Long-term outcomes after surgical dissection of inguinal lymph node metastasis from rectal or anal canal adenocarcinoma

Anal canal cancer is the most common type of gastrointestinal malignancy that metastasizes to inguinal lymph nodes (LNs). Whereas inguinal LN metastasis from anal canal cancer is classified as N2 in the 7th edition of the tumor-node-metastasis (TNM) classification when metastasis is unilateral, or as N3 when metastases are bilateral [1], it is categorized in the 8th edition as N1a (N1a: metastases in inguinal, mesorectal, and/or internal iliac nodes) [2, 3]. This classification was modified based on accumulating evidence from studies on anal canal squamous cell carcinoma [4, 5].

Most anal canal cancer cases in Western countries involve squamous cell carcinoma, which accounts for almost 90% of these cases [6]. In contrast, adenocarcinoma is the predominant histological subtype of malignancy arising in the anal canal in Asian countries such as Japan and China [7]. Specifically, adenocarcinomas account for 63% of anal canal cancers in China [8] and 74% in Japan [7], although anal canal cancer itself is a rare disease in these countries. Given the rarity of this disease, little is known about the long-term outcomes of inguinal LN metastasis from anal canal adenocarcinoma. The largest study cohort of patients (21 patients) with inguinal LN metastasis from anal canal adenocarcinoma to date was reported by Su et al., showing 5-year overall survival (OS) rate as 19.1% [8].

Inguinal LNs in rectal carcinoma are classified as non-regional LNs in the TNM classification [2]. Adenocarcinomas that originate from the lower rectum occasionally metastasize to inguinal LNs in a manner similar to anal canal cancer, with an incidence of approximately 2.0–4.5% [9, 10]. Some studies have reported that inguinal LN metastasis from rectal adenocarcinoma occurs as a consequence of locally advanced primary tumors or recurrent pelvic malignancy, and that in these cases, only systemic chemotherapy and radiotherapy should be considered due to the frequency of distant metastasis and poor prognosis [9, 11]. Other studies reported that solitary inguinal LN metastasis from rectal adenocarcinoma showed a favorable prognosis after LN excision and thus surgical treatment may be a reasonable therapeutic option for such patients [12, 13]. Accordingly, appropriate treatment strategies for inguinal LN metastasis from rectal adenocarcinoma are unclear, and surgical treatment for inguinal LN metastasis remains controversial.

The TNM 8th edition classifies inguinal LNs as regional LNs for anal canal carcinoma, but non-regional for rectal carcinoma [2]. No study to date has adequately accounted for this difference. Survival is thought to be an adequate indicator for determining regional versus distant metastasis. In this respect, this study aimed to investigate the long-term outcomes, specifically with respect to OS, of inguinal lymph node metastasis from rectal or anal canal adenocarcinoma, which makes it possible to speculate whether inguinal LN metastasis is regional or distant. In this study, because anorectal adenocarcinoma is sometimes difficult to determine its anatomical origin (rectum or anus) and thus rectal adenocarcinoma and anal adenocarcinoma sometimes overlap, and because treatment strategies for rectal adenocarcinoma and for anal adenocarcinoma are completely same according to the National Comprehensive Cancer Network (NCCN) guidelines 2018 [14, 15] (surgery, and sometimes followed by chemotherapy), and because of the limited sample size, inguinal LN metastasis from these two types was considered as a single entity and the combined data were analyzed.

The present study found that, for long-term outcomes after inguinal LN dissection from rectal or anal canal adenocarcinoma with curative intent, MST was 66.6 months and 5-year OS was 55.2%. These results are noticeably better than previous data reported for inguinal LN metastasis from anal canal or rectal adenocarcinoma (MST, 8–14.8 months; 5-year OS, 0–19.1%) [8, 9, 11, 20]. This discrepancy could be due to the small sample size in the previous studies (8–32 patients) [8, 9, 11, 20], as well as recent developments in chemotherapy and the multidisciplinary team approach. In our study, although almost 80% of patients experienced recurrence after inguinal LN dissection, a multidisciplinary team approach that included surgical treatment and chemotherapy for recurrent tumors could have led to the better prognosis. Our MST of 66.6 months was also better than those reported for colorectal cancer patients with distant metastasis. According to the Analysis and Research in Cancers of the Digestive System database, MST was 19.3 months in colorectal cancer patients with liver metastasis, 24.6 months in those with lung metastasis, and 16.3 months in those with peritoneal metastasis [21]. Patients who underwent curative resection of liver metastasis, and thus are expected to have a favorable prognosis among stage 4 colorectal cancer patients, had 5-year survival rates of about 40% [22, 23], whereas patients who underwent curative resection of peritoneal metastasis had 5-year survival rates of about 30% [24, 25]. Thus, from the perspective of long-term outcomes, inguinal LN metastasis from rectal or anal canal adenocarcinoma appears to be regional rather than distant.

Previous studies have reported that, for rectal or anal canal adenocarcinoma with inguinal LN metastasis, unilateral inguinal LN metastasis, metachronous LN metastasis, and solitary inguinal LN metastasis are independent factors associated with a longer OS [12, 13, 20]. In contrast, we found that the absence of lateral LN metastasis and histological type of well or moderately differentiated adenocarcinoma were independent factors associated with longer OS in patients with inguinal LN metastasis from rectal or anal canal adenocarcinoma.

Lymph drainage at and proximal to the dentate line is directed toward the anorectal, perirectal, and paravertebral nodes and to some extent, the internal iliac system nodes, and lymph drainage below the dentate line mainly is directed to superficial inguinal LNs [26, 27]. There are two lymphatic routes from the rectum to inguinal LNs; one is a direct route [9], and the other is an indirect route which passes through internal and external iliac vessels. As shown in Fig. 2, we classified patterns of LN metastasis into four types based on the presence or absence of mesorectal LN and lateral LN metastasis. Figure 2a and b show inguinal LN metastasis via the direct route, and Fig. 2c and d by the indirect route (though lateral LNs), direct route, or both routes. Among the 10 patients with independent inguinal LN metastasis without metastasis to other areas, seven had a relatively small primary tumor (< 5 cm). In contrast, among the 14 patients with a tumor > 5 cm, 11 had mesorectal LN and/or lateral LN metastasis, indicating that large tumors invaded multiple lymphatic routes. According to multivariate analysis, patients with lateral LN metastasis had a poorer prognosis than patients without lateral LN metastasis. This suggests that inguinal LN metastasis by the indirect route leads to more progressive disease.

The TNM classification defines rectal carcinoma and anal canal carcinoma based only on the anatomical location of the primary tumor, without accounting for histological type. One issue with this is that both adenocarcinoma and squamous cell carcinoma, which originate from the anal canal, are classified in the same category despite their different treatment strategies. Namely, standard treatment for primary anal canal squamous cell carcinoma is chemoradiotherapy [4, 6], whereas that for adenocarcinoma is surgery. With regard to squamous cell carcinoma of the anal canal with inguinal LN metastasis, a previous study reported that the 5-year OS in patients with synchronous inguinal LN metastasis was 54.4%, and primary local control in the inguinal area after inguinal LN dissection was 68% [6]. In the present study of rectal and anal canal adenocarcinoma, 5-year OS was 55.2%, which is similar to that reported for anal canal squamous cell carcinoma patients.

This study has some limitations. First, since the study was a single-center retrospective analysis, biases may exist. Prospective studies will be needed to confirm our results. Second, the sample size was relatively small due to the rarity of inguinal LN metastasis from rectal or anal canal adenocarcinoma, although the number of patients who underwent inguinal dissection represented the largest sample reported to date. Third, treatment regimens varied among patients after inguinal LN dissection. Further prospective studies will be needed to confirm that inguinal LN metastasis from both rectal and anal canal adenocarcinoma is regional rather than distant.

Based on the acceptable prognosis of patients who underwent inguinal LN dissection with curative intent, the presence of inguinal metastasis in patients with lower rectal and anal canal adenocarcinoma can be considered regional LN metastasis. If R0 resection can be achieved, inguinal LN dissection may be indicated in patients with inguinal LN metastasis from both rectal and anal canal adenocarcinoma.