Colorectal cancer (CRC) outcomes vary, even among patients with node-negative disease. While the absence of lymph node involvement often suggests a better prognosis and less aggressive treatment, not all cases follow this pattern.
Perineural invasion (PNI), cancer spreading to or around nerves, can signal a higher risk despite negative nodes. Its presence prompts new discussions about post-surgical chemotherapy. As research deepens, PNI is becoming a key factor in shaping evolving treatment strategies for node-negative CRC patients, highlighting that even within lower-risk groups, personalized care is crucial.
Understanding Node-Negative Colorectal Cancer and Perineural Invasion
Node-negative colorectal cancer (CRC), typically stage I or II, has not spread to regional lymph nodes and usually has a favorable prognosis with surgery alone. However, staging doesn’t reveal every risk.
Perineural invasion (PNI), cancer cells growing in or around nearby nerves, offers a hidden pathway for cancer to spread, even when nodes are clear. Detected microscopically, PNI increases the chance of local or distant recurrence.
Though still under study, PNI appears to help cancer cells evade the immune system and survive in the tissue environment, suggesting a more aggressive disease that may require closer monitoring or additional treatment.
Methods for Identifying Perineural Invasion in CRC Specimens
Diagnosing PNI requires careful pathological sampling and review. After surgical removal of the tumor, pathologists slice the specimen and examine the tissue under a microscope. They look for cancer cells encasing or tracking along nerves in the colorectal wall or surrounding fat.
Typical diagnostic criteria include the presence of tumor cells within any of the three layers covering a nerve or in direct contact with neural structures. This process is not always straightforward. The nerves involved are often tiny, and tangles of fibrous tissue can make these details hard to spot.
Fixation quality, the number of tissue blocks examined, and the experience of the pathologist all influence detection rates. Some studies suggest that PNI is underreported when the search is not intentional or when only a few slides are reviewed. Variability in detection complicates comparison between studies and presents a challenge for uniform clinical management.
Immunohistochemical stains can help, highlighting nerves for easier identification. Still, routine use of these stains is not common in standard pathology practice, owing to time and cost constraints. This underlines a need for clear protocols and ongoing training to ensure that PNI is recognized and reported accurately.
Role of Adjuvant Chemotherapy in Node-Negative CRC with Perineural Invasion
Adjuvant chemotherapy has an established benefit in stage III CRC, where lymph nodes are positive. For node-negative (stage II) patients, the decision is less clear-cut. Traditionally, chemotherapy is reserved for high-risk patients, but what qualifies as high risk continues to shift as evidence accumulates. Perineural invasion now stands among the risk features that may tip the scale toward recommending additional treatment.
Current thought leaders and guideline bodies have considered studies showing that patients with PNI, even in node-negative stage II disease, have a recurrence risk similar to some patients with node-positive disease. That observation has prompted calls to treat these individuals more aggressively, seeking to reduce the chance of recurrence and prolong survival.
However, most trials that established the benefit of adjuvant chemotherapy in CRC either excluded or did not separately analyze PNI-positive, node-negative subgroups. As such, direct evidence is limited. Some pooled analyses suggest a modest survival benefit from adjuvant chemotherapy in high-risk stage II patients that includes those with PNI, but results are mixed across different studies and populations. Much of the data comes from retrospective analyses or population-based registries.
Guideline Recommendations and Areas of Uncertainty
National and international guidelines take a cautious but increasingly proactive approach. Most expert panels list perineural invasion among the features that define high-risk stage II CRC, alongside tumor perforation, obstruction, lymphovascular invasion, poor differentiation, T4 staging, or inadequate lymph node sampling.
The National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), and similar groups advise considering adjuvant chemotherapy for these patients. Despite clear recognition of the risk, specific recommendations vary. Some guidelines suggest strong consideration of adjuvant therapy for any patient with PNI.
Others recommend discussing the option and weighing patient factors, as the benefit in this subgroup does not reach the level of proof seen in stage III disease. There is ongoing debate regarding the relative impact of PNI compared with other unfavorable features, and whether single agents (such as fluoropyrimidine) or combination regimens (adding oxaliplatin) are best.
The uncertainties stem from the lack of randomized controlled trials that isolate PNI as the only high-risk factor. As a result, some physicians favor a case-by-case discussion, incorporating comorbidities, age, personal preferences, and pathology findings. Calls for dedicated prospective research continue, as precision in decision-making remains elusive.
Potential Benefits and Risks of Adjuvant Chemotherapy
“For patients facing the possibility of recurrence, adjuvant chemotherapy can be appealing,” says Dr. Omar Marar, a prominent colorectal surgeon. “It offers hope of reducing the risk of cancer coming back after complete surgical removal. Particularly in those with a risk factor like PNI, even small improvements in outcomes can mean extra years of healthy life.”
However, chemotherapy is not without cost. The most commonly used agents, such as 5-fluorouracil with or without oxaliplatin, can produce short-term side effects such as fatigue, nausea, hair thinning, diarrhea, mouth sores, and, less commonly, infections. There can also be rare but serious complications, such as blood clots, liver toxicity, or nerve damage.
For many patients, the risk of developing long-term numbness or tingling from oxaliplatin can be a key concern. Beyond physical symptoms, the diagnosis and management of CRC can create psychological distress, and the prospect of chemotherapy may heighten anxiety.
Some patients find reassurance in taking extra steps to fight cancer, while others prioritize quality of life and want to avoid unnecessary intervention. Every choice brings a mix of hope and worry, demanding honest guidance from the care team.
Balancing these considerations is never easy. Long-term follow-up studies indicate that the absolute benefit of chemotherapy in high-risk stage II CRC, including those with PNI, is modest compared with the risk reduction seen in stage III patients. Individual risk factors, such as PNI, likely add only a few percentage points to survival in most cases. These small gains must be matched against the cumulative burden of possible toxicity.
Adjuvant chemotherapy in node-negative CRC with perineural invasion sits at the intersection of science and patient values. Perineural invasion, even without nodal involvement, signals a higher chance of recurrence.
While evidence supports considering adjuvant chemotherapy for these patients, the benefit in absolute terms may be small, and not every patient will choose the same path. Professional guidelines recognize PNI as a marker of high risk, but differing interpretations and a lack of robust prospective data continue to fuel debate.
As research continues, clearer answers may come, but for now, each decision is shaped not just by science but also by patient priorities and circumstances. This is why ongoing dialogue and shared decision-making should remain at the heart of managing node-negative CRC with perineural invasion.
