biologically aggressive recurrence generally warrants intervention rather than continued observation.

The 2025 American Thyroid Association guidelines continue to support selective AS, but emphasize that documented progression is a major trigger for treatment escalation.  

What the 2025 ATA Guidelines Say

The new 2025 ATA DTC guidelines acknowledge that:

“Low-volume recurrent nodal disease can be indolent and approached through active surveillance.”  

However, the same guidelines also state that:

Some patients under AS should proceed to surgery “if there is concern for disease progression.”  

The ATA framework therefore supports:

Appropriate Candidates for Active Surveillance

  • Small-volume nodal recurrence
  • Stable lesions over time
  • Slow thyroglobulin kinetics
  • No invasion of critical structures
  • High-risk reoperative field
  • Elderly/comorbid patients
  • Patient preference

Poor Candidates for Active Surveillance

  • Progressive enlargement
  • FDG-PET avid disease
  • Aggressive histology
  • Bulky nodal disease
  • Extrathyroidal extension
  • Radioiodine-refractory disease
  • Threatened RLN/trachea/esophagus/carotid
  • Rapid thyroglobulin doubling time

Evidence Supporting Active Surveillance

Memorial Sloan Kettering Cancer Center Experience

The strongest AS data comes from Memorial Sloan Kettering Cancer Center and the group led by Michael Tuttle.

Observational studies demonstrated that many small-volume recurrent lymph nodes:

  • remain stable for years,
  • enlarge very slowly,
  • and never become clinically significant.

These data support avoiding unnecessary reoperative surgery in selected patients.  

The Major Argument Against Active Surveillance

The major concern is that:

Progression May Represent Aggressive Biology

Once recurrent disease demonstrates:

  • serial growth,
  • shortening Tg doubling time,
  • PET avidity,
  • extranodal extension,
  • or invasion,

continued surveillance becomes harder to justify.

Progressive recurrence may lead to:

  • loss of surgical planes,
  • recurrent laryngeal nerve invasion,
  • tracheal/esophageal invasion,
  • carotid encasement,
  • and loss of curative opportunity.

This is especially relevant in younger patients with long life expectancy.

Important ATA Size Thresholds

The ATA historically suggested observation may be reasonable for:

  • Central compartment nodes ≤8 mm
  • Lateral neck nodes ≤10 mm

provided they are stable and away from critical structures.  

But the key principle is:

Stability

Not merely size alone.

Progressive Disease Usually Pushes Toward Treatment

Most experienced thyroid cancer centers favor intervention when there is:

  • Structural progression
  • Multiple enlarging nodes
  • Tg doubling time <1–3 years
  • FDG avidity
  • Aggressive molecular profile (TERT/BRAF)
  • Threatened aerodigestive structures
  • Symptomatic disease
  • Bulky lateral neck recurrence

Modern Treatment Options Besides Surgery

When AS is no longer appropriate, management may include:

  • Reoperative neck dissection
  • Radiofrequency ablation (RFA)
  • Ethanol ablation
  • Radioactive iodine (if iodine avid)
  • External beam radiation
  • Systemic therapy (TKIs, targeted therapy)

depending on biology and extent of disease.

Important References

ATA Guidelines

American Thyroid Association

Ringel MD et al.
2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer.
Thyroid. 2025;35(8):841-985.  

Active Surveillance vs Surgery Review

Tufano RP, Clayman G, et al.
Management of Recurrent/Persistent Nodal Disease in Patients with Differentiated Thyroid Cancer: A Critical Review of the Risks and Benefits of Surgical Intervention Versus Active Surveillance.
Thyroid. 2015;25(1):15-27.  

ATA 2025 Summary Statements

“Low-volume recurrent nodal disease can be indolent and approached through active surveillance.”  

“Patients under active surveillance may require surgery if there is concern for disease progression.”  

Bottom Line

Active surveillance is:

✔ Evidence-based
✔ Accepted by ATA guidelines
✔ Appropriate for selected stable low-volume recurrences

Active surveillance becomes difficult to defend when disease is:

✘ Progressive
✘ FDG avid
✘ Biologically aggressive
✘ Threatening critical structures
✘ Rapidly enlarging

In progressive recurrent thyroid cancer, many experts would argue that progression itself is evidence that surveillance is failing.

Tall Cell Subtype of Papillary Thyroid Carcinoma: A Comprehensive Review

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Epidemiology:
    • The tall cell subtype of papillary thyroid carcinoma (PTC-TC):
      • Accounts for approximately 3% to 5% of all PTCs
        • Its incidence has been rising:
          • Partly due to evolving diagnostic criteria
    • The WHO 5th edition (2022) defines PTC-TC as:
      • PTC with ≥ 30% tall cells:
        • Height-to-width ratio ≥ 3:1
    • Patients tend to be older:
      • Mean ~ 50 years vs. 42 for classic PTC
    • PTC-TC have higher rates of:
      • Extrathyroidal extension (~ 60%)
      • Vascular invasion (~ 15%)
      • Lymph node metastasis
      • Advanced stage at presentation
    • Recurrence rates range from:
      • 27% to 42% compared to 16% to 31% for classic PTC
    • 5-year disease-specific survival of:
      • Approximately 82% vs. 98% for all PTC
    • An important recent distinction is:
      • Between PTC-TC (without high-grade features) and high-grade differentiated thyroid carcinoma with tall cell phenotype (HGDTC-TC):
        • Defined by ≥ 5 mitoses / 2 mm² and / or tumor necrosis
          • When HGDTC-TC is excluded PTC-TC has a more indolent course (10-year disease-specific survival ~99%)
  • Genetics and Molecular Features:
    • BRAF V600E mutation:
      • Present in ~ 80% to 90% of cases:
        • Drives MAPK pathway activation and suppresses sodium-iodide symporter expression:
          • Contributing to RAI refractoriness
    • TERT promoter mutations:
      • Independent predictor of recurrence:
        • More frequent in PTC-TC
    • BRAF V600E + TERT co-mutation:
      • Identifies a subset with particularly poor outcomes
  • Surgical Management:
    • Type of Thyroidectomy:
      • Standard indications for total thyroidectomy apply:
        • Distant metastases
        • Extrathyroidal extension
        • Lateral or gross central neck node metastases
        • Tumor > 4 cm
        • Bilateral disease
      • For tumors 1 cm to 4 cm without these features:
        • Either total thyroidectomy or lobectomy may be considered
    • Key evidence:
      • A 2026 SEER analysis of 1,463 PTC-TC patients showed total thyroidectomy had superior cancer-specific survival vs. lobectomy:
        • 5-year CSS 97.8% vs. 90.7%, p = 0.019, independent of RAI
      • A Memorial Sloan Kettering study of T1 / T2 N0 PTC-TC:
        • Found no difference in outcomes with lobectomy alone, with 100% disease-specific survival in both groups
    • Summary:
      • For small (T1 / T2), node-negative PTC-TC without high-grade features:
        • Lobectomy may be adequate
      • Larger or higher-stage tumors:
        • Should undergo total thyroidectomy
  • Central Compartment Neck Dissection:
    • Therapeutic central neck dissection:
      • Recommended for clinically involved nodes (cN1a)
    • Prophylactic central neck dissection:
      • Not routinely indicated per NCCN
    • Thorough preoperative ultrasound of central and lateral compartments is essential:
      • With FNA of suspicious lateral nodes
  • Radioactive Iodine (RAI):
    • NCCN classifies tall cell histology as a “high-risk subtype”:
      • For which RAI is selectively recommended based on the combination of clinical factors
    • PTC-TC is classified in the ATA intermediate risk category
    • Key considerations:
      • BRAF V600E-driven PTC-TC downregulates the sodium-iodide symporter:
        • Making these tumors frequently RAI-refractory
      • For tumors > 2 cm:
        • RAI after total thyroidectomy improved overall survival:
          • 83.4% vs. 70.0%
      • For tumors ≤ 2 cm:
        • No survival benefit from RAI was demonstrated
      • A SEER-based propensity-matched study:
        • Found no significant CSS benefit from RAI in PTC-TC overall:
          • HR 0.54, 95% CI 0.25–1.17
      • Repeated RAI should be limited to patients demonstrating continued therapeutic response
  • Follow-Up:
    • After total thyroidectomy with RAI, recommended surveillance includes:
      • Physical examination, TSH, thyroglobulin (Tg), and anti-thyroglobulin antibodies (TgAb)
      • Neck ultrasound at 6 to 12 months, then every 1 to 3 years for 5 to 8 years, then discontinue
    • Rising Tg or new TgAb:
      • Should prompt additional imaging:
        • Neck CT / MRI, chest / abdomen CT, FDG-PET, or RAI imaging
    • TSH suppression with levothyroxine:
      • Per risk stratification
    • For patients with no evidence of disease (NED) at low risk after 10 to 15 years:
      • No further thyroid cancer monitoring is indicated
  • RAI-Refractory Disease:
    • For RAI-refractory progressive disease:
      • Molecular analysis for actionable alterations should be pursued:
        • BRAF V600E → dabrafenib / trametinib or vemurafenib / cobimetinib
        • RET fusions → selpercatinib or pralsetinib
        • NTRK fusions → larotrectinib or entrectinib
        • ALK fusions → targeted therapy
  • References:
    • Shi X, Liu R, Basolo F, et al. Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants. J Clin Endocrinol Metab. 2016.
    • Wu SS, Joshi N, Sharrett J, et al. Risk Factors Associated With Recurrence and Death in Patients With Tall Cell Papillary Thyroid Cancer. JAMA Otolaryngol Head Neck Surg. 2023.
    • Holoubek SA, MacKinney EC, Khokar AM, et al. Radioactive Iodine Does Not Improve Overall Survival for Patients With Aggressive Variants of Papillary Thyroid Carcinoma Less Than 2 Cm. Surgery. 2022.
    • Jin X, Koga S, Zhou X, Khan NZ, Baloch ZW. Clinicopathologic Characteristics of Papillary Thyroid Carcinoma, Tall Cell Subtype and Subtype With Tall Cell Features, an Institutional Experience. Hum Pathol. 2025.
    • Parvathareddy SK, Siraj AK, Qadri Z, et al. Tall Cell Variant Histology Predicts Poorer Disease-Free Survival in Papillary Thyroid Carcinoma: A Propensity-Matched Cohort Study. World J Surg. 2025.
    • Ghossein R, Katabi N, Dogan S, et al. Papillary Thyroid Carcinoma Tall Cell Subtype (PTC-TC)