Skip to content
How It Works
Explore
Resources Ask a Question
Who It's For
Patients
Decode results, prep for appointments, weigh options.
Caregivers & advocates
Carry the research load for someone you love.
Providers & clinicians
Resources for patients in your practice.
Log In Ask a Question
PubMed This is a summary of 19 peer-reviewed journal articles Updated
Oncology · Poorly Differentiated Thyroid Carcinoma

PDTC, High-Grade, and Oncocytic (Hürthle Cell) Guide

At a Glance

Poorly Differentiated (PDTC) and Oncocytic (Hürthle Cell) thyroid cancers are intermediate tumors that often stop responding to standard radioactive iodine (RAI) therapy. Treatment typically involves extensive surgery followed by careful monitoring or targeted therapies like TKIs if the cancer grows.

Cancers like Poorly Differentiated (PDTC), Differentiated High-Grade (DHGTC), and Oncocytic (Hürthle Cell) Carcinoma are often described as “intermediate” [1][2]. They are more aggressive than common thyroid cancers but less explosive than Anaplastic cancer [3]. Managing these requires a specialized “step-up” approach as the cancer cells begin to lose their normal thyroid functions [4].

The Challenge: Losing the “Iodine Memory”

Normal thyroid cells are experts at taking up iodine. This allows doctors to use Radioactive Iodine (RAI) to find and kill cancer cells [5]. However, as cancers like PDTC or DHGTC become more aggressive, they undergo dedifferentiation—they “forget” how to be thyroid cells [6][7].

When this happens, the cancer becomes Radioactive Iodine (RAI) Refractory. This means the cells have turned off the “gatekeeper” (called the NIS) that lets iodine into the cell [6][8]. This is particularly common in Oncocytic (Hürthle Cell) Carcinoma, where the cells are filled with abnormal mitochondria that interfere with normal iodine metabolism [5][9].

The Step-Up Treatment Pathway

Step 1: Surgery

Surgery is the most important step for these intermediate cancers [4]. Because they are more likely to spread, the surgery is often more extensive than for common types, frequently involving a total thyroidectomy and a thorough cleaning of the lymph nodes in the neck [10][11].

Step 2: Testing for RAI Response

After surgery, doctors will test to see if the remaining cancer cells still take up iodine. This is usually done with a diagnostic scan [5].

  • If it works: RAI therapy is given to “mop up” any microscopic disease [4].
  • If it fails: The cancer is labeled RAI-refractory, and the team moves to other options [4][12].

Step 3: Active Surveillance (Watchful Waiting)

If your cancer is RAI-refractory but stable or growing very slowly, the standard of care is often simply to monitor it closely with regular scans [4][12]. You do not necessarily have to immediately start harsh systemic therapies if the tumor is small and not causing symptoms [4].

Step 4: Targeted Therapy (TKIs)

If the cancer is visibly growing on scans, progressing rapidly, and does not respond to iodine, doctors use Tyrosine Kinase Inhibitors (TKIs) like Lenvatinib or Sorafenib [13][12]. These are daily pills that work by cutting off the blood supply to the tumor and blocking the signals that tell the cancer to grow [12].

Important Note on Side Effects: While TKIs can be very effective at controlling tumor growth, they carry significant side effects that require close management by an experienced medical oncologist. Patients frequently experience high blood pressure, extreme fatigue, diarrhea, weight loss, and potential liver toxicity [13][12].

The Role of Genetic Drivers

Certain mutations are “red flags” that a cancer might be more aggressive or resistant to iodine:

  • TERT Promoter Mutations: When found alongside RAS or BRAF mutations, TERT is a strong predictor that the cancer will be RAI-refractory and behave more aggressively [14][15][16].

A Glimmer of Hope: Redifferentiation

A new area of research called redifferentiation therapy aims to “teach” the cancer cells how to take up iodine again [17]. By using targeted drugs (like MEK or BRAF inhibitors) for a few weeks, doctors can sometimes turn the NIS gatekeeper back on, allowing a successful dose of radioactive iodine to be delivered [17][18]. While not yet standard for everyone, it is an important option to discuss with a specialist [19].

Common questions in this guide

What does it mean if my thyroid cancer is RAI-refractory?
If your thyroid cancer is RAI-refractory, it means the cancer cells have lost their ability to absorb iodine. Because of this, standard radioactive iodine (RAI) therapy will no longer work, and your doctor will consider other approaches like active surveillance or targeted therapies.
What treatments are available for poorly differentiated thyroid cancer (PDTC)?
Treatment usually begins with extensive surgery to remove the thyroid and surrounding lymph nodes. If the cancer is resistant to radioactive iodine and actively growing, daily targeted therapy pills like Lenvatinib or Sorafenib may be used to block tumor growth.
What are the common side effects of TKIs like Lenvatinib?
Tyrosine Kinase Inhibitors (TKIs) like Lenvatinib can effectively control tumor growth but may cause side effects. Common side effects include extreme fatigue, high blood pressure, diarrhea, and weight loss, requiring close monitoring by your medical oncologist.
What is redifferentiation therapy for thyroid cancer?
Redifferentiation therapy is an emerging treatment that aims to teach RAI-refractory cancer cells how to absorb iodine again. By using specific targeted drugs for a short period, doctors may be able to successfully treat the tumor with a dose of radioactive iodine.
How do TERT, RAS, and BRAF mutations affect my thyroid cancer?
These genetic mutations can indicate that your thyroid cancer may behave more aggressively and is more likely to become resistant to radioactive iodine. Knowing your tumor's genetic makeup helps your medical team choose the most effective treatment strategy.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which of the 'intermediate' rare cancers do I have: PDTC, the new High-Grade (DHGTC) category, or Oncocytic (Hürthle Cell) Carcinoma?
  2. 2.Has my tumor been tested for the TERT promoter mutation, and if so, what does that mean for my response to radioactive iodine?
  3. 3.Is my cancer currently considered 'radioactive iodine (RAI) refractory'? If so, what was the evidence for that (e.g., negative scan vs. rising markers)?
  4. 4.Are we considering a 'redifferentiation therapy' trial to see if we can make my cells take up iodine again?
  5. 5.If I need a TKI like Lenvatinib, what are the most common side effects I should prepare for?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (19)
  1. 1

    Management of Poorly Differentiated Thyroid Cancer and Differentiated High-Grade Thyroid Carcinoma.

    Alam IS, Patel KN

    The Surgical clinics of North America 2024; (104(4)):751-765 doi:10.1016/j.suc.2024.02.005.

    PMID: 38944496
  2. 2

    Incidence and Clinicopathological Features of Differentiated High-Grade Thyroid Carcinomas: An Institutional Experience.

    Jeong SI, Kim W, Yu HW, et al.

    Endocrine pathology 2023; (34(3)):287-297 doi:10.1007/s12022-023-09778-w.

    PMID: 37515661
  3. 3

    Fine needle aspiration cytology features of poorly differentiated thyroid carcinoma.

    Purkait S, Agarwal S, Mathur SR, et al.

    Cytopathology : official journal of the British Society for Clinical Cytology 2016; (27(3)):176-84 doi:10.1111/cyt.12270.

    PMID: 26662642
  4. 4

    Thyroid Carcinoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

    Haddad RI, Bischoff L, Ball D, et al.

    Journal of the National Comprehensive Cancer Network : JNCCN 2022; (20(8)):925-951.

    PMID: 35948029
  5. 5

    Somatic genetic alterations in the development and progression in thyroid tumors of follicular cells.

    Calafato G, Di Paola FJ, De Leo A, et al.

    European thyroid journal 2025; (14(5)).

    PMID: 41175860
  6. 6

    Radioiodine-refractory differentiated thyroid cancer: Molecular mechanisms and therapeutic strategies for radioiodine resistance.

    Shen H, Zhu R, Liu Y, et al.

    Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 2024; (72()):101013 doi:10.1016/j.drup.2023.101013.

    PMID: 38041877
  7. 7

    A somatic mutation of RasGRP3 decreases Na+/I- symporter expression in metastases of radioactive iodine-refractory thyroid cancer by stimulating the Akt signaling pathway.

    Song J, Qiu W, Deng X, et al.

    American journal of cancer research 2018; (8(9)):1847-1855.

    PMID: 30323976
  8. 8

    Gene Expression Analysis of Papillary Thyroid Carcinoma With Lymph Node Metastasis and Radioiodine Refractivity.

    Mohamad Pakarulrazy NF, Abu N, Abdullah Suhaimi SN, et al.

    Cureus 2025; (17(6)):e87001 doi:10.7759/cureus.87001.

    PMID: 40746809
  9. 9

    Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma.

    Gopal RK, Vantaku VR, Panda A, et al.

    Cancer discovery 2023; (13(8)):1904-1921 doi:10.1158/2159-8290.CD-22-0976.

    PMID: 37262067
  10. 10

    Could SLC26A7 Be a Promising Marker for Preoperative Diagnosis of High-Grade Papillary Thyroid Carcinoma?

    Titov SE, Kozorezova ES, Lukyanov SA, et al.

    Diagnostics (Basel, Switzerland) 2024; (14(23)) doi:10.3390/diagnostics14232652.

    PMID: 39682560
  11. 11

    No Longer Well-Differentiated: Diagnostic Criteria and Clinical Importance of Poorly Differentiated/High-Grade Thyroid Carcinoma.

    Cracolici V

    Surgical pathology clinics 2023; (16(1)):45-56 doi:10.1016/j.path.2022.09.006.

    PMID: 36739166
  12. 12

    NCCN Guidelines® Insights: Thyroid Carcinoma, Version 1.2025.

    Haddad RI, Bischoff L, Applewhite M, et al.

    Journal of the National Comprehensive Cancer Network : JNCCN 2025; (23(7)).

    PMID: 40639400
  13. 13

    Novel Targeted Therapies for Metastatic Thyroid Cancer-A Comprehensive Review.

    Al-Jundi M, Thakur S, Gubbi S, Klubo-Gwiezdzinska J

    Cancers 2020; (12(8)) doi:10.3390/cancers12082104.

    PMID: 32751138
  14. 14

    The ability of anexelekto (AXL) expression and TERT promoter mutation to predict radioiodine-refractory differentiated thyroid carcinoma.

    Agustina H, Ayni TN, Azhar Y, et al.

    Diagnostic pathology 2025; (20(1)):46 doi:10.1186/s13000-025-01643-0.

    PMID: 40241101
  15. 15

    Clinical, Pathological, and Molecular Characteristics Correlating to the Occurrence of Radioiodine Refractory Differentiated Thyroid Carcinoma: A Systematic Review and Meta-Analysis.

    Luo Y, Jiang H, Xu W, et al.

    Frontiers in oncology 2020; (10()):549882 doi:10.3389/fonc.2020.549882.

    PMID: 33117686
  16. 16

    Molecular Alterations in Thyroid Carcinoma.

    Haroon Al Rasheed MR, Xu B

    Surgical pathology clinics 2019; (12(4)):921-930 doi:10.1016/j.path.2019.08.002.

    PMID: 31672298
  17. 17

    TGF-β1-based restoration of sodium iodide symporter expression in radioiodine-refractory differentiated thyroid cancer via engineered MSCs.

    Han Y, Koehler VF, Nagarajah J, et al.

    Molecular therapy : the journal of the American Society of Gene Therapy 2025; (33(12)):6130-6145 doi:10.1016/j.ymthe.2025.10.033.

    PMID: 41109953
  18. 18

    [18F]TFB PET/CT misses intense [124I]iodine-avid metastases after redifferentiation therapy in metastatic thyroid cancer.

    Backhaus P, Pentlow KS, Ho AL, et al.

    EJNMMI research 2024; (14(1)):91 doi:10.1186/s13550-024-01138-x.

    PMID: 39377970
  19. 19

    Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs.

    Wächter S, Wunderlich A, Greene BH, et al.

    International journal of molecular sciences 2018; (19(7)) doi:10.3390/ijms19072077.

    PMID: 30018229

This page explains intermediate and rare thyroid cancers for educational purposes only. Always consult your endocrinologist or oncologist to determine the best treatment pathway for your specific diagnosis.

Get notified when new evidence is published on Rare thyroid carcinoma.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.