Combined therapy of intraoperative radiotherapy and surgery for rectal cancer with inguinal lymph node metastasis: a case description

Introduction

With an incidence rate of about 1.2–2.4%, rectal cancer with inguinal lymph node (ILN) metastasis is a rare yet challenging disease that is associated with proximal end lymphatic vessel obstruction leading to tumor downward dissemination (1-3). The current therapeutic strategy for this disease is surgical resection in combination with radiotherapy or chemotherapy. Patients with multiple lymph node metastases may be complicated with peripheral metastasis and micrometastasis that are difficult to remove by surgery. Radiotherapy and chemotherapy can cause serious side effects which result in the low quality of life of patients. Intraoperative radiotherapy (IORT) is a method by which a critical radiation dose is delivered to the tumor bed immediately after surgical excision (4), with the advantages of accurate irradiation, reduced complications, and smaller doses (5). The technique of IORT is being increasingly used in the treatment of patients with cancer, particularly breast cancer (5). There is no relevant report on IORT combined with surgery in the treatment of rectal cancer with ILN metastasis. Here, we report the first case of rectal cancer with ILN metastasis treated by laparoscopic transabdominal perineal combined with radical resection of rectal cancer (Miles operation), pelvic lymph node dissection in association with inguino-pelvic resection, and IORT.

Case presentation

A 68-year-old male patient was admitted to The Second Hospital of Jilin University with a 6-month change in bowel habit, aggravated with intermittent blood in the stool for more than 3 months. The hard mass with poor mobility was palpable by digital rectal exam, and the proximal border of the mass was 1 cm from the anal verge. The rectal stricture was not passable by the examining finger. Concurrently, palpable left ILNs were observed. Coloscopy with biopsy revealed an adenocarcinoma of the rectum. Tumor marker findings were as follows: carcinoembryonic antigen (CEA), 8.90 ng/mL; and cancer antigen 199, 101.04 U/mL. Abdominal computed tomography (CT) revealed space-occupying lesions in the lower segment of the rectum and malignancy was suspected. Soft tissue density shadows were apparent around the rectum, in the left groin, and in the left ischiorectal fossa, indicating lymph node metastasis, and the ctTNM staging was ctT3N2M1 (Figure 1A-1D). Rectal magnetic resonance imaging (MRI) demonstrated irregular thickening of the rectal wall, the lumen of the bowel was narrow (Figure 2A-2F), the demarcation of the lesion from the right levator ani muscle was unclear (Figure 2C,2F), and bilateral inguinal lymphadenopathy and multiple perirectal enlarged lymph nodes were also observed, with the largest measuring about 20 mm in the left inguinal region (Figure 3A-3C). A multidisciplinary team meeting was held to discuss the patient’s case, with rectal cancer with lymph node metastasis being considered. We did not perform a puncture biopsy of the ILNs because the patient had symptoms of incomplete intestinal obstruction at the time but no metastases to other organs. The patient did not show significant improvement in the symptoms of intestinal obstruction after conservative treatment. The patient was concerned about tumor progression during neoadjuvant therapy and refused neoadjuvant therapy, requesting surgery as soon as possible. After obtaining the consent of the patient and his family, we decided to perform Miles operation combined with IORT.

Figure 1 Abdominal CT showed multiple soft tissue density shadows, suggesting lymph node metastasis. (A) The red arrow indicates the enlarged lymph node in the left ischiorectal fossa. (B) The red arrow indicates the enlarged lymph node along the superior rectal artery. (C) The red arrow indicates the enlarged lymph node in the left inguinal area. (D) The red arrow indicates the enlarged lymph node in the left obturator. CT, computed tomography.

Figure 2 Rectal MRI indicated irregular thickening of the rectal and a narrow lumen of the bowel. (A) T2W axial MRI. The red arrow indicates the rectal tumor. (B) Enhanced axial MRI scans. The red arrow indicates the rectal tumor. The thickness of the tumor was 10 mm. (C) Coronal T2W MRI. The red arrow indicates that the boundary between the lesion and the right levator anal muscle was not clear. (D) Diffusion-weighted imaging. The red arrow indicates rectal tumor. (E) Enhanced sagittal MRI scans. The red arrow indicates rectal tumor. (F) Enhanced coronal MRI scans. The red arrow indicates that the boundary between the lesion and the right levator anal muscle was not clear. MRI, magnetic resonance imaging; T2W, T2-weighted.

Figure 3 Rectal magnetic resonance imaging indicated lymph node metastases. (A) The red arrow indicates the left inguinal lymph node metastases. (B) The red arrow indicates the left obturator lymph node metastases. (C) The red arrow indicates the lymph node metastases in the front of the sacrum.

The colorectal surgery and radiotherapy department performed the surgery. Radical local excision of the tumor and resection of the lateral lymph nodes were performed. The tumor was excised from the perineum, and the surgical incision was covered with wet gauze. The great saphenous vein was exposed through the left oblique inguinal incision. The great saphenous vein trunk was dissociated, followed by a high ligation of the great saphenous vein and its branch and the surrounding tissues, with the peripheral lymph nodes also being removed. The tumor tissue was carefully excised, and no residual tumor was palpable or evident macroscopically. Two IORTs were performed at a dose of 20 Gy. The source applicator was placed at the left inguinal area to irradiate the wounds after the ILN dissection. Subsequently, radiotherapy to the pelvic cavity was continued via the perineal incision. After IORT, permanent laparoscopic-assisted sigmoid colostomy was performed (Figures 4A-4I,5A-5C).

Figure 4 Surgical procedures for rectal cancer. (A) Devascularization of the IMA (red arrow). (B) The red area is the open pelvic space. (C) The sigmoid colon was severed with a linear stapler. The red arrow indicates the severed proximal end of the sigmoid. (D) The end of the sigmoid colon was used for colostomy via an extraperitoneal approach. The red arrow indicates the peritoneum. (E) The red arrow indicates sigmoid colostomy. (F) The red arrow indicates the perineum incision after Miles operation. (G) The source applicator was placed at the perineum incision. The red arrow indicates the source applicator. (H) The source applicator was placed. The red arrow indicates where the perineal incision was temporarily and partially sutured to fix the source applicator, which was followed by IORT. (I) Visualization of IORT in laparoscopy. The red arrow indicates the source applicator. IMA, inferior mesenteric artery; IORT, intraoperative radiotherapy.

Figure 5 Inguinal lymph node surgery procedure. (A) Separation and ligation of the great saphenous vein. (B) Wet gauze applied for protecting the surrounding tissues during intraoperative radiotherapy. (C) The source applicator placed at the left inguinal area.

The pathological findings were in agreement with moderately differentiated rectal adenocarcinoma and ILN metastasis. The tumor had invaded the bowel wall, involved the dentate line, and focally infiltrated the external anal sphincter, with intravascular invasion. No cancer was found at intestinal, anal, or circumferential resection margins. Metastases were observed in the lymph node along the rectum (3/15), the left obturator artery (1/5), and the left ILN (2/9). No pathological metastasis was observed in the other surgically removed lymph nodes. The pathological tumor node metastasis (pTNM) stage was pT3, N2a, and M1. The immunohistochemical staining findings were as follows: the Ki-67score was 70%, and there was positivity for SMA, CDX2, EGFR, CD34 (positive vessels), PMS2, MLH1, MSH6, and MSH2 positive (Figure 6A-6H). After the surgery, the first cycle of chemotherapy with 1.5 g of capecitabine twice per day plus 150 mg of oxaliplatin was initiated on postoperative day 21. No recurrence was found on regular reexamination in the 8 months following the operation, and no adverse events such as IORT-related complications were found.

Figure 6 Postoperative pathology images of the patient. (A) Image of the rectal cancer specimen. (B) HE staining confirmed that the resected specimen was rectal adenocarcinoma (40×). (C) HE staining of the inguinal lymph nodes. (D) HE staining of the pelvic lymph nodes. (E) Specimens of surgically removed inguinal lymph nodes. (F) Immunohistochemical staining showed the tumor cells were positive for CDX2. (G) Immunohistochemical staining showed the tumor cells were positive for SMA. (H) Immunohistochemical staining showed the tumor cells were positive for Ki-67 (70%). HE, hematoxylin and eosin.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Lymphatic metastasis is one of the most common metastatic routes of rectal cancer and is bounded by the peritoneal fold. Metastasis of upper rectal cancer follows the course of lymph nodes around the superior rectal artery, inferior mesenteric artery, and the abdominal aorta. Lower rectal cancer metastasis dissemination upward may also occur, but lymph node metastasis of lower rectal cancer is predominantly to the lateral lymph nodes. Tumors located below the dentate line drain upward along the mesenteric lymphatics and also laterally to the superficial ILN (6). ILN metastasis from rectal cancer occurs most often in low-grade rectal cancers, which have an average distance of 1.1 cm from the anus and invade the dentate line in about 76% of patients (7). Dentate line infiltration and lymphovascular infiltration are two independent risk factors for ILN metastasis from lower rectal cancer involving the anal canal (8).

The pelvic side wall lymph nodes can be divided into the common iliac, external iliac, and internal iliac (hypogastric) types based on neighboring vessels. The external iliac lymph node can be classified into medial, medium, and lateral chains. The lateral and intermediate lateral chains receive their lymphatic supply mainly from the lower limbs. The medial chain is in close proximity to the obturator lymph nodes, and it is difficult to distinguish between them. Lymph nodes in the dentate line and under the anal canal run through the perineum and medial thighs to the medial cluster of the superficial ILN, which converge on the external iliac lymph nodes via the deep vein hiatus of the fascia lata. The internal iliac lymph nodes are connected through the lymphatics of the middle and lower rectum, the bladder, and uterus. Thus, pelvic malignancies are often accompanied by metastases to the internal iliac lymph nodes. In this patient, metastasis to the ILN via the internal iliac lymph nodes and the obturator lymph nodes was the most likely case. For patients with ILN metastasis from rectal cancer, single or fused lymph nodes in the inguinal region that are hard and with low mobility can be palpated on examination. Diagnosis can also be aided by imaging. Common tests include plain or contrast-enhanced CT of the pelvis. The effacement of the nodal architecture can be observed on CT. The diagnosis of ILN metastasis requires a combination of lymph node size, morphology, and medical history. Positron emission tomography-CT (PET-CT) can also help diagnosis. PET-CT evaluates the presence of metastasis by observing the metabolic status of lymph nodes and can be used to assess systemic metastasis and staging of tumors. A punch biopsy of the lymph nodes is the gold-standard procedure to confirm the diagnosis. This biopsy accuracy of complete lymph node dissection under local anesthesia is higher than that of puncture biopsy.

Metastases to the ILNs from rectal adenocarcinoma are infrequent occurrences, typically indicative of advanced disease. The majority of affected patients exhibit concurrent pelvic involvement, with a significant portion also demonstrating metastases to the liver and/or lungs (2). According to the eighth edition of the American Joint Committee on Cancer (AJCC) staging guidelines, ILN in rectal cancer is defined as nonregional or metastatic lymph nodes, and the M-stage of TNM staging in such patients is considered as M1. Patients with ILN have a poor prognosis, with an average survival of about 8–15 months (1,2,8). The survival rate of patients with synchronous ILN metastasis from rectal cancer is significantly lower than that of those with locally advanced rectal cancer lacking synchronous ILN metastasis. Moreover, patients with unresectable rectal cancer and synchronous ILN metastasis demonstrate a decreased median survival rate. The mainstream treatment options for ILN metastasis of rectal cancer are radical resection of the primary rectal cancer tumor and ILN dissection combined with radiotherapy and chemotherapy. ILN metastasis from rectal cancer is a specific subtype of metastatic rectal cancer. A combined regimen of pelvic radiation and systemic chemotherapy may be worthwhile due to the potential complication of distant metastases and poor prognosis in these patients (2). Abd El Aziz et al. (9) found that of 13 patients with synchronous ILN metastasis from rectal cancer and R0 resections, 8 developed disease recurrence at a median of 15 months (range, 9–81 months). All of them received external beam radiotherapy before the surgery. Sato et al. (10) found that patients with ILN metastases from rectal cancer undergoing ILN dissection and chemotherapy and/or radiotherapy had a high recurrence rate, and some patients developed ILN recurrence after treatment. In a 16-participant comparative study of extracorporeal radiotherapy combined with total mesorectal excision (TME) for lymph nodes in the inguinal region, Chen et al. (11) found that most patients had concurrent grade 1 and 2 radiation-related toxicity including inguinal dermatitis and edema. In addition, grade 3 radiation enteritis was observed in two patients and grade 3 anastomotic inflammation in three patients. Extracorporeal irradiation radiotherapy has a relatively high number of complications and causes severe pain to patients. It is hoped that a therapeutic intervention capable of effectively reducing the recurrence rate and mitigating the adverse effects of radiotherapy in patients can be found.

IORT has the advantages of reduced complications, a lower dose, and a rapid rate of decay, with shorter exposure times and more accurate exposure compared to extracorporeal radiotherapy. Cancer cells become more susceptible to DNA damage after IORT, through which the toxicity associated with extracorporeal radiotherapy can be effectively avoided. Patients with multiple lymph node metastases are at risk of combined lymph node micrometastasis or peripheral tissues metastasis (12). IORT combined with surgical resection can achieve better local control and prolong survival. Studies have shown that IORT is a feasible technique that can be explored in tailored treatment for patients with locally recurrent rectal cancer, and thus it may be an option for minimizing radiation toxicity to the bladder, prostate, vagina, uterus, small bowel, and ureters (13). In their study, Xue et al. (14) found that more than 4 years of follow-up, surgery for rectal cancer combined with IORT resulted in no significant radiotoxicity, with a median follow-up of 18.5 months (range, 3–45 months) and no deaths. The National Comprehensive Cancer Network (NCCN) guidelines recommend extracorporeal radiotherapy for rectal cancer at a dose of 45–54 Gy for 25–28 sessions, which represents a massive financial burden for some patients. Thus, some patients abandon or refuse extracorporeal radiotherapy in the middle of the treatment, which increases the risk of local recurrence. The IORT radiation dose of 18–20 Gy is equivalent to a 50-Gy dose of external irradiation (15,16). The routine dose of IORT for patients with rectal cancer is about 10–30 Gy, and the radiation time is about 30 minutes (17). IORT is completed under intraoperative anesthesia and provides precise irradiation of the tumor bed area under direct vision, without the problem of displacement during radiotherapy or pain. Currently, there is a lack of literature reporting the treatment of ILN metastasis with IORT. Radiotherapy can be used to reduce cancer cells remaining after surgery for ILN metastases, and to prevent tumor recurrence, radiotherapy is typically administered after surgery to ensure that as many of the remaining cancer cells as possible are eliminated. Although there is a lack of detailed literature on the specific side effects and potential risks of IORT for patients with rectal cancer and ILN metastasis, one study did provide initial insight through a case study. In this study, a patient with recurrent ovarian cancer who received 14-Gy IORT combined with postoperative radiotherapy in the groin area experienced severe complications of grade 3 inguinal dermatitis and wound rupture; meanwhile, another patient who received 12.5-Gy IORT did not experience any significant complications after surgery (18). This comparison suggests a possible association between IORT dose and subsequent side effects. In a systematic review comprising 3,003 patients with locally advanced primary or recurrent colorectal cancer, IORT was found to be significantly associated with improved local control and survival rates, without an increase in overall, urologic or anastomotic complications. However, an elevated risk of wound complications was observed following IORT, with wound infections and pelvic abscesses being the most frequently reported complications (19). The applicability and safety of IORT in patients with rectal cancer with ILN metastasis should be further studied with large-sample data. Our center innovatively applied radiotherapy intraoperatively, and no signs of recurrence were found during the postoperative follow-up and no related adverse reactions occurred in the short-term.

The Chinese Society of Clinical Oncology (CSCO) guidelines indicate that both local therapy for the primary tumor and systemic therapy for distant metastases are necessary for patients with metastatic rectal cancer. A multidisciplinary team meeting should be held for these patients. The sequence of local and systemic treatments should be arranged according to the degree of threat to health, resectability, and risk of recurrence of the primary and metastatic tumors. The primary lesion should be treated systematically with surgical resection. IORT and intracavitary irradiation or external irradiation can be used to target localized lesions if necessary. IORT significantly shortens treatment time while optimally distributing the dose, reducing patient displacement errors during treatment. For patients with lateral lymph node metastases, the addition of radiotherapy via a postoperative incision may be considered in addition to surgical resection of the metastatic lymph nodes.

In conclusion, in our case, surgical treatment combined with IORT was effective in accurately irradiating the tumor bed, and the patient did not experience tumor recurrence or IORT-related side effects during short-term follow-up. However, this report is of a single case, and a clinical trial with a larger sample should be conducted to confirm the efficacy of IORT.

Acknowledgments

Funding: This study was supported by Graduate Innovation Fund of Jilin University (No. 2023CX114).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-638/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Tocchi A, Lepre L, Costa G, Liotta G, Mazzoni G, Agostini N, Miccini M. Rectal cancer and inguinal metastases: prognostic role and therapeutic indications. Dis Colon Rectum 1999;42:1464-6. [Crossref] [PubMed]
2. Graham RA, Hohn DC. Management of inguinal lymph node metastases from adenocarcinoma of the rectum. Dis Colon Rectum 1990;33:212-6. [Crossref] [PubMed]
3. Hamano T, Homma Y, Otsuki Y, Shimizu S, Kobayashi H, Kobayashi Y. Inguinal lymph node metastases are recognized with high frequency in rectal adenocarcinoma invading the dentate line. The histological features at the invasive front may predict inguinal lymph node metastasis. Colorectal Dis 2010;12:e200-5. [Crossref] [PubMed]
4. Armoogum KS, Parry JM, Souliman SK, Sutton DG, Mackay CD. Functional intercomparison of intraoperative radiotherapy equipment - Photon Radiosurgery System. Radiat Oncol 2007;2:11. [Crossref] [PubMed]
5. Sethi A, Gros S, Brodin P, Ghavidel B, Chai X, Popovic M, Tomé WA, Trichter S, Yang X, Zhang H, Uhl V. Intraoperative radiation therapy with 50 kV x-rays: A multi-institutional review. J Appl Clin Med Phys 2024;25:e14272. [Crossref] [PubMed]
6. Kaur H, Ernst RD, Rauch GM, Harisinghani M. Nodal drainage pathways in primary rectal cancer: anatomy of regional and distant nodal spread. Abdom Radiol (NY) 2019;44:3527-35. [Crossref] [PubMed]
7. Wyatt J, Powell SG, Ahmed S, Arthur J, Altaf K, Ahmed S, Javed MA. Inguinal lymph node metastases from rectal adenocarcinoma: a systematic review. Tech Coloproctol 2023;27:969-78. [Crossref] [PubMed]
8. deLahunta D, Nalamati S. Management of Surgically Accessible Lymph Nodes Beyond Normal Resection Planes. Clin Colon Rectal Surg 2024;37:71-9. [Crossref] [PubMed]
9. Abd El Aziz MA, McKenna NP, Jakub JW, Hallemeier CL, Kelley SR, Jin Z, Mathis KL. Rectal cancer with synchronous inguinal lymph node metastasis without distant metastasis. A call for further oncological evaluation. Eur J Surg Oncol 2022;48:1100-3. [Crossref] [PubMed]
10. Sato H, Maeda K, Kinugasa Y, Kagawa H, Tsukamoto S, Takahashi K, et al. Management of inguinal lymph node metastases from rectal and anal canal adenocarcinoma. Colorectal Dis 2022;24:1150-63. [Crossref] [PubMed]
11. Chen M, Liu S, Xu M, Yi HC, Liu Y, He F. Radiation boost for synchronous solitary inguinal lymph node metastasis during neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Discov Oncol 2021;12:59. [Crossref] [PubMed]
12. Herskind C, Ma L, Liu Q, Zhang B, Schneider F, Veldwijk MR, Wenz F. Biology of high single doses of IORT: RBE, 5 R's, and other biological aspects. Radiat Oncol 2017;12:24. [Crossref] [PubMed]
13. Calvo FA, Sole CV, Rutten HJ, Dries WJ, Lozano MA, Cambeiro M, Poortmans P, González-Bayón L. ESTRO/ACROP IORT recommendations for intraoperative radiation therapy in locally recurrent rectal cancer. Clin Transl Radiat Oncol 2020;24:41-8. [Crossref] [PubMed]
14. Xue W, Wang S, Zhao Z, Li Y, Shang A, Li D, Yang J, Wang T, Wang M. Short-term outcomes of laparoscopic intersphincteric resection with intraoperative radiotherapy using low-energy X-rays for primary locally advanced low rectal cancer: a single center experience. World J Surg Oncol 2020;18:26. [Crossref] [PubMed]
15. Willett CG, Czito BG, Tyler DS. Intraoperative radiation therapy. J Clin Oncol 2007;25:971-7. [Crossref] [PubMed]
16. Dragovic J. Intraoperative radiation therapy. Jpn J Cancer Res 1992;83. inside front cover.
17. Hashiguchi Y, Sekine T, Kato S, Sakamoto H, Kazumoto T, Sakura M, Tanaka Y. Applicability of a mobile accelerator for intraoperative radiation therapy to colorectal cancer. Dis Colon Rectum 2001;44:1481-8. [Crossref] [PubMed]
18. Yap OW, Kapp DS, Teng NN, Husain A. Intraoperative radiation therapy in recurrent ovarian cancer. Int J Radiat Oncol Biol Phys 2005;63:1114-21. [Crossref] [PubMed]
19. Mirnezami R, Chang GJ, Das P, Chandrakumaran K, Tekkis P, Darzi A, Mirnezami AH. Intraoperative radiotherapy in colorectal cancer: systematic review and meta-analysis of techniques, long-term outcomes, and complications. Surg Oncol 2013;22:22-35. [Crossref] [PubMed]