APPENDICURE

A new study maps the genetic landscape of appendiceal cancer by subtype and stage. Here is what the data shows, and where it still has limits. Here is the original article from ScienceDirect and The American Journal of Surgery: Uncovering Molecular Pathways in Appendiceal Cancer: A Comprehensive Characterization for Precision Oncology

A study published this month in The American Journal of Surgery analyzed the molecular makeup of 861 appendiceal cancer tumors, one of the largest genomic datasets ever assembled for this disease. The researchers mapped alterations across seven major signaling pathways and asked whether those patterns differ by tumor subtype and disease stage. In most cases, they do.

The findings matter because appendiceal cancer is not one disease. The four main histologic subtypes: Low-grade mucinous tumors, moderate- to high-grade adenocarcinoma, goblet cell adenocarcinoma, and signet ring cell adenocarcinoma — behave differently, spread differently, and respond to treatment differently. This study adds molecular evidence to that clinical reality.

Before getting into the subtypes: most of the survival findings in this study apply to primary appendiceal cancer as a whole and metastatic appendiceal cancer as a whole, not to individual histologic groups separately. Where the data is subtype-specific, we say so. Where it is not, we say that too.

LAMN and Low-Grade Mucinous Adenocarcinoma

Also called: Low-grade appendiceal mucinous neoplasm (LAMN). When these tumors spread within the abdomen, they can cause pseudomyxoma peritonei (PMP). Labeled Group 1 in this study.

Low-grade mucinous tumors are the most common appendiceal diagnosis. They tend to grow slowly, and when they spread, they usually do so along the peritoneal lining rather than through the bloodstream — which is why the treatment approach for advanced disease often involves cytoreductive surgery and HIPEC rather than systemic chemotherapy alone.

This study does not separately report pathway frequencies or survival outcomes for Group 1 tumors. What it reports, across primary appendiceal cancers overall, is that RTK/RAS and MAPK pathway alterations were associated with better survival, and that PI3K pathway alterations and SMAD4 mutations were more common in primary than metastatic tumors. Those findings apply to the full primary tumor cohort, which includes Group 1, but cannot be attributed to low-grade tumors specifically based on what the paper reports.

Within the RTK/RAS pathway, specific genes – SOS1, KIT, and RAF1 – were significantly more common in primary than metastatic tumors overall. Whether that pattern holds within Group 1 specifically is a question this paper does not answer.

The PI3K finding is worth noting across the cohort: PI3K alterations appeared in 18.2% of primary tumors versus 12.9% of metastatic tumors. The PI3K/AKT pathway is one of the most actively studied in oncology drug development, so knowing whether your tumor carries those alterations may become relevant as research advances. This paper does not establish a treatment implication, but it is a reasonable data point to have.

What this means if this is your diagnosis

The study does not establish subtype-specific survival findings for low-grade tumors. The overall primary tumor survival associations are encouraging context, but should not be applied to your individual prognosis without your care team’s input.

Ask whether your tumor has been molecularly profiled and what pathway alterations were identified. That baseline may matter if treatment decisions become more complex over time.

PMP is a clinical syndrome caused by mucinous spread to the peritoneum, not a separate tumor type. If your LAMN has spread, ask whether you have been evaluated by a team experienced in CRS/HIPEC for PMP.

Moderate- to High-Grade Adenocarcinoma

Also called: Mucinous adenocarcinoma (high grade), colonic-type adenocarcinoma. Labeled Group 2 in this study — the most common subtype in this dataset (36.1% of primary, 43.6% of metastatic cases).

Moderate- to high-grade adenocarcinoma was the most frequently represented subtype in this study, which itself reflects something clinically true: this subtype tends to present at more advanced stages.

Group 2 is where this study provides its most specific pathway data. PI3K pathway alterations appeared in 22.1% of primary Group 2 tumors versus 11.0% of metastatic Group 2 tumors, a statistically significant difference. What that difference means biologically is less certain. It could reflect different natural histories for PI3K-altered tumors, or it could reflect that those tumors are more likely to be caught earlier. The paper reports the association; it does not establish a mechanism.

On TP53: the study’s overall finding is that TP53 pathway alterations in metastatic appendiceal cancer were associated with worse survival. That finding applies to the metastatic cohort as a whole. The paper does not provide a TP53 frequency comparison specific to Group 2, and it does not establish a Group 2-specific survival analysis.

Given that Group 2 makes up such a large share of the metastatic cohort, the overall finding is worth discussing with your oncologist, but the data should not be read as Group 2-specific proof.

The study also found that tumor mutational burden rises with disease stage across the full cohort.

Patients may want to ask whether TMB and mismatch repair status were tested, since those results can be relevant for immunotherapy eligibility in some cancers. This paper found TMB rose with stage but did not establish an immunotherapy benefit in appendiceal cancer.

What this means if this is your diagnosis

Ask about PI3K pathway alteration status. This is one of the most actively studied pathways in drug development, and knowing whether your tumor carries it may matter for future trial eligibility.

Ask about TP53 pathway status, particularly if you have metastatic disease. The study’s overall metastatic cohort finding on TP53 is worth raising with your oncologist, even though it is not Group 2-specific.

Ask whether TMB and MMR/MSI status were tested. These can be relevant for immunotherapy eligibility, though this paper did not establish immunotherapy benefit in appendiceal cancer specifically.

Goblet Cell Adenocarcinoma (GCA)

Also called: Goblet cell carcinoid (older terminology, no longer preferred). Labeled Group 3 in this study.

Goblet cell adenocarcinoma occupies a biological space between appendiceal adenocarcinoma and neuroendocrine tumors. It has long been recognized as one of the more aggressive appendiceal subtypes, and this study adds molecular data consistent with that clinical picture.

The most specific finding for GCA in this study is a frequency comparison: TP53 pathway alterations appeared in 15.7% of primary GCA tumors and 30.0% of metastatic GCA tumors. That nearly two-fold increase is the sharpest stage-related jump of any subtype reported in this paper.

The framing here matters. The study found that TP53 pathway alterations in metastatic appendiceal cancer overall were associated with worse survival. It does not separately establish a GCA-specific survival effect. The higher rate of TP53 disruption in metastatic GCA is consistent with the recognized aggressiveness of this subtype, and it raises the possibility that TP53 involvement plays a role in disease progression. But this paper shows association, not causation, and not a GCA-specific survival analysis.

The finding is consistent with current clinical practice, where GCA is typically managed with aggressive staging and close monitoring for progression.

What this means if this is your diagnosis

GCA has distinct biology from other appendiceal subtypes and should be managed by a team with GCA-specific experience. Not all appendiceal cancer centers see high volumes of this subtype.

Ask whether your tumor has been tested for TP53 pathway alterations. This study found TP53 disruption was substantially more common in metastatic GCA than primary GCA, which is consistent with its recognized aggressiveness.

Because GCA can spread via both peritoneal and hematogenous routes, make sure your staging workup addresses both. CT of the chest, abdomen, and pelvis at minimum.

Ask about GCA-specific or appendiceal-specific clinical trials. This subtype is increasingly recognized as molecularly and clinically distinct from the rest of the appendiceal cancer spectrum.

Signet Ring Cell Adenocarcinoma

Also called: Signet ring cell carcinoma of the appendix. Labeled Group 4 in this study.

Signet ring cell adenocarcinoma is the rarest of the four major subtypes and is associated with poor outcomes. The name refers to how the tumor cells appear under a microscope: the nucleus is pushed to the edge of the cell, resembling a signet ring.

This study included signet ring cell cases in the overall cohort, but the published abstract does not provide subtype-specific pathway frequencies or survival data for Group 4. That reflects the reality that signet ring cell tumors are rare enough that even a dataset of 861 cases may not yield statistically robust subgroup results for this histology on its own.

The honest summary for this subtype, from this paper, is that there is not much to report specifically. The overall cohort findings — different pathway signatures in primary versus metastatic disease, and TMB rising with stage — apply to the dataset as a whole. Whether and how those patterns play out within signet ring cell disease is not established here.

Because the evidence base for this subtype is thin across the literature generally, molecular profiling at diagnosis is particularly important. Not because this paper prescribes a specific treatment based on those results, but because having a full molecular profile may support trial eligibility and contributes to the research base that the field needs to build.

What this means if this is your diagnosis

Seek care at a center with experience in rare and aggressive appendiceal subtypes. Volume matters for surgical and medical decision-making alike.

Ask for comprehensive molecular profiling at diagnosis, including TMB, MSI/MMR status, and a full pathway panel. This paper does not establish a signet-ring-specific molecular signature, but your profile may still be relevant for trial eligibility.

Ask specifically about clinical trial options. Given the limited standard-of-care evidence for this subtype, trials may represent an important pathway at various treatment stages.

Ask about mismatch repair and microsatellite instability status. MMR deficiency (dMMR) or high MSI (MSI-H) can make patients eligible for immunotherapy under existing approvals, independent of the findings of this paper.

At a Glance: What This Study Found by Subtype

The table below summarizes the key findings and their limits for each subtype. Where a finding applies to the full cohort rather than a specific subtype, it is labeled accordingly.

Subtype	Key Pathway Findings (from this study)	Survival Signal	Worth Asking About
LAMN / Low-Grade Mucinous Adenocarcinoma (Group 1)	RTK/RAS and MAPK alterations in primary AC overall were associated with better survival. PI3K and SMAD4 alterations more frequent in primary than metastatic tumors overall. Subtype-specific pathway data not separately reported for Group 1.	RTK/RAS and MAPK alterations associated with better survival in primary AC overall. Not established separately for low-grade tumors.	Molecular profiling at diagnosis; PI3K and RTK/RAS alteration status for future trial awareness.
Moderate- to High-Grade Adenocarcinoma( Group 2)	PI3K alterations significantly higher in primary vs. metastatic Group 2 tumors (22.1% vs. 11.0%). No Group 2-specific TP53 frequency comparison reported.	TP53 pathway alterations in metastatic AC overall were associated with worse survival. No Group 2-specific survival analysis reported.	TP53 and PI3K status; TMB and MMR/MSI testing; clinical trial eligibility.
Goblet Cell Adenocarcinoma (Group 3 / GCA)	TP53 pathway alterations nearly double from primary to metastatic GCA: 15.7% vs. 30.0% — the largest stage-related jump of any subtype reported.	TP53 alterations in metastatic AC overall were associated with worse survival. Paper does not establish a GCA-specific survival effect separately.	TP53 pathway status; GCA-experienced center; aggressive staging workup.
Signet Ring Cell Adenocarcinoma (Group 4)	Included in the dataset. The published abstract does not provide subtype-specific pathway results for Group 4.	No Group 4-specific survival data reported in this study.	Full molecular panel at diagnosis; enrollment in appendiceal-specific trials.

What Ties It All Together

Across all four subtypes, this study reinforces a point the appendiceal cancer community has long made: these tumors are not molecularly uniform, and neither are their outcomes. Pathway activity differs between primary and metastatic disease. The molecular landscape of early-stage disease looks different from the landscape of spread disease. And subtypes that have been clinically distinct for years are now starting to be distinguished at the genomic level as well.

This study is strongest in its size and in its overall cohort comparisons: primary versus metastatic pathway signatures, survival associations for RTK/RAS, MAPK, and TP53, and the subtype-specific frequency data for Group 2 and Group 3. It is more limited in subtype-specific survival analysis and in treatment guidance, which is not a critique so much as a description of what a retrospective genomic study is designed to do.

For patients, the takeaway is not that this paper changes what treatment you should receive today. It is that it builds the scientific foundation for a future where treatment can be tailored to what your tumor actually looks like at the molecular level — and that foundation requires profiling data on patients like you to exist at all.

The research was supported by the National Cancer Institute and published in The American Journal of Surgery in March 2026. At Appendicure, we will keep tracking the science that matters for this community. If you have questions about your diagnosis or want help finding a specialist, reach out at appendicure.com.

Questions to Ask Your Doctor — Regardless of Subtype

Has my tumor been molecularly profiled? If so, which pathways were altered?

What is my TP53 pathway status? Is that relevant to my prognosis given my stage?

Were TMB and MMR/MSI status tested? Could those results affect my treatment options?

Are there clinical trials enrolling appendiceal cancer patients based on my subtype or molecular markers?

If my disease progresses, would re-profiling my tumor be useful to look for new alterations?

Source: Lwin TM et al., Uncovering Molecular Pathways in Appendiceal Cancer: A Comprehensive Characterization for Precision Oncology. The American Journal of Surgery, March 2026. doi:10.1016/j.amjsurg.2026.116941