Stricturing Diseases of the Gastrointestinal Tract-Current Clinical Practice.

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Structuring diseases of the GIT are not uncommon in our day‐to‐day clinical practice. Any part of the GIT can be affected. Most strictures are acquired, but they can rarely be congenital. The stricture is either benign or malignant. The etiology and symptomatology vary with the location of the stricture. The stricture can be mild, moderate, or severe. Imaging studies and endoscopic procedures are essential to evaluate these strictures. Treatment depends on the underlying cause of the stricture. Medications are necessary for certain diseases like GERD, EoE, Crohn's disease, eosinophilic gastroenteritis, certain infections, and malignancies. In most benign strictures, EBD is the most common treatment modality. Other treatment modalities include stricturotomy, strictureplasty, stent placement, and surgical resection. Malignant strictures are usually managed by stenting and/or chemoradiation and/or surgery. Presenting symptoms, investigations, and the treatment algorithm for different types of GIS are summarized in Table  6 . The prognosis of GIS is highly individualized and depends on multiple factors like underlying etiology, severity, location, response to treatment, age, nutritional status, and comorbidities. Approach to patients with gastrointestinal stricture. Drugs, dilation ↓ Stricturotomy ↓ Stenting ↓ Surgery Correction of fluid and electrolytes followed by EBD ↓ Laparoscopic pyloromyotomy EBD ↓ FCSEMS ↓ LAMS ↓ Surgical conversion to RYGB EBD ↓ LAMS ↓ Redo of gastrojejunostomy Crohn's inflammatory SIS—Anti‐TNF Crohn's fibrotic SIS—EBD If stricture is refractory to anti‐TNF or EBD, or stricture is complex—surgery Benign short segment CS—EBD ↓ LAMS Refractory anastomotic stricture in distal colon or rectum—endoscopic strictureplasty If endoscopic treatment fails or complex stricture or malignancy cannot be excluded—surgery Benign mild AS—conservative treatment or lateral internal sphincterotomy Benign moderate to severe AS—surgical interventions like sphincterotomy, anoplasty, and lateral mucosal advancement flap Malignant AS—chemoradiation ↓ Stenting ↓ Palliative care

Dysphagia is the most common symptom of ES. Solid food dysphagia occurs when the esophageal lumen becomes narrower than 12 mm. With the progression of stricture, patients develop difficulty in swallowing a semisolid to liquid diet. Patients may have other associated symptoms due to underlying causes of ES. Patients with GERD can have a history of long‐standing or uncontrolled heartburn in the past. Patients with EoE may give a history of prior food bolus impaction, bronchial asthma, atopic dermatitis, or chronic spontaneous urticaria. Patients with underlying malignancy may suffer from anorexia and weight loss. A history of prior surgery, endoscopic intervention, radiation, or medication can give essential clues to the diagnosis of esophageal stricture. Irrespective of the etiology, ES causes weight loss due to inadequate food intake and poor quality of life.

Peptic esophageal stricture due to gastroesophageal reflux disease (GERD) is by far the most common cause of benign ES, accounting for 70% to 80% of adult cases [ 21 ]. Over the last two decades, the prevalence of ES has markedly increased in newly diagnosed eosinophilic esophagitis (EOE) patients (8% in 2006 to 54% in 2019) [ 22 ]. Another benign cause of ES is caustic stricture secondary to intentional or accidental ingestion of caustic substances. One‐third of patients with severe caustic esophageal injury (grade IIB or III) usually develop stricture 2 months after the injury. But it can vary from 2 weeks to many years [ 23 ]. Radiation‐induced ES occurs when thoracic external beam radiation therapy with a mean dose of > 50 Gy is administered for various malignancies like lung cancer, head and neck cancer, esophageal cancer, thymic cancer, malignant mesothelioma, and lymphoma. When the thoracic radiation dose is 50 Gy or less, symptomatic ES occurs in less than 2% of cases compared to approximately 15% of cases when treated with 60 Gy [ 24 ]. Iatrogenic ES can occur following ablation of Barrett's esophagus with different modalities of treatment: (a) radiofrequency ablation (5% to 10% of cases), (b) liquid nitrogen cryotherapy ablation (3% of cases), (c) carbon dioxide cryotherapy ablation (1.5% of cases), and (d) photodynamic therapy (34% of cases) [ 25 , 26 , 27 , 28 ]. Endoscopic submucosal dissection (ESD) of early‐stage esophageal cancer (T1a lesion) can also have a high chance of developing ES (70% to 80% if the resection is > 60% of esophageal circumference) [ 29 ]. Post‐peroral endoscopic myotomy (POEM) ES is uncommon (1.1 per 10 000 person‐years) when treated for achalasia [ 30 ]. The incidence of anastomotic stricture following Ivor‐Lewis esophagectomy for esophageal cancer may vary from 9.1% to 46% [ 31 ]. Drug‐induced ES has been reported to be caused by a variety of medications, which include alendronate, potassium chloride, tetracycline, ferrous sulfate, non‐steroidal anti‐inflammatory drugs, quinidine, phenytoin, and ascorbic acid [ 32 ]. Prolonged use of the nasogastric tube can cause ES. Rarely, ES can be caused by CD, graft versus host disease (GVHD), pemphigus vulgaris, pemphigoid, esophagitis dissecans superficialis associated with celiac disease, collagen vascular diseases such as SLE or scleroderma, tuberculosis, and Plummer‐Vinson syndrome [ 33 ]. The etiology of IHPS and INHPS is unknown. Adult PS is most likely secondary to PUD [ 34 ]. Pre‐pyloric ulcer, pyloric channel ulcer, and duodenal bulbar ulcer may develop PS. Other causes include non‐steroidal anti‐inflammatory drugs, CD, tuberculosis, intra‐abdominal adhesions secondary to surgery, and gastric malignancy [ 35 , 36 , 37 ]. Gastric cancer is the most common malignant cause of PS. Certain technical factors may predispose the sleeve to develop sleeve stenosis. These include the use of staples with a closed height of less than 2 mm on any part of the sleeve gastrectomy, stapling too close to the incisura angularis, use of smaller (< 32 F) diameter bougie, oversewing of the staple line, staple line edema or hematoma, and prolonged operative time [ 38 , 39 , 40 ]. The exact cause of GJAS is not known. However, certain risk factors can predispose gastrojejunal anastomosis to develop GJAS. These include anastomotic site ischemia, ulceration, tension, and excessive scarring. Circular mechanical stapling has a higher chance of developing GJAS than hand‐sewn anastomosis [ 41 ]. Gastrogastric fistula is another risk factor that can cause GJAS. A large amount of gastric acid can come from the secluded stomach into the gastric pouch, resulting in anastomotic ulcers and stenosis [ 42 ]. CD is by far the most common cause of SIS. About 25% of patients with CD were found to have SIS as per the National Cooperative Crohn's Disease Study in 1979 [ 43 ]. This figure might have decreased with the advent of various immunosuppressive, biologic, and small molecule agents. Crohn's SIS can occur anytime during CD, and the most common site is the terminal ileum and ileocecal region. Other causes of SIS include non‐steroidal anti‐inflammatory drugs (NSAIDs), radiation enteritis, ischemic bowel disease, post‐surgical, eosinophilic enteritis, infectious enteritis (TB, Schistosomiasis, Strongyloides stercoralis), Behcet's disease, neoplastic lesions, and cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) [ 44 , 45 ]. NSAID‐induced stricture can occur anywhere in the small intestine, but the ileum is the most common site. Radiation‐induced SIS occurs when the small intestine falls in the field of radiation therapy for various intra‐abdominal and pelvic malignancies. The terminal ileum and duodenum are more commonly involved as they are immobile and vulnerable to higher radiation doses [ 46 ]. The ileum is the most common site of ischemic SIS. Mesenteric vessel thrombosis, thrombangitis obliterans, acute pancreatitis, and blunt abdominal trauma can cause ischemic SIS [ 47 , 48 , 49 , 50 ]. Post‐surgical SIS occurs at the site of anastomosis, more commonly seen in patients with CD in 3 to 30% of cases 5 to 12 months after surgery [ 51 ]. The muscular form of eosinophilic enteritis can cause bowel wall thickening due to fibrosis and SIS [ 52 ]. Intestinal tuberculosis occurs in 1 to 3% of cases of all tuberculosis and commonly involves the ileocecal region, leading to stricture [ 53 ]. CMV infection has been reported to cause SIS in immunocompromised patients, particularly in the terminal ileum [ 44 ]. Rarely Entamoeba histolytica can cause terminal ileal stricture [ 54 ]. Multiple deep and superficial ulcers characterize gastrointestinal Behcet's disease and can cause SIS. Although any part of the small intestine can be involved, the ileocecal region is most commonly involved [ 55 ]. Malignant SIS can occur from small intestinal neuroendocrine tumors, adenocarcinoma, lymphoma, sarcoma (most commonly leiomyosarcoma), gastrointestinal stromal tumors, or metastatic involvement of the small intestine. In one study, malignancy was the cause in 16% of patients with isolated small bowel strictures [ 56 ]. The most common causes of benign CS include diverticular disease, Crohn's disease, ischemic colitis, and radiation colitis. Other benign causes include post‐surgical anastomotic stricture, infectious colitis (TB. Lymphogranuloma venereum/LGV), endometriosis and amyloidosis [ 57 ]. Malignant colon stricture is mostly caused by intrinsic colon cancer and rarely by metastatic deposits from extracolonic malignancies [ 58 ]. Benign AS occurs mostly due to iatrogenic reasons, 90% of the time happens following hemorrhoidectomy [ 59 ]. Total colectomy with ileal pouch‐anal anastomosis, fistulotomy, sphincteroplasty, excision of low rectal tumor or perineal lesion, and radiation to the anorectal area can cause anal stenosis [ 60 ]. Other benign causes include PFCD, traumatic injuries to the perineum, and sexually transmitted anorectal infections like genital herpes, CMV, human papillomavirus (anal warts), chlamydia, gonorrhea, syphilis, LGV, and HIV infection [ 61 ]. Perianal abscesses and fistula can also contribute to the development of anal stenosis significantly. Chronic overuse of laxatives, particularly mineral oil, can lead to anal stenosis. Adenocarcinoma of the rectum can cause malignant rectal stricture. Malignant anal stenosis occurs most commonly due to anal squamous cell cancer and rarely due to other malignancies, which include adenocarcinoma, clonogenic carcinoma, melanoma, neuroendocrine carcinoma, and undifferentiated carcinoma [ 62 ].

The prognosis of GIS can vary significantly depending on several factors, which include the underlying etiology of the stricture, severity and location of the stricture, promptness of treatment, response to treatment, and the patient's overall health condition. Benign strictures like peptic strictures or Crohn's strictures have better outcomes if the underlying disease is well‐controlled. Malignant strictures have a poor prognosis. Complex, severe, and refractory strictures need surgical intervention and have a worse prognosis, whereas simple or mild strictures respond to endoscopic treatment and carry a better prognosis [ 169 ]. Colorectal strictures or Crohn's strictures have a higher chance of having malignancy. In Crohn's disease, ileal strictures carry a better prognosis than duodenal strictures as they respond to EBD with long surgery‐free intervals, and strictureplasty is more effective in the ileal region [ 170 , 171 ]. If the patient has a severe stricture, immediate treatment may change the outcome. If the stricture is refractory to endoscopic treatment, surgical intervention will be necessary. Successful treatment can improve a patient's quality of life significantly. Poor nutritional status and the presence of complications like obstruction or perforation worsen the prognosis. The patient's overall health, age, and comorbidities also influence prognosis. Good overall health, young age, and fewer comorbidities are good prognostic indicators.

The main principle of treating ES is symptomatic improvement with relief of dysphagia. The treatment of symptomatic ES depends on whether it is a benign or malignant lesion. The treatment modalities for benign ES include drugs, dilation, stricturotomy, and surgery as shown in Table  5 . Treatment modalities for benign esophageal stricture. PPI—peptic stricture, EoE, post‐EMR, post‐ESD, post‐Barrett's ablation. Steroid, biologics, immunomodulators—Crohn's disease. Systemic steroid and immunosuppressive agents—GVHD, pemphigus vulgaris, pemphigoid, collagen vascular diseases. Pneumatic dilation. Bougie dilation. Temporary placement of FCEMS, SEPS or BDS for refractory and recurrent strictures. Refractory stricture, short‐segment non‐angulated fibrotic stricture (< 1 cm), and anastomotic stricture. Esophageal resection—distal ES. Transhiatal esophagectomy with gastric pull‐up and cervical anastomosis—mid or proximal ES. Colonic transposition—when gastric reconstruction is not suitable. Collis gastroplasty with Belsey herniorrhaphy—when esophagus becomes excessively short due to stricture. ES bypass with gastric pull‐up or colonic interposition—in case of long segment ES. Long‐term double‐dose proton pump inhibitors (PPI) or daily P‐CAB (potassium‐competitive acid blocker) should be given to patients to prevent the recurrence of peptic ES and promote healing of esophagitis [ 119 ]. P‐CAB offers superior efficacy and a similar safety profile to PPIs for rapid healing and maintenance of LA grade C/D esophagitis and thus can prevent peptic stricture. Patients with EoE should continue to receive PPI, topical steroids, or dupilumab pre and post‐dilation of the ES [ 120 ]. PPI should also be given after endoscopic resection (EMR or ESD) or ablation to reduce the formation of ES [ 121 ]. Other medications can be helpful depending on the cause of stricture, like in the case of Crohn's stricture—steroid, biologics, immunomodulators; in GVHD, pemphigus vulgaris, and pemphigoid—topical steroid and systemic immunosuppression [ 122 ]; esophagitis dissecans superficialis associated with celiac disease—gluten‐free diet [ 33 ]; and collagen vascular diseases—systemic steroid and immunosuppressive therapy [ 123 ]. Endoscopic dilation of a benign ES (either by balloon or bougie) is considered the first‐line treatment to improve dysphagia. Bougie (push‐type dilators: wire‐guided Savary‐Gilliard dilator or blind Maloney dilator) dilators exert radial and longitudinal force, whereas, through the scope (TTS), pneumatic or balloon dilators only exert radial force. Maloney dilators are suitable for distal single strictures with a luminal diameter of 10 mm or more. In the case of mid‐esophageal or proximal ES, a pneumatic or Savary‐Gilliard dilator should be used. Fluoroscopy should be used in case of complex ES. It can help the advancement of the guidewire and the balloon catheter through the stricture. It can also assess the length and diameter of the stricture before and after dilation, as well as the presence of any fistula and post‐dilation extravasation of contrast. The goal is to achieve a luminal diameter of 14 mm or more so the patient can tolerate a regular diet. It is recommended to pass no more than 3 dilators of progressively larger diameter (with an increment of 1.5 mm) per session (rule of three) in the presence of moderate to severe resistance to avoid adverse effects like perforation of the esophagus [ 124 ]. The risk of perforation is 0.1 to 0.4% during ES dilation [ 125 ]. Dilation is effective in at least 90% of patients with simple ES [ 126 ]. Intralesional steroid injection should be considered in refractory and recurrent ES as it can decrease collagen and fibrous tissue deposition into the stricture. It has been shown that four quadrant injections of steroid (triamcinolone acetonide, 40 mg/mL, 0.2 to 0.5 mL aliquots) into the stricture before or after dilation can improve post‐dilation diameter and delay the need for subsequent dilation [ 21 ]. If the stricture is refractory, recurrent, and/or non‐responsive to steroid injection, temporary (at least 6–8 weeks, maximum 3 months) placement of a fully covered self‐expanding metal stent (FCSEMS) made of mostly nitinol (Figure  8 ) or a self‐expanding plastic stent (SEPS) made of silicone with polyester braid or a biodegradable esophageal stent (BDS) should be considered [ 127 ]. FCEMS and SEPS placement complications include stent migration (in 4% to 36% of cases), tissue hyperplastic reaction, gastroesophageal reflux, fistula formation, Globus sensation, chest pain, fever, and bleeding [ 128 ]. The stent migration rate can be reduced with endoscopic suturing (15.9% lower than without intervention) or fixation with an over‐the‐scope clip (OTSC) system (8.3% with fixation vs. 35.4% without fixation) [ 129 ]. BDS is made from polydioxanone and can provide constant radial force for 4 to 5 weeks without tissue overgrowth. Then, it slowly dissolves over 11 to 12 weeks due to progressive hydrolysis and degradation. As a result, the BDS does not need to be removed endoscopically [ 130 ]. Long‐term relief of dysphagia in refractory benign ES can be achieved in 30% to 40% of cases with the temporary placement of an esophageal stent [ 131 ]. FCSEMS placed in a benign esophageal stricture. Endoscopic stricturotomy/strictureplasty/electroincision is an endoscopic procedure in which the fibrous tissue under the mucosa at the most prominent part of the esophageal stricture is carefully cut in layers with a needle knife in a circumferential manner (electrocautery technique). Endoscopic ultrasound with a linear probe can be done before this procedure to evaluate the wall thickness of the stricture [ 132 ]. An advanced, proficient endoscopist usually does this procedure, and it is helpful in refractory stricture, short‐segment non‐angulated fibrotic stricture (< 1 cm), and anastomotic stricture [ 133 ]. There are few case reports in which refractory complex ES was treated by endoscopic stricturotomy [ 134 ]. Surgery is considered as the last resort when endoscopic therapy fails. A laparoscopic or open esophageal resection is performed for distal ES. Partial or complete fundoplication is done simultaneously in the case of peptic ES [ 135 ]. For mid or proximal ES, particularly in corrosive strictures, transhiatal esophagectomy with gastric pull‐up and cervical anastomosis is considered safe. As colonic transposition changes gastrointestinal anatomy and carries increased morbidity and mortality, it is performed when gastric reconstruction is not suitable [ 136 ]. Collis gastroplasty with Belsey herniorrhaphy is considered when the esophagus becomes excessively short due to stricture [ 137 ]. ES bypass with gastric pull‐up or colonic interposition can be done in case of long segment strictures, particularly those involving the upper esophagus when resection is not feasible [ 138 ]. Malignant ES is managed by stent placement, chemoradiation, or surgery. If the patient's life expectancy is less than 3 months or if the malignancy is inoperable, palliative self‐expanding metal stent (Wallstent, Ultraflex stents, or Niti‐S) placement expands the esophageal lumen and rapidly improves the patient's dysphagia. Esophageal brachytherapy is mainly used in patients with a life expectancy of more than 3 months [ 139 ]. Pre‐operative chemoradiation followed by surgery/esophageal resection is done in case of resectable or early malignant ES [ 125 ]. It is treated in two stages. Correction of fluid and electrolytes is done first, followed by surgical intervention. Normal saline is the intravenous fluid of choice in adults as it can correct hypochloremic metabolic alkalosis. 5% dextrose in normal saline is infused at 1.5 times the maintenance rate (25–30 mL/kg/day) if the patient's urine output is less than 1 mL/kg/h. Once urine output is satisfactory, potassium chloride 20 meq is added to the maintenance infusion fluid. 20 mL/kg of normal saline intravenous boluses can be given 1 to 3 times depending on the severity of hypokalemia (K < 3.1 mmol/L), hypochloremia (Cl < 100 mmol/L), and metabolic alkalosis (HCO 3  ≥ 30 mmol/L). Then, 1.5× maintenance infusion fluid is continued. Endoscopic balloon dilation (EBD) of pyloric stenosis is considered as the first‐line therapy in adults with pyloric stenosis. It can give rapid symptomatic relief, and surgery can be avoided in many cases [ 140 ]. But it is associated with a high recurrence rate [ 141 ]. Patients requiring more than two dilations may need surgical intervention. A laparoscopic pyloromyotomy is usually performed [ 142 ]. Other surgical interventions include distal gastrectomy, gastrojejunostomy, Billroth I or Billroth II surgery, and surgical pyloroplasty. Pneumatic balloon dilation using achalasia balloon is considered the primary modality of treatment of SS. It has an overall success rate of 78.2% [ 143 ]. Temporary esophageal FCSEMS placement is also safe and effective, with a clinical success of 85.7% [ 144 ]. Lumen‐apposing metal stent (LAMS) placement has also been effective. These stents are removed after 3 months by a rat‐tooth forceps [ 145 ]. If the endoscopic interventions fail, the next step is surgical conversion to Roux‐en‐Y gastric bypass (RYGB) [ 146 ]. EBD through a TTS balloon is the primary treatment for GJAS. The American Society of Gastrointestinal Endoscopy (ASGE) recommends dilating the stricture to at least 15 mm to reduce further dilations without affecting the weight loss program [ 147 ]. Generally, 1 to 3 sessions are required for successful dilation. Endoscopic balloon dilation is successful in 95% of cases, but complications like perforation can occur in 3% of cases [ 148 ]. If the endoscopic dilation fails, the next step is to place a LAMS, which has shown stricture resolution in many patients [ 149 ]. In cases of GJAS refractory to endoscopic intervention, a laparoscopic redo of the gastrojejunostomy is required [ 150 ]. The treatment of SIS depends on whether it is Crohn's or non‐Crohn's stricture, inflammatory or fibrotic stricture, and simple or complex stricture. In the case of Crohn's inflammatory stricture, the first line of treatment is the administration of an anti‐TNF agent, either infliximab or adalimumab. It can prevent the progression of inflammatory SIS; patients can become steroid‐free and avoid surgery [ 151 ]. Recently, anti‐TL1A monoclonal antibody has shown promise in the treatment of Crohn's disease and ulcerative colitis, due to its dual role in inflammatory and fibrotic pathways [ 152 , 153 , 154 ]. The primary treatment of Crohn's fibrotic simple stricture, particularly in the ileocecal anastomotic region, is EBD as recommended by the ASGE [ 94 ]. EBD can widen the narrowed segment with a less than 3% complication rate. If the stricture is refractory to medical therapy or EBD, or if the stricture is complex, the next step to consider is a surgical intervention, which includes either strictureplasty or surgical resection. In strictureplasty, the stricture is cut open; the narrowed segment is widened and repaired without removing any part of the intestine. It is reserved for multiple or recurrent strictures to preserve the bowel. Surgical resection is done for complex strictures, localized strictures, or if there is a concern for malignancy [ 155 ]. The treatment of colon stricture depends on the nature (benign or malignant), severity and length of the stricture, presence of any associated complication, and overall clinical condition of the patient. Benign short segment (< 4 cm), narrow (1 cm), uncomplicated colon stricture is usually treated by EBD [ 156 ]. Sequential balloon dilation is done over two to three sessions to achieve long‐term success. Symptomatic stricture resolution can occur in 77% of patients immediately and in 44% of patients long‐term [ 157 ]. Recently, the placement of LAMS has emerged as another treatment option in this cohort of patients. One study showed that symptomatic improvement occurred in 85% of patients after placement of LAMS, and 89% of them remained recurrence‐free in the first 6 months of follow‐up [ 158 ]. A comparison of LAMS vs. EBD for the treatment of benign colorectal anastomotic strictures showed that both LAMS and EBD had similar technical success, clinical success, similar rate of recurrence, and crossover to another intervention. 16.7% of EBD‐treated patients vs. 0% of LAMS‐treated patients had adverse events (pain, bleeding, perforation) [ 159 ]. In the case of refractory anastomotic stricture in the distal colon and rectum, endoscopic strictureplasty using a linear stapler is considered safe and effective [ 160 ]. Surgery is indicated if endoscopic intervention is unsuccessful or unsuitable, stricture is complex, and malignancy cannot be excluded [ 161 ]. Malignant colon stricture is usually managed by placing a SEMS. It can be used as a bridge to surgery when a patient comes with acute colonic obstruction, as stenting allows relief of obstruction to prepare for elective curative surgery. In case of incurable disease or non‐surgical candidates, insertion of SEMS is used as a palliative treatment [ 162 ]. The treatment of benign anorectal stenosis depends on the severity of the stenosis and the patient's overall condition. Mild anorectal stenosis is managed by conservative treatment, which includes a high‐fiber diet, fiber supplements, plenty of water, and a daily intake of a stool softener. Patients are instructed to do daily digital or manual dilation. Patients can sit down on the toilet, bear down, and gradually dilate the anal canal by introducing the smallest lubricated dilator [ 163 ]. Sometimes, partial lateral internal sphincterotomy may be necessary to treat mild anal stenosis. Surgical interventions like sphincterotomy, anoplasty, and lateral mucosal advancement flap manage moderate and severe anal stenosis. However, patients should continue to take high fiber and plenty of water. Sphincterotomy is done to allow the release of the scar tissue. In severe anal stenosis, the anal canal is widened by lateral internal sphincterotomy and anoplasty (creation of flaps such as Y‐V flap, diamond flap, and house flap to deliver viable anoderm into the anal canal). In lateral mucosal advancement flap surgery, a transverse incision is made at the dentate line, and the anal and rectal mucosa are undermined, followed by the advancement of the flap distally near the anal verge [ 164 ]. This operation has shown good results in moderate to severe anal stenosis [ 165 ]. A multidisciplinary team should manage malignant anorectal stenosis. Chemoradiation is the first‐line treatment for anal squamous cell cancer [ 166 ]. In non‐responders, surgical reconstruction of the anal canal may be necessary. Palliative management with pain relief and supportive care tailored to the patient's needs and health condition is required when curative treatment cannot be offered [ 167 ]. Treatment options for malignant rectal stricture include low anterior resection (LAR) (resection of the rectum with preservation of the anal sphincter, followed by colorectal anastomosis) or abdominoperineal resection (APR) (resection of the entire rectum and anus and creation of a permanent colostomy). The National Comprehensive Cancer Network (NCCN) recommends considering palliative stent placement to relieve the patient's symptoms in inoperable cases of malignant rectal stricture [ 168 ].

The prevalence of ES in the United States is between 1/100 and 1/1000 patients. It was 203.14 cases/100000 people in 2021, as per MarketScan databases [ 1 ]. ES can affect patients of any age, but patients 75 years or older are more commonly affected. Benign strictures are more common in the younger population, whereas malignant strictures are more widely seen in the older population. White persons are 10 times more commonly affected by peptic strictures than Asian or black persons. Although the incidence of different ES increases with age, children and young adults are more widely affected by strictures secondary to eosinophilic esophagitis and caustic esophagitis. The annual incidence of IHPS is 2.4 per 1000 live births in Whites, 0.7 in Blacks, 1.8 in Hispanics, and 0.6 in Asians [ 2 ]. INHPS is more rarely seen than IHPS [ 3 ]. AHPS is rarely encountered in clinical practice, and only a few hundred cases have been described in the literature [ 4 ]. Most of the PS seen in adults are ANHPS. The estimated prevalence of peptic ulcer disease (PUD) is 5% to 10% in the general population [ 5 ]. Less than 5% of patients with PUD develop PS [ 6 ]. 0.07% of total CD patients may develop isolated gastroduodenal CD and rarely they present with PS [ 7 ]. About 3.5% (0.6% to 4%) of patients develop sleeve stenosis following laparoscopic sleeve gastrectomy [ 8 , 9 ]. The stenosis occurs most often in the middle of the gastric sleeve near the incisura angularis [ 10 ]. The overall incidence of GJAS following LRYGB varies from 3% to 27% [ 11 ]. The epidemiology of SIS largely depends on the incidence and prevalence of CD. In 2023, the incidence of CD in the United States was 4.1 per 100 000 person‐years, and prevalence was 305 per 100 000 population [ 12 ]. 25% of patients with CD can develop SIS within 20 years [ 13 ]. It is more commonly seen in patients with Crohn's colitis than those with ulcerative colitis. In Crohn's colitis, the prevalence is 8.71% compared to 1.06% in ulcerative colitis [ 14 ]. A multicenter study found that the incidence of colon stricture in ulcerative colitis was about 3.6% over a median follow‐up of 9.6 years, the cumulative probability being 1% at 5 years and 2.3% at 10 years [ 15 ]. The incidence of CS is 10% within 20 years after the diagnosis of CD. The incidence of high‐grade dysplasia or cancer is high in CS associated with IBD, both in the pre‐biologic and post‐biologic era (20.4% vs. 23.6%) [ 16 ]. The exact incidence and prevalence of AS are unknown. The incidence of anorectal malformations, including congenital anal stenosis, is 1 in 5000 live births [ 17 ]. Adult anal stenosis can occur in 1% to 7.5% of cases following a radical or stapled hemorrhoidectomy [ 18 ]. In perianal fistulizing CD (PFCD) with a disease duration of more than 5 years, the incidence of anal stenosis is 47.4%. Older age at diagnosis and higher Crohn's disease activity index (CDAI) are associated with a higher chance of developing anorectal stenosis [ 19 ]. The incidence of AS following radiation to the anorectal region is 2% to 30%. One study showed that pre‐operative radiotherapy for rectal cancer caused AS in 26% of cases [ 20 ].

A gastrointestinal stricture (GIS) or stenosis is an abnormally narrow area of the gastrointestinal tract (GIT), leading to difficulty in passage of food or fluid through the lumen. It can occur in any part of the GIT from the esophagus to the anus and can be benign or malignant. Some benign GISs are inflammatory, and some are fibrotic. Esophageal stricture (ES) is an abnormal narrowing of esophageal lumen (normal diameter 20 to 30 mm) and can occur in distal, mid, or proximal esophagus. It is the most common type of benign GIS. Gastric stricture (GS) generally occurs at the level of the pylorus. Pyloric stenosis (PS) can be infantile hypertrophic pyloric stenosis (IHPS), infantile non‐hypertrophic pyloric stenosis (INHP), adult hypertrophic pyloric stenosis (AHPS), or adult non‐hypertrophic pyloric stenosis (ANHPS). Post‐bariatric surgery stricture (PBSS) includes SS and GJAS secondary to Laparoscopic sleeve gastrectomy and laparoscopic Roux‐en‐Y gastric bypass (LRYGB) surgery respectively. Most of the SS occurs at the site of incisura angularis or proximal third of the sleeve. GJAS is defined as narrowing of the gastrojejunostomy to 10 mm or less, preventing the endoscope from traversing. Small intestinal stricture (SIS) can occur anywhere in the small intestine. In imaging studies, SIS is defined as localized luminal narrowing (less than 1 cm or less than 50% of normal adjacent bowel) and bowel wall thickening (> 3 mm) with pre‐stenotic luminal dilation of more than 2.5 cm. Endoscopically, SIS is recognized when an adult endoscope cannot pass through a narrowed segment of the small bowel even after applying a reasonable amount of pressure. The location of the stricture depends on the underlying cause. Colonic stricture (CS) is a localized area of narrowing of the colon that can slow down or completely block the passage of stool. On imaging studies (CT or MRI), it is characterized by wall thickening, luminal narrowing, and pre‐stenotic upstream dilation of the colon. Anorectal stricture (AS) is narrowing of the anal canal or rectum. Patients with GIS can remain asymptomatic if the lumen is not narrow enough to cause obstruction. Patients with significant GIS can present a variety of symptoms depending on the area of involvement. GIS, if left untreated, can cause considerable morbidity and mortality. Various GIS treatment methods are now available with the advancement of interventional endoscopy. The epidemiology, etiology, pathophysiology, clinical manifestations, investigations, and treatment of esophageal stricture, gastric stricture, post‐bariatric surgery stricture, small intestinal stricture, colonic stricture, and anorectal stricture will be discussed in this review.

The author declares no conflicts of interest.

ESs are broadly classified into simple strictures and complex strictures. Simple strictures are characterized by short ( 12 mm) with smooth surfaces and borders. Common causes of simple esophageal strictures include peptic esophageal strictures and EoE‐induced strictures. Complex esophageal strictures are long (> 2 cm), asymmetrical or angulated, and narrower (< 12 mm) with uneven surfaces and borders [ 84 ]. Caustic stricture, radiation‐induced stricture, anastomotic stricture, and post‐ESD strictures are usually complex esophageal strictures and are generally refractory and recurrent [ 85 ]. The stricture is labeled as refractory when there is an inability to successfully dilate the stricture to ≥ 14 mm over 5 sessions at 2‐week intervals. About 10% of benign esophageal strictures are refractory. Recurrent stricture is defined as the inability to maintain a satisfactory luminal diameter (≥ 14 mm) for 4 weeks once the target diameter has been achieved, resulting in return of dysphagia [ 86 ]. ES can also be classified based on radiologic and endoscopic assessment of length, internal diameter, and difficulty in dilation of the stricture (Table  1 ) [ 87 , 88 ]. Classification of ES based on radiologic and endoscopic assessment. A multivariable analysis done at Mayo Clinic recently showed a strong predictive model associated with a higher risk of refractory benign ES if the stricture length is ≥ 2 cm, the diameter is ≤ 7 mm, and the proximal location of the stricture or diffuse stricture [ 89 ]. Patients usually present with nausea, vomiting, early satiety, epigastric pain, and weight loss. Physical examination may show signs of dehydration. It usually occurs 4 to 6 weeks after surgery. Patients present with intolerance to solid food, nausea, vomiting, regurgitation, heartburn, dysphagia, abdominal pain, and excessive weight loss. Patients present with nausea, vomiting, early satiety, dysphagia, and abdominal pain [ 90 ]. GJAS can occur following LRYGB both in the early and late postoperative period. Early GJAS generally occurs in the first 30 days of surgery. In contrast, late GJAS occurs more than 30 days after surgery, usually 52 days after surgery, when patients change their diet from a soft to a solid diet but can occur several years after surgery [ 91 , 92 ]. Most of the GJAS happen in the first 3 to 4 months of the postoperative period. The symptomatology may vary depending on the severity of the SIS and its underlying etiology. Patients usually present with crampy abdominal pain, nausea, and vomiting, particularly after eating food. The pain is sometimes localized to the site of the stricture. If the stricture is severe enough, patients may develop obstructive symptoms like abdominal distension, constipation, or obstipation [ 93 ]. Symptoms of colon stricture depend on the underlying etiology and can be non‐specific. Patients generally present with constipation, changes in bowel habits, abdominal pain, abdominal distension, nausea, vomiting, and weight loss. Patients may come to the emergency room with large bowel obstruction when the stricture is tight enough to block the passage of stool partially or completely. A colon stricture should be considered malignant in the setting of ulcerative colitis unless proven otherwise [ 94 ]. In the case of malignant colonic stricture, patients may have abdominal mass, anemia, and significant weight loss. Patients usually present with constipation with narrow caliber stool, feeling of incomplete evacuation, painful defecation and sometimes bleeding. Visualization of the perianal skin may give a clue to the underlying cause of anal stenosis. Inspection and digital examination of the anal canal usually can make the diagnosis and assess severity of anal stenosis. Anal stenosis can be classified as mild, moderate, or severe stenosis (Table  2 ) [ 95 ]. Severity of anal stenosis.

Barium Swallow (BS) and upper endoscopy (Figures  1 and 2 ) are critical tests in diagnosing ES. BS is particularly valuable in suspected complex strictures. Upper endoscopy is essential to find out the underlying cause of ES; biopsy should be taken from all strictures, and it also has therapeutic options. Sometimes, it is difficult to differentiate benign from malignant ES. In suspected malignant stricture with negative mucosal biopsy, endoscopic ultrasound (EUS) with fine needle aspiration (FNA) is an essential diagnostic tool [ 96 ]. Both EUS and computerized tomography (CT) help evaluate the depth of invasion of malignant ES [ 97 ]. BS showing ES. Endoscopic view of ES. In infants and children, abdominal ultrasound is considered the primary method of investigation to diagnose PS. Diagnosis of IHPS can be certain if the antropyloric muscle thickness is more than 3 mm [ 98 ]. Upper gastrointestinal series (UGIS) and upper endoscopy are done to diagnose pyloric stenosis in adults. UGIS may show convex indentation of the base of the duodenal bulb—a mushroom‐like deformity (Kirklin's sign), concentric or eccentric narrowing of the pylorus (string sign), or a barium‐filled cleft proximal to the base of the duodenal‐bulb (Twining's sign) [ 99 ]. Upper endoscopy shows a fixed narrowing of the pylorus and an inability to advance the scope into the duodenum (cervix sign). CT scan of the abdomen may show secondary causes of pyloric stenosis. Abdominal ultrasound is not routinely done in the investigation of adult PS. In AHPS, pyloric muscle thickness is more than 8 mm [ 100 ]. The classical biochemical abnormalities include hypokalemic, hypochloremic metabolic alkalosis with hypocalcemia, paradoxical aciduria, and pre‐renal failure. These are rarely seen in current medical practice as these patients seek and receive early medical management [ 101 ]. Upper gastrointestinal series (UGIS) while the patient continuously swallows barium for adequate gastric distension. This should be done in upright and recumbent positions to avoid false positive results from spasms. Usually, a short (8 mm) segment smooth narrowing (7.5 mm) is seen (Figure  3 ) [ 102 ]. Upper endoscopy can visualize the stenotic area and better assess the severity of SS alongside the UGIS. Endoluminal functional impedance planimetry (EndoFLIP) can measure SS's luminal diameter and distensibility indices. It can be done pre‐ and post‐dilation of SS and thus can be helpful in both diagnosis and treatment [ 103 ]. Upper gastrointestinal series (UGIS) while the patient continuously swallows barium for adequate gastric distension. This should be done in upright and recumbent positions to avoid false positive results from spasms. Usually, a short (8 mm) segment smooth narrowing (7.5 mm) is seen (Figure  3 ) [ 102 ]. Upper endoscopy can visualize the stenotic area and better assess the severity of SS alongside the UGIS. Endoluminal functional impedance planimetry (EndoFLIP) can measure SS's luminal diameter and distensibility indices. It can be done pre‐ and post‐dilation of SS and thus can be helpful in both diagnosis and treatment [ 103 ]. Sleeve stenosis seen during UGIS. Upper endoscopy is the investigation of choice in diagnosing GJAS (Figure  4 ) [ 104 ]. It can be graded into four grades as shown in Table  3 [ 105 ]: Endoscopic view of GJAS. Grades of gastrojejunal anastomotic stricture. UGIS also plays a vital role in evaluating GJAS as it can reveal the stricture at the anastomotic site. Steep oblique or lateral spot images should be obtained to detect the stricture. However, UGIS has less specificity and positive predictive value in diagnosing GJAS [ 106 ]. A combination of imaging studies and endoscopy (Figure  5 ) is required to diagnose and evaluate SIS. Imaging studies include computed tomography enterography (CTE), magnetic resonance enterography (MRE), cross‐sectional imaging (CT or MRI), and intestinal ultrasound (IUS). Both CTE and MRE are highly sensitive (CTE—67%–79% and MRE 71%–87%) in detecting the location and extent of SIS [ 107 ]. MRE has the advantage of being radiation‐free and having the capability of assessing inflammatory vs. fibrotic stricture [ 108 ]. IUS is also highly sensitive (80%–100%) and accurate in diagnosing SIS. An inflammatory stricture is associated with a hypoechoic pattern (loss of stratification), fibrotic stricture with a stratified pattern, and fibroinflammatory stricture with a mixed pattern [ 109 ]. Cross‐sectional imaging like CT (sensitivity 85%–100%) or MRI (sensitivity 75%–100%) can evaluate SIS's wall thickness and nature [ 110 ]. Elevated biomarkers like CRP and fecal calprotectin go in favor of inflammatory SIS. DBE has high diagnostic yield in detecting SIS [ 111 ]. In one study, DBE detected 92.7% of SIS compared to 85.5% for CTE [ 112 ]. The American College of Gastroenterology recommends DBE when tissue is needed or when therapeutic intervention such as stricture dilation is required, as it should be reserved for cases where less invasive methods are insufficient [ 113 ]. SIS can be classified based on imaging feature, etiology, and anatomic location (Table  4 ). Terminal ileal stricture seen during ileoscopy. Classification of Small intestinal stricture. Inflammatory stricture fibrotic stricture Crohn's stricture: simple stricture ( 5 cm long with penetrating complications). Non‐Crohn's stricture. Anastomotic stricture: when prior site of intestinal resection and anastomosis is affected. Naïve (de novo) stricture: when previously unaffected bowel is involved. Cross‐sectional imaging, such as a CT scan or MRI of the abdomen and pelvis, is initially done to diagnose colon stricture. It can assess the extent and nature (benign vs. malignant, inflammatory vs. fibrotic) of stricture and the presence of any associated complication like fistula or perforation [ 114 ]. Water soluble or double contrast barium enema (DCBE) is also very helpful in finding the site, severity, and stricture length (Figure  6 ). Colonoscopy is the gold standard for assessing CS as it allows direct visualization of the stricture, tissue diagnosis of the underlying cause, and possible therapeutic intervention [ 94 ]. Barium enema showing colonic stricture. Proctoscopy can assess the severity and lining of the rectum and anal canal (Figure  7 ), and a biopsy can be taken. Gastrograffin Enema can reveal the length and severity of stricture. MRI helps evaluate the underlying cause of anorectal stenosis. Rectal cancer can be staged and restaged after chemoradiation therapy [ 115 ]. Anal sphincter complex injuries, perianal fistula, and abscesses can be imaged in detail in MRI [ 116 ]. But the sensitivity of diagnosing anal stenosis by MRI is limited [ 117 ]. EUS plays a critical role in the staging and follow‐up of rectal cancer patients. It also allows FNA of suspicious local lymph nodes [ 118 ]. Proctoscopy can assess the severity and lining of the rectum and anal canal (Figure  7 ), and a biopsy can be taken. Gastrograffin Enema can reveal the length and severity of stricture. MRI helps evaluate the underlying cause of anorectal stenosis. Rectal cancer can be staged and restaged after chemoradiation therapy [ 115 ]. Anal sphincter complex injuries, perianal fistula, and abscesses can be imaged in detail in MRI [ 116 ]. But the sensitivity of diagnosing anal stenosis by MRI is limited [ 117 ]. EUS plays a critical role in the staging and follow‐up of rectal cancer patients. It also allows FNA of suspicious local lymph nodes [ 118 ]. AS seen during proctoscopy.

Benign ES generally occurs secondary to the long‐standing inflammatory process in the esophagus wall, irrespective of the underlying etiology. Chronic inflammation leads to intramural fibrosis with subsequent narrowing of the lumen of the esophagus. Malignant ES usually occurs due to adenocarcinoma (involving the lower third of the esophagus) or squamous cell carcinoma of the esophagus (involving the middle or upper third of the esophagus). Rarely, pulmonary or mediastinal malignancy or enlarged mediastinal lymph nodes can affect the esophagus, leading to stricture. In IHPS and AHPS, hyperplasia and hypertrophy of pyloric circular and longitudinal muscles occur, causing elongation and narrowing of pyloric channels [ 63 ]. In the case of PUD, a significant number of inflammatory cells, mainly neutrophils, infiltrate initially. This is followed by granulation tissue formation, mild to moderate chronic inflammation, and scar tissue formation, which thickens and causes stricture of the pyloric canal. Gastroduodenal CD can cause granulomatous or non‐granulomatous inflammation of the pyloric canal with inflammatory or fibrotic stricture [ 64 ]. Gastric tuberculosis can cause necrotizing granuloma in the gastric wall and pyloric outlet obstruction [ 36 ]. Technical and mechanical factors during surgery lead to ischemia that can trigger local inflammation, subsequent fibrosis, and progressive luminal narrowing. In the majority of cases, twisting of gastric sleeve can cause functional obstruction [ 65 ]. Excessive tissue tension, tissue manipulation, and thermal injury lead to ischemia, inflammation, and subsequent fibrosis. Other risk factors to develop stricture include marginal ulceration, anastomotic leak, use of fibrin sealant at the anastomosis, and antecolic LRYGB rather than retrocolic LRYGB. Multiple factors play into the pathophysiology of Crohn's stricture. These include genetic susceptibility, aberrant immune and inflammatory response, dysbiosis of gut microbiota, and environmental factors. Mutation of Nucleotide‐binding oligomerization domain 2 (NOD2) gene leads to activation of fibroblasts with CD14 and platelet‐derived growth factor receptor alpha (PDGFRA) expression and rich in IL‐6, IL‐11, and oncostatin M (OSM). As a result, dysregulated homeostasis leads to uncontrolled proliferation of fibroblasts and intestinal stricture. Mast cells, macrophages, circulating fibrocytes, molecules, and signaling pathways play important roles in the development of Crohn's stricture. Mast cells in the gastrointestinal tract can release tryptase and facilitate the differentiation of fibroblasts to myofibroblasts. Crohn's stricture shows a subgroup of macrophages with high expression of fibrotic genes, TGF‐β1, and M2 signature genes. Bone marrow‐derived circulating fibrocytes are also involved in the formation of fibrosis. Certain novel molecules and signaling pathways involved in the activation of fibroblasts are tumor necrosis factor‐like ligand 1A (TL1A), Yes‐associated protein and transcriptional coactivator with PDZ‐binding motif (YAP/TAZ), and Wnt/βcatenin signaling pathway [ 47 ]. Dysbiosis of gut microbiota also plays a role in Crohn's SIS. Bacteroides fragilis was found to be associated with stricturing CD in one study [ 66 ]. Smoking is the most established environmental risk factor that can contribute to Crohn's SIS [ 67 ]. Crohn's SIS is subdivided into inflammatory, fibrotic, and mixed types. Chronic inflammation with disorganized healing leads to fibrosis. Activated fibroblasts and myofibroblasts deposit collagen subtypes I, III, and V in the submucosa and muscular layers and form extracellular matrix (ECM). Matrix metalloproteinases (MMPs) degrade ECM, and tissue inhibitors of metalloproteinases (TIMPs) inhibit this degradation. In patients with Crohn's SIS, the downregulation of some MMPs and upregulation of TIMPs leads to the deposition of excessive ECM with thickening and stiffening of the bowel wall [ 68 ]. Creeping mesenteric fat, “a pathognomonic sign of CD,” can secrete free fatty acids, TNFα, IL‐6, and IL‐8, and induce muscular propria hyperplasia and intestinal fibrosis [ 69 ]. Thus, a combination of inflammation, fibrosis, and muscular propria hyperplasia leads to Crohn's SIS. NSAIDs can cause multiple diaphragm‐like obstructions in the intestinal lumen, also called “diaphragm disease.” The pathogenesis involves direct mucosal injury and decreased synthesis of prostaglandin due to inhibition of cyclooxygenase. NSAIDs can solubilize lipids of mucosal membrane phospholipids and damage epithelial mitochondria. Mitochondrial injury results in free radical formation, epithelial barrier disruption, and increased mucosa permeability [ 70 ]. Cyclooxygenase inhibition may decrease mucosal blood flow, mucus production, and mucosal defense mechanisms, increasing mucosal permeability. As a result, intestinal bacteria, toxins, bile acids, and proteolytic enzymes can enter the mucosal layer and cause inflammation. Long‐term use of NSAIDs can cause submucosal fibrosis with the formation of circumferential collagenous diaphragm‐like and stricture‐like drawstring [ 71 ]. Radiation‐induced SIS can occur in patients with chronic radiation enteritis. Segmental inflammation and obliterative endarteritis due to damage to the blood vessels of the intestinal wall are the two main pathophysiological mechanisms. Chronic mesenteric ischemia develops due to obliterative endarteritis, which can lead to mesenchymal cell activation, collagen deposition, progressive transmural fibrosis, and stricture [ 72 ]. Ischemic SIS develops due to diminished blood flow to the intestine. Lack of oxygen in the tissue initiates a healing process that results in inflammation, fibrosis, and stricture [ 73 ]. Post‐surgical SIS is caused by decreased blood supply to the anastomotic site during surgery, tissue hypoxia, excessive inflammation, collagen deposition, and fibrosis [ 74 ]. In eosinophilic enteritis, various cytokines and chemokines (IL‐6, CCL17, and CCL26) are released. They cause tissue remodeling, fibrosis, wall thickening, and stricture formation [ 75 ]. Infectious enteritis can cause SIS through chronic inflammation and fibrosis. In Behcet's disease, the intestinal mucosa is infiltrated by cytotoxic Th1 and Th17 cells with the production of high levels of pro‐inflammatory cytokines like TNF‐α and IFN‐γ. This results in mucosa ulcerations and chronic inflammation that leads to fibrosis and SIS [ 76 ]. Behcet's disease can also cause vasculitis of small intestinal vasculature, leading to ischemic SIS [ 77 ]. Jejunoileal neuroendocrine tumor (JI‐NET) can cause desmoplastic reaction and mesenteric fibrosis by secreting various profibrotic factors (epidermal growth factor, fibroblast growth factor 2, TGF beta and alpha, fibroblast growth factor β, Insulin‐like growth factor 1, connective tissue growth factor and platelet‐derived growth factor (PDGF) [ 78 ]). This fibrotic process usually starts at the site of local lymph node metastasis and can cause SIS. Other malignant SIS occurs secondary to malignant infiltration of the intestinal wall and luminal narrowing. Benign CS occurs as a sequelae of chronic inflammation which triggers hyperplasia of mesenchymal cells—fibroblasts, myofibroblasts, and smooth muscle cells. Cytokines like transforming growth factor‐beta stimulate collagen synthesis. M2 macrophages also promote proliferation of smooth muscle cells. Both fibrosis and smooth muscle hyperplasia/hypertrophy contribute to the development of benign CS [ 79 ]. Malignant CS is caused by proliferation of malignant cells leading to luminal narrowing. Benign AS occurs due to chronic inflammation, which causes secretion of cytokines like TGF‐beta, deposition of collagen in the extracellular matrix, hypertrophy of the muscularis propria, and loss of elasticity of the anal canal [ 80 ]. Surgical and non‐surgical trauma, inflammatory bowel disease, radiation therapy, and sexually transmitted infections can cause chronic inflammation leading to fibrous stricture of the anal canal. In immunocompetent individuals, malignant anal stenosis occurs due to persistent human papillomavirus (HPV) infection, which can cause loss of heterozygosity (LOH) of chromosomes 11q23, 17p, 18q, and 5q and mutation of tumor suppressor genes like p53, DCC, and APC, whereas in HIV‐infected individuals, persistent HPV infection leading to microsatellite instability is the preferred pathway for rapid development of anal cancer [ 81 ]. Dysregulation in autophagy in persistent HPV infection is another factor causing anal carcinogenesis [ 82 ]. Chronic inflammation in CD can also develop squamous cell carcinoma or adenocarcinoma from the ulcerated area or fistula‐lining epithelium [ 83 ].