Lateral Neck Nodes Are Not Automatically Stage IV: Medullary Thyroid Cancer Staging
In this article
Lateral Neck Nodes Are Not Automatically Stage IV: Medullary Thyroid Cancer Staging
Stage is one of the most loaded words a cancer patient hears. In medullary thyroid cancer, the staging system used today calls even a patient with a single involved lymph node in the side of the neck "stage IV", yet most of these patients go on to live well for many years after surgery. An international study published in the Journal of Clinical Oncology on November 4, 2026 pooled the data of 2,573 patients from 43 centers in 15 countries, including Türkiye, and proposed a more realistic staging system. The proposal has two parts: defining the lymph nodes of the upper mediastinum as a separate, highest-risk category, and rebuilding the stage groups from scratch. In this article we explain what is changing and why, what it means for patients, and where the proposal falls short. You can find the basics of how cancer is staged in our article on stage and metastasis (in Turkish).
- What is the problem? In the AJCC TNM-8 system, every patient with lymph node involvement in the side of the neck (levels I-V) is automatically counted as stage IV. This piles more than 40% of patients into stage IV and leaves no real difference in risk between stages I, II and III.
- Two changes: Lymph node involvement in the upper mediastinum (level VII) moves from N1a in the current system to a new, highest-risk N1c category. The stage groups are rebuilt by choosing the statistically best-fitting arrangement out of 116,284 possible ones.
- Result: The share of patients classed as stage IV falls from 42.4% to 20.2%. The survival gap between stages becomes clearer; discrimination (C-index) rises from 0.856 to 0.892.
- What does not change? The patient's tumor, its biology and the real survival outlook stay the same. This is an update to a measuring tool; it does not directly change treatment decisions. The proposal has not yet been adopted by the AJCC.
Why does this topic matter?
Staging is a way of describing how far a cancer has spread in a common language. It makes communication between physicians, comparison of cancer registries and the design of clinical trials possible. For the patient, however, the stage number has another meaning: it is the first and most memorable piece of information they read about their own future. To most people, the words "stage IV" suggest an advanced, irreversible disease (fear of recurrence, in Turkish).
In medullary thyroid cancer this creates a particular problem. The disease often spreads to the lymph nodes of the neck, yet its course is frequently good once these are removed surgically. Because even one involved lymph node in the side of the neck puts a patient into stage IV in the current system, many patients who will live healthily for years find themselves labeled "end stage". The authors of the study describe this plainly as an unnecessary source of anxiety (what are lymph nodes?, spread to lymph nodes; both in Turkish).
There is a technical side to this as well: the job of a staging system is to separate patients with different courses from each other. In the current system, 10-year survival in stages I, II and III comes out almost the same, so these three steps carry practically no information. At the same time, patients with very different courses are gathered in the same box within stage IV (cancer biology, in Turkish).
What is medullary thyroid cancer?
Medullary thyroid cancer arises not from the hormone-producing follicular cells of the thyroid gland, but from parafollicular C cells that secrete calcitonin; it is a neuroendocrine cancer. It makes up about 3% of all thyroid cancers but accounts for about 13% of lives lost to thyroid cancer. About one in five cases is hereditary and linked to changes in the RET gene.
This origin also determines how the disease behaves. Medullary thyroid cancer does not respond to radioactive iodine treatment, so surgery is the foundation of treatment. Calcitonin and carcinoembryonic antigen (CEA) measured in the blood are the most important markers used to follow the presence and course of the disease. In advanced disease, multitargeted drugs such as vandetanib and cabozantinib are used, and in those carrying a RET change, selective RET inhibitors such as selpercatinib (vandetanib, neuroendocrine tumors; both in Turkish).
The characteristics of the 2,573 patients in the study reflect the typical picture of the disease: median age 52, female-to-male ratio about 1.25 to 1, median follow-up 76.3 months. Of the 2,186 patients in whom heredity could be assessed, the disease was sporadic (non-familial) in 1,765 and hereditary in 421. The whole thyroid had been removed in 81.9% of patients. Disease-related loss of life during follow-up was recorded at 9.1% (hereditary cancer syndromes, in Turkish).
Why does the location of lymph node involvement matter?
As medullary thyroid cancer spreads, it first reaches the central neck lymph nodes right around the thyroid (level VI), then the nodes in the side of the neck (levels I-V). There is also a third region: the upper mediastinum (level VII), below the level of the collarbone in the upper part of the chest. Because it cannot be reached through a standard neck incision, involvement here both signals a more advanced disease and is technically harder to treat surgically (head and neck region, in Turkish).
Figure 1 · Where is the involvement?
Neck regions and N categories
The study clearly showed the effect of this distinction. 10-year disease-specific survival was 98.32% in those without lymph node involvement, 94.24% with central neck involvement, 81.36% with lateral neck involvement and 68.37% with upper mediastinal involvement. All the differences between the four groups were statistically significant, and the same ranking was repeated in the US SEER data.
How strongly is the location of lymph node involvement related to survival?
10-year disease-specific survival; international group of 2,573 patients. N1c is the newly proposed category.
Level VII involvement is counted as N1a in the current system; these data support moving it to the highest-risk group. The rates were calculated from retrospectively collected data.
In patients with upper mediastinal involvement the T category was higher and distant spread was more frequent; in other words, involvement in this region is a sign of a heavier disease burden. For this reason the study proposes moving level VII from N1a in the current system to a new N1c category.
How were the stage groups rebuilt?
The second and bolder step of the study was to redesign the stage groups from the ground up. The researchers first fixed patients with distant spread as stage IVC. For the remaining patients, they calculated in how many different ways all possible combinations of the T category (tumor size and spread beyond the thyroid) and the new N category could be distributed into five stage groups: 116,284 arrangements that made clinical sense. They fed every arrangement into a statistical model adjusted for age, sex, geographic region, extent of surgery, heredity and year of diagnosis, and chose the arrangement that fit best (reading research results correctly, in Turkish).
Figure 2 · How was the study done?
The method in five steps
There is one more important methodological choice: disease-specific survival, not overall survival, was chosen as the main measure. Because the course of medullary thyroid cancer lasts many years, losses from other causes such as heart disease during that time distort the overall survival calculation and hide the true discriminating power of staging.
The resulting system
In the new proposal the T category does not change at all; only the N category and the arrangement of the stage groups change. Lateral neck involvement (N1b) no longer automatically means stage IV; depending on tumor size it can be stage II, III or IVA. In contrast, upper mediastinal involvement moves the patient to at least stage III even if the tumor is small.
Figure 3 · The newly proposed stage groups
Same T category, different arrangement
The effect of this change at the individual level can be shown with three examples. A patient with a 1.5 cm tumor and involvement only in the central neck is stage III in the current system but becomes stage I in the new proposal. A patient with a 2 cm tumor and involvement in the lateral neck drops from stage IVA to stage III. In contrast, a patient with a 3 cm tumor and involvement in the upper mediastinum, who is stage III in the current system, rises to stage IVA in the new proposal (reading the pathology report, in Turkish).
Figure 4 · The same patient, two systems
How does the stage change in three examples?
How much improvement was achieved?
The pile-up in stage IV is reduced
In the current system, 42.4% of patients in the international group were classed as stage IV; in the new proposal this falls to 20.2%. In the SEER data the share drops from 27.7% to 20.4%. In contrast, the share of patients in stage I rises from 31.0% to 50.1% in the international group and from 38.2% to 57.7% in SEER. In other words, in the new system more than half of patients are gathered in the lowest-risk group, which fits the true course of the disease much better.
Figure 5 · How are patients distributed across stages?
Current system and new proposal, in two separate patient groups
The gap between stages becomes clearer
The real test is how well the stage number reflects true risk. In the current system, 10-year disease-specific survival was 99.17% in stage I, 98.63% in stage II, 95.89% in stage III and 77.13% in stage IV; in other words, the first three steps barely separate from one another. When the same patients are restaged under the new proposal, the rates are 99.49%, 94.33%, 86.42% and 60.63%; the steps descend in an orderly way.
Survival by stage in the two systems
10-year disease-specific survival; the same 2,573 patients restaged under the two systems.
In the current system, stages I, II and III are very close to each other; the stage number creates no real difference in risk between patients. In the new proposal the steps separate clearly. Because the same patients are reclassified under both systems, this comparison is direct.
The same picture appears statistically. In the current system the adjusted hazard ratios relative to stage I are 0.84 for stage II (not significant), 1.48 for stage III (not significant) and 7.95 for stage IV; in the new proposal they are 2.22, 4.81 and 15.75 respectively, all significant. The C-index, which measures discrimination, rises from 0.856 to 0.892 in the international group (difference 0.035; p<0.001) (reading the numbers in the report, in Turkish).
The inside of stage IV improves too
Another problem of the current system is that the subgroups of stage IV do not fit each other. In patients in stage IVA, 10-year survival is 83.54%, close to stage III (95.89%), while stage IVB (45.94%) and IVC (41.48%) are far worse. In other words, the name "stage IVA" carries far more weight than the risk it holds. In the new proposal, survival in stage IVA is 73.27%, falling neatly between stage III (86.42%) and stage IVB (54.95%).
Figure 6 · Inside stage IV
Do the subgroups separate from one another?
What does this proposal change and not change?
The most common confusion has to be spelled out here: a change in the stage number does not mean a change in the patient's disease. It is the same tumor, the same lymph nodes, the same treatment and the same real survival outlook. The only thing that changes is the name this picture goes by. Staging is a measuring tool; treatment decisions are made according to the tumor's biology, calcitonin level, completeness of surgery and the course of the disease (biopsy and the diagnostic process, in Turkish).
That said, correct staging is not an empty formality either. It plays a direct role in selecting patients for clinical trials, comparing cancer registries between countries and planning the intensity of follow-up. In addition, how well patients understand their own situation affects their adherence to treatment and their mental health (a similar reappraisal in breast cancer, how are classification systems updated?; both in Turkish).
Figure 7 · What changes and what does not
What does staging tell and not tell?
What are the limits of this study?
- Retrospective data: Patients were treated between 1977 and 2025 and the data were collected afterward. Over such a long period, surgical techniques, imaging and drug treatments changed considerably.
- Only patients who had surgery: Patients who had not had lymph node surgery were not included in the international group. This means those whose disease was too advanced for surgery were left out, which limits generalizing the results to the whole range of patients.
- Detection of level VII depends on the center: Seeing upper mediastinal involvement depends on a CT scan before surgery, which varies by country, period and center. Indeed, upper mediastinal involvement appears to have been detected more often in the international group because of the weight of centers where routine CT is common.
- Calcitonin could not be taken into account: Calcitonin is the most important marker of medullary thyroid cancer, but because measurement methods and reference ranges differ greatly between centers, it could not be included in the analysis. Likewise, tumor grading was defined in 2022, so it was missing in older patients (follow-up with blood markers, in Turkish).
- External validation was partly successful: In the SEER data the new system again separated the stages neatly; however, the gain in discrimination there was not statistically significant (from 0.852 to 0.860; p=0.280). In other words, the size of the improvement may vary with the data source.
- Not yet official: This is a proposal. The AJCC now updates staging systems disease by disease rather than as a whole "edition", and the current version for the thyroid is still the 8th edition. Until the proposal is accepted, the current system will be used in pathology and clinical reports (how are guidelines updated?, in Turkish).
The situation in Türkiye
- Türkiye is part of the study: Ankara Bilkent City Hospital joined the consortium with 67 patients, and researchers from Türkiye are among the authors. This means the proposal also covers the patient profile in Türkiye.
- What should be done in reporting? Until the proposal becomes official, AJCC TNM-8 should continue to be used in pathology and clinical reports. At the same time, clearly writing the level of the involved lymph nodes in surgery and pathology reports is valuable so that restaging can be done in the future.
- Screening for hereditary disease: Every patient diagnosed with medullary thyroid cancer is advised to have hereditary testing for the RET gene; if the result is positive, first-degree relatives also need to be evaluated (hereditary gene analysis, in Turkish).
- Access to drugs: The license and reimbursement status in Türkiye of the targeted drugs used in advanced disease changes over time; ask your treatment team for current information (access to FDA-approved drugs in Türkiye, SGK reimbursement conditions; both in Turkish).
- Follow-up: Follow-up after surgery is planned less by the stage number than by the course of calcitonin and CEA levels, their doubling time and imaging findings (cancer statistics in Türkiye, in Turkish).
Questions you can ask your doctor
- At which levels are the involved lymph nodes in my pathology report; is there involvement in the upper mediastinum?
- What is my stage in the current system; would it change under this new proposal?
- Does my stage number determine my follow-up frequency or treatment plan, or is the course of calcitonin more decisive?
- Could my surgery be completed fully; were any suspicious lymph nodes left behind?
- Has hereditary testing for the RET gene been done; does my family need to be screened?
- "If my stage drops, my disease has become milder." No. A staging system is a measuring tool; only the naming changes. The tumor, the involvement and the real course stay the same.
- "Stage IV in medullary thyroid cancer means a short life expectancy." No. In the current system, 10-year disease-specific survival in patients in stage IVA was 83.54%; part of the problem comes precisely from how misleading this naming is.
- "This system is already in use." No. The proposal has not yet been accepted by the AJCC; the current system applies in official reports (from scientific proposal to practice, in Turkish).
- "Radioactive iodine is also given in medullary thyroid cancer." No. Because this cancer arises from C cells, it does not take up iodine; radioactive iodine treatment is not effective.
- "Diarrhea or facial flushing is not a side effect." In advanced disease, high levels of calcitonin and related substances can cause diarrhea and flushing of the skin; these complaints should be reported and treated (managing diarrhea, common misconceptions about cancer; both in Turkish).
Frequently Asked Questions
- What is medullary thyroid cancer?
- It is a neuroendocrine cancer arising from the calcitonin-secreting C cells of the thyroid gland. It makes up about 3% of all thyroid cancers, does not respond to radioactive iodine, and surgery is the foundation of its treatment. About one in five cases is hereditary.
- Why is staging changing in medullary thyroid cancer?
- In today's system, even a single involved lymph node in the side of the neck takes the patient to stage IV, which piles more than 40% of patients into the same box. The new proposal aims for the stage number to reflect true risk more accurately.
- What changes in the new proposal?
- Two things: involvement of upper mediastinal (level VII) lymph nodes moves to a new, highest-risk N1c category, and the stage groups are rebuilt. As a result, the share of patients classed as stage IV falls from 42.4% to 20.2%.
- If my stage changes, will my treatment change too?
- No. Staging is a measuring tool that describes how far the disease has spread. Treatment decisions are made according to the tumor's features, completeness of surgery, the course of calcitonin and imaging findings. In addition, this proposal has not yet been officially accepted.
Glossary
- Medullary thyroid cancer
- A neuroendocrine cancer type arising from the calcitonin-secreting C cells of the thyroid.
- Calcitonin
- The hormone secreted by C cells; the main blood marker used for diagnosis and follow-up in this cancer.
- RET gene
- A gene whose changes can cause medullary thyroid cancer, seen in both hereditary and acquired forms.
- TNM system
- A classification that describes how far a cancer has spread by tumor size (T), lymph node involvement (N) and distant spread (M).
- AJCC
- The American joint committee that publishes cancer staging systems.
- Level VI (central neck)
- The lymph node region right around the thyroid gland.
- Level VII (upper mediastinum)
- The lymph node region below the level of the collarbone, in the upper part of the chest.
- Disease-specific survival
- A survival measure that counts only losses of life due to the cancer in question.
- C-index
- A measure, from 0 to 1, of the power of a model or staging system to correctly rank which patients will do worse.
- Adjusted hazard ratio
- The value showing the difference in risk between two groups after factors such as age and sex are taken into account.
DROZDOGAN Academy Commentary
This study does not offer a new treatment, but it brings a proposal that will change how patients name their own disease. Collecting data from 15 countries for a rare cancer is valuable in itself.
⚡ Why it matters
The pile-up in stage IV has long been a known problem in medullary thyroid cancer and one that places an unnecessary burden on patients. The study not only describes this problem, but builds the replacement system from data and tests it in an independent data source.
✅ Strengths
A very large and geographically broad patient group for a rare disease; a shared data dictionary and central verification; choosing disease-specific survival as the main measure; trying every possible stage arrangement one by one; sensitivity analyses removing centers one at a time, showing that no single center drove the result.
⚠️ Limits
A retrospective design and a very long treatment period; including only patients who had surgery; detection of level VII involvement depending on imaging habits; calcitonin and tumor grade not being part of the analysis; the gain in discrimination in the SEER data not being significant.
🩺 In practice
We tell our patients that the stage number is a communication tool, and that the treatment and follow-up plan are built on the course of calcitonin and the completeness of surgery. We see stating the lymph node levels separately in surgery and pathology reports as a habit to start today.
❓ Open questions
Can the calcitonin level and its doubling time be added to the staging system? Will discrimination improve further when the tumor grading defined in 2022 is added? When, and to what extent, will the AJCC adopt this proposal?
Conclusion: The proposal brings the stage number closer to reality in medullary thyroid cancer and has the potential to free many patients with lateral neck involvement from a label they do not deserve. For it to become official, AJCC evaluation and independent validation are needed.
- This article was prepared in November 2026.
- The information is taken from the study by Shi and colleagues published in the Journal of Clinical Oncology on November 4, 2026. The study is retrospective, and the proposed system has not yet been accepted by the AJCC.
- Survival rates are disease-specific survival; that is, losses of life due to other causes are not counted. Overall survival rates will be lower than these values.
- The license and reimbursement status in Türkiye of the drugs used in medullary thyroid cancer has not been verified in detail in this article. The drawings are simplified. The Academy commentary is our own.
- This article is not medical advice; make your health decisions together with your doctor.
Sources
- Shi X, Liu Q, Xu B, et al; International Medullary Thyroid Cancer Staging Consortium. International initiative on a refined staging system for medullary thyroid cancer: a multinational multicenter study. J Clin Oncol 2026. doi:10.1200/JCO-26-01146. doi.org
- Adam MA, Thomas S, Roman SA, et al. Rethinking the current American Joint Committee on Cancer TNM staging system for medullary thyroid cancer. JAMA Surg 2017;152:869-876. doi.org
- American Joint Committee on Cancer. AJCC Cancer Staging System, Version 9 (disease-based update model and current version list). facs.org
- Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers; LIBRETTO-531 results and FDA full approval (September 27, 2024). esmo.org
- OncLive. Selpercatinib significantly improves PFS and responses in advanced RET-mutant medullary thyroid cancer. onclive.com
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