Characteristics of tumor thrombosis in the inferior mesenteric vein from colorectal cancer: A report of three cases and review of the literature

Introduction Intravenous tumor thrombosis is a rare condition in colorectal cancer and shows a locally aggressive biological behavior. We herein report three cases of colorectal cancer with tumor thrombosis in the inferior mesenteric vein (IMV) treated by colorectal resection combined with resection of the IMV under laparoscopic surgery. Case presentation In these three colorectal cancer patients with IMV tumor thrombus, IMV tumor thrombus was detected in all instances on preoperative computed tomography. Preoperative chemotherapy was also performed in one patient with concurrent liver metastasis. All patients underwent laparoscopic locally R0 resection; however, the pathological findings showed a positive margin for IMV resection in all patients. Clinical discussion We reviewed 19 previously reported cases along with our 3 present cases and clarified the characteristics of colorectal cancer accompanied by IMV tumor thrombosis. IMV tumor thrombosis may be a risk factor for liver metastasis and R1 resection, and systemic treatment, including neoadjuvant chemotherapy (NAC), may be quite important. Conclusion IMV tumor thrombosis may have a tendency to cause hematogenous metastasis. Systemic therapy, including NAC, may be useful, but since this is a rare condition, the accumulation of further cases is needed.


Introduction
Intravenous tumor thrombosis is a relatively common pathology in some cancers, such as portal vein thrombosis from hepatocellular carcinoma and vena cava tumor thrombosis from renal cell carcinoma. However, it is rare in colorectal cancer [1].
We herein report three cases of colorectal cancer with tumor thrombosis in the IMV treated with laparoscopic surgery and combined resection of the IMV. In addition, to consider the treatment strategies, we reviewed 19 previously reported cases along with our 3 present cases and investigated the characteristics of colorectal cancer accompanied by IMV tumor thrombosis. This research work is reported in line with the SCARE 2020 criteria [2].

Case presentation
Three female patients (Patients 1, 2 and 3: 66, 67 and 77 years old) had been diagnosed with colorectal cancer with tumor thrombosis in the IMV. No patients had any comorbidity or remarkable medical history, drug history, family history or psychosocial history. Their symptoms were shortness of breath in Patient 1, lower abdominal pain and hematochezia that had persisted for six months in Patient 2 and abdominal pain and difficulty in defecation in Patient 3. Laboratory data showed an increased level of carcinoembryonic antigen (CEA) at 59.9 ng/ml in Patient 1, an increased level of carbohydrate antigen 19-9 (CA19-9) at 194.7 U/ml in Patient 2 and an increased level of CEA at 33.7 ng/ml in Patient 3.
Colonoscopy showed a circumferential type 3 tumor in the left side of the transverse colon in Patient 1, a circumferential type 2 tumor in the rectosigmoid colon in Patient 2 and a circumferential type 2 tumor in the sigmoid colon in Patient 3, and the scope could not pass through due to strong stenosis in Patients 1 and 3 (Fig. 1). Abdominal contrastenhanced computed tomography revealed an enhanced mass in the endoscopically observed lesions, and IMV tumor thrombosis was suspected due to an intraluminal filling defect in the dilated IMV in all cases. An irregular ring-enhancing lesion in segment (S) 6 of the liver was found in Patient 2 (Fig. 2). Patient 1 underwent laparoscopic partial colectomy of the transverse and descending colon with D3 lymphadenectomy and combined resection of the small intestine and the IMV. We performed touch confirmation of the IMV with laparoscopic forceps and identified a location where the vein wall was soft and considered free from tumor invasion. We then isolated the IMV at the level of the inferior margin of the pancreas (Fig. 3a).
Patient 2 underwent preoperative chemotherapy of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus panitumumab for four courses. The primary lesion and metastasis were reduced in size and showed a partial response to chemotherapy, so the patient was scheduled to undergo radical resection. The patient underwent laparoscopic low anterior resection with D3 lymphadenectomy and combined resection of the small intestine and IMV. We identified a location where the IMV could be isolated, as in Patient 1, and isolated the IMV at as central a point as possible to the extent that it is safely operable (Fig. 3b).
Patient 3 underwent laparoscopic sigmoid colectomy with D3 lymphadenectomy and combined resection of the retroperitoneum and IMV. We isolated the IMV as in Patient 2 (Fig. 3c).
All three surgeries were performed using the endoscopic surgical skill qualification system, involving a qualified surgeon assisted by a senior specialist general surgeon and a surgical resident. All patients had smooth postoperative courses and were discharged without major complications.
A pathological examination showed that the tumor was a moderately differentiated adenocarcinoma in Patients 1 and 2 and a poorly differentiated adenocarcinoma in Patient 3. Lymph node metastases and lymphovascular invasion were observed in all cases. While the circumferential resection margin at the primary lesion was negative, tumor cells were found at the cut-end of the IMV, leading to the diagnosis of R1 resection in all cases (Fig. 4). The histological response to preoperative chemotherapy was Grade 1a in Patient 2. The pathological staging was T4bN1aM0, stage IIIC in Patient 1; T3N2bM1a, stage IVA (KRAS wild type, BRAF wild type) in Patient 2; and T4bN2aM0, stage IIIC in Patient 3 (8th edition of the UICC TNM classification). Patients 1 and 3 received eight courses of capecitabine plus oxaliplatin (CAPOX) as adjuvant chemotherapy. No recurrence has been noted in the 19 months in Patient 1 and 11 months in Patient 3 since surgical resection. Patient 2 underwent right hepatic lobectomy three months after the first surgery. However, one month after this second surgery, liver metastases and multiple lung metastases were detected. mFOLFOX6 plus panitumumab was subsequently resumed, and she is currently alive 17 months after the first surgery. Adherence and tolerability to chemotherapy were found to be acceptable in all patients.
The localization of the primary tumor was the left transverse colon in one case, the descending colon in four cases, the sigmoid colon in seven cases, the rectosigmoid in six cases, and the upper rectum in four cases, all showing primary lesions in the IMV drainage area. The histological types were highly differentiated adenocarcinoma in 5 cases, moderately differentiated adenocarcinoma in 15 cases, poorly differentiated adenocarcinoma in 1 case, and mucinous carcinoma in 1 case, with most cases being highly and moderately differentiated adenocarcinomas, showing a similar tendency to usual colorectal cancer.
In the cases for which pathology results were available, the mean tumor diameter was 54.8 mm, all cases had T3 or T4 depth and positive vascular invasion, and 17 of the 19 cases had positive lymph node metastasis. The isolating location of the IMV varied, including the root of the IMV, at the level of the inferior margin of pancreas and the confluence of the portal vein and IMV, in addition to other points. In some cases, an intraoperative rapid pathological diagnosis, vasectomy for tumor removal and cleaning were performed. Laparoscopic surgery was performed in six cases, including our three cases. Although laparoscopic surgery for colorectal cancer has been widely used in recent years and become a standard procedure in more advanced cases, it may be inferior to open surgery due to the lack of tactile sensation, and there is some concern that R1 resection may be performed in cases with intravenous tumor thrombosis. Therefore, it was considered necessary to select the surgical technique carefully.
Among the 22 total cases, 11 showed synchronous or metachronous metastasis, of which liver metastasis was the most common, occurring in 7 cases. This suggests that colorectal cancer with IMV tumor thrombosis should be considered a highly advanced status and prone to vascular metastasis. Since such extensive vascular invasion is certainly suggestive of at least micro-metastatic spread, it may be worth considering prioritizing chemotherapy as a treatment option. While postoperative adjuvant chemotherapy was administered in 16 of the 19 patients, preoperative chemotherapy was administered in only 2 patients, including one of our patients. Both cases had synchronous liver metastases, and the chemotherapy was initiated as a systemic therapy for stage IV colorectal cancer, not as NAC. NAC has an established role in many solid tumors, including rectal cancer, but its utility has not previously been formally evaluated in colon cancer. In recent years, there have been many reports on the midto long-term results of NAC for colon cancer [19,20]. In the FOxTROT trial, the R0 resection rate was 95.2 % in the NAC group and 90.9 % in the surgery-precedent group (p = 0.01), showing a significantly better rate in the NAC group. The 22 cases we reviewed are not identical to those in the FOxTROT trial, so we cannot say anything definitive, but they all had highly locally invasive cancer, so it is quite possible that NAC may be an effective treatment option for R0 resection. Prioritizing chemotherapy may not only increase the R0 resection rate but also potentially spare the patient pointless surgery by treating micrometastases and allowing time for the development of extensive metastatic lesions that were not clear at the time of the initial evaluation.

Conclusions
Since colorectal cancer with IMV thrombus showed aggressive behavior and a tendency to develop liver metastasis, systemic treatment can thus be considered instead of simply assuming that radical resection is possible before surgery. Colorectal cancer with IMV thrombus is a rare condition, so the accumulation of more cases in retrospective observational studies is needed, even if randomized controlled trials are difficult to perform. These findings suggest that NAC may become a useful systemic treatment option in the future.

Provenance and peer review
Not commissioned, externally peer-reviewed.

Consent
Written informed consents were obtained from three patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Funding
This research does not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical approval
This study was approved by the Institutional Review Board (reference number 2019-D34) of Saiseikai Yokohamashi Nanbu Hospital. c) Circumferential wall thickening with contrast enhancement was observed in the rectosigmoid colon in Patient 2. d) A mass lesion with irregular ring enhancement was found in liver (S6) in Patient 2. e) IMV tumor thrombosis was suspected due to poor contrast and dilation of the IMV in Patient 2. f) Circumferential wall thickening with contrast enhancement was observed in the sigmoid colon in Patient 3. g) IMV tumor thrombosis was suspected due to poor contrast and dilation of the IMV in Patient 3.

Author contribution
Substantial contributions to conception and design by Shota Izukawa MD and Hiroyuki Mushiake MD, PhD.
Acquisition of data by Shota Izukawa MD.
Drafting the article by Shota Izukawa MD. Critical revision of manuscript for intellectual content by Hiroyuki Mushiake MD, PhD.
All members have been approved the final version to be published. Fig. 3. Intraoperative findings. a) We isolated the IMV at the level of the inferior margin of pancreas where the vein wall was soft and considered free from tumor invasion in Patient 1. b) We isolated the IMV at as central a point as possible to the extent that it is safely operable where the vein wall was soft and considered free from tumor invasion in Patient 2. c) We isolated the IMV at as central a point as possible to the extent that it was safely operable where the vein wall was soft and considered free from tumor invasion in Patient 3.

Research registration number
Not applicable.

Declaration of competing interest
We have nothing to declare in any categories.