Cancer accounts for almost 20% of premature death worldwide [1]. Peritumoral tissues (PTT), which are non-tumor tissues located in close proximity to a tumor and originate from the same organ, are increasingly recognized to harbor complementary information on early tumorigenesis, metastasis, recurrence, and treatment response, as well as prognosis [2,3,4,5,6]. While most cancer studies focus on cancer itself, this growing body of research suggests the importance of also investigating PTT. To emphasize that PTT differs from healthy tissue (referring to tissue from individuals unaffected by cancer), and to facilitate scientific communication and knowledge dissemination, we draw attention to the growing need for an appropriate naming convention. Additionally, we will highlight key information about the peritumoral tissue sampling procedure that can enhance the precision and informativeness of bioinformatics analysis.

Advancements in molecular biology and sequencing technologies, along with reduced costs and increased accessibility, have revolutionized cancer research. These approaches have resulted in a more profound understanding of cancer pathology, as well as molecular abnormalities that lead to cancer formation, sustenance, progression, and metastasis. In many studies, tumors are analyzed alongside PTT, where PTT serves as a control or baseline [7, 8]. Due to the absence of macroscopicFootnote 1 and microscopicFootnote 2 signs of malignancy, PTT is considered to adequately represent morphologically healthy, non-tumoral tissue and is often used as a “healthy” control [5, 7]. Furthermore, the use of paired tumor-PTT samples is often justified due to the experimental advantages it brings. First, the use of paired tumor-PTT samples reduces interpatient genetic variability, as both tumor and PTT samples originate from the same patient. The second advantage is decreased anatomical variability as PTT samples are taken from the same tissue type from which the tumor originated. This is usually the case for proteomic, transcriptomic, and epigenetic studies (methylation and genome-wide associations), as for genomic studies, DNA is often isolated from peripheral blood leukocytes. The third advantage is that PTT samples are more accessible than healthy tissue samples from non-cancer patients, especially in cases where radical surgeries (partial or total organ removal) are necessary steps in cancer treatment.

While most studies operate under the assumption that PTT is representative of healthy tissue, a growing amount of evidence suggests that this is not the case. The concept that PTT is “healthy” was first debated by Slaughter et al. in 1953 [9]. Namely, the authors propose that the high rate of recurrence of Oral Squamous Cell Carcinoma originates from the fact that PTT has been preconditioned by the same carcinogenic event that led to the rise of tumors in the first place, leading to the formation of “field cancerization”. Since this seminal paper, genetic and epigenetic abnormalities that lead to the formation of cancerized fields have been described in various tumors and pre-malignant diseases [5, 8, 10]. In 2017, Aran and colleagues conducted a pan-cancer study, comparing the transcriptomic profiles of primary tumors, corresponding PTT (from the TCGA database), and healthy tissues from autopsies (from the GTEx database) of eight tumor types [7]. They found that PTT is transcriptionally different from both primary tumor tissues and healthy tissues and is instead found in the transcriptional middle ground. Similar results, showing that PTT is transcriptionally distinct from healthy tissues of corresponding organs, have been reported by other groups as well [6, 11,12,13,14,15]. Aran and colleagues suggested that the distinct transcriptome of PTT could arise from the process of field cancerization, as well as from the cancer-induced inflammation and putative signals that originate from the tumor with the latter being the most probable source [7].

Additionally, the authors show that increased expression of a tumor-adjacent-specific signature can be detected up to 4 cm from the tumor (maximum distance in the dataset), with a tendency for gradual decrease after 2 cm [7]. Other groups, as reviewed by Gadaleta et al., have also shown that genomic instability, telomere content, allelic imbalance, and transcriptomic aberrations decrease as a function of distance from the tumor [8]. On the other hand, a recent study that investigated the impact of the distance of the transcriptomic subtype of PTT of breast cancer patients showed no clear distinction in PTT subtype based on the distance from the tumor [16]. Overall, the impact of distance from the tumor on peritumoral tissue, as well as the underlying cause, is still elusive, and more research is needed.

Furthermore, an increasing body of evidence suggests that PTT could be useful in understanding early mutational events in tumorigenesis, as well as understanding the impact of tumors on surrounding tissue, angiogenesis, and even serve as a source of prognostic and diagnostic biomarkers [2,3,4,5,6,7,8, 10, 16, 17].