Publications Update # 74

Last updated on Oct 6, 2024

Source: Wikipedia

Non-Medical Article of the Week

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How to find Laughter Everywhere by Chris Duffy

FIGO 2023 Endometrial Cancer Staging

I am sure you are all aware of FIGO 2023 endometrial staging by now. Whether you are using it or not is a different question. The changes in endometrial cancer staging have been unsettling. A lot has been written about these in the last year, and I am going to try to summarize these in this newsletter.

The primary issue with this staging system lies in the interpretation of the term "staging." Does "staging" refer to a hierarchical representation of the anatomical and/or histopathological spread of the disease, or is it intended to function as a risk stratification system?

What are the new changes in FIGO 2023?

Here is a better way to look at the 2023 staging. I recommend that you print this paper and keep it handy in your Apple Notes/Google Keep apps on the phone (or whatever system for storage on the go you use)

Staging System

Let's discuss some controversies with this staging system:

Controversy # 1: Lymphovascular Space Invasion

This system would require pathologists to report lymphovascular invasion in three categories: absent, focal, or substantial.

Anyone with non-aggressive histology with "substantial LVSI" will be upstaged to stage IIB

Determining LVSI

Problems in reporting LVSI are highlighted nicely in this paper:

Some critical issues highlighted by the authors include:

The definitions of “multifocal” or “diffuse” LVSI are not standardized, leading to inconsistency in reporting.
The reported LVSI foci can vary significantly due to the non-standardized number of microscopic sections examined.
There is poor reproducibility among pathologists, leading to inconsistencies in diagnosing LVSI.
The interpretation of LVSI can be impacted by necrosis and pre-analytical phase issues, affecting accuracy.

What is "focal" and "substantial" LVSI?

Focal LVSI is defined as <5 vessels involved.

Substantial LVSI is defined as ≥5 vessels involved

A combined analysis of PORTEC trials reported that substantial LVSI was present in nearly 5% of the patients. These patients had a much higher rate of locoregional recurrences.

It is important to remember that PORTEC trial patients did not have lymph node analysis. It is very likely that the substantial LVSI was just a proxy for undetected Stage III disease in this cohort. Neverthless, the definitions were created by the same team that lead PORTEC studies.

Is there any evidence to suggest that substantial LVSI could be a proxy to lymph node positivity?

Two papers address this question:

Study # 1

It is a small study but concludes the following:

Our results suggest that substantial LVSI does not predict worse survival endpoints or different recurrence patterns in women with stage-I EC with PNNE when compared to focal LVSI.

Study # 2

In this study, the risk of recurrence was elevated for both focal and substantial LVSI cohorts. Although LVSI was an independent predictor of recurrence, there was no difference between focal and substantial LVSI.

What happens now that substantial LVSI upstages patients to stage 2B?

LVSI predicts worse outcomes, but the difference between substantial and focal is not meaningful in patients who have undergone lymph node evaluation and are node-negative. LVSI in the FIGO 2023 staging system is an unvalidated metric, poorly studied, lacks reproducibility, and is highly subjective. Using just "substantial" LVSI to upstage patients is a theoretical exercise that ultimately provides no real benefit to patient care in patients who have undergone lymph node assessment. It may be helpful to centers where lymph node dissection is not routinely performed. The WORST part is that it will likely increase the EBRT utilization by upstaging patients to stage 2b.

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I speculate that no one on the FIGO committee has ever done an implementation science project. Otherwise, they would have known that a more complex message always brews a fierce shitstorm.

Controversy # 2: Molecular Classification

The staging system does not mention MMRd and the NSMP except in the footnote. It should either include all molecular classifiers or not include them at all.

In colon cancer, recent data shows that treating locally advanced colon cancer patients with immunotherapy alone generated a 100% complete response. Not creating a separate category for MMRd seems counterintuitive.

Controversy # 3: Loss of Information

For those working with large databases, collecting data in discrete fields that capture individual elements is crucial rather than merging information into a single field. For example, when using the Charlson Comorbidity Scoring System to assess patient comorbidities, it's more effective to record each component of the score (e.g., heart failure, diabetes) as separate yes/no entries. This granular approach not only allows the creation of an overall score but also enables a deeper analysis of which specific components impact outcomes most. In contrast, combined data lose the nuanced value of each element.

Consider these examples: two patients with Charlson scores of 2.

A 65-year-old with congestive heart failure
A 75-year-old with no comorbidities.

Although both scores are the same, the clinical implications differ significantly. Viewing only the combined score obscures important details that could influence decision-making.

Similarly, this approach applies to staging systems. For instance, these three patients are classified as stage 2c:

A 65-year-old with uterine papillary serous carcinoma, 3/11 mm depth of invasion, and p53 mutation.
A 65-year-old with uterine papillary serous carcinoma, 10/11 mm depth of invasion, and p53 mutation.
65-year-old with Grade 2 endometrial cancer, 2/11 mm depth of invasion, p53 mutation, and negative lymphovascular space invasion (LVSI).

Why not just keep the stage and the prognostic factors separate?

What changes should I expect in my practice if I adopt FIGO 2023?

Short answer - None for now!

Long answer: An excellent paper from the City of Hope Cancer Center explores this question.

Several patients will experience a stage shift. Ultimately, however, how you treat these patients may not be so different. Let's take a look at some of these newly formed stages:

Stage IC: Aggressive histology limited to a polyp or confined to the endometrium, currently known as Stage IA ____(e.g., Stage IA UPSC or Stage IA clear cell). Impact: No management change is likely. For those confined to polyps with no residual disease, NCCN recommends observation. We will call them stage IC, but nothing changes.
Stage IIB: Non-aggressive histology with substantial LVSI (See the section above for detailed discussion). Impact - Likely increased utilization of EBRT with unclear benefit, unless NCCN guidelines specify that stage IIB should get EBRT only if the absence of nodal evaluation.
Stage IICmp53abn: Aggressive histologies with myometrial invasion. Currently, they fall under IA or IB, depending on the depth of invasion. Impact - none likely. They all get treated with chemotherapy anyway - except endometrioid p53 mutated tumors. Perhaps chemotherapy for these patients is reasonable in the future.
Stage IIIA1 and IIIA2: The current stage IIIA is now split between these two stages: IIIA1 ovarian or fallopian tube invasion and IIIA2 uterine serosa. Impact: None, but the treatment will be the same.

What is good about this new staging system?

According to the NCDB, restaging (although this does not include molecular classification) improves prognostication. However, the number of stages and sub-stages is directly proportional to the staging system's prognosticating ability. Therefore, this enhanced prognostication ability might reflect the increased number of substages in the new staging system.

What do the new staging system authors have to say about their work?

One word: Defiant!

One word: Defiant! This paper showcases the extraordinary lengths these eight experts go to assert their vision of the right course for navigating the complex waters of endometrial cancer management.

Is there a solution?

To understand the root cause of why it's all very confusing, you have to step back and appreciate that gynecologic malignancies are the only cancers not staged by TNM staging. If we switch to TNM staging, we could use a system analogous to breast cancer where TNM staging categories are blended with molecular results to create the final stage.

Here is how breast cancer handles this in their staging system:

Breast cancer Staging System (TNM with molecular features). Source: Medscape

My solution, switch to TNM staging with molecular markers incorporated in the staging system.