Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and remains a major cause of cancer-related morbidity and mortality. The disease typically follows a well-characterized adenoma-carcinoma sequence, progressing from benign adenomatous polyps to intramucosal carcinoma and ultimately to invasive cancer that penetrates the submucosa. Once the tumor invades beyond the mucosal layer, it gains access to lymphatic channels and blood vessels, which facilitates the spread to regional lymph nodes and distant organs.

According to the American Joint Committee on Cancer (AJCC) staging system, tumors confined to the mucosa, including the lamina propria and muscularis mucosae, are classified as carcinoma in situ (Tis) and designated as Stage 0(1). These lesions are considered to have an extremely low risk of metastasis, based on the long-standing belief that the colonic mucosa lacks lymphatic vessels. In contrast to other segments of the gastrointestinal tract - where basement membrane invasion often signifies the onset of metastatic potential- in colorectal cancer, only tumors that infiltrate the submucosa are regarded as biologically capable of metastasizing.

However, this traditional understanding has been increasingly challenged by emerging evidence. Several reports have described rare instances of local recurrence of distant metastasis arising from Tis-stage colorectal tumors, raising the possibility that lymphatic dissemination may occur even in the absence of submucosal invasion. Some of these atypical cases have involved poorly differentiated histology, extensive inflammation, or other high-risk features, but definitive lymph node metastasis in well-differentiated intramucosal carcinoma has remained undocumented.

Herein, we report a rare and unusual case of histologically confirmed lymph node metastasis in a 70-year-old female patient with Tis-stage rectal cancer, who initially presented to our hospital in December 2018. This case challenged the current staging paradigm and raises important questions regarding the metastatic potential of early-stage colorectal cancer. It underscores the need for reevaluation of staging criteria and highlights the importance of individualized clinical judgement even in lesions that are presumed to be biologically indolent.

A 70-year-old female presented to Kangwon National University School of Medicine in December 2018 for endoscopic removal of colon polyps identified during a screening colonoscopy. She had no prior history of colonoscopy and no significant medical history other than hypertension. Laboratory examination showed a white blood cell, hemoglobin, platelet count, blood urea nitrogen, creatinine, and carcinoembryonic antigen levels of 7,700/ul, 13.2 g/dl, 386,000/ul, 12.2 mg/dl, 0.8 mg/dl, and 4.2 ng/ml, respectively. Abdominopelvic computed tomography (CT) revealed multiple polypoid lesions with conglomeration in the rectum with no other remarkable findings (Fig. 1). Colonoscopy identified two lesions, one in the ascending colon and another in the rectum (Figs. 2 and 3). In the ascending colon, 2 cm laterally spreading tumor (LST) was observed, and a biopsy revealed a tubulovillous adenoma with focal high-grade dysplasia. In the rectum, diffuse circumferential nodular mucosa with friability involving the whole rectum from the rectosigmoid junction to the anorectal junction was noted, and a biopsy of the most prominent nodular lesion revealed tubulovillous adenoma with low-grade dysplasia.

For the ascending colonic LST lesions, endoscopic submucosal dissection was performed, which revealed a well-differentiated adenocarcinoma with a maximum submucosal invasion depth of 1 mm. Both the deep and lateral resection margins were clear, with no evidence of lymphovascular or perineural invasion. Due to extensive involvement of the entire rectal mucosa, the patient was referred for surgery for a large circumferential rectal lesion and underwent a laparoscopic ultra-low anterior resection (Fig. 4).

Histopathological examination of the resected specimen revealed a well-differentiated intramucosal adenocarcinoma (Tis) confined to the mucosa (Fig. 5). However, one regional lymph node adjacent to the rectum revealed metastasis (Fig. 6). Positron emission tomography-CT performed after surgery showed no evidence of distant metastasis. Although the current AJCC on Cancer TNM staging system (8th edition) for rectal cancer does not include a staging group for TisN1M0, the patient was classified as having stage IIIa rectal cancer following a multidisciplinary discussion. She underwent concurrent chemoradiotherapy for stage IIIa rectal cancer and has been followed up at an outpatient clinic for the past 6 years with no evidence of recurrence.

Tis refers to ‘carcinoma in situ,’ meaning that cancer cells are localized to their site of origin and have not invaded the surrounding tissue. In the gastrointestinal tract, Tis typically indicates a tumor confined to the epithelium without invasion of the lamina propria (i.e., intraepithelial tumor) but with penetration through the basement membrane, considered invasive cancer. However, in colorectal cancer, Tis refers to tumors that may invade up to the muscularis mucosa (i.e., intramucosal tumors) (1). It is generally believed that Tis-stage colorectal cancer confined to the mucosa has no potential for metastasis since the colonic mucosa lacks lymphatic vessels (2). Although some studies have reported cases of local recurrence or distant metastasis during follow-up of Tis-stage cancer (3-6), and there have been concerns regarding the potential for metastasis in poorly differentiated Tis colorectal cancer (7), no cases of lymph node metastasis have been confirmed in well-differentiated Tis tumors at the time of diagnosis. This study reports the first documented case of lymph node metastasis in a well-differentiated Tis tumor.

Recent research indicates that lymph node metastasis may be possible even in Tis-stage colorectal cancer. Previous study xplored the potential for cancer cell metastasis to lymph nodes in patients with Tis-stage colorectal cancer and confirmed the presence of lymphatic vessels in the lamina propria (8). Some studies have highlighted the challenges in detecting micrometastases in lymphatic vessels using hematoxylin and eosin staining in early-stage colorectal cancer, emphasizing the need for special staining techniques (9,10). By utilizing specific immunohistochemical staining methods, previous study accurately identified lymphatic vessels in the lamina propria of patients with early-stage colorectal cancer and assessed the potential for cancer cell metastasis. It has been proposed that a neoplastic or inflammatory microenvironment, which induces fibrotic or desmoplastic reactions, may facilitate focal lymphatic invasion, providing a pathway for metastasis in intramucosal colorectal cancer; however, the precise mechanism underlying lymph node metastasis in this case still remains unclear (3,6).

This case raises various important considerations for the diagnosis and treatment of Tis colorectal cancer. First, it suggests a novel metastatic pathway that differs from the current understanding and requires further research to elucidate the mechanisms underlying lymph node metastasis at this stage. Second, it underscores the need to consider the possibility of lymph node metastasis even at the Tis stage in clinical practice. It might be a prudent approach to include the evaluation of perirectal lymph nodes in the diagnosis and management of very early-stage colorectal cancer, despite the very low risk of lymph node metastasis.

Although traditionally considered non-metastatic, emerging evidence suggests that Tis-stage rectal cancers may, in rare cases, demonstrate lymphatic dissemination, necessitating a re-examination of current staging assumptions.

In addition to pathological findings, imaging studies also play a crucial role in the diagnosis and staging of colorectal cancer. However, conventional imaging modalities such as CT and PET-CT have limited sensitivity in detecting micrometastases in regional lymph nodes, particularly in Tis-stage tumors. In this case, no lymph node involvement was suspected preoperatively based on imaging studies, highlighting the limitations of current radiologic assessments.

Recent advancements in imaging, including radiomics and artificial intelligence, have opened new possibilities in preoperative lymph node evaluation. Radiomics-based approaches extract quantitative features-such as shape, texture, and enhancement patterns-from both intratumoral and peritumoral regions on CT, enabling the development of predictive models that outperform traditional size-based assessments (11). Furthermore, deep learning algorithms, such as convolutional neural networks, have shown promising results in identifying subtle imaging patterns associated with nodal metastasis, although challenges remain (12) regarding generalizability, dataset diversity, and clinical applicability. Meanwhile, PET-CT has demonstrated greater sensitivity than CT alone for detecting both nodal and distant metastases in colorectal cancer. In a recent study, PET-CT achieved a sensitivity of 66.7% for nodal metastasis, compared to 55.2% with CT, and 82.5% for distant metastasis (13). Nonetheless, the sensitivity of PET-CT for micrometastasis in early-stage tumors is still suboptimal. These findings suggest that although imaging technology continues to evolve, it remains imperfect in identifying lymph node involvement in Tis-stage cancer.

In conclusion, current colorectal cancer treatment protocols often overlook lymph node evaluation in Tis-stage colorectal cancer. However, this case highlights the need for a more comprehensive approach that considers the potential for lymph node metastasis, even in patients with Tis-stage cancer. Continued research integrating advanced imaging, pathological staining, and molecular analysis is warranted to better understand and detect early lymphatic dissemination.