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Ronny Allan
Stage of cancer
What is stage? The extent of a cancer in the body. Staging is usually based on the size of the tumour, whether lymph nodes contain cancer, and whether the cancer has spread from the original site to other parts of the body.
What are the stage numbers? Most types of cancers have 4 stages, numbered from 1 to 4 indicating a rising spread as the number is bigger. Some cancers have a stage 0 but I don’t believe this applies to Neuroendocrine Neoplasms (NENs). Often doctors write the stage down in Roman numerals, so you may see stages written as I, II, III and IV.
Wil my staging ever change? You may be given an initial staging based on physical examination, imaging tests, and biopsies of affected areas. After any surgery, pathologists combine the results of both the clinical staging with the surgical results which may result in an update. In certain scenarios, a recurrence or retreatment staging is used to determine the extent of the disease if a cancer comes back after treatment. Recurrence or retreatment staging helps determine the best treatment options for cancer that has returned.
Restaging may also be done to find out how the cancer responded to treatment. If restaging is done and a new stage is assigned, the new stage will be marked with an “r” in front of it to show that it’s different from the original stage. Usually, the original stage stays the same, even if the cancer comes back or gets worse. The same tests that were carried out to diagnose the cancer are usually carried out again. Restaging helps doctors plan the best treatment for cancer that has come back or become worse.
Staging Models
There are two main staging systems in use: American Joint Committee on Cancer (AJCC) and European Neuroendocrine Tumour Society (ENETs). Both are based on the TNM Staging System although the content may differ (in my own research, not that different).
Edit: May 2nd 2024. See a new section below summarising the 2024 update to the AJCC ninth edition covering Gastroenteropancreatic Neuroendocrine Tumors (GEPNETs). This is one of the first cancers to convert from eighth to ninth edition.
What is the TNM Staging System?
The TNM Staging System was developed and is maintained by the AJCC and the Union for International Cancer Control (UICC). It is the most commonly used staging system by medical professionals around the world. The TNM classification system was developed as a tool for doctors to stage different types of cancer based on certain, standardised criteria. Please note with different TNM models, there could be different stage descriptions depending on the location of the primary tumour and similarly different TNM models for different tumour locations. Although most seem to synchronise, this is a really important point for Neuroendocrine Neoplasms (NENs) interpretation due to their multiple primary locations.
The TNM Staging System includes the extent of the tumor (T), extent of spread to the lymph nodes (N), and presence of metastasis (M).
The T category describes the original (primary) tumor.
TX
Primary tumor cannot be evaluated
T0
No evidence as primary tumor
Tis
Carcinoma in situ (early cancer that has not spread to neighboring tissue)
T1–T4
Size and/or extent of the primary tumor
The N category describes whether or not the cancer has reached nearby lymph nodes
NX
Regional lymph nodes cannot be evaluated
N0
No regional lymph node involvement (no cancer found in the lymph nodes)
N1-N3
Involvement of regional lymph nodes (number and/or extent of spread)
The M category tells whether there are distant metastases (spread of cancer to other parts of the body).
M0
No distant metastasis (cancer has not spread to other parts of the body)
M1
Distant metastasis (cancer has spread to distant parts of the body)
Because each cancer type has its own classification system, letters and numbers do not always mean the same thing for every kind of cancer.
Once the T, N, and M are determined, they are combined and an overall stage of 0, I, II, III, IV is assigned. Sometimes these stages are subdivided using letters such as IIIA and IIIB.
Staging of NETs
As above, each cancer type has a different staging definition based on the TNM template. NENs are unique in that there are multiple types based on different organs. Consequently each NET type has its own staging definition. NET staging is therefore more complex than most other cancer types.
Access to AJCC and ENETS staging info is difficult, normally behind a paywall and only accessible to healthcare professionals. However, there are some sites providing useful and up to date extracts. To those reading, it’s worth pointing out that certain NET types may have different TNM definitions in AJCC and ENETS although most are synchronised.
Until this is more publicly available, I will use one of these sources which I know is kept up to date. They also quite often quote from both AJCC and ENETS when there are differences. Click as required.
Lung NET (use Lung Cancer staging definitions)
Pheochromocytoma/Paraganglioma
I will update as I find it. Neuroendocrine Carcinoma (NEC) is more complex, I’m working on it. Also working on access to ENETS, although some are referenced in the above abstracts along with AJCC.
Miscellaneous Pathology terms supporting TNM
You may see some letters preceding or succeeding TNM data. The most common are listed here.
Other descriptors
| Optional descriptors | |
|---|---|
| Pn – Perineural invasion | |
| PnX | Perineural invasion cannot be assessed |
| Pn0 | No perineural invasion |
| Pn1 | Perineural invasion |
| L – Lymphatic invasion | |
| LX | Lymphatic invasion cannot be assessed |
| L0 | No lymphatic invasion |
| L1 | Lymphatic invasion |
| V – Venous invasion | |
| VX | Venous invasion cannot be assessed |
| V0 | No venous invasion |
| V1 | Microscopic venous invasion |
| V2 | Macroscopic venous invasion |
Prefix modifiers
- c: stage is determined from evidence acquired before treatment (including clinical examination, imaging, endoscopy, biopsy, surgical exploration). The c-prefix is implicit in absence of the p-prefix.
- p: stage given by histopathologic examination of a surgical specimen
- y: stage assessed after chemotherapy and/or radiation therapy; in other words, the individual had neoadjuvant therapy.
- r: stage for a recurrent tumor in an individual that had some period of time free from the disease.
- a: stage determined at autopsy.
- m: tumor is multifocal (more than 1 tumors). The opposite, s, can be used when there is particular reason to emphasize that the tumor is solitary/single.
2024 Update to the AJCC Staging Manual for Site-Agnostic Changes to Gastroenteropancretic Neuroendocrine Tumors (GEPNETs)
- General. The 9th edition updates to the new grading system whereby a Grade 3 well differentiated NET is introduced (prior to that all Grade 3 cases used Neuroendocrine Carcinoma nomenclature. The term Neuroendocrine Carcinoma is now by default a poorly differeniated case. The overarching term Neuroendocrine Neoplasm is introduced to group both well and poorly differentiated tumours into a single entity encompassing both.
- Endoscopically Treated NETs – Gastric (stomach), Duodenal, and Colorectal NETs. In the eighth edition, T1NX NETs were not staged. However, it is now acknowledged that most early stage NETs in the stomach, duodenum, and colorectum, are treated endoscopically. More importantly, T1NXM0 tumors have similar/no worse survival compared with T1N0M0 tumors. Therefore, T1NXM0 is recognized as stage I in these sites, which is a major change from the eighth edition.
- PPI-related Gastric NET. Given the association between proton pump inhibitor (PPI) use and hypergastrinemia and the common use of PPIs, there has been concern for a rise in PPI-related gastric NETs. Although this has not occurred, experts now recognize the existence of PPI-associated tumors, which seem to demonstrate indolent behavior (similar to type 1 tumors).
- Pancreatic NETs. There are no changes in the T, N, or M categories for pancreatic NETs in AJCC version 9. However, several emerging prognostic markers were reviewed in this update. However, currently, the routine use of these markers was not suggested.
- Small Intestine NETs (Ileum/Judenum). Prognostic factors were mentioned, specificaly studies found that there was no significant difference in survival between stage I/II and III midgut NETs. further analysis showing that, among patients who had stage III NETs. The 5-year survival for those with resectable tumors who also underwent a lymph node dissection was significantly better than for those whose tumors were unresectable. Additional studies have demonstrated that the number of lymph nodes removed has prognostic significance, with better survival in patients who underwent a more extensive lymphadenectomy. The lack of hierarchical prognostication by stage group observed in the AJCC survival analysis may be caused by insufficient lymph node dissection, leading to inaccurate staging. Importantly, the current AJCC version 9 staging rules do not include a recommendation for the minimum lymph nodes assessed in resection specimens of jejunal/ileal NETs. The pathologic N2 category (pN2), introduced in the AJCC eighth edition (released in 2018) and maintained in the ninth edition, is defined by the presence of large mesenteric masses (>2 cm) and/or extensive (≥12) nodal deposits, especially those that encase the superior mesenteric vessels. The data element of mesenteric masses was not collected and thus could not be considered in the construction of the survival curves presented here. It has been reported that mesenteric tumor deposits (irregular mesenteric tumor masses with entrapped, large vessels and nerves) may be a stronger prognostic predictor than lymph node metastasis for the development of liver metastases and for survival.
- Appendiceal NETs. Tumor size and invasion of the mesoappendix have been thought to be important prognosticators; however, contemporary studies have shown that mesoappendix invasion may not be an independent predictor of lymph node metastases. Emerging data suggest similar long-term outcomes with conservative appendectomy compared with a definitive right hemicolectomy for 1–2 cm appendiceal NETs. T1–T2 tumors are typically managed by appendectomy alone without lymph node sampling, thus no pathologic stage was assigned for this group of tumors. A review of available data revealed that patients who had T1NXM0 and T1N0M0 tumors had similar survival. Therefore, T1NXM0 has been added to stage I in AJCC version 9. In addition, T2NXM0 has been added to stage II because patients who have tumors with negative lymph nodes (N0) and unknown nodal status (NX) have similar survival.
- Colorectal NETs. The ninth edition confirmed that Rectal NETs have the highest incidence in US (closely followed by small intestine NETs). Rectal NETs comprise around 85% of all colorectal NETs and are typically incidentially diagnosed and have an indolent beheviouer. Colon NETs tend to be more biologically aggressive, with most patients treated surgically. Up to 90% of Rectal NETs are less than 1cm on discovery and normally endoscopically treated. Above that size, the size and margins tend to dictate treatment.
References
- The Eighth Edition AJCC Cancer Staging Manual (p.s Ninth edition being rolled out 2024 and NET is front of the line!).
- ENETS
- Pathology Outlines
Critical updates in neuroendocrine tumors: Version 9 American Joint Committee on Cancer staging system for gastroenteropancreatic neuroendocrine tumors. Aman Chauhan MD, Kelley Chan MD, Thorvardur R. Halfdanarson MD, Andrew M. Bellizzi MD, Guido Rindi MD, PhD, Dermot O’Toole MD, Phillip S. Ge MD, Dhanpat Jain MD, Arvind Dasari MD, Daniel A. Anaya MD, MSHCT, Emily Bergsland MD, Erik Mittra MD, PhD, Alice C. Wei MD, Thomas A. Hope MD, Ayse T. Kendi MD, Samantha M. Thomas MS, Sherlonda Flem BS, CTR, James Brierley MB, Elliot A. Asare MD, MS, Kay Washington MD, PhD, Chanjuan Shi MD, PhD First published: 29 April 2024 https://doi.org/10.3322/caac.2184
Now read about Grade and the WHO 2022 Classification
Click here or on the graphic below
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