Rectal cancer with extensive distal intramural spread treated by abdominoperineal resection

Abstract

Distal intramural spread refers to microscopic tumor implantation in the intestinal wall, distal to the inferior edge of a macroscopic tumor but rarely beyond 2 cm. We report a case of rectal cancer with preoperatively diagnosed distant intramural spread to approximately 6.5 cm. A 75-year-old woman diagnosed with upper rectal cancer was scheduled to undergo low anterior resection 5 weeks after initial presentation. However, preoperative digital rectal examination and anoscopy under general anesthesia revealed a rectal tumor 4 cm proximal to the anal verge; adenocarcinoma was diagnosed based on frozen section analysis of the rectal tumor. Therefore, abdominoperineal resection was performed, and histopathological examination confirmed a moderately differentiated adenocarcinoma with distal intramural spread of 6.5 cm. The patient died 18 months postoperatively owing to lung metastasis. Although distal intramural spread is rare and can be difficult to detect prior to surgery, repeated rectal examination, with prompt histological examination of suspicious lesions, can ensure earlier diagnosis to achieve better local control by radical surgery including sufficient distal margin.

Introduction

Microscopic tumor implants in the intestinal wall, distal to the inferior edge of a macroscopic tumor, are collectively known as distal intramural spread (DIS) [1]. In cases of rectal carcinoma, the existence of DIS is a key factor when determining the extent of an anal resection margin to avoid local recurrence [2-4]. A distal margin of 2 cm from the tumor is recommended when a performing a sphincter-preserving surgery on the basis that DIS rarely exceeds 2 cm in rectal cancer [5, 6]. Here we report a rare case of rectal cancer in which DIS extended to approximately 6.5 cm, which was diagnosed by preoperative examination, and required treatment by abdominoperineal resection (APR).

Case report

A 75-year-old woman was referred to Rokuwa Hospital with a history of anal pain for 3 months. At initial presentation, there were no abnormal findings in the chest or abdomen except for a tumor palpated at 8 cm from the anal verge, as observed by digital rectal examination. Her laboratory results, including those of carcinoembryonic antigen (4.7 ng/ml) and carbohydrate antigen 19–9 (37 U/ml), were normal. A barium enema study revealed a defect in the upper rectum; this defect measured approximately 6 cm in length and had an irregular surface (Fig. 1). Colonoscopy then confirmed the presence of a tumor with ulceration that was located 8 cm proximal to the anal verge (Fig. 2). Results of biopsy indicated that this was a well-differentiated adenocarcinoma. Results of chest and abdominal computed tomography did not reveal any abnormality, except swollen lymph nodes around the rectum.

Fig. 1.

Barium enema image of the upper rectum. Barium enema revealed a defect in the upper rectum measuring approximately 6 cm in length with an irregular surface (arrow). a Front view. b Side view

Fig. 2.

Representative colonoscopy images. a Colonoscopy revealed an ulcerated tumor 8 cm proximal to anal verge. b No tumor was seen anally to the tumor in the upper rectum

The patient was then transferred to Fujita Health University Hospital for treatment of rectal cancer. A low anterior resection with lymph node dissection with a 2-cm distal margin was planned 5 weeks after the initial presentation. However, preoperative digital rectal examination and anoscopy under general anesthesia showed a tumor with an appearance of a submucosal tumor 4 cm proximal to the anal verge. Frozen section analysis of the tumor confirmed the diagnosis of adenocarcinoma; therefore, an APR with lateral lymph node dissection was performed.

The resected specimen revealed two ulcerated tumors in the upper rectum (65 × 35 × 10 mm and 20 × 10 × 5 mm) and a submucosal tumor with a surface ulcer in the lower rectum (15 × 10 × 5 mm) (Fig. 3a). Macroscopically, there was normal surface mucosa between the three tumors, though the two tumors in the upper rectum were mainly continuous in the submucosal and muscle layers (Fig. 3b). Histological examination of larger tumor in the upper rectum revealed a moderately differentiated adenocarcinoma that was similar to the other two tumors (Fig. 3c, d), with subserosal invasion and lymph node metastasis, including obturator lymph node. Final pathologic staging was stage IIIc (T3 N3 M0) using the Japanese classification of colorectal carcinoma [7], and stage IVA (T3 N2b M1a) using TNM classification. Lymphatic and vascular invasion were evaluated using immunohistochemical analysis by D2-40 and Factor 8 staining. There was severe lymphangitic and venous invasion according to the Japanese classification of colorectal carcinoma [7]. Adenocarcinoma in the lower rectum had proliferated mainly in the submucosal and muscular layers (Fig. 3d). Furthermore, many tumor emboli were observed within vascular and lymphatic vessels in continuity between the tumors of the upper and lower rectum (Fig. 3e, f, g). Based on these findings, the patient was diagnosed as having cancer with intramural spread of approximately 16 cm, including DIS of approximately 6.5 cm. The investigation of KRAS status in cancer tissue revealed a point mutation at codon 12.

Fig. 3.

Findings at histopathological examination. a Macroscopic appearance of the resected specimen of the rectum. b Macroscopically, the cut surface revealed that two tumors in upper rectum were continuous in the submucosal and muscle layers. c The tumors in the upper rectum were moderately differentiated adenocarcinoma and were mainly continuous in the submucosal and muscular layers. d The moderately differentiated adenocarcinoma in the lower rectum had proliferated mainly in the submucosal and muscular layers. e Numerous tumor emboli were observed within the vascular and lymphatic vessels between the tumors of the upper and lower rectum. Tumor emboli are shown within the lymphatic “ly” (f) and vascular “v” (g) vessels. c–e are with hematoxylin and eosin staining, at ×12.5 magnification. f is with D2-40 staining, and g is with Factor 8 staining (×40 magnification)

The postoperative course of the patient was uneventful. Adjuvant chemotherapy with mFOLFOX6 [200 mg/m² l-leucovorin simultaneously administered with 85 mg/m²oxaliplatin, followed by a 400-mg/m² bolus of fluorouracil (5-FU) on day 1 and then 2,400 mg/m² 5-FU as an intravenous infusion over 46 h, every 2 weeks] was given for 6 months on an outpatient basis according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines [8]. After the adjuvant chemotherapy, she developed edema in her left leg for which she received rivaroxaban based on ultrasound diagnosis of a left popliteal vein thrombosis. Computed tomography showed lung metastasis and hilar lymph node metastasis 10 months after the operation, so chemotherapy was started with FOLFIRI (200 mg/m² l-leucovorin simultaneously administered with 150 mg/m²irinotecan, followed by a 400-mg/m² bolus of 5-FU on day 1 and then 2,400 mg/m² 5-FU as an intravenous infusion over 46 h, every 2 weeks). No molecular targeting drugs were used because of KRAS status and left popliteal vein thrombosis. By 14 months after the operation, bone metastasis had developed in her lumbar vertebra for which chemoradiotherapy based on TS-1 (tegafur/gimeracil/oteracil) was given. Finally, 18 months after the operation, she was admitted to Fujita Health University with dyspnea due to lung metastasis and died.

Discussion

The local recurrence rate of rectal cancer after a curative operation is reported to be 6–9.7%, with local recurrence being particularly frequent [9-11]. Therefore, it is important to keep a proper distal resection margin. DIS beyond 1 cm reportedly occurs in 10% of rectal cancers, whereas that beyond 2 cm reportedly occurs in only 1.3–6%. Consequently, a 2-cm distal resection margin is considered acceptable for most rectal cancers [2, 5, 6, 12]. In research by Williams et al., it was also reported that no patient had DIS beyond 5 cm (n = 50) [6]. Our patient had a rectal cancer with intramural spread of 16 cm, including DIS of approximately 6.5 cm.

To date, DIS has been thought to result from direct tumor extension, cancer cell implantation, or vessel invasion [6]. In our case, the histological findings of all three tumors were similar, and normal mucosa histologically existed among the three tumors. The two tumors in the upper rectum were connected submucosally, so considered to have occurred through direct extension. However, no direct extension was detected between the tumors of the upper and lower rectum. Histologically, there were multiple tumor emboli within the vascular and lymphatic vessels of the submucosal and muscular layers, indicating that DIS was caused by vessel invasion.

DIS is diagnosed by pathological findings, making it difficult to diagnose preoperatively. There have been a few reports of DIS suspected by mucosal abnormalities observed at endoscopy [13, 14] or by transrectal ultrasonography [15]. In the present case, colonoscopy was not suggestive of DIS at the initial presentation, but the rapid progression meant that DIS was detected by digital rectal examination 1 month later. This necessitated a change to APR despite planning a sphincter-preserving operation.

Stage III or IV rectal cancer is reported to be more likely to be associated with DIS than stage II disease [12, 16]. In patients with higher stage disease, frequent rectal examination may be appropriate to monitor for DIS when planning a sphincter-preserving operation. Prompt pathological examination can then be performed to diagnose or exclude DIS when suspected, thereby ensuring appropriate therapy.

Previous research has indicated that DIS is not only significantly associated with lymph node and distant metastases but also that it is a risk factor for local recurrence and poor prognosis [2, 12, 16, 17]. Shirouzu et al. reported that 65.5% rectal cancers with DIS and 77.2% with ≥ 2-cm DIS were stage IV cancers [16]. Furthermore, Shimada et al. reported that 42.8% rectal cancers with DIS and 75.0% with long DIS, defined as distal spread longer than the distal resection margin given in the Japanese classification of colorectal carcinoma ( ≥ 3 cm in rectosigmoid or upper rectum cancers and ≥ 2 cm in lower rectum cancer) [7], were stage IV cancers [12]. Although Williams et al. reported that all patients with DIS beyond 1 cm were dead from distant metastases within 3 years after operation, despite undergoing APR; however, local recurrence only appeared in one of these cases [6]. By contrast, other reports have indicated that patients with rectal cancer can survive without recurrence, even when DIS is present, if a sufficiently large distal margin is resected [13, 14, 18]. Our patient had a long DIS of approximately 6.5 cm, and she had several lymph nodes involved, including the lateral lymph node, and died of distant metastases early after her operation. However, she had no pelvic recurrence, which has often been associated with a reduced quality of life, and could continue treatment as an outpatient.

In conclusion, DIS is rare and is not easy to detect preoperatively. However, repeat rectal examinations and prompt histological examination of suspicious lesions can ensure early diagnosis and can facilitate radical treatment with a large distal margin. In doing so, we may achieve better local control and better outcomes for patients.

Funding

No financial support was received for the work described in this manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Informed consent

The patient provided informed consent prior to treatment and publication.