https://orcid.org/0000-0003-1066-4671
Colorectal Cancer (CRC) is one of the most common and heterogeneous cancers. For this reason, over the years, its treatment and prognosis have undergone several variations caused by both the discovery of new molecular and non-molecular markers, and factors such as the Circumferential Resection Margin, number of involved lymph nodes, depth of wall’s penetration, tumor budding, and many others [Citation1–3].
Currently, the most used staging system is the TNM (Tumor, Node and Metastasis). It was first developed by Pierre Denoix, a French Surgeon, in the 1940s and it still continues to strongly influence the therapeutic approach in CRC [Citation4]. However, originally this system did not include Tumor deposits (TDs).
TDs are currently defined as microscopic or macroscopic focal aggregates of cancer cells located in subserosa, mesentery, and non-peritonealized pericolic or perirectal fat. These aggregates are discontinuous with the primary tumor and independent from the lymph node, vascular or neural tissues involvement.
In 1935, Gabriel and colleagues first introduced this concept in negative specimens for regional lymph nodes [Citation5]. Since that time its prognostic role has been growing up until its integration into the 5th edition of the TNM, classifying the nodules as TDs if < 3 mm and as N + if ≥ 3 mm in size. Later, in the 7th TNM edition, it has been classified as an independent factor, indeed the staging system reports CRC as N1c.
Moreover, the incidence of TDs is highly variable both according to the location of the CRC and to the definition used discretionally by the pathologist [Citation6]. Indeed, although TDs have been shown to be decisive, it is not yet clear how they should be classified.
According to Belt et al [Citation7] TDs can be considered as metastases in lymph nodes that are no longer recognizable due to the previous tissue’ destruction. The latter scenario would be consistent with the increased finding of TDs in patients with lymph nodes involvement.
A recent retrospective study assessed the prognostic role of N1c in stage III and IV CRC in a large population-base database [Citation8].
In particular, the authors extracted, from the Surveillance, Epidemiology, and End Results (SEER) database, 224,785 patients with diagnosis of CRC. After the exclusion criteria were applied, 25,868 patients were included in the study analysis (Stage III N = 18,968; Stage IV N = 6900).
According to the multivariate analysis, there was no statistically significant difference in terms of cause specific survival (CSS) between N1c and N1b in both tumor stages (III p = 0.4; IV p = 0.7) while patients with N1c had a higher mortality than those with N0 (p = 0.001) and N1a (p < 0.001), and a lower mortality in comparison with N2a (p = 0.004) and N2b (p < 0.001).
In the attempt of reducing the bias due to confounding variables, minimizing the difference between treatment and control group (N1a and N1b represented the largest sample as expected), a propensity score matching analysis was performed. Notwithstanding, the results were consistent with those found in the previous analysis.
Lastly, the authors, based on the finding of another analysis of the SEER database which demonstrated how the number of TDs can severely modify the prognosis [Citation9], considered N1c patients with only one tumor deposit in stage III CRC. Surprisingly, N1c had a better CSS (p = 0.039) and overall survival (p = 0.037) compared to N1b and no difference was found with respect to N1a (p = 0.420).
Nor the 7th edition neither the 8th of the TNM comprehend patients with concomitant positive TDs and lymph node metastases. This concept is crucial for understanding the impact of TDs. In fact, its role as an independent negative prognostic factor seems to be clear both in the presence and absence of lymph node metastases [Citation10]. Unfortunately, most of the studies published so far are retrospective with several limitations which contributed to the lack of consensus.
In fact, in the study by Liu and colleagues [Citation8] a more accurate analysis could not be performed in stage IV CRC patients with resectable metastatic CRC. However, despite the limited number of enrolled patients, the critical issues that have emerged are a starting point to definitively clarify the identity of TDs and their role in CRC.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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