The surgical treatment of inflammatory bowel disease-associated dysplasia

Abstract

Surgical management of colonic dysplasia discovered in the inflammatory bowel disease patient is controversial. Total proctocolectomy (TPC) is the most definitive treatment for the eradication of undiagnosed synchronous dysplasias and/or carcinomas and the prevention of subsequent metachronous lesions in both Crohn’s disease (CD) and ulcerative colitis (UC). However, TPC is not always an attractive option owing to patient comorbidities and patient preference. Historically, dysplasia has been most studied in patients with UC, where the option of reconstruction without a stoma makes TPC more acceptable. Due to a relative lack of research on CD-related dysplasia, surveillance and treatment of CD dysplasia has followed paradigms based on UC data. However, due to pathophysiological differences in CD versus UC, options for surgical management in CD may be more varied than simple TPC, particularly in the less healthy surgical candidate and those who refuse end ileostomy.

Keywords::

• colorectal carcinoma
• Crohn’s disease
• dysplasia
• inflammatory bowel disease
• total proctocolectomy
• ulcerative colitis

Medscape: Continuing Medical Education Online

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Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)^™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/expertgastrohep; (4) view/print certificate.

Release date: 3 May 2013; Expiration date: 3 May 2014

Learning objectives

Upon completion of this activity, participants will be able to:

• • Analyze the risk of cancer among patients with IBD

• • Distinguish screening recommendations for colorectal cancer among patients with IBD

• • Assess management options based on the histopathological findings on colonoscopy of patients with IBD

• • Evaluate surgical treatment options for patients with IBD

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Associate Professor and Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Tara M Connelly

Division of Colon and Rectal Surgery, Penn State Milton S Hershey Medical Center, Hershey, PA, USA

Disclosure: Tara M Connelly has disclosed that the Division of Colon and Rectal Surgery is the recipient of the Carlino Fund for IBD Research.

Walter A Koltun

Division of Colon and Rectal Surgery, Penn State Milton S Hershey Medical Center, Hershey, PA, USA

Disclosure: Walter A Koltun has disclosed that the Division of Colon and Rectal Surgery is the recipient of the Carlino Fund for IBD Research.

Figure 1. Staged pouch reconstruction.

Three techniques are commonly used for colectomy and the creation of ileal pouch–anal anastomosis. The one-stage technique, where colectomy and pouch reconstruction are performed during the same operation (avoiding ileostomy), is performed in the healthy patient not on immunosuppressants. In the most commonly performed two-stage procedure, colectomy and pouch reconstruction with a defunctioning ileostomy is performed, followed by a reversal of ileostomy approximately 2 months later. This operation is most appropriate in the relatively healthy outpatient with minimal–moderate immunosuppressant use and a relatively good nutritional status. The three-stage technique involves colectomy and end ileostomy performed during the first operation, with proctectomy and pouch construction along with the creation of a diverting ileostomy performed during a second operation. The ileostomy is reversed during a third operation. This three-stage approach is taken most frequently in the acute/emergency setting and/or in the malnourished patient on large doses of immunosuppressants. A fourth sequence of the procedure (not illustrated), the modified two-stage procedure, comprises colectomy with ileostomy performed in a first operation, followed by pouch reconstruction without a diversion ileostomy in a second procedure approximately 6 months later, after the patient has been weaned from immunosuppressants, has an improved nutritional status and is relatively healthy.

Figure 2. Suggested paradigm for the surgical treatment of ulcerative colitis-associated colitis based on grade of dysplasia (low grade vs high grade), location of dysplasia (colon vs rectum) and patient morbidity (healthy vs moderate morbidity vs extreme morbidity).

Under ideal conditions, TPC is the surgery of choice. Under less optimal conditions, including patient comorbidities or patient refusal of more aggressive surgical options, lesser resections may be considered, as suggested earlier. Choice of surgery should always be made on an individual patient basis. After TPC, either IPAA or permanent ileostomy is chosen, based on the regcognition that an IPAA is associated with longer operative times and greater subsequent postoperative complications, such as pouchitis, bowel obstruction and increased need for repeat laparotomy. Therefore, an IPAA is less preferred vs permanent ileostomy in the morbid patient.

^†Reconfirm with complete biopsy and/or second pathologist confirmation.

^‡If no inflammation is detected in the rectum (i.e., ‘burned out’ colitis).

IPAA: Ileal pouch–anal anastomosis; IRA: Ileorectal anastomosis; SR: Segmental resection; TAC: Total abdominal colectomy; TPC: Total proctocolectomy; UC: Ulcerative colitis.

Figure 3. Suggested paradigm for the surgical treatment of Crohn’s disease-associated colitis based on grade of dysplasia (low grade vs high grade), location of dysplasia (colon vs rectum), presence or absence of rectal inflammation and patient morbidity (healthy vs moderate morbidity vs extreme morbidity).

Under ideal conditions, TPC is the surgery of choice. Under less optimal conditions, including patient comorbidities or patient refusal of more aggressive surgical options, lesser resections may be considered, as suggested above. Choice of surgery should always be made on an individual patient basis, balancing the risks of surgery versus those of residual or metachronous lesions.

^†Reconfirm with repeat biopsy and/or second pathologist confirmation.

CD: Crohn’s disease; IRA: Ileorectal anastomosis; SR: Segmental resection; TAC: Total abdominal colectomy; TPC: Total proctocolectomy.

Opinion on the appropriate extent of resection when colonic dysplasia is discovered on a background of inflammatory bowel disease (IBD) varies and ranges from colonoscopic resection to total proctocolectomy (TPC). High rates of multifocal dysplasia, metachronous neoplasia and undiagnosed synchronous lesions lead most surgeons to advocate a TPC. Any lesser resection bears the risk of leaving undetected dysplasia or carcinoma behind in the remaining colorectum, a potentially life-threatening consideration. However, a permanent end ileostomy is not always desirable or even safe in patients with comorbidities, and some are unable to care for an ileostomy. The ileal pouch–anal anastomosis (IPAA) is a more feasible option for the ulcerative colitis (UC) patient, but even then, comorbidities and anal sphincter dysfunction, especially in older patients, can make this option less attractive. As a result of its specific confinement to the colon and ability to be evaluated fully by colonoscopy, dysplasia in UC has been more fully studied than that in Crohn’s disease (CD). Therefore, due to the relative lack of studies on Crohn’s colitis patients, surgical recommendations tend to be based on those made for UC, although their pathobiology may be very different. When dysplasia is discovered in UC, surgical decision-making is more straightforward with TPC and pouch reconstruction is an acceptable treatment for most. However, CD, with its patchy inflammation, increased likelihood of anal disease and propensity towards rectal sparing, affords greater consideration of alternate choices for surgery besides TPC. Less aggressive surgery than TPC has also been suggested in UC for certain lesions, such as adenoma-like masses within areas of colitis that are amenable to complete colonoscopic removal. The surgical choices must be individualized and based on chance of recurrence versus risks of surgery.

The dysplasia–carcinoma sequence

The development of both sporadic colorectal carcinoma (CRC) and CRC on the background of the chronic inflammation of IBD involves p53 and APC mutations and microsatellite instability. The sequence of these genetic alterations is, however, different in the two groups [1]. Sporadic CRC tends to be more predictable with its adenoma–carcinoma sequence, typically taking approximately 10 years to develop into invasive carcinoma. The current IBD dysplasia–carcinoma model is that of a progression from no dysplasia to low-grade dysplasia (LGD) to high-grade dysplasia (HGD) to carcinoma. This model can only be thought of as a very rough guide, as patients commonly have HGD discovered without prior evidence of LGD, and carcinoma often develops at an accelerated pace when compared with sporadic CRC. This unpredictability often leads to difficulty in detecting dysplasia, even with regular surveillance. Inflammation has long been associated with metaplasia, dysplasia and progression to carcinoma. Several other clinical examples illustrate this sequence: the progression from esophagitis to Barrett’s to adenocarcinoma; chronic gastritis to gastric carcinoma and chronic dermatitis to squamous cell carcinoma of the skin. Supporting this pathophysiology are studies suggesting decreased rates of both sporadic and inflammation-related CRC in patients on long term anti-inflammatory (NSAIDs or aminosalicylic acid) treatment and successful use of proton-pump inhibitors and other antacid treatment in the prevention of carcinoma in Barrett’s esophagus [2]. The role of inflammation in the development of IBD-related carcinoma is supported by the discovery of cancer predominately in tissue with evidence of current or past inflammation. Similarly, the risk of cancer developing in the colon not involved with IBD is similar to that of the non-IBD population [3–7]. Possibly due to the more common finding of rectal sparing in CD, rectal cancer is relatively rare in CD. However, rates of non-CRC cancers, such as small bowel carcinoma and fistuli-related squamous cell cancers, are greater in CD. Colon cancer rates are similar in UC patients and CD patients with pancolitis. The differing patterns of inflammation seen in UC versus CD lend themselves to debate over resection type and extent, with the segmental inflammation of CD leading more often to the consideration of segmental resection.

Cancer rates in IBD

IBD is a known risk factor for CRC, with increased rates related to disease extent and duration. The overall risk is significant since CRC is the cause of death in approximately 15% of IBD patients [6]. As UC is more common and has slightly higher rates of CRC, it is better studied than CD. Meta-analysis of 116 studies of 54,478 IBD patients (with 1698 CRCs detected) confirmed a slightly higher risk of CRC in UC than CD. The overall prevalence of CRC in all UC patients was 3.7% with cumulative probabilities of 2% by 10 years, 8% by 20 years and 18% by 30 years [8]. Increased risk is seen in patients with longer disease duration, pancolitis, primary sclerosing cholangitis (PSC) and in those with a family history of CRC [9–11]. Reported relative risk for colon cancer in CD varies from an average of two- to five-times that of the non-IBD population, with incidence increasing with disease duration to as high as 8.3% after 30 years [5,12–14]. It is agreed that the highest risk is found in patients with colonic disease, followed by those with ileal disease [15]. However, studies differ on the risk of rectal cancer in CD, with some showing no increased risk and others showing a relatively mild 1.5× increased risk [5,16].

Types of dysplasia in IBD

The dysplasia found in IBD is of several different types, varying in risk of cancer progression and thus type of resection possible. The five main categories are as follows: LGD, HGD, dysplasia-associated lesion or mass (DALM), adenoma-like mass (ALM) and adenoma-like DALM (Table 1).

Low-grade dysplasia

LGD shares several histopathologic features with inflammation, such as being characterized by elongated, closely packed nuclei with dense chromatin. It is most commonly found during random colonic biopsying. Due to high interobserver variability and varying data on the likelihood of progression to a more advanced lesion, when LGD is discovered, current practice includes confirmation by additional biopsies and/or specimen examination by a second pathologist, followed by resection if dysplasia is confirmed in a high-risk patient.

High-grade dysplasia

HGD is differentiated by irregularly shaped nuclei with loss of polarity and frequent mitoses and shares similarities with CRC. Due to the high likelihood of progression to CRC, HGD mandates resection.

Dysplasia-associated lesion or mass

DALM is found in an area of inflammation and, by definition, is difficult if not impossible to remove colonoscopically. DALMs, which frequently have associated HGD, have also been found to be associated with CRC in up to 46% of CD specimens and 62.1% of UC specimens, supporting the requirement for immediate and aggressive surgical resection [7,17].

Adenoma-like mass & adenoma-like dysplasia-associated lesion or mass

An ALM is a lesion found in an area without inflammation, which is also readily amenable to complete endoscopic excision, essentially mimicking an adenoma found in a non-IBD patient. These lesions typically require circumferential biopsies to rule out inflammation in the vicinity and can then be removed endoscopically. Conversely, an adenoma-like DALM is a lesion that resembles an adenoma morphologically but is located within an area of inflammation.

Adenoma-like lesions present a unique challenge as they are technically amenable to endoscopic resection, particularly ALMs, due to their lack of associated inflammation. However, research is limited on the risk of progression to CRC and the safety of simple endoscopic resection in these lesions. Torres et al. investigated ALMs and DALMs in 59 IBD patients and found that dysplasia and carcinoma only developed in lesions that were found in areas of inflammation. However, the reported results were from a highly selected, low-risk group [18]. In the case of adenoma-like DALMs excised endoscopically, subsequent close 6-month interval colonoscopic surveillance was recommended. Frequently, such lesions bring the patient to the surgeon’s care for a definitive procedure to avoid this surveillance that many patients and caregivers find burdensome and nerve wracking. Endoscopic resection is, therefore, a more practical consideration in cases of ALMs than DALMs. Due to the lack of studies including large patient numbers, conflicting study results, the risk of progression to malignancy secondary to the associated inflammation, the need for frequent surveillance and the likelihood of recurrence after endoscopic resection is still strongly recommended for all adenoma-like DALMs, in spite of their theoretic ability to be removed colonoscopically [19,20].

Progression from LGD to HGD & carcinoma

Difficulty in studying the natural progression of LGD is encountered due to the current paradigm of resection of all dysplasia (low or high grade) in the majority of patients. The majority of studies that have been performed confirm that progression from LGD to HGD occurs in IBD; however, at a variable rate ranging from 20 to 53% at 5 years. This variation is probably attributable to lesion morphology (i.e., flat vs raised, polypoid vs nonpolypoid) and poorly defined biologic features [3,17,21–23]. One study of 46 UC patients diagnosed with flat LGD on surveillance colonoscopy found an equal progression to either HGD or cancer. As concerning, unifocal dysplasia progressed to an advanced lesion at the same rate as multifocal dysplasia, independent of disease duration, age of UC onset or mesalamine use [21]. A larger study of UC patients undergoing at least two surveillance colonoscopies between 1994 and 2006 found that out of 121 UC patients with LGD, eight progressed to HGD and seven progressed to CRC [3]. However, the study by Befrits et al. on 60 UC patients with mostly multifocal LGD showed no progression to HGD during 10 years of follow-up, except in two cases of patients with DALMs [22]. Perhaps the most definitive study to date is a meta-analysis of over 1200 IBD patients, which reported that 16–29% of patients with untreated LGD progressed to DALM, HGD or cancer, with an overall CRC risk of 42% for HGD and 19% for LGD [24].

Studies on the progression of dysplasia in CD are limited. The majority of such studies are retrospective, and usually involve after-the-fact review of resection specimens instead of prospectively following patients with known LGD. However, progression rates from LGD to HGD or CRC are thought to be similar to those of UC, particularly in cases of pancolitis.

Risk of synchronous & metachronous lesions

Relatively high risk of both synchronous and metachronous lesions in IBD-related dysplasia and carcinoma provide powerful impetus for extensive resection when dysplasia is discovered. Owing to the stricturing nature of Crohn’s inflammation compared with the more uniform inflammation found in UC, high rates of undiagnosed dysplasias and cancers have been noted in CD colectomy specimens. The study by Friedman et al. found multifocal or recurrent LGD in approximately 25% of Crohn’s colitis patients with difficult-to-detect, flat LGD [25]. Sigel et al. looked at a group of 30 patients undergoing resection for CD and found an alarming 67% incidence of small- and large-bowel carcinomas at surgery or postoperatively [26]. A larger study of approximately 200 IBD patients with small- or large-bowel cancer found that 4% of CD patients had synchronous tumors and 30% had synchronous dysplasia. Importantly, they also found that 15% of patients who had undergone segmental resection developed a metachronous tumor within 4 years [27].

Studies on UC have shown up to a 71% rate of synchronous dysplasia and a 43% risk of synchronous cancer when dysplasia is discovered [24,28]. Such high rates of synchronous cancer when dysplasia is identified led Gorfine et al. to define colonoscopically diagnosed dysplasia as a marker for synchronous CRC with a sensitivity and specificity of approximately 80%, particularly in cases of HGD [29]. Approximately 18–30% of UC-associated CRCs studied have been found to have synchronous tumors (compared with 2.5% of sporadic CRCs in one study) [28,30], and similar rates of synchronous tumors have been noted when compared with CD-related CRC (12 vs 11%) [31]. Risk of metachronous cancer in IBD CRC has been reported to be as high as 17% [25,27,32].

Surveillance guidelines

Routine colonoscopic surveillance is crucial in colitic patients due to increased rates and younger age of onset of CRC, and the increased likelihood of synchronous lesions in the IBD population. Current practice does not separate Crohn’s colitis colonoscopic surveillance guidelines from that of UC, despite differing patterns of inflammation and disease extent. The American Gastroenterological Association guidelines recommend an annual full colonoscopy commencing no later than 8 years after initial IBD symptoms. However, if risk factors such as PSC, family history of sporadic CRC, longer disease duration, more extensive disease, multiple inflammatory pseudopolyps or colonic strictures are present, more frequent surveillance is advised and may also stress the patient to consider colectomy. Multiple four-quadrant biopsies of 10 cm each is the recommendation [33], but it is not frequently practiced. In the study by Eaden et al., approximately 300 British gastroenterologists were polled, but only 2% routinely performed more than 20 random biopsies [34]. Although the recommended biopsy routine only has a 0.08% yield, it is critically important in order to assess for the possibility of multifocal dysplasia, which will significantly alter surgical decision-making [35].

Several studies have reinforced the need for frequent surveillance colonoscopy in IBD colitis, demonstrating high discovery rates of neoplasia during routine surveillance. A study by Friedman et al. over the duration of 30 years, following 259 CD patients, found the probability of detecting dysplasia or cancer in CD patients after an initial negative screening colonoscopy to be 22% by the fourth colonoscopy [25,36]. A more recent study of 411 CD patients who underwent 904 screening and surveillance colonoscopies noted the finding of neoplasia in 5.6% of patients (2.7% had LGD, 7% had HGD and 2.2% had carcinoma) with a higher mean interval between examinations found in HGD (31.5 ± 9.4 months) [37]. A retrospective study of 332 IBD patients by Connell et al. revealed 11 asymptomatic carcinomas and 12 cases of asymptomatic dysplasia found on surveillance colonoscopy. Notably, they also highlighted six symptomatic tumors that presented 10–43 months after a negative colonoscopy [38].

Difficulty in detection of dysplasia/chromoendoscopy

Colonoscopy in the IBD population presents unique challenges. First, the most common symptom of CRC that brings patients to colonoscopy, rectal bleeding, is commonly present in IBD patients and would not necessarily prompt colonoscopy. Second, the stricturing and fistulizing nature of CD presents unique technical challenges to screening and surveillance colonoscopy, which may require other surveillance modalities, such as MRI. Moreover, when compared with sporadic CRC, the endoscopic appearance of IBD-related neoplasia is different, commonly being less ‘mass-like’ and more easily missed on colonoscopy. In addition, the presence of multiple pseudopolyps, often present in severe- or long-standing colonic inflammatory disease, may lead to adenomas or cancerous lesions being overlooked on colonoscopy. The presence of an excess of pseudopolyps may precipitate a decision for surgery, especially if other risk factors (i.e., long disease duration, presence of PSC) exist, lending additional risk to a nonoperative approach. It is also important to recognize the need to biopsy tissue between pseudopolyps, to rule out flat dysplasia.

Often, diagnosis is made on specimens obtained by random biopsy. In a prospective 4-year study of more than 100 UC patients with long-standing disease, dysplasia was discovered incidentally in random biopsies of flat mucosa in 27 patients. One of the 27 patients was subsequently found to have CRC [17]. As mentioned earlier, it is not uncommon for lesions to be found unexpectedly in a specimen resected for medically refractive IBD without a prior diagnosis of dysplasia or carcinoma. An additional difficulty in the detection and treatment of dysplasia is variable congruity between initial biopsy results and final histopathology [39]. Lim et al. have shown that pathologists only agreed on a diagnosis of LGD in only 38–62% of cases [40].

Due to this relatively poor ability of simple colonoscopic biopsy to accurately diagnose dysplasia, technological advances such as chromoendoscopy and confocal laser endoscopy have been developed and are changing the surveillance protocols of colitis patients. Colonoscopic detection of flat dysplasias/non-adenoma-like DALMs is increasing, closing the gap between what was previously seen as endoscopically normal but histologically active IBD. Chromoendoscopy utilizes a traditional colonoscopy with the application of an absorptive dye to highlight otherwise difficult to visualize mucosal abnormalities. This novel approach to lesion detection and targeted biopsies has brought conventional colonoscopy with random biopsies into question. Its ability to not only detect lesions but to visually differentiate between neoplastic and non-neoplastic lesions using pit pattern recognition is a clear advantage. With a reported 93–95% sensitivity and 88–94% specificity and a threefold reported increase in the number of lesions detected, this technique is gaining rapid acceptance and widening use in the USA [41,42]. A recent meta-analysis of 1277 patients in six studies showed a 7% increase in overall detection of dysplasia when chromoendoscopy was used compared with conventional white light colonoscopy.

Notably, chromoendoscopy was found to be 27% more effective in detecting flat lesions, which are typically difficult to detect via conventional endoscopy [43]. Yield can also be increased with the use of narrow band imaging, but this technique has been found to be less accurate than dye-based chromoendoscopy.

Although not readily available in the USA, confocal light endoscopy uses a miniature confocal scanner or probes in the endoscope to improve visual resolution and provide histology by imaging the mucosal layer at a cellular level during endoscopy. Confocal light endoscopy has been shown to increase yield and decrease number of biopsies needed to detect dysplasia, particularly when combined with chromoendoscopy. Kiesslich and Neurath reported the need for only 3.9 biopsies compared with the traditional random 40–50 biopsies, with a fourfold increase in the rate of detection of neoplasia when compared with conventional colonoscopy [44]. Newer techniques such as narrow band imaging, which uses green and blue wavelengths to enhance visualization of the mucosa, and i-scan, a software-based method of enhancing images seen on endoscopy, can be less time consuming and also offer the opportunity to increase yield over traditional colonoscopy without the use of dyes.

However, all forms of colonoscopy, biopsy and pathological diagnosis remain user dependant, often with significant individual variation [40]. For example, in the study by Blackstone et al., which included 112 long-standing UC patients, 12 patients were found to have DALMs. Five of these were single polypoid masses and contained CRC. However, multiple endoscopic biopsies did not reveal invasive carcinoma in any of these masses prior to colectomy [17].

Surgical options in UC

Presently, the discovery and confirmation of any focus of dysplasia (low grade or high grade) in the IBD colon mandate the evaluation of the patient for a surgical procedure (Tables 1 & 2). In UC, two surgical choices dominate; the TPC with end ileostomy or TPC and IPAA. The total abdominal colectomy (TAC) with ileorectal anastomosis (IRA) or end ileostomy with blind Hartmann’s pouch are less ideal options due to the retained rectum that is left in place, which would represent a continued cancer risk. The continent Kock ileal pouch created after TPC is essentially an archaic procedure, replaced by the continence-preserving IPAA. There is some limited debate regarding segmental colectomy in patients with ‘burned out’ colitis in UC. However, this argument is usually superseded by the considerable risks of synchronous and metachronous lesions, and is therefore not considered an appropriate option in the fit UC patient (Table 2).

TPC & IPAA versus end ileostomy

Similar to the treatment of medically refractive pancolitis with rectal involvement, TPC is the definitive procedure of choice in patients with dysplasia and is usually performed in conjunction with IPAA in a staged fashion. This procedure eliminates the risks of synchronous and future colon and rectal cancer due to complete organ removal, and also avoids a permanent stoma. However, the risk of development of cancer in the ileal pouch or at the anal anastomosis is still present and warrants regular surveillance. Reported incidences of neoplasia in all patients with the IPAA are approximately 1% at 5 years and up to 5% at 25 years, with higher rates in patients who have had previous resections for colonic cancer [45,46]. Most of these neoplastic events are found in the 1–2 cm strip of retained rectal mucosa at the pouch–anal anastomosis. However, a TPC with ileostomy eliminates completely any risk of subsequent cancer development by virtual removal of the anus. A permanent ileostomy, instead of an IPAA, is usually performed in the patient who has sphincter weakness or involvement with tumor, wants to avoid multiple operations (as would be necessary for the IPAA) or has comorbidities that would make living with the expected five to six bowel movements a day problematic (e.g., wheelchair-bound patients).

IPAA surgical techniques: one- versus two- versus three-stage procedures

TPC involves either a laparoscopic approach or a midline incision, removing the colon followed by careful dissection deep into the pelvis with subsequent mobilization and excision of the entire rectum, while minimizing risk to the pelvic nerves. Several techniques are used for pouch reconstruction (Figure 1). A one-stage TPC/IPAA is uncommonly performed, but when it is, it is performed in patients with optimal health and tissue quality and those who have no or minimal steroid or immunosuppressant use. Both the colectomy and pouch reconstruction are performed during a single procedure and no temporary diverting stoma is done. This is done when the TPC has been a technically straightforward operation with minimal blood loss. Postoperatively, the pouch is usually drained with a rectal tube while a nasoduodenal tube minimizes the delivery of succus to the pouch for approximately a week to minimize risk of pouch leak.

In the most commonly performed two-stage procedure, a diverting loop ileostomy upstream of the pouch is performed at the time of TPC and ileal pouch reconstruction, allowing for fecal diversion and pouch healing, obviating the need for nasoduodenal or pouch draining tubes. The ileostomy is then reversed 2–3 months later, which is typically a short, technically easy procedure. The use of a stoma with an IPAA is associated with a lower rate of pelvic sepsis, especially in steroid-dependant or malnourished patients. The three-stage IPAA procedure is usually used in the setting of a severely ill patient, where tissue quality is poor due to malnutrition or high doses of steroids, dictating that the added operative time and stress for pouch reconstruction should be avoided. In the three-stage procedure, a total abdominal colectomy and ileostomy is performed during the first operation, leaving behind the rectum as a blind Hartmann cuff. Proctectomy and pouch creation with diverting loop ileostomy is performed during a second operation, usually 6 months later after the patient has recovered from the initial surgery and has been weaned from their steroids and recovered nutritionally. The ileostomy is subsequently reversed during a third operation.

Importantly, if a TAC is performed for dysplasia in an ill patient, preoperative biopsies should confirm the lack of dysplasia or other premalignant lesions in the rectum to be left behind for this 6-month period.

Pouch formation & anastomosis: mucosectomy versus double-stapled technique

The ileal–anal pouch is comprised of two loops of terminal ileum typically folded together into a J-shaped configuration. The pouch itself is fashioned using either absorbable sutures or a stapling device that simultaneously cuts the adjacent bowel walls and creates one large pouch from the two limbs. Stapling is by far the more commonly performed technique. Limb length should be 18–25 cm, as shorter pouches are associated with decreased continence due to persistent peristalsis. The pouch is then anastomosed just proximal to the dentate line using either a hand-sewn technique or a transanal circular stapling device. In cases of a hand-sewn anastomosis, mucosal stripping of the distal rectum (mucosectomy) is performed. However, with this technique, 1–1.5 cm of transitional anal mucosa is retained to preserve sensation, which is essential for continence. When compared with a stapled anastomosis, the hand-sewn technique is a more difficult procedure with less favorable functional outcomes, presumably due to the anal dilation required for the mucosectomy. The stapled anastomosis is technically easier and avoids the mucosectomy, but arguably leaves the patient at an increased risk for cancer in the retained rectal mucosa. However, studies do not necessarily support this notion. A 2011 meta-analysis of 12 retrospective studies and 15 case reports of UC-associated CRC cited 43 reported cases of pouch-related cancers, with 11 cancers within the pouch and 32 cancers in the anal transition zone, and with 28 out of these 32 patients having undergone a mucosectomy [47]. This finding of cancer in the anal transition zone following mucosectomy is not surprising, given the nature of the procedure where microscopically residual inflamed tissue may be ‘hidden’ behind the distal end of the pouch as it is brought down over the excised area and anastomosed near the dentate line. In a stapled procedure where rectal mucosa is left behind, the area is clearly visible, which facilitates subsequent surveillance and presumably earlier detection of any malignant transformation. If such a transition then occurs, transanal mucosectomy of the residual mucosa is relatively straightforward.

Although the exact frequency is controversial, regular surveillance of both the pouch and the retained rectal mucosa with simple rigid proctoscopy or flexible sigmoidoscopy should be completed. When the IPAA is performed for dysplasia or cancer, proctoscopy/pouchoscopy with biopsies of any retained rectal mucosa is typically done on an annual basis. With no history of dysplasia or cancer, longer periods between surveillance proctoscopy are common.

Contraindications to IPAA

IPAA is contraindicated in those with poor anal sphincter function, a particular concern in the elderly postpartum female population. Patients with questionable sphincter function warrant physiological studies, such as manometry as part of a preoperative work up. For these patients, TPC with end ileostomy is most often the more appropriate choice. However, IPAA, once reserved for the younger patient, has been shown to be a viable option in appropriate older patients as seen in several large retrospective studies. Although women and those older than 55 years of age experience slightly higher rates of incontinence, they have been found to experience similar rates of postoperative complications, significant improvement in the quality-of-life and comparable rates of pouchitis when compared with men and those older than 55 years of age [48–50].

When IPAA is appropriately performed, the expected result is 4–8 pasty bowel movements per day. Complications are most commonly attributable to poor tissue quality and wound healing, particularly in patients on high-dose preoperative steroids, but may also include sexual and urinary dysfunction (1–5%), female infertility, complications associated with the temporary stoma, such as skin irritation, electrolyte and fluid imbalances and the psychological effects of even a temporary stoma. An early study at the Mayo Clinic (MN, USA) looked at IPAAs performed for UC-related CRC and familial polyposis coli together. They cited a 0% operative mortality, 35% relaparotomy rate, 17% daytime seepage rate and one death from metastatic disease, and concluded that IPAA is a reasonable option in nonadvanced, distal CRC in the setting of UC-related dysplasia [51]. A subsequent 2002 Cleveland Clinic (OH, USA) study reported favorable pouch outcomes, with 55 out of 70 UC-associated CRC patients undergoing IPAA reporting good or excellent pouch function at follow-up (1–17 years). Of note, they also reported five deaths from metastatic disease in this group [52].

Comparison of IPAA versus TAC as the first procedure for dysplasia/cancer

In IBD-related CRC, pouch creation or restoration of continuity after TAC is intuitively guided by the timing of possible cancer recurrence, with 80% of CRCs recurring within 2 years of the index lesion. Thus, some surgeons will wait 18 months to 2 years after a colonic resection to perform the pouch reconstruction after first removing the cancer with a TAC, particularly if chemotherapy is required to treat the primary lesion. During this time, the retained rectum should be monitored for malignant transformation with sigmoidoscopy every 6–12 months. However, Gorfine’s study of 143 patients argued for pouch creation without ileostomy at the initial operation in patients with UC-associated dysplasia and familial adenomatous polyposis who were not on immunosuppressants or steroids. Their results showed that when compared with patients who underwent IPAA with ileostomy, patients who underwent IPAA without ileostomy had shorter hospital stays, decreased subsequent bowel obstruction rates and similar rates of dehiscence and incontinence, suggesting this may be a very reasonable option for non-immunosuppressed patients with IBD-associated CRC or dysplasia [53].

TAC (with IRA vs end ileostomy)

In the few patients who have no evidence of inflammation or dysplasia in the rectum, a TAC/ileostomy with a blind Hartmann’s rectal stump or TAC with IRA may be offered as an alternative to the TPC. Leaving the rectum has the advantage of a significant decrease in the morbidity of the operation by avoiding pelvic dissection. Before the advent of the IPAA, the TAC with IRA was the main continence-sparing procedure for IBD-related dysplasia. As a prerequisite, a relatively healthy, less diseased rectum is necessary; a typically unusual circumstance, but one that may be induced by the administration of transanal medications such as steroid enemas.

Similar to the IPAA, a continence-preserving IRA is only appropriate in those with good anal sphincter tone. The TAC has several advantages over the TPC; most importantly, the avoidance of pelvic dissection and possible subsequent pelvic nerve damage that compromises sexual or urinary function or adhesions that worsen female fertility. The TAC has been associated with decreased risk of infertility in young females with UC, as opposed to the IPAA, and, when combined with IRA, is performed more frequently as a one-stage procedure than TPC with IPAA. Patients who have undergone TAC/IRA may in the future undergo completion proctectomy if rectal dysplasia is subsequently discovered. However, failure rates of IRA are as high as 50% at 5 years and, in the case of dysplasia, close surveillance of the retained rectum with flexible sigmoidoscopy every 6–12 months is still required due to increased risk of metachronous cancer. This was highlighted in the study by Johnson et al., in which ten out of 273 patients undergoing TAC with Hartmann’s for medically refractive disease and/or dysplasia subsequently developed rectal cancer [54]. Two to four patient-formed stools per day is expected following TAC and IRA if the rectum is not inflamed.

Surgical options in CD

Currently, predominately using studies from the UC literature, the choice of the appropriate operative procedure in all IBD-related dysplasia is influenced by both lesion morphology and patient fitness for surgery. CD presents challenges distinct to UC in this regard. In CD, once dysplasia is identified, segmental resection is a more feasible option than in UC, especially if there has been a consistent lack of inflammation elsewhere in the colon. However, extended colectomy or even total proctocolectomy with end ileostomy are often more practical choices due to the significant risk of synchronous dysplasia or cancer, similar to that of UC. In the patient with multifocal dysplasia or rectal dysplasia, the need for an aggressive approach, namely TPC, is easily justified. Moreover, in CD patients with severe perianal disease or incontinence, TPC with end ileostomy offers treatment of the anal disability not provided by lesser resections such as segmental colectomy or IRA (Table 3) [55].

IPAA reconstruction is a very rare option in CD patients with dysplasia, and it requires an entirely normal small bowel and no evidence of anal disease, thus it is rarely completed knowingly. Up to 50% of CD patients undergoing IPAA suffer CD complications, such as stricturing, fistulization and intractable inflammation in the pouch. Although recent studies have shown no difference in pouch failure between CD and UC patients, this study was conducted on CD patients who had a preoperative diagnosis of UC and then received the CD diagnosis postoperatively after developing signs of CD, such as anal or pouch fistuli. Such patients are probably very different than those who are known preoperatively to have CD, and who have a significant IPAA failure rate overall [56].

Total abdominal colectomy

If the patient is not an appropriate candidate for a TPC due to comorbidity issues or refusal of an ileostomy, the segmental distribution of CD may suggest the consideration of a lesser resection. If rectal biopsies show no dysplasia, a TAC with either a Hartmann’s pouch and end ileostomy or reconstruction with an IRA is possible in CD, particularly in those less surgically fit. An IRA would require a relatively healthy rectum, where a Hartmann’s pouch could be left if inflammation was present. This may offer a middle ground between TPC and segmental resection, decreasing the risk of synchronous and metachronous colonic lesions but still preserving continence (in the case of IRA) with a less risky operation. For this procedure, anal disease must be absent and continence good. Moreover, this procedure does not address the increased risk of metachronous rectal or small bowel cancer in CD. Therefore, close postoperative surveillance is still necessary, although rates of rectal cancer (including that in the retained stump post-colectomy) in CD is lower than that in UC, presumably due to the relative lack of inflammation in the rectum in CD versus UC patients [7,57]. TAC with IRA is a more viable option in CD patients, as rectal inflammation is less common, making anastomosis creation less challenging. In addition, surveillance of the rectum using flexible sigmoidoscopy, whether it is in continuity or not, is easier than full colonoscopy.

Lesser resections in UC & CD

Despite convincing evidence for TPC as the superior procedure for both treatment and prevention, three groups of patients can be considered for lesser resection in both UC and CD-related dysplasia/CRC; those who are not physically fit for TPC or TAC, those who may not be able to care for a stoma or the five to six bowel movements a day associated with an IPAA (e.g., mentally or physically disabled patients) and those who simply refuse an end ileostomy. Segmental resection may be the most appropriate choice for these patients, particularly in CD patients, but also in the UC patient with ‘burned out’ colitis. Segmental resection is a shorter operative procedure, often performed laparoscopically, and usually avoids stoma creation. However, the patient must be counseled on the risk of both synchronous and metachronous cancers, and must undergo frequent postoperative surveillance for metachronous lesions. In addition, preoperative biopsy must exclude synchronous colorectal lesions in the bowel to be left behind. In the very unfit patient, particularly the one with LGD, close surveillance with colonoscopy every 6 months, if possible, may be the only option, albeit one that will probably fail as time passes. Presently, such a plan should be made for those with limited life expectancy (Figures 2 & 3).

5-aminosalicylic acid or 6-mercaptopurine treatment should be considered in any surgical resection leaving behind colonic or rectal tissue. These treatments, by virtue of their anti-inflammatory effect, have been associated with a decreased risk of CRC. However, biologics should be used judiciously as they appear to compromise tumor surveillance and are associated with increased risks of lymphoma and skin cancer. Thus, treating a patient with a known predisposition to malignant degeneration with biologics should be carefully considered [58].

Surgical options in indeterminate colitis

Indeterminate colitis is seen in approximately 10% of patients when features attributable to both UC and CD are seen simultaneously. Dysplasia on a background of indeterminate colitis warrants surgical resection based on the same principles of management for either UC- or CD-associated dysplasia. However, the specific surgical approach is based on the clinician’s impression of whether CD or UC is more likely. In this circumstance, anti-neutrophil cytoplasmic antibody and anti-Saccharomyces cerevisiae antibody testing to assist in differentiating between CD and UC may be helpful. At times – especially when disease is more severe – completing TAC first to assist in making a pathological diagnosis may be effective. This can be followed by a proctectomy (CD) or IPAA (UC). In cases where UC is suggested, and in a highly select group of patients with a CD-like phenotype without ileal or anal disease, an IPAA may be considered. Overall, treatment is often based on likely phenotype and patients should be advised that if CD manifests itself after an IPAA, conversion to an end ileostomy is likely.

Conclusion

In conclusion, all IBD-associated dysplasia discovered on colonoscopy requires consideration for surgical resection due to the high risk of synchronous and metachronous lesions. Although differing in patterns of inflammation, UC and CD colitis are often grouped together for both surveillance and treatment recommendations, with TPC being the only definitive procedure to treat all synchronous and metachronous colonic and rectal lesions. Although a relatively more straightforward choice in UC where IPAA can maintain gastrointestinal continuity, TPC is not always an option in all colitis patients, particularly in those with comorbidities and/or those who refuse a stoma.

CD presents unique surgical decision-making challenges due to the segmental nature of inflammation, the presence of perianal disease, malignant transformation of fistuli and risk of small bowel carcinoma. Most surgeons favor TPC when cancer or dysplasia is discovered, but this usually results in a permanent ileostomy. Both TAC and segmental colectomy in CD patients (as well as in UC patients) with comorbidities are possible alternatives but require careful preoperative patient counseling regarding cancer risk and compulsive postoperative surveillance of any remaining colorectum.

Expert commentary & five-year view

With the improvement of current diagnostic tools and development of new technologies, such as chromoendoscopy, the ability to find foci of dysplasia in the patient with colitis will increase, probably leading to an increasing need for surgical evaluation and treatment in both UC and CD colitis. With improvements in perioperative management, including laparoscopic and robotic techniques, total proctocolectomy may become an option for patients previously considered unfit for such a major procedure. However, there will always be those who refuse ileostomy or who are too morbid for major surgery. If dysplasia is discovered sooner in the disease process through more effective screening, surgery may be applied at a time when the patient has less operative risk. With recent gene discoveries and the increasing use of genotyping in clinical medicine, genetic markers may soon be used to identify which patients with colitis will develop dysplasia, allowing for an even earlier, possibly prophylactic colectomy to avoid cancer development.

Table 1. Inflammatory bowel disease-related dysplastic lesions.

Lesion	Features
LGD	Enlarged, elongated, crowded nuclei Shares histological features with inflammation
HGD	Pleomorphic, stacked nuclei Shares histological features with carcinoma
DALM	Raised lesion located in an area of inflammation Unable to be removed colonoscopically
ALM	Raised lesion in a noninflamed area Amenable to colonoscopic removal
Adenoma-like DALM	Raised lesion morphologically resembling a colonoscopically resectable adenoma but located in an area of inflammation

ALM: Adenoma-like mass; DALM: Dysplasia-associated lesion or mass; HGD: High-grade dysplasia; LGD: Low-grade dysplasia.

Table 2. Surgical options for premalignant lesions in ulcerative colitis.

	TPC/IPAA	TPC/end ileostomy	TAC/IRA	Segmental resection
Advantages	Resection of possible synchronous colonic and rectal dysplasia/cancer; metachronous colonic and rectal lesion prophylaxis; ‘cures’ UC; maintains continence	Resection of possible synchronous colonic and rectal dysplasia/cancer; metachronous colonic and rectal lesion prophylaxis; ‘cures’ UC; no further colonic surveillance needed; single operation	Prophylaxis of metachronous colonic lesions; resection of synchronous colonic lesions; maintains continence; can be performed as single operation; shorter, less extensive operation procedure than TPC; can perform IPAA later if desired; decreased risk of urinary and sexual complications; decreased risk of infertility in young females	Short operative procedure; maintains continence; better tolerated in those less fit
Disadvantages	Risk of malignancy in pouch and retained rectal mucosa necessitates regular surveillance; >15% complication rate; multiple operations are common; increased risk of urinary and sexual complications; decreased fertility in young females; pouchitis	Permanent stoma; >15% complication rate; increased risk of urinary and sexual complications; perineal wound healing complications	Does not treat rectal dysplasia or the risk of dysplasia developing in rectum; requires continuing surveillance sigmoidoscopy; up to 50% failure at 5 years; few patients are candidates because a healthy rectum is required	No treatment of synchronous colonic or rectal lesions or prophylaxis of metachronous lesions; requires regular postoperative surveillance colonoscopy; frequently performed with ‘protecting’ ileostomy as a two-stage procedure
Indication	Any colonic or rectal lesion in the surgically fit patient who refuses a stoma; unifocal or multifocal dysplasia	Any colonic or rectal lesion in the surgically acceptable patient; unifocal or multifocal dysplasia; poor sphincter function; very low rectal or anal dysplasia typically requiring removal of the anus and sphincters	Colonic lesion(s) with no rectal inflammation or dysplasia	Isolated foci of dysplasia or malignancy; patient unfit for TPC or refuses more extensive resection; ‘burned out’ colitis
Relative contraindications	Incontinence/poor anal sphincter tone prior to operation; severe backwash ileitis suggesting CD; surgically unfit patient; very low rectal or anal dysplasia threatening sphincters	Patient refusal of stoma; inability to care for a stoma; surgically unfit patient	Less surgically fit patients; incontinence/poor anal sphincter tone prior to operation (IRA); anal or rectal dysplasia/cancer; rectal inflammation	Patient not fit for surgery; synchronous lesions; multifocal dysplasia; active colitis

CD: Crohn’s disease; IPAA: Ileal pouch–anal anastomosis; IRA: Ileorectal anastomosis; TAC: Total abdominal colectomy; TPC: Total proctocolectomy; UC: Ulcerative colitis.

Table 3. Surgical options for premalignant lesions in Crohn’s disease.

	TPC/end ileostomy	TAC/IRA or Hartmann	Segmental resection
Advantages	Resection of possible synchronous colonic and rectal dysplasia/cancer Metachronous colonic and rectal lesion prophylaxis No further colonoscopic surveillance needed Single operation	Resection of possible synchronous colonic lesions Prophylaxis of metachronous colonic lesions Shorter, less extensive operation procedure than TPC Maintains continence Can be performed as single operation Decreased risk of urinary and sexual complications Decreased risk of infertility in young females	Short procedure duration Appropriate in those less fit for longer, more extensive procedure Maintains continence
Disadvantages	Permanent stoma >15% complication rate Increased risk of urinary and sexual complications 1–2% non-healing perineal wound complication rate	Does not address the risk of dysplasia developing in rectum May require multiple operations/temporary stoma Requires continuing rectal surveillance Up to 50% failure at 5 years	No treatment of synchronous colonic or rectal lesions or prophylaxis of metachronous lesions Requires continued colonoscopic surveillance Frequently performed with ‘protecting’ ileostomy as a two-stage procedure
Indication	Any colonic or rectal lesion in the surgically fit patient with more extensive colonic CD Unifocal or multifocal dysplasia	Colonic lesion(s) with no rectal inflammation or dysplasia Anal disease not present Patient not fit for TPC	Isolated foci of dysplasia with minimal inflammation elsewhere in the colon Patient unfit for TPC or refuses more extensive resection
Relative contraindications	Patient refusal of stoma Inability to care for a stoma Surgically unfit patient Young women wishing to maximize fertility	Incontinence/poor anal sphincter tone prior to operation (if IRA) Patient refuses stoma (if Hartmann’s and ileostomy) Anal dysplasia or disease Rectal dysplasia	Patient not fit for more extensive surgery Synchronous lesions Rectal dysplasia/cancer

CD: Crohn’s disease; IRA: Ileorectal anastomosis; TAC: Total abdominal colectomy; TPC: Total proctocolectomy.

Key issues

• • Rates of colorectal carcinoma (CRC) are increased in both ulcerative colitis (UC) and Crohn’s disease (CD) compared with the non-inflammatory bowel disease (IBD) population.

• • CRC in IBD is due to genetic insults on a background of chronic inflammation.

• • CD differs from UC due to its pattern of patchy inflammation and relative rectal sparing.

• • High rates of synchronous and metachronous dysplasia and carcinoma are found in IBD-related colonic dysplasia.

• • Low-grade dysplasia has a high likelihood of progressing to high-grade dysplasia and CRC.

• • Any dysplasia seen on screening or surveillance colonoscopy warrants surgical evaluation.

• • Total proctocolectomy is the only definitive surgical procedure for the treatment of synchronous lesions and the prevention of metachronous lesions.

• • Ileal pouch–anal anastomosis effectively treats the dysplastic UC patients while maintaining continence. However, continued surveillance of the retained rectal mucosa and ileal pouch itself are necessary.

• • Anything less than total proctocolectomy (TPC) in CD leaves the patient at risk for synchronous and metachronous lesions.

• • Segmental colectomy and abdominal colectomy, although not ideal, are options for patients who refuse an end ileostomy, are unable to care for one or are not fit for TPC.

• • Any patient who has less than TPC requires continual lifelong postoperative colonoscopic surveillance.

Acknowledgements

The authors were involved in the concept development, research and writing of this article. The authors thank Emanuelle Williams for her assistance with the chromoendoscopy/confocal light endoscopy section.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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The surgical treatment of inflammatory bowel disease-associated dysplasia

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1. You are seeing a 40-year-old man recently diagnosed with ulcerative colitis (UC) but with no other colorectal cancer (CRC) risk factors. He wants to understand the risk of CRC associated with this diagnosis. What can you tell him?

• □ A CRC is the cause of death in approximately half of patients with IBD

• □ B The risk of CRC is similar among patients with UC and Crohn disease (CD)

• □ C The progression of dysplasia to cancer is faster in cases of IBD vs cases of sporadic CRC

• □ D The rate of synchronous cancer is similar in comparing patients with UC vs patients with sporadic CRC

2. What can you advise this patient regarding screening colonoscopy?

• □ A Colonoscopy needs to be performed immediately

• □ B Multiple 4 quadrant biopsies every 10 cm are recommended but frequently not performed

• □ C Recommendations call for less frequent screening among CD vs UC patients

• □ D Chromoendoscopy is only more effective than conventional endoscopy in detecting raised lesions

3. The patient eventually undergoes colonoscopy. Which of the following statements regarding colonic dysplasia in cases of IBD is most accurate?

• □ A Low-grade dysplasia (LGD) should be confirmed with additional biopsies or a review with a second pathologist

• □ B Patients with high-grade dysplasia (HGD) can undergo more frequent surveillance without resection

• □ C Most dysplasia-associated mass or lesion (DALM) can be removed endoscopically

• □ D If excision of an adenoma-like DALM is successful, no special screening is necessary

4. The patient requires surgery. What should you consider in surgical planning for this patient?

• □ A There is no additional risk of cancer at the pouch-anal anastomosis after IPAA

• □ B One-stage TPC/IPAA has emerged as the most common method of resection

• □ C The use of a stoma with an IPAA offers no clinical benefit

• □ D Ileal pouch anal anastomosis (IPAA) may be a good option for older adults