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Surg TodayDOI 10.1007/s00595-016-1431-4

ORIGINAL ARTICLE

Current status of prophylactic surgical treatment for familial adenomatous polyposis in Japan

Masato Yamadera1 · Hideki Ueno1 · Hirotoshi Kobayashi2 · Tsuyoshi Konishi3 · Fumio Ishida4 · Tatsuro Yamaguchi5 · Takao Hinoi6 · Yasuhiro Inoue7 · Yukihide Kanemitsu8 · Naohiro Tomita9 · Hideyuki Ishida10 · Kenichi Sugihara11

Received: 15 June 2016 / Accepted: 1 September 2016 © Springer Japan 2016

Conclusion Prophylactic surgery for FAP results in good short-term surgical outcomes in Japan. The current surgical approach is characterized by limited surgical indications for patients with attenuated FAP, delayed timing of colec-tomy, and the increasing standardization of laparoscopic surgery.

Keywords Hereditary colorectal cancer · Familial adenomatous polyposis · Prophylactic surgery · Total colectomy · Proctocolectomy

AbbreviationsFAP Familial adenomatous polyposisIPAA Ileal pouch anal anastomosisIRA Ileorectal anastomosisIACA Ileoanal canal anastomosisIAA Ileoanal anastomosisAPC Adenomatous polyposis coli

Abstract Purpose We conducted this study to clarify the current clinical practice of prophylactic colectomy for patients with familial adenomatous polyposis (FAP) in Japan.Methods This retrospective multi-center cohort study involved 23 specialized institutions for colorectal disease in Japan. We analyzed the records of 147 patients who under-went prophylactic surgical treatment between 2000 and 2012. Patients were divided into Group 1 (2000–2006) and Group 2 (2007–2012) based on their date of surgery.Results Age at the time of prophylactic surgery was 27 and 31 years in Groups 1 and 2, respectively. The proportion of attenuated FAP was significantly lower in Group 2 than in Group 1 (1.0 vs. 13 %, respectively). Pathological examina-tion revealed an increased incidence of malignant polyps in the resected specimens from Group 2 patients (10 vs. 23 %, respectively; P = 0.034). Laparoscopic surgery was more frequent in Group 2 than in Group 1 (61 vs. 40 %, respec-tively). There was no surgical mortality in either group.

* Hideki Ueno ueno_surg1@ndmc.ac.jp

1 Department of Surgery, National Defense Medical College, Saitama, Japan

2 Center for Minimally Invasive Surgery, Tokyo Medical and Dental University, Tokyo, Japan

3 Gastroenterological Center, Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

4 Digestive Disease Center, Showa University Northern Yokohama Hospital, Kanagawa, Japan

5 Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan

6 Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

7 Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Mie, Japan

8 Division of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan

9 Department of Surgery, Hyogo College of Medicine, Hyogo, Japan

10 Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan

11 Department of Surgical Oncology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

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Introduction

Familial adenomatous polyposis (FAP) is a genetic disease occurring in 1 in 7000–10,000 births in Western countries and 1 in 17,400 births in Japan [1, 2]. Colorectal adenomas develop in most patients with FAP in their second decade of life. If not aggressively treated, colorectal cancer will subsequently develop in their third or fourth decade of life [3, 4]. Although non-steroidal anti-inflammatory drugs may have an antineoplastic effect on colonic adenomas [5], pro-phylactic surgery of the colon remains the only curative treatment for polyposis.

In general, the surgical options for patients with FAP include restorative proctocolectomy with an ileal pouch anal anastomosis (IPAA) and colectomy with an ileorectal anastomosis (IRA). In Japan, IPAA has been categorized into two types to distinguish the level of anastomosis: ile-oanal canal anastomosis (IACA) for anastomosis above the sphincter muscle and ileoanal anastomosis (IAA) for anastomosis above the dentate line [6, 7]. IRA is associated with substantial mortality from rectal cancer. In fact, Vasen et al. reported that IPAA can lead to a 1.8-year increase in life expectancy compared with IRA [8]. Restorative proc-tocolectomy with IPAA, particularly IAA, involves higher morbidity and poorer functional outcome but eliminates the risk of subsequent rectal cancer [9]. IRA was the most common procedure performed for FAP before 1980; how-ever, since its introduction in the 1980s, IPAA has become increasingly popular [8]. It is now regarded as the standard procedure for many patients with FAP, except those with attenuated FAP [10].

In 2004, Iwama et al. [11] reported the results of an analysis of the database of the Japanese Polyposis Registry to clarify the surgical treatment of FAP in Japan. This was one of the large-scale clinical studies on FAP and some of the findings were cited in the Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines, 2012 for the Clinical Practice of Hereditary Colorectal Cancer. How-ever, there have been no attempts to investigate changes to the surgical approach for FAP in Japan since 2004, despite recent improvements in colorectal surgical techniques.

We conducted this study to investigate the trends in the surgical treatment of FAP over 13 years in specialist insti-tutions for colorectal disease in Japan to discern the current status of prophylactic colectomy for patients with FAP.

Methods

Data source

We analyzed data from the multi-institutional FAP dataset collected in the “multi-institutional retrospective cohort

study for FAP” by the JSCCR. A total of 303 patients from 23 specialized institutions for colorectal disease were included in this database. All patients diagnosed with FAP met one of the following criteria: more than 100 polyps present in the colon and rectum; or genetic testing identi-fying an adenomatous polyposis coli (APC) gene mutation [6, 12]. There was no intentional inclusion or exclusion of patients into the registry, which might have introduced any bias into the results. This study was approved by the JSCCR Institutional Review Board and the institutional ethics committees.

Patient and data analysis

From the abovementioned FAP data source, a total of 147 patients who underwent a prophylactic surgery for FAP between January, 2000 and December, 2012 were included in this study (Fig. 1). No patients who underwent a colec-tomy for the purpose of cancer removal were included. The following data were collected in this study: patient charac-teristics (age and sex), type of polyp burden, pathological data, details of the operation [type of surgery, type of anas-tomosis, use of temporary stoma, age at surgery, operating time, blood loss, and American Society of Anesthesiologists (ASA) score], and postoperative morbidity. A family history of colonic or colorectal cancer was also obtained. The phe-notype of the polyp burden was classified as one of three types: profuse type (≥1000 polyps), classical type (100–999 polyps), or attenuated type (<100 polyps) [13]. In the pre-sent study, IPAA was classified into two categories using the Japanese conventional methods, thus enabling close distinc-tion of the level of anastomosis; namely, IAA for the anasto-motic procedure at the dentate line after the mucosectomy; and IACA for stapled or hand-sewn anastomosis above the sphincter muscle. Postoperative complications were classi-fied based on the Clavien–Dindo classification [14, 15].

Statistical analysis

We divided the series into two periods. Period 1 was from January, 2000 to December, 2006 and period 2 was from January, 2007 to December, 2012. We defined the patients who underwent prophylactic surgery in period 1 as Group 1 and those who underwent surgery in period 2 as Group 2. Descriptive analyses are presented as the mean ± standard deviation or the median (ranges) for quantitative data and as the number of cases (percentage of cases) for categorical var-iables. Comparisons were analyzed using Student’s t test or the Mann–Whitney U test for quantitative data and the Chi-square test or, where appropriate, Fisher’s exact probability test for categorical variables. The statistical analysis was performed using JMP software version 11.0 (SAS Institute, Cary, NC). A P value of <0.05 was considered significant.

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Results

Patient backgrounds

Groups 1 and 2 comprised 78 and 69 patients, respectively (total n = 147). The median patient age at the time of the operation was 28 years (range 12–66 years). Figure 2 shows the patient age distribution according to the year of surgery. The proportion of patients aged <20 years who underwent surgery was lower in Group 2 than in Group 1, suggesting that delayed surgery was adopted in the Group 2 period as these patients were an average 4 years older than those in Group 1 at the time of surgery (P = 0.006) (Table 1). The ratio of men to women was 1.1:1 and was not signifi-cantly different between the groups. Considering polyp phenotype, 40 (27 %), 96 (65 %), and 11 (8 %) patients had profuse, classical, and attenuated types, respectively. The proportion of patients with the attenuated type was sig-nificantly lower in Group 2 (1 %) than in Group 1 (13 %, P = 0.025). The ASA score, method of anastomosis, operating time, and blood loss did not differ significantly between the groups.

Incidence of neoplasia

The incidence of a malignant polyp, including carci-noma in situ, revealed by pathological examination of the resected surgical specimen was higher in Group 2 (23 %)

than in Group 1 (10 %, P = 0.034). However, there was no significant difference in the incidence of carcinoma at stage pT1 or deeper between the Group 1 (1 %) and Group 2 (1 %) patients (P = 1.0).

Surgical procedures

There was no significant difference in the use of IAA between Groups 1 and 2 (Table 1). Diverting ileostomy was performed in 42, 54, and 10 % of patients who underwent IAA, IACA, and IRA, respectively, over the duration of this

Fig. 1 Patient inclusion and exclusion criteria Patients with familial adenomatous polyposis

assessed for inclusion (n = 303)

Excluded patients undergoing colectomy

for the purpose of cancer removal

(n = 154)

Patients undergoing prophylactic surgery (n = 155)

Excluded patients undergoing partial colectomy

or permanent ileostomy (n = 4)

Data was partially unknown (n = 3)

Eligible patients (n = 147)

Fig. 2 Patient age at operation according to the year of surgery

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study. The frequency of diverting ileostomy did not differ significantly between the groups. The rate of laparoscopic procedures was higher in Group 2 (61 %) than in Group 1 (40 %, P = 0.011; Fig. 3). Notably, the laparoscopic approach was adopted in 75 % of patients who underwent colectomy from 2009 onward.

Considering the type of laparoscopic colectomy, IAA was more likely to be performed in the Group 2 patients (55 %) than in the Group 1 patients (13 %, P < 0.001) (Fig. 4, Table 1). The use of a diverting ileostomy with lap-aroscopic colectomy was more common in Group 2 (52 %) than in Group 1 (29 %, P = 0.046). However, in patients

Table 1 Clinical characteristics of the patients in Groups 1 and 2

SD standard deviation, IAA ileoanal anastomosis, IACA ileoanal-canal anastomosis, IRA ileorectal anastomosis, ASA American Society of Anesthesiologistsa Familial history of colonic or colorectal cancer

Overall P value Laparoscopic P value

Group 1 (2000–2006) (n = 78) Group 2 (2007–2012) Group 1 (2000–2006) (n = 31)

Group 2 (2007–2012) (n = 42)

(n = 69)

Age (years)

Median (range) 27 (12–58) 31 (18–66) 0.006 26 (12–57) 28 (18–60) 0.048

Gender

Men 41 (53 %) 37 (54 %) 0.90 18 (58 %) 37 (52 %) 0.63

Women 37 (47 %) 32 (46 %) 13 (42 %) 22 (48 %)

Type of polyp burden

Profuse 22 (28 %) 18 (26 %) 0.025 11 (36 %) 13 (31 %) 0.017

Classical 46 (59 %) 50 (73 %) 15 (48 %) 29 (69 %)

Attenuated 10 (13 %) 1 (1 %) 5 (16 %) 0 (0 %)

Procedure

IAA 39 (50 %) 38 (55 %) 0.66 4 (13 %) 23 (55 %) <0.001

IACA 17 (22 %) 11 (16 %) 10 (32 %) 4 (9 %)

IRA 22 (28 %) 20 (29 %) 17 (55 %) 15 (36 %)

Approach

Open 47 (60 %) 27 (39 %) 0.011

Laparoscopy 31 (40 %) 42 (61 %)

Diverting ileostomy

Yes 22 (28 %) 29 (42 %) 0.10 9 (29 %) 22 (52 %) 0.046

No 56 (72 %) 40 (58 %) 22 (71 %) 20 (48 %)

Operation time (min)

Mean ± SD 334 ± 148 366 ± 158 0.21 393 ± 126 429 ± 151 0.36

Blood loss (g)

Median (range) 205 (0–2150) 183 (0–1142) 0.31 139 (0–600) 140 (0–1142) 0.89

ASA score

1 69 (89 %) 63 (91 %) 0.60 27 (87 %) 38 (90 %) 0.72

2 8 (10 %) 6 (9 %) 4 (13 %) 4 (10 %)

3 1 (1 %) 0 (0 %) 0 (0 %) 0 (0 %)

Familial historya

Yes 46 (59 %) 45 (65 %) 0.44 24 (77 %) 32 (76 %) 0.90

No 32 (41 %) 24 (35 %) 7 (23 %) 10 (24 %)

With colorectal carcinoma

Absence 70 (90 %) 53 (77 %) 0.034 28 (90 %) 31 (74 %) 0.13

Presence 8 (10 %) 16 (23 %) 3 (10 %) 11 (26 %)

Tis 7 (9 %) 15 (22 %) 0.030 3 (10 %) 10 (24 %) 0.14

T1 or deeper 1 (1 %) 1 (1 %) 1.0 0 (0 %) 1 (2 %) 1.0

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who underwent open laparotomy, the rate of diverting ile-ostomy in Group 2 (26 %) was similar to that in Group 1 (26 %, P = 0.97).

Complications

Table 2 summarizes the types and grades of postoperative complications. There were significant differences in the incidence of intraperitoneal abscess, which occurred more frequently in Group 2. There were no significant differ-ences in the rate of severe postoperative morbidity between Group 1 (23, 6, and 5 % in patients undergoing IRA, IACA, and IAA, respectively) and Group 2 (15, 9, and 18 % in patients undergoing IRA, IACA, and IAA, respectively). The mortality rate in the perioperative period (<30 days) was 0 % in both groups.

Fig. 3 Distribution of the rate of surgical approaches used each year

Fig. 4 Distribution of the types of surgical procedures performed each year

Table 2 Incidence of morbidity and mortality in Groups 1 and 2

a Postoperative complication was not limited to a single disease

Group 1 (2000–2006) (n = 78) Group 2 (2007–2012) (n = 69) 　 P value

Mortality 0 (0 %) 0 (0 %) 1.0

Anastomotic leakage 1 (1 %) 0 (0 %) 1.0

Anastomotic stricture 3 (4 %) 3 (4 %) 1.0

Intraperitoneal abscess 0 (0 %) 4 (6 %) 0.046

Small bowel obstruction 13 (17 %) 12 (17 %) 0.91

Others 4 (5 %) 8 (12 %) 0.23

Overalla 18 (23 %) 20 (29 %) 0.31

Clavien–Dindo classification

I 3 (4 %) 4 (6 %) 0.64

II 7 (9 %) 5 (7 %)

IIIa 7 (9 %) 8 (12 %)

IIIb 1 (1 %) 3 (4 %)

IV 0 (0 %) 0 (0 %)

V 0 (0 %) 0 (0 %)

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Discussion

This multi-center study investigated the current status of prophylactic surgery for FAP in specialist institutions in Japan. Our findings highlighted three clinically important changes in the surgical treatment of FAP during the last 13 years.

First, the surgical indications for prophylactic colectomy in patients with attenuated FAP have become increasingly limited in recent years. Attenuated FAP is characterized by a more benign disease course with a lower risk of malig-nant transformation than the profuse or classical forms of FAP [16]. It was previously reported that attenuated FAP accounts for approximately 8 % of all cases of FAP, which concurs with our findings over the 13-year period of the present study [17]. However, we found that the incidence of surgery for attenuated FAP was 12 % lower in Group 2 than in Group 1. The decreased number of patients with attenuated FAP undergoing colectomy may be attributable to the increased use of endoscopic polypectomy in these patients. While prophylactic colectomy with IRA is still recommended for patients with attenuated FAP [17–19], some recent reports argue that endoscopic management of polyps may be feasible for patients with this type of FAP [20, 21].

Second, we found that the incidence of surgical speci-mens containing a malignant tumor was greater in period 2. The reason for this is uncertain because the pathological diagnostic criteria in Japan did not change over the period of this study [12, 22, 23]. However, the delay in perform-ing prophylactic surgery could be a contributing factor as the Group 2 patients underwent surgery an average of 4 years later than the Group 1 patients. The average age of the patients with a malignant tumor (32 years old) was greater than that of the patients without a malignant tumor (28 years old), although this difference was not significant in our cohort. It has been reported that the cumulative can-cer risk of FAP exceeds 1 % at the age of 20 years, 5 % at the age of 25 years, and 10 % at the age of 30 years [6]. Furthermore, approximately half of untreated patients with FAP will have colorectal cancer by the age of 40 [3, 11]. There have been no studies on the influence of delayed sur-gery for FAP on the progression of malignant colorectal polyps. Once FAP has been diagnosed, surgery should be performed when the patient is 15–25 years old, or sooner if diffuse polyposis or carpeting is evident [24–26]. In the present study, the incidence of malignant tumors, includ-ing in situ colorectal cancer, was greater in patients treated in the latter period. Profuse or classical FAP has a greater malignant potential than attenuated FAP. The finding that the proportion of classical FAP was higher in Group 2 may influence the higher incidence of colorectal cancer in this group to some degree, although both groups have about

the same percentage of profuse FAP. Moreover, delayed surgical intervention could be a reason for the increased proportion of patients with in situ colorectal cancer. The risk of colorectal cancer in patients with FAP is a major consideration in the timing of prophylactic surgery, which may be delayed because of social factors, such as pursuing higher education, finding employment, or marital status. This study indicates that the incidence of invasive colorec-tal carcinoma was not increased in period 2 and no patients with malignant polyps died of recurrent colorectal cancer. These results suggest that a 4-year delay in adopting pro-phylactic surgery is still acceptable in clinical practice in Japan. However, the appropriateness of delaying surgery should be carefully interpreted, particularly in clinical prac-tice, because this study has the following important limita-tions: patients undergoing surgery for the purpose of cancer removal were excluded from this study, so the incidence of patients with colorectal cancer according to age at the time of surgery was unknown; and the equivalence of long-term outcomes between the two groups was unclear because we do not have data on the long-term outcomes of the patients in Group 2.

The third recent change in FAP treatment was the increased use of a laparoscopic approach, which would influence the type of surgery performed and the frequency of a diverting stoma [27]. Some studies demonstrate that laparoscopic surgery for FAP is safe and feasible, the trend in laparoscopic surgery for FAP is unclear because previ-ous studies have been based on relatively small cohorts in a single institution [28–31]. In our series, the use of laparoscopic colectomy increased by 22 % in the latter period. Laparoscopic surgery for colorectal carcinoma has increased over time and comprises >30 % of all colorectal surgery performed in Japan since 2008 [32]. Subsequently, the indications for prophylactic laparoscopic surgery in patients with FAP have increased since 2009. Because it is less invasive, laparoscopic surgery has been adopted not only for the treatment of colorectal cancer, but also for the prophylactic treatment of FAP.

In conclusion, this multi-center study on prophylactic surgery for patients with FAP in Japan revealed three recent trends: more limited surgical indications for the treatment of patients with attenuated FAP; the association of prophy-lactic colectomy at a later age with an increasing incidence of malignant colorectal polyps; and the increasing use of laparoscopic prophylactic colectomy.

Acknowledgments We thank the following investigators in the “multi-institutional retrospective cohort study for FAP” by JSCCR for collecting the data on patients with FAP: Dr. N. Matsubara, Hyogo College of Medicine, Hyogo; Dr. K. Komori, Aichi Cancer Center Hospital, Aichi; Dr. H. Ozawa, Tochigi Cancer Center, Tochigi; Dr. T. Nagasaka, Okayama University Graduate School of Medicine, Den-tistry and Pharmaceutical Sciences, Okayama; Dr. H. Hasegawa, Keio

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University School of Medicine, Tokyo; Dr. M. Koyama, Hirosaki Uni-versity Graduate School of Medicine, Aomori; Dr. Y. Akagi, Kurume University School of Medicine, Fukuoka; Dr. T. Yatsuoka, Saitama Cancer Center, Saitama; Dr. K. Kumamoto, Fukushima Medical Uni-versity School of Medicine, Fukushima; Dr. K. Kurachi, Hamamatsu University School of Medicine, Shizuoka; Dr. K. Tanakaya, Iwakuni Clinical Center, Yamaguchi; Dr. K. Yoshimatsu, Tokyo Women’s Medical University Medical Center East, Tokyo; Dr. T. Watanabe, Graduate School of Medicine, The University of Tokyo, Tokyo.

Compliance with ethical standards

Conflict of interest None declared.

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