Most thyroid cancers are papillary carcinomas, slow-growing tumors with cure rates above 95 percent. The rarer forms, including medullary, anaplastic, and poorly differentiated thyroid carcinomas, behave very differently and often demand treatment strategies that go well beyond standard surgery and radioiodine. These uncommon subtypes together account for a small fraction of all thyroid cancers, yet they are responsible for a disproportionate share of thyroid cancer deaths. Understanding what sets each type apart, and what treatments have emerged in recent years, matters both for patients facing a diagnosis and for anyone trying to make sense of a landscape that has changed dramatically with the arrival of targeted drugs.
Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) arises from the parafollicular C cells of the thyroid, the cells that produce the hormone calcitonin. Because it originates from a completely different cell type than the more common papillary and follicular cancers, MTC behaves distinctly and does not respond to radioiodine therapy. It accounts for fewer than one case per 100,000 people annually in most countries studied.1PubMed. Thyroid cancer incidence trends by histology in 25 countries: a population-based study
A defining feature of MTC is its relationship with the RET gene. In hereditary forms, which make up roughly a quarter of all MTC cases, a person inherits a germline RET mutation that dramatically raises their risk. Sporadic (non-inherited) MTC also frequently involves RET mutations, though these arise within the tumor itself rather than being passed down through families.2PubMed Central. Genetic alterations in medullary thyroid cancer: diagnostic and prognostic markers These mutations drive tumor growth by keeping certain cell-signaling pathways permanently switched on.3PubMed. The importance of the RET gene in thyroid cancer and therapeutic implications
Calcitonin is both a hallmark and a monitoring tool. Elevated calcitonin in the blood can point toward MTC before imaging even detects a mass, and tracking calcitonin levels after treatment helps doctors gauge whether the cancer has been fully removed or is growing back. Carcinoembryonic antigen (CEA) is another blood marker that, together with calcitonin, gives clinicians a way to estimate how fast any remaining disease is progressing.4PubMed Central. Serum Biochemical Markers for Medullary Thyroid Carcinoma: An Update How quickly calcitonin and CEA levels double is itself considered a strong predictor of outcome.5PubMed. Medullary thyroid carcinoma surgical cytoreduction induces an increase in serum calcitonin and carcinoembryonic antigen doubling times
Symptoms of MTC often start with a painless lump in the neck, sometimes accompanied by swollen lymph nodes. In advanced cases, patients can develop diarrhea or flushing from hormones the tumor secretes. Because hereditary MTC is linked to well-characterized RET mutations, family members of a diagnosed patient can be tested. When a mutation is found, preventive thyroid removal in childhood can eliminate the cancer risk before it materializes.
Targeted Drugs for Medullary Thyroid Cancer
For years, the treatment options for advanced MTC that could not be cured by surgery were limited to two multi-kinase inhibitors, vandetanib and cabozantinib, both of which block RET along with several other targets.6PubMed Central. Targeted Therapy for Medullary Thyroid Cancer: A Review These drugs slow tumor growth but come with significant side effects because of how broadly they act across the body.
That picture shifted with the approval of selpercatinib, a drug designed to block RET far more precisely. In a phase 3 trial, patients receiving selpercatinib had roughly 87 percent progression-free survival at one year compared with about 66 percent in the control group receiving an older multi-kinase inhibitor. The tumor response rate was also markedly higher: about 69 percent versus 39 percent.7PubMed. Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer A network analysis comparing the available drugs ranked selpercatinib first for both tumor response and progression-free survival, with a safety profile that largely avoided the off-target problems like severe high blood pressure and diarrhea that commonly affect patients on older multi-kinase inhibitors.8PubMed Central. Selpercatinib versus multi-kinase inhibitors for advanced medullary thyroid cancer: A network meta-analysis of RET-targeted therapies
However, cancers can eventually develop resistance even to selective RET inhibitors. Research has identified several escape routes tumors use, including gaining extra copies of the RET gene, acquiring new secondary mutations, or activating alternative signaling pathways. Early clinical evidence suggests that combining a RET inhibitor with a drug that blocks the downstream signaling pathway can overcome this resistance in at least some patients.9PubMed Central. Combination of Selpercatinib and Trametinib Overcomes Resistance to RET Inhibitors in RET-Mutant Medullary Thyroid Carcinoma
Anaplastic Thyroid Carcinoma
Anaplastic thyroid carcinoma (ATC) is the rarest major thyroid cancer subtype and by far the most lethal. It makes up fewer than 2 percent of thyroid cancers, with incidence rates below 0.2 cases per 100,000.10Journal of the Endocrine Society. 12205 Challenging Case Of Anaplastic Thyroid Cancer With Unusual Histological Features: A Diagnostic Dilemma With High Grade Sarcoma ATC tends to strike older adults and grows with alarming speed. A neck mass that was barely noticeable a few weeks ago can double or triple in size within a month, pressing on the windpipe and esophagus. Patients frequently present with difficulty swallowing, shortness of breath, and voice changes caused by the tumor’s rapid invasion of surrounding structures.
Historically, median survival after an ATC diagnosis was measured in months. Aggressive multimodal treatment, combining surgery with radiation and chemotherapy, offers the best chance of extending life. An analysis of over 3,400 ATC patients found that those receiving all three treatment modalities had a median survival of about 9 months, compared with under 2 months for those receiving only one type of treatment or none at all.11Journal of Clinical Oncology. Impact of intensive multimodal treatment on the outcomes of patients with anaplastic thyroid cancer Concurrent radiation and chemotherapy has been specifically linked to better survival compared with sequential approaches.12PubMed. Prognostic Factors for Survival in Patients Treated with Multimodal Therapy for Anaplastic Thyroid Cancer
The real game-changer for a subset of ATC patients has been targeted therapy. About 38 percent of ATCs carry the BRAF V600E mutation, the same mutation found in some melanomas.13International Journal of Radiation Oncology*Biology*Physics. Comprehensive Genomic Characterization of Thyroid Cancers: Real-world Implementation and Impact on Clinical Decisions The combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) produced tumor responses in 69 percent of patients with BRAF-mutated ATC in the initial study.14PubMed Central. Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer Updated follow-up data confirmed that about half of patients who responded maintained that response for at least a year, with a median overall survival of 14.5 months and a two-year survival rate of about 32 percent.15PubMed Central. Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study For a cancer that historically killed most patients within a few months, these numbers represent a genuine shift. Immune checkpoint inhibitors are also showing promise in ATC, with biomarker-guided combinations demonstrating the greatest effectiveness among thyroid cancer subtypes.16PubMed. Effectiveness of immune checkpoint inhibitor therapy in thyroid cancer: A systematic review
Poorly Differentiated Thyroid Carcinoma
Poorly differentiated thyroid carcinoma (PDTC) occupies an uncomfortable middle ground. It arises from the same follicular cells as the common papillary and follicular cancers, but its cells have lost much of their original structure and function. That loss of differentiation makes it more aggressive and less responsive to radioiodine than its well-differentiated cousins. Though PDTC is rare, it accounts for most deaths from non-anaplastic follicular cell-derived thyroid cancer.17PubMed Central. Poorly Differentiated Carcinoma of the Thyroid Gland: Current Status and Future Prospects
Patients with PDTC tend to present at an older age, with larger tumors that have already extended beyond the thyroid or spread to distant sites. Survival estimates vary depending on which diagnostic criteria pathologists use to define PDTC, which has been a longstanding source of confusion. A meta-analysis found five-year disease-free survival rates ranging from roughly 49 percent under one set of criteria to about 74 percent under another, with the spread of the tumor beyond the thyroid gland consistently emerging as a key predictor of worse outcomes.18Endocrinology and Metabolism. Prognosis of Poorly Differentiated Thyroid Carcinoma: A Systematic Review and Meta-Analysis In a smaller single-center study using strict Turin criteria, five-year survival was only 18 percent, with tumor extension beyond the thyroid and distant spread identified as independent risk factors for poor outcomes.19PubMed. Clinicopathological Characteristics and Prognosis of Poorly Differentiated Thyroid Carcinoma Diagnosed According to the Turin Criteria
Treatment typically begins with surgery, often followed by radioiodine if the tumor retains enough differentiation to absorb it. When it does not, external beam radiation and systemic therapies become the main options. This is the subtype where the question of radioiodine refractoriness becomes especially important.
Primary Thyroid Lymphoma
Primary thyroid lymphoma (PTL) is not a carcinoma at all but a cancer of immune cells that starts within the thyroid gland. It is uncommon, but it has a striking connection to Hashimoto’s thyroiditis, the most common cause of an underactive thyroid. People with Hashimoto’s face a risk of developing PTL that is estimated to be 40 to 80 times higher than in the general population.20PubMed Central. Thyroid B-Cell Lymphoma in the Background of Hashimoto’s Thyroiditis: A Case Report and Literature Review A pooled analysis of 38 studies found that nearly 79 percent of PTL cases showed some evidence of Hashimoto’s.21PubMed. Hashimoto Thyroiditis in Primary Thyroid Non-Hodgkin Lymphoma
The clinical presentation is often a rapidly enlarging neck mass in an older person already known to have Hashimoto’s. That rapid growth in a patient with longstanding thyroid disease is one of the most important red flags. PTL is typically treated with chemotherapy and sometimes radiation rather than thyroid surgery, making early and accurate diagnosis critical. Standard fine-needle aspiration can be inconclusive for lymphoma because diagnosing it requires assessing tissue architecture. Core needle biopsy or surgical biopsy is often needed to confirm the diagnosis.22PubMed Central. Recent Advances in Core Needle Biopsy for Thyroid Nodules
Ultra-Rare Subtypes
Beyond the major rare types, a handful of thyroid cancers are so uncommon that most endocrinologists and surgeons encounter them only a few times in a career, if ever. Thyroid angiosarcoma is one such tumor, a malignancy of the blood-vessel lining that tends to appear in elderly patients, often in the setting of a goiter that has been present for decades. It has historically been reported more frequently in Alpine regions of Europe with a history of iodine deficiency.23PubMed. Thyroid angiosarcoma: a comprehensive review Diagnosis is tricky because fine-needle aspiration often yields inconclusive results, and the tumor can mimic a variant of anaplastic carcinoma under the microscope. Specialized staining is needed to confirm it.24PubMed Central. A Case Report of Surgical and Postoperative Treatment for Thyroid Angiosarcoma with Pulmonary Metastasis
How Rare Thyroid Cancers Are Diagnosed
The diagnostic workup for a suspicious thyroid nodule usually starts with ultrasound and fine-needle aspiration. For common papillary cancers, this approach works well. For rarer subtypes, it often falls short. Fine-needle aspiration collects loose cells, which is enough for identifying most carcinomas but can miss the tissue-architecture clues needed to diagnose lymphoma, angiosarcoma, or poorly differentiated tumors. Core needle biopsy, which retrieves a small cylinder of intact tissue, allows pathologists to examine how cells are organized relative to each other and to run additional staining tests. This makes it a valuable backup tool, though it requires an experienced operator because the needles are larger.25Thyroid Radiofrequency Ablation: A Comprehensive Guide. Fine-Needle Aspiration and Core Needle Biopsy of Thyroid Nodules
Molecular profiling has become increasingly central to managing rare thyroid cancers. Next-generation sequencing of tumor tissue can identify specific mutations and gene fusions that determine which targeted drugs a patient might respond to. In one multicenter study of advanced thyroid cancers, over 80 percent of tested tumors harbored at least one potentially actionable genetic finding, and every anaplastic cancer in the series had something targetable.26PubMed Central. Next-generation sequencing in thyroid cancers: do targetable alterations lead to a therapeutic advantage? A multicenter experience Among medullary cancers specifically, about 81 percent had RET mutations identified through sequencing.13International Journal of Radiation Oncology*Biology*Physics. Comprehensive Genomic Characterization of Thyroid Cancers: Real-world Implementation and Impact on Clinical Decisions
A practical sequencing strategy that has emerged is to start with a single-gene BRAF test, then move to broader panel testing if BRAF is negative. This stepwise approach is especially useful for younger patients with papillary cancer that has stopped responding to radioiodine, where targetable gene fusions like RET or NTRK rearrangements may be present in roughly 30 percent of BRAF-negative cases.27PubMed. Next-generation sequencing of targetable gene fusions in radioiodine-refractory thyroid cancer: a multicenter study
When Radioiodine Stops Working
Radioiodine therapy works because normal thyroid cells, and many thyroid cancer cells, actively absorb iodine. When cancer cells lose that ability through dedifferentiation, the treatment becomes useless. This is called radioiodine-refractory disease, and it is a turning point in the management of any follicular cell-derived thyroid cancer. The main molecular culprit is overactivation of the MAPK signaling pathway, which shuts down the proteins responsible for pulling iodine into cells.28PubMed Central. Redifferentiation Therapies in Thyroid Oncology: Molecular and Clinical Aspects
Redifferentiation therapy is the attempt to reverse this process using drugs that quiet the overactive signaling pathway, coaxing cancer cells back into a state where they absorb iodine again. In one study, about 58 percent of patients treated with redifferentiation drugs regained radioiodine uptake. The results were most striking in tumors driven by RAS mutations: all 11 RAS-mutant cancers in the study redifferentiated, compared with about 39 percent of BRAF-mutant tumors.29PubMed. Clinical Outcomes of Radioactive Iodine Redifferentiation Therapy in Previously Iodine Refractory Differentiated Thyroid Cancers This approach is still relatively new and is being tested in larger studies, but for patients whose cancer has stopped responding to radioiodine and who carry the right mutations, it represents a way to reactivate a treatment that was once considered exhausted.30PubMed. Redifferentiation-facilitated radioiodine therapy in thyroid cancer
Surgery for Locally Invasive Disease
Rare thyroid cancers, particularly anaplastic and poorly differentiated types, are more likely to invade the trachea and other structures in the neck. When a tumor grows into the windpipe, patients face bleeding, airway obstruction, and difficulty breathing. In some cases, an emergency thyroidectomy is needed simply to keep the airway open.
For tumors that have invaded the trachea but are otherwise resectable, removing a segment of the windpipe and reconnecting the ends is considered safe and effective by experienced surgical teams. The procedure provides immediate relief from obstruction and has produced long-term survivors in series where patients were carefully selected. The limit is generally around five or six tracheal rings; beyond that, the remaining trachea cannot be stretched enough to reconnect without excessive tension.31Archives of Surgery. Resectional Treatment for Thyroid Cancer With Tracheal Invasion: A Long-term Follow-up Study A single-center series of 22 patients confirmed that this type of surgery can provide both symptom relief and prolonged survival in patients with deeply invasive disease.32PubMed Central. Laryngotracheal Resection in Thyroid Cancer – Experience from a Single Centre Series of 22 Cases
Peptide Receptor Radionuclide Therapy
For thyroid cancers that no longer absorb radioiodine and do not carry an easily targetable mutation, options thin out. Peptide receptor radionuclide therapy (PRRT) is being explored as an alternative. It works by attaching a radioactive atom to a molecule that binds to somatostatin receptors, which some thyroid cancer cells express on their surface. The drug seeks out those receptors and delivers radiation directly to the tumor. PRRT has shown particular promise in medullary thyroid cancer and in Hürthle cell cancers, a subtype that tends to be less responsive to conventional treatments.33PubMed Central. Peptide Receptor Radionuclide Therapy in Thyroid Cancer The treatment is generally well tolerated, though it remains an option reserved for patients whose cancers express the right receptor target.34PubMed Central. Peptide receptor radionuclide therapy of differentiated thyroid cancer: efficacy and toxicity
Managing the Side Effects of Targeted Therapies
The newer targeted drugs for rare thyroid cancers are a clear advance over older chemotherapy, but they are not side-effect-free. Multi-kinase inhibitors like vandetanib, cabozantinib, and lenvatinib can cause high blood pressure, diarrhea, skin reactions on the palms and soles, fatigue, and weight loss. Dose reductions and temporary pauses are common, and some patients ultimately have to stop treatment because of toxicity.35PubMed. Management of tyrosine kinase inhibitors (TKI) side effects in differentiated and medullary thyroid cancer patients The selective RET inhibitor selpercatinib avoids many of those off-target effects but carries its own risks, including liver toxicity that requires regular monitoring.36PubMed Central. Selpercatinib versus multi-kinase inhibitors for advanced medullary thyroid cancer: A network meta-analysis of RET-targeted therapies – Section: Results
Staying on treatment long enough to benefit requires proactive side-effect management. Both patients and their medical teams need to recognize drug-related problems early so they can be addressed before they become severe enough to force a dose change or treatment stop.37PubMed. Managing tyrosine kinase inhibitors side effects in thyroid cancer This is one of the strongest arguments for having rare thyroid cancers managed at a center with experience in these drugs. A team that has seen dozens of patients on a particular inhibitor can recognize a skin rash or a blood pressure spike as treatable and keep the patient going, where a less experienced team might stop the drug prematurely.
Familial Syndromes and Childhood Risk
While most rare thyroid cancers appear sporadically, a handful are tied to inherited genetic syndromes. The hereditary form of medullary thyroid carcinoma, discussed earlier, is the most well-known. A less familiar syndrome involves mutations in the DICER1 gene, which predisposes carriers to a range of tumors starting in childhood. In the thyroid, DICER1 mutations are associated with early-onset goiter and thyroid carcinomas, including poorly differentiated types that are otherwise almost unheard of in children.38PubMed Central. Proceedings of the North American Society of Head and Neck Pathology, Los Angeles, CA, March 20, 2022: DICER1-Related Thyroid Tumors Carriers of germline DICER1 mutations have a 16- to 18-fold increased risk for thyroid cancer compared with the general population.39Modern Pathology. Poorly differentiated thyroid carcinoma in children and adolescents: a distinct entity characterized by DICER1 mutations
For families where a DICER1 mutation is known, regular thyroid surveillance starting in childhood allows early detection. Unlike hereditary MTC, where preventive thyroid removal is standard practice, the management of DICER1-related thyroid risk is still evolving, and guidelines vary. The key takeaway for parents and pediatricians is that a child or teenager with a rapidly growing multinodular goiter and a family history of unusual tumors deserves genetic evaluation, not just reassurance that thyroid nodules in young people are almost always benign.