Section 2 Symptomatology

#### **Chapter 3**

## Complications of Ulcerative Colitis in Children

*Sabina Wiecek*

#### **Abstract**

Inflammatory bowel disease is a group of chronic disorders of the gastrointestinal tract, including Lesniowski-Crohn disease, ulcerative colitis, and indeterminate colitis. The most frequently occurring symptoms in patients with IBD, including ulcerative colitis, involve abdominal discomfort, recurring and often bloody diarrhoea, weight loss, and the resulting anaemia and/or cachexia. Extraintestinal manifestations of ulcerative colitis may precede the diagnosis of inflammatory bowel disease, they may also occur during remission (pyoderma gangrenosum, uveitis, spondylitis, and PSC) or accompany an exacerbation of the disease (erythema nodosum, episcleritis, aphthae, and some forms of peripheral spondyloarthritis). This study focuses on the most common extraintestinal manifestations and complications in ulcerative colitis in paediatric patients.

**Keywords:** ulcerative colitis, parenteral symptoms, complications, children

#### **1. Introduction**

Inflammatory bowel disease is a group of chronic disorders of the gastrointestinal tract, including Lesniowski-Crohn disease, ulcerative colitis, and indeterminate colitis. The course of these disorders is characterised by alternating periods of remission, which may last even a few years, and exacerbation. Chronic inflammatory bowel diseases develop as a result of coexisting genetic, immunological and environmental factors, and the immune system, which is linked to the digestive system and constitutes a vast proportion of the whole defence mechanism of our body. Among the most frequently occurring symptoms in patients with IBD, including ulcerative colitis, are abdominal discomfort, recurring and often bloody diarrhoea, weight loss, and the resulting anaemia and/or cachexia. The aspects of extraintestinal symptoms of inflammatory bowel diseases are not discussed often, and yet in as many as 40–50% of patients, at least one extraintestinal manifestation of IBD occurs with even 25% of patients reporting two or more symptoms not related to the digestive system. The causes of the occurrence of extraintestinal symptoms in the course of ulcerative colitis have been widely discussed. Increased permeability of the intestinal wall allows for the contents of the bacterial wall (endotoxins) and other components to enter the bloodstream, which may cause inflammation. Extraintestinal manifestations of ulcerative colitis may precede the diagnosis of inflammatory bowel disease, occur during remission (pyoderma gangrenosum, uveitis, spondylitis, and primary sclerosing cholangitis)


#### **Table 1.**

*Extraintestinal symptoms of ulcerative colitis.*

or accompany an exacerbation (erythema nodosum, episcleritis, aphthae, and some forms of peripheral spondyloarthritis). The course of inflammatory bowel diseases in children is more severe than in adults. Extraintestinal manifestations may precede intestinal ones by months or years and may lead to false diagnoses and delayed treatment. Patients with extraintestinal manifestations often first consult other specialists, such as ophthalmologists, orthopaedic surgeons, or rheumatologists, before being diagnosed with a gastroenterological disorder. Ankylosing spondylitis or primary sclerosing cholangitis, which co-occur in patients with ulcerative colitis pose a greater health problem for some patients than the main intestinal disease(**Table 1**) [1–6].

Gastrointestinal complications are as follows:

a.Toxic megacolon (megacolon toxicum): a potentially lethal complication was observed in 3–4% of all patients with ulcerative colitis. Toxic megacolon usually occurs in patients whose whole area of the large intestine (pancolitis) has been affected shortly after the onset of the disease. Pathophysiological factors include inflammation-induced severe damage to the intestinal wall, electrolyte imbalance, and hypoproteinemia. Antidiarrheals and a barium enema may additionally contribute to the development of the complication. The removed intestine is characterised by significant thinning, fragility of the walls, and segmental mucosal atrophy. Histopathological examination shows significant hyperaemia, infiltration of all layers of the intestinal walls, and multiple small microperforations. Diagnostic criteria for megacolon toxicum involve radiological symptoms of large bowel distension, clinical symptoms (fever, HR >120/min and leukocytosis), and at least one of the following symptoms—dehydration, impaired consciousness, and decreased RR. The physical examination reveals increased tension and tenderness of the abdominal wall to palpation, as well as absent or subdued peristaltic sounds. In some cases, peritoneal symptoms occur, which may indicate an intestinal perforation. The diagnosis of toxic megacolon is based on the clinical picture and X-ray picture of the abdomen, which will show extensive distension of the colon filled with gas. A radiological criterion for megacolon is the transverse colon exceeding 6 cm in diameter in the body's midline. Laboratory tests show leukocytosis, anaemia, hypoalbuminaemia, and hypokalemia.

#### *Complications of Ulcerative Colitis in Children DOI: http://dx.doi.org/10.5772/intechopen.102080*


*Extraintestinal symptoms*. Many patients with ulcerative colitis experience symptoms from other organs and systems. Comorbidities, also referred to as systemic complications can be divided into two groups—conditions that occur mainly in the exacerbation of colitis ulcerosa (e.g., arthritis of the large joints, iritis, and erythema nodosum) and conditions occurring independently from the activity of colitis (e.g., ankylosing and most complications from the liver and bile ducts).

*Ulcerative Colitis - Etiology, Diagnosis, Diet, Special Populations, and the Role of Interventional…*


#### **Table 2.**

*Intestinal complications of ulcerative colitis.*

#### **2. Malnutrition**

Malnutrition is a significant complication in children with inflammatory bowel disease that results in delayed growth and puberty. Fatigue and loss of appetite are sometimes also observed. They may imitate anorexia nervosa.

*Inhibition of growth and/or puberty*. The main causes include chronic inflammation, abnormal level of nutrition, and intake of glucocorticoids for medicinal purposes [2, 4, 5].

#### **3. Hepatic lesions**

Liver-related symptoms may present as hypertransaminasemia caused by the disease or as a result of the treatment (sulfasalazine, steroids, azathioprine, and parenteral nutrition). Other serious complications include autoimmune hepatitis and primary sclerosing cholangitis. Liver-related symptoms are observed in about 50% of patients with ulcerative colitis. *Primary sclerosing cholangitis* (*PSC*). A total of 90% of patients with primary sclerosing cholangitis have ulcerative colitis. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of complex aetiology that leads to damage to intra- and extrahepatic bile ducts. The following factors play a part in the etiopathogenesis—genetic (HLAA1, B8, DR3), autoimmune, infectious, and environmental (the impact of diet and the gastrointestinal microbiome). The disease is characterised by the narrowing of the bile ducts that impairs the flow of the bile and leads to cholestasis. Consequently, it may result in portal hypertension, cirrhosis/ liver failure, maldigestion, and malabsorption of fat and vitamins. Europe and North America report the highest incidence rate, at 4.1–16/100,000 of inhabitants. The highest incidence rate is among 20–40-year-olds. The incidence rate of PSC in the paediatric population is reported at 0.2/100,000/year, with a higher rate among the adult population, at 0.5–1/100,000/year.

The clinical manifestation is not characteristic. In 40–60%, there are no clinical symptoms, and the observed abnormal parameters of cholestasis and damage to the liver suggest primary sclerosing cholangitis.

#### *Complications of Ulcerative Colitis in Children DOI: http://dx.doi.org/10.5772/intechopen.102080*

In some patients, the skin and the sclera turn yellow, and other symptoms involve itching, fatigue, loss of body weight, weakness, epigastric pain, andor episodes of fever. PSC is a progressive condition leading to cirrhosis and liver failure. A total of 50% of patients with primary sclerosing cholangitis require a liver transplant within 10–15 years of diagnosis. A total of 50–80% of patients with PSC have a co-existing inflammatory bowel disease (ulcerative colitis more often than Lesniowski-Crohn's disease). Lesions more often affect the right colon, with the rectum remaining unaffected (free). Interestingly, only 2–4% of patients with ulcerative colitis, and 1.4–3% of those with Lesniowski-Crohn's disease have co-existing PSC. Other autoimmune conditions often co-exist in patients with PSC. They are type 1 diabetes mellitus, coeliac disease, autoimmune pancreatitis and Hashimoto thyroiditis, glomerulonephritis, and/or arthritis. *Diagnosis*. Laboratory tests reveal elevated parameters of cholestasis and damage to the liver. A total of 40–50% of patients have increased IgM and IgG, and in 20–50%, there are anti-nuclear antibodies and/or anti-smooth muscle antibodies. In 50–70% of patients, pANCA antibodies are present. Cholangio-MRI reveals the characteristic picture of strictures with subsequent dilatations of the intraand/or extrahepatic bile ducts. Retrograde cholangiopancreatography (ERCP) is performed in the case of clinical uncertainty, or a need for treatment (sphincterotomy, stenting) and/or for cytology to confirm or exclude cholangiocarcinoma. Similarly, histopathological assessment of liver biopsies is only conducted in the case of diagnostic uncertainty. Histopathological examination reveals fibrosis around bile ducts— "onion skin" in 20–40%, inflammatory infiltrate in portal areas, the proliferation of the bile ducts, and subsequent biliary ductopenia. *Complications*. Inflammation and fibrosis lead to the development of cirrhosis of the liver. Patients with PSC are at a higher risk of developing cholangiocarcinoma and/or hepatocellular carcinoma. Primary sclerosing cholangitis is linked with an increased risk of colorectal cancer (in 9% after 10 years of diagnosis, in 31% after 20 years, and in 50% after 25 years), cholangiocarcinoma, and/or gallbladder cancer (400× greater risk). Close to 50% of gallbladder polyps in patients with PSC is malignant. 1/3 of cholangiocarcinoma in adults is diagnosed at the same time as PSC. The treatment of primary sclerosing cholangitis involves ursodeoxycholic acid, which, despite being controversial, reduces the risk of dysplasia within the large intestine. It is possible that ursodeoxycholic acid lowers the concentration of endogenic, harmful metabolites of bile acids. There has been research on the inclusion of vancomycin in the treatment of patients with PSC, but its efficacy was not proven. In the case of strictures in bile ducts and cholelithiasis, the procedure of ERCP is adopted. A liver transplant is necessary in the case of recurrent cholangitis, end-stage liver failure, portal hypertension, and/or treatmentresistant pruritus. *Autoimmune hepatitis*. In some patients, it accompanies primary sclerosing cholangitis. The clinical manifestations are not characteristic—sometimes weakness, the yellowing of the skin and the sclera, pruritis and hepatosplenomegaly. Laboratory tests reveal elevated parameters of liver damage and cholestasis, hypergammaglobulinemia, and high levels of IgG. Histopathological assessment of a liver biopsy is crucial for the final diagnosis. The treatment involves immunosuppressive drugs (glucocorticoids, azathioprine, and cyclosporine). *Cholelithiasis*. Cholelithiasis is more frequently observed in patients with Lesniowski-Crohn disease than in those with ulcerative colitis, especially with the lesions affecting the ileum terminale and after ileocecal resection (link with interrupted enterohepatic circulation). In patients with ulcerative colitis, cholelithiasis occurs noticeably and frequently following large bowel resection and is linked to the abnormal absorption and transport of bile acids. The problem may affect even 10–30% of patients. *Liver steatosis* is the most frequently

observed liver pathology in the course of inflammatory bowel disease. The aetiology highlights the role of an unhealthy diet, loss of body weight, and steroid therapy. Hepatic steatosis may affect even 40% of patients with ulcerative colitis. Hepatic steatosis often correlates with the severity of the inflammatory bowel disease and often subsides once treated. *Hepatic amyloidosis*—the problem concerns 0.07% of patients with ulcerative colitis. The aggregation of amyloid in the liver leads to asymptomatic hepatomegaly. No correlation has been shown between the occurrence of amyloidosis and the advancement of intestinal lesions, the scope and duration. *Liver abscess*. It occurs more often in the course of Lesniowski-Crohn disease. Laboratory tests show leukocytosis and elevated activity of alkaline phosphatase. Liver abscesses may develop as a result of direct contact with an abdominal abscess or the hematogenous spread of inflammation. *Drug-induced hepatotoxicity*:


#### **4. Pancreatic complications**

*Pancreatitis*. Increased activity of amylase/lipase in the blood serum is observed in 14% of patients with inflammatory bowel disease. It is most often asymptomatic and has no link with the activity of bowel disease. *Acute pancreatitis* may be a side-effect of treatment with the following drugs—azathioprine, sulfasalazine, and mesalazine. The symptoms usually occur within the first weeks of treatment. The course of the disease is usually mild and rapidly subsides once the triggering factor has been withdrawn. Apart from the impact of the applied treatment, the pathomechanism has not been entirely determined. It may be connected with autoimmunological factors and the formation of antibodies. *Autoimmune pancreatitis*. The impact of inflammatory mediators and the presence of anti-pancreatic antibodies has been considered. It is very rarely observed in the paediatric population [1–6, 17, 18].

#### **5. Skin lesions**

Skin lesions are observed in about 3–10% of patients with ulcerative colitis. *Erythema nodosum* is an inflammatory condition that affects the subcutaneous fat in the skin and is characterised by the formation in the subcutaneous tissue of weakly delineated, flatly elevated, tender, red and warm nodules of 1–1.5 cm in diameter (the nodules may merge). They usually appear on both sides of the lower leg (less commonly on the calves), but they are not uncommon on the thighs, buttocks, arms, and torso. The nodules do not fade after 2–9 weeks, they subside without leaving scars, and they may leave post-inflammatory discolouration. It usually precedes a relapse of the intestinal condition and related gastrointestinal manifestations. However, in some patients, the course of this skin complication is independent of the activity of ulcerative colitis. It may affect even 10–15% of patients with ulcerative colitis, more

#### *Complications of Ulcerative Colitis in Children DOI: http://dx.doi.org/10.5772/intechopen.102080*

of whom are women. The treatment involves the treatment of the intestinal disease, and glucocorticoids also render good results. *Pyoderma gangrenosum*. It occurs very rarely in the paediatric population with inflammatory bowel disease, affecting less than 1% of patients. Pyoderma gangrenosum most often presents in its severe, classic form (skin ulcers) or milder, pustular form. The lesions rapidly transform into ulcers affecting the skin and the superficial layer of the subcutaneous tissue. They are mainly located within the pretibial region, but they may affect every body part. They may lead to abscesses, ulcers, and osteomyelitis. Pyoderma gangrenosum does not always correlate with the activity of intestinal disease. Histopathological examination shows necrotic lesions in the skin, substantial leukocyte infiltrations, thrombosed veins, and petechiae. The healing process is difficult and leaves behind anthropic scars. The treatment involves high doses of glucocorticoids and in some cases cyclosporine and infliximab. *Sweet's syndrome* is a form of erythema exsudativum multiforme with accompanying fever and neutrophilia, also seen in patients with ulcerative colitis. Lesions may resemble erythema nodosum but steroid treatment rapidly brings improvement. *Psoriasis*. Occurs five times more frequently in patients with ulcerative colitis than in the population. It may be a side effect of the applied biological treatment. *Epidermolysis bullosa acquisita*. Following a mechanical injury, large subepithelial blisters form, often blood-filled. The lesions are most often located on the hands, the soles of the feet, in the elbow creases and behind the knees. Erosions within the oral cavity are observed in some patients. *Necrotizing vasculitis*. May lead to peripheral gangrenous lesions.

*Stomatitis aphthosa* occurs in around 3% of patients with ulcerative colitis. Mouth ulcers most often present as small and rather shallow erosions in the mucosal surfaces of the cheeks, soft palate, and/or the tongue. Such ulcers require differential diagnosis with moniliasis, which is another complication following severe lapses of ulcerative colitis treated with glucocorticoids and antibiotics [19, 20].

#### **6. Rheumatoid symptoms**

*Arthritis* may affect single or many joints, including knees, elbows, and/or hips (around 3.8%). Ankylosing spondylitis and sacroiliitis may also occur. Manifestations from the musculoskeletal system are the most common extraintestinal symptoms of inflammatory bowel disease, with as many as 25% of patients with UC affected. Arthritis may occur together with, or irrespective of the level of activity of inflammatory bowel disease. Lesions of the joints occur more often in patients with intestinal and extraintestinal complications, such as abscesses, pseudopolyps, perirectal lesions, and/or lesions in the mouth, erythema nodosum or pyoderma gangrenosum. The location of arthritis may change and may move from one joint to another. It usually lasts several weeks, rarely leading to joint deformity, and subsides following standard treatment for IBD. Patients are diagnosed with arthralgia (the presence of pain not linked with the inflammation) and spondyloarthropathies (arthritis with swelling, pain, redness, impaired mobility, and lesions seen in the imaging tests). The pathophysiology of these conditions is not fully known. *Classification*: A. Type I arthritis—type I arthropathy—axial type—typically affects several large peripheral joints (usually fewer than five), with often nonsymmetric and self-limiting lesions, and linked with the activity of the primary condition. It may precede the intestinal symptoms. It does not lead to the destruction of the affected joints. B. Type II arthritis—type II arthropathy—peripheral type—concerns at least five small peripheral

joints, symmetric and with no link to the primary condition. Lesions occurring in this type are usually chronic and recurring. Synovitis occurs in both types. Synovial biopsies indicate non-characteristic lesions in the form of increased blood flow, ependymal proliferation, and mononuclear cell infiltration. Laboratory tests in arthritis are not specific. Leukocytosis, the ESR, and C-reactive protein correlate more with the activity of the intestinal disease and are of little value in the diagnostics of lesions in the joints. Synovial fluid analysis shows an increased count of leukocytes with the majority of neutrophils. Radiological analysis of peripheral joints shows mild oedema of the tissue, osteoporosis, periostitis, and exudation, usually without erosions or bode destruction. CT and/or MRI scans prove very useful for the assessment of lesions within the sacroiliac joints. Axial spondyloarthropathy is treated with relevant physiotherapy, rest, and specialist medication (sulfasalazine and mesalazine, among others)—as the only treatment of the primary condition, which, once in remission will also result in the withdrawal of the manifestations from the musculoskeletal system. Lesions in type II inflammation are often chronic and recurring, with both rheumatological and physiotherapy assistance necessary.

*Ankylosing spondylitis* occurs in 4–8% of patients with IDB. Men are affected more often than women. In around 60% of patients, the HLA-B27 antigen is present. The occurrence of ankylosing spondylitis is over 30 times higher in patients with ulcerative colitis compared to the general population. No correlation between the advancement of lesions in the joints and that of the lesion of the large intestine has been shown. The clinical manifestations of AS involve pain and stiffness in the lumbar spine, in particular in the morning or after a period of rest. The disease is progressing and is characterised by periods of relapse. It may lead to significant impairment of mobility. First-line treatment involves physiotherapy and in some cases immunosuppressants. *Sacroiliitis* occurs in around 14% of patients with inflammatory bowel disease but is mildly symptomatic in 90% of cases. There is no link between sacroiliitis and the activity of intestinal disease. The course is often asymptomatic, and the condition is diagnosed incidentally during radiological tests. The treatment involves sulfasalazine, analgesics, and physiotherapy. *Fibromyalgia syndrome* affects soft tissues, and its clinical manifestations are typical of the area affected. The most frequent symptoms are muscular pain and pain in the areas of tendon insertion points, for example, within the shoulder girdle, elbow joints, pelvis, knee joints, and rib attachments. In the physical examination, tenderness of the tendon insertion points is noticeable (tender points). The treatment involves anti-inflammatory and analgesic medication, as well as regular physiotherapy [1–6, 21–24].

#### **7. Opthalmological manifestations (1%)**

Ophthalmological manifestations concern mainly patients with ulcerative colitis, with the whole area of the large intestine affected and accompanying lesions in the joints. They occur in 6–60% of patients with IBD, almost twice as frequently in men as in women. These complications are typically one-sided, and their presence is linked with the activity of the primary condition. The most common ones involve watering eyes, burning eyes, pain in the eyes, light sensitivity, conjunctival hyperaemia, scleral hyperaemia, impaired visual acuity, or complete vision loss. Ophthalmological complications may also be asymptomatic. Inflammation may develop in any part of the eye. Episcleritis, together with uveitis is the most common ophthalmological complication of inflammatory bowel disease. Less frequent conditions include iritis

*Complications of Ulcerative Colitis in Children DOI: http://dx.doi.org/10.5772/intechopen.102080*

scleritis, keratitis, and conjunctivitis. Among complications related to the treatment of IBD, cataract is often observed, which is probably linked to the prolonged use of glucocorticoids.

*Iritis*. It presents with blurred vision, headache and pain in the eye, photophobia, and irritated conjunctiva. *Uveitis*. Its course is often insidious and chronic. The clinical manifestations involve painful eyes, blurred vision, photophobia, and/or headaches. This disease occurs four times more frequently in women. In the physical examination, inflammatory lesions are concluded in the front area of the uvea, corneal opacity, and/or conjunctivitis. Lesions are usually both-sided. In 75% of patients arthritis also occurs. The treatment involves glucocorticoids, used topically and systemically. *Episcleritis*. Its course may be asymptomatic (2–5%) or may present as burning and sore eyes. The physical examination shows vascular injection of the ciliary body and visible inflammation in the episclera. The treatment involves treating the primary disease and topical steroids. *Cataract*. May be linked with the use of glucocorticoids.

Rare opthalmological complications are as follows:


#### **8. Haematological complications**

Anaemia concerns almost 30% of patients with IBD. It significantly affects the quality of life. Chronic blood loss, impaired absorption, and the impact of cytokines play an important role. Similarly, the applied treatment, involving sulfasalazine, methotrexate, and azathioprine also contributes to the condition. In the treatment of anaemia linked to ulcerative colitis, an early therapeutic intervention that is suited to the deficiencies and activity of the intestinal disease is extremely important.

Hypochromic anaemia is caused by microhaemorrhages within the gastrointestinal tract and ongoing inflammation. Anaemia caused by B12/folic acid deficiency includes autoimmune haemolytic anaemia and thrombocytopenia/thrombocytosis [1–6, 25–27].

#### **9. Osteoporosis/osteopenia**

Reduced bone mineral density has a complex mechanism and is related to deficiencies in protein and calories, abnormal absorption of calcium, vitamin D deficiency, glucocorticoid therapy, and the adverse impact of proinflammatory cytokines (TNF-alpha, IL-1alpha, IL-1Beta, and IL-6) on the bone tissue metabolism. Osteoporosis occurs in approximately 15% of patients with inflammatory bowel disease. Osteoporosis and osteopenia develop particularly often in patients with co-existing sclerosing cholangitis, probably as a result of the abnormal transportation and absorption of bile acids. It has been shown that patients with IBD statistically significantly more often experience fractures of long bones and the corpus vertebrae.

Densitometry is a screening test and should be performed in particular in groups of patients with severe IBD, especially treated with glucocorticoids [1–6].

#### **10. Nephrological complications**

In patients, especially in paediatric ones, the calcium obtained from food interacts with unabsorbed fatty acids. This leads to an increase in urine oxalate excretion, and significantly increases the risk of urolithiasis. Some studies concerning IBD mention cases of glomerulonephritis caused by concentrations of immune complexes in patients affected. Recurring urinary tract infections, hydronephrosis, and renal amyloidosis are reported relatively more frequently compared to the general population.

*Urolithiasis*. Occurs particularly often in patients with Lesniowski-Crohn disease and with the affected small intestine or following its resection. It develops as a result of calcium-binding with unabsorbed fatty acids.

*Interstitial nephritis*. Also known as tubulointerstitial nephritis is an inflammation process that develops mainly in the areas of the kidney other than the glomeruli. Those areas, that is, the renal interstitium and renal tubules become infiltrated with inflammatory cells, which leads to abnormal renal functions. The symptoms of acute interstitial nephritis may occur from the 1st day to over 2 months (on average within 3 weeks) after the triggering factor (e.g., the intake of new medication). The most common manifestations include fever and pain within the lumbar area. Chronic interstitial nephritis may be asymptomatic for many years. *Glomerulonephritis* is a group of diseases characterised by the inflammation of the glomeruli, which impairs normal kidney functions. Inflammatory cells (lymphocytes and leukocytes) and antibodies concentrate within the glomeruli that trigger the hyperplasia of the normal glomerular cells. If the inflammation is chronic, the glomeruli become fibrotic over time, and this leads to renal failure. *Infections of the urinary tract*. Frequently recurring cystitis; E.coli being the most frequently isolated pathogen. *Hydronephrosis is* caused by the obturation of the ureter by inflammatory lesions within the abdominal cavity. Renal amyloidosis [1–6, 28–30].

#### **11. Cardiological complications**

Pericarditis, including drug-induced; sulfasalazine/mesalazine [1–6, 31, 32]. Myocarditis occurs in patients with ulcerative colitis twice as frequently as in the healthy population.

#### **12. Pulmonary complications**

The following occur with a greater frequency—pulmonary vasculitis, chronic bronchitis and bronchiolitis, and bronchiectasis (more extensive and more rapidly developing compared to those of another aetiology). It is sometimes difficult to determine whether the pulmonary lesions are an extraintestinal manifestation or independent comorbidity. *Interstitial pneumonia*. Interstitial lung diseases are characterised by progressive damage to the architecture of the alveoli and the lungs, which leads to the loss of normal pulmonary functions.

Drug-induced pulmonary complications are as follows:


Opportunistic infections. Infections with Mycobacterium tuberculosis, Pneumocystis carini, Listeria monocytogenes, Aspergillus fumigatus, Histoplasma capsulatum, and Cytomegalovirus.

The pulmonary lesions are usually either asymptomatic or oligosymptomatic. Pulmonary function tests show abnormalities in over 40% of patients. The classic thoracic X-ray in the majority of patients is non-characteristic. A High-resolution CT scan, on the other, is a helpful diagnostic tool.

Also, patients with inflammatory bowel disease develop asthma more often [1–4, 33, 34].

#### **13. Arterial/vein thrombosis**

Occurs 3–4 times more often in patients with inflammatory bowel disease compared with the healthy population. The frequency of occurrence increases with age and concerns 2–10% of patients with IBD. Vein thrombosis is the dominant condition. The treatment involves low molecular weight heparin.

Types of thrombosis are as follows:


The significance of these complications are mainly due to the young age of the affected patients, a large percentage of deaths and complex treatment (the use of anticoagulants in patients with gastrointestinal bleeding). It is often recurring. Vein thrombosis in the course of IBD is characterised by the atypical location of the thrombotic lesions, correlates with the activity of the intestinal disease and has a proven link with the use of glucocorticoids. Active intestinal disease with thrombocythaemia and increased activity of blood coagulation factors, as well as an increase in the concentration of homocysteine, are additional factors contributing to the development of

thrombosis. Thromboprophylaxis should be adopted in patients with medium/acute exacerbation of inflammatory bowel disease [27].

#### **14. Neurological complications**


Vascular lesions in the central nervous system occur equally frequently in patients with ulcerative colitis and those with Crohn's Disease. They usually develop 5–6 years following the onset of the intestinal disease and often coincide with other extraintestinal manifestations of IBD [1–6, 35, 36].

### **15. Summary**


### **Author details**

Sabina Wiecek Faculty of Medical Sciences, Department of Paediatrics, Medical University of Silesia, Katowice, Poland

\*Address all correspondence to: sabinawk@wp.pl

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Complications of Ulcerative Colitis in Children DOI: http://dx.doi.org/10.5772/intechopen.102080*

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[24] Engelhard S, Bajwa A, Reddy A. Causes of uveitis in children without juvenile idiopathic arthritis. Clinical Ophthalmology. 2015;**25**(9):1121-1128. DOI: 10.2147/OPTH.S83950

[25] Krzesiek E, Flis A, Iwańczak B. Frequency of anemia in ulcerative colitis in children. Polski Merkuriusz Lekarski. 2012;**33**(195):138-142

[26] Chaubal A, Pandey V, Choksi D, et al. Anemia in patients with ulcerative colitis in remission: A study from western India. Indian Journal of Gastroenterology. 2017;**36**(5):361-365. DOI: 10.1007/ s12664-017-0791

[27] Jaqua N, Stratton A, Yaccobe L, et al. A review of the literature on three extraintestinal complications of ulcerative colitis: An ulcerative colitis flare complicated by Budd-Chiari syndrome, cerebral venous thrombosis and idiopathic thrombocytopenia. Acta Gastroenterologica Belgica. 2013;**76**(3):311-316

[28] Corica D, Romano C. Renal involvement in inflammatory bowel disease. Journal of Crohn's & Colitis. 2016;**10**(2):226-235. DOI: 10.1093/ ecco-jcc/jjv138

[29] Ambruzs J, Larsen C. Renal manifestation of inflammatory bowel disease. Rheumatic Diseases Clinics of North America. 2018;**44**(4):699-714. DOI: 10.1016/j.rdc.2018.06.007

[30] Tokuyama H, Wakino S, Konishi K, et al. Acute interstitial nephritis associated with ulcerative colitis. Clinical and Experimental Nephrology. 2010;**14**(5):483-486. DOI: 10.1007/s10157-010-0294-

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*Complications of Ulcerative Colitis in Children DOI: http://dx.doi.org/10.5772/intechopen.102080*

[32] Caio G, Lungaro L, Caputo F, et al. Recurrent myocarditis in a patient with active ulcerative colitis: A case report and review of the literaturę. BMJ Open Gastroenterology. 2021;**8**(1):e000587. DOI: 10.1136/bmjgast-2020-000587

[33] Majewski S, Piotrowski W. Pulmonary manifestations of inflammatory bowel disease. Archives of Medical Science. 2015;**11**(6):1179-1188. DOI: 10.5114/aoms.2005.56343

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[36] Scheid R, Teich N. Neurologic manifestations of ulcerative colitis. European Journal of Neurology. 2007;**14**(5):483-493. DOI: 10.1111/j.1468- 1331.2007.01718.x

## Section 3 Diagnosis of Ulcerative Colitis

#### **Chapter 4**

## Histomorphological Diagnosis of Ulcerative Colitis and Associated Conditions

*Jera Jeruc*

#### **Abstract**

Ulcerative colitis (UC) is a chronic, idiopathic inflammatory disease that affects mainly young adults. The histologic examination of endoscopic biopsies or resection specimens plays an important part in the diagnosis and follow up of patients with inflammatory bowel disease, including UC. In this chapter, we discuss on main histological features that can be used when analyzing endoscopic biopsies, as well as features that can be evaluated in surgical samples of patients with UC. The differential diagnosis toward Crohn's disease and other mimickers is emphasized. In addition, the main complications associated with treatment and long-standing diseases, such as infection colitis and dysplasia are presented.

**Keywords:** ulcerative colitis, histology, biopsy, inflammatory bowel disease, inflammatory bowel disease-associated dysplasia, chronic active colitis, cryptitis, crypt abscess, CMV colitis, differential diagnosis, complications

#### **1. Introduction**

Ulcerative colitis (UC) is a chronic, idiopathic inflammatory disease that affects mainly young adults with no sex predominance. Its incidence is rising worldwide and is higher in developed countries [1–3].

The disease is characterized by relapsing and remitting mucosal inflammation, starting in the rectum and extending to proximal segments of the colon. Clinically, UC usually presents with chronic bloody diarrhea. Extraintestinal manifestations, including peripheral arthritis, primary sclerosing cholangitis, and pyoderma gangrenosum occur in about a third of patients [4, 5].

The diagnosis of UC is based on a combination of clinical presentation, endoscopic findings, histology, and the exclusion of alternative diagnoses. The histopathological examination of biopsy specimens is fundamental, not only for making a specific diagnosis but also in determining the state of disease activity and evaluating the prospect of healing and risk of relapse [6]. Even further, histology is essential in assessing the response to treatment and diagnosing complications of treatment and longstanding UC, such as dysplasia and cytomegalovirus (CMV) infection.

#### **2. Histological characteristics of UC**

For a reliable diagnosis of IBD, at least two endoscopic biopsies each should be taken from at least five sites along the ileum, colon, and rectum [7–11]. The histological features of UC include non-active inflammation, active inflammation, structural changes, and epithelial abnormalities [5, 8]. The inflammation is concentrated in the mucosa, only occasionally the inflammation may spread into the superficial part of the submucosa.

Non-active inflammation includes the presence of lymphocytes and plasma cells in the lamina propria that could be associated with edema and hyperemia. Apart from areas of ulceration, the inflammatory infiltrate in untreated UC is limited to the mucosa, diffuse or continuous without any variations in intensity or skip lesions, and its severity increases characteristically toward the rectum [5, 12, 13]. When three or more plasma cells accumulate in the mucosal lamina propria around the crypt base or between the crypt base and the muscularis mucosae, a condition is termed basal plasmacytosis [11, 14]. This phenomenon is observed already in biopsies obtained at early onset, sometimes it is the first lesion to appear. Although limited and focal in the initial phase of UC, it later spreads to more colonic segments [15, 16]. The occurrence of eosinophils in the lamina propria, between the crypts, and within the muscularis mucosae, has been associated with aggressive disease and a high risk of relapse [17].

Active inflammation is defined by the presence of neutrophils in the lamina propria, crypts, or surface epithelium. The term cryptitis is used when neutrophils are found penetrating the crypt epithelium, and crypt abscess is a term describing neutrophils occupying the crypt lumens [11]. Neutrophils infiltrating the surface epithelium lead to mucosal erosions or ulcerations, on the other hand, cryptitis and crypt abscesses are associated with crypt destruction, all features of structural changes of the mucosa [8, 18].

Structural changes of the mucosa include crypt distortion and changes in surface topography (surface irregularity). Chronic inflammation leads to irregular size and shape of crypts (e.g., branching and shortening), irregular distribution of the crypts in the lamina propria, and crypts with loss of parallelism. Crypt atrophy is defined as shortened crypts, accompanied by an increased layer of lamina propria stroma between the crypt basis and the muscularis mucosae [5, 11, 19, 20]. Irregular mucosal surface or pseudovillous transformation means wide crypt mouths giving the mucosal surface a finger-like appearance [15].

Epithelial abnormalities include surface epithelial damage, metaplastic changes, and mucin depletion. Surface epithelial damage, such as flattening, focal cell loss, erosions, and ulcers reflect the activity of the disease. Ulcers in UC colitis are always associated with mucosal inflammation in contrast with Crohn's disease, in which the surrounding mucosa can appear uninflamed [5]. In addition, UC ulcerations tend to be more superficial, broad based and continuous [21]. In severe disease, these ulcers may undermine the adjacent mucosa, finally resulting in denudation of the mucosal surface or deep penetration through the muscularis mucosae [8]. Extensive ulceration with sparing of remaining mucosal islands may give rise to inflammatory pseudopolyps, which are common in the sigmoid and descending colon, but rare in the rectum [9, 20]. Hypertrophy of the muscularis mucosae and submucosal fibrosis is rarely identified in UC [22]. Paneth cell metaplasia, a term used when pyramidal crypt epithelial cells with supranuclear eosinophilic granular cytoplasm are present in the transverse and left

*Histomorphological Diagnosis of Ulcerative Colitis and Associated Conditions DOI: http://dx.doi.org/10.5772/intechopen.102364*

#### **Figure 1.**

*Diffuse continuous inflammation with basal plasmacytosis, active inflammation with cryptitis, and structural changes including crypt distortion and atrophy. An erosion is present on the far right.*

#### **Figure 2.**

*Cryptitis and crypt abscess are shown on the left, while on the right Paneth cell metaplasia and cryptolytic granuloma are present.*

colon [11], is an epithelial abnormality that can help in the diagnosis of long-standing UC [16, 19, 23]. Mucin depletion, defined as a reduction in number of goblet cells or depleted mucin within cells is additional epithelial abnormality frequently encountered in UC [11]. Characteristic histological features are shown in **Figures 1** and **2**.

#### **3. Distribution of changes in UC**

UC generally begins in the rectum, extending proximally in a continuous, circumferential pattern. The inflammatory infiltrate is diffuse or continuous without any variations in intensity and its severity increases characteristically toward the rectum. There are no skip-areas characteristics for Crohn's disease. The demarcation between inflamed and normal mucosa is sharp, although histological inflammation can be found in normal-appearing mucosa [22, 24]. Based on the spread of disease, three subtypes of UC are distinguished in Montréal classification—ulcerative proctitis where the proximal extent of inflammation is distal to the rectosigmoid colon, leftsided colitis, and extensive colitis when involvement extends proximal to the splenic flexure. The later also includes pancolitis [7, 25].

However, unusual inflammation patterns can occur, such as rectal sparing, cecal patch, and backwash ileitis. Rectal sparing should not be interpreted as evidence of Crohn's disease, as it can be the result of topical or systemic medications. The rectum may be spared in some adults with fulminant colitis [26, 27]. In up to 75% of patients with left-sided UC an isolated area of inflammation around the appendiceal orifice can be appreciated; this association is referred to as cecal patch [28]. In some patients with pancolitis, the ileum too is affected by acute or chronic inflammation. This condition has been termed "backwash ileitis" [29]. The ileal lesions in "backwash ileitis" are characterized by active inflammation in the villi and lamina propria, together with shortening and blunting of the villi. Focal erosions, mucous gland metaplasia, or patchy edema with mild active inflammation are features suggestive of Crohn's disease [29, 30].

#### **4. Histological changes in different stages of the disease**

UC is a chronic disease with the relapsing-remitting course and histological alterations are changing during the course of the disease. They are further influenced by medical treatment. In early-stage disease, the diagnosis of UC can be challenging due to the fact, that crypt architecture may still be preserved [17]. In longstanding disease, with widespread architectural crypt distortion and increased cellularity of the lamina propria the diagnosis of UC is more obvious. However, in this situation, rectal sparing, cecal patch, and backwash ileitis can be found that should not lead to misdiagnosis. Under treatment, the extent of involvement of the colon tends to decrease and the distribution pattern may change from diffuse (continuous) to patchy (discontinuous). Complete restoration of the rectal mucosa can be found in 34–44% of patients [5, 18]. In quiescent (clinically inactive) disease neutrophils are not observed, the mucosa may look nearly normal, however, some features, related to chronic mucosal injuries, such as architectural abnormalities, reduced crypt density, and basal plasmacytosis remain [13] (**Figure 3**). Histological mucosal healing is characterized by the resolution of crypt architectural distortion and inflammatory infiltrate. Nevertheless, the mucosa can still show some features of sustained damage, such as decreased crypt density with branching and shortening of crypts.

*Histomorphological Diagnosis of Ulcerative Colitis and Associated Conditions DOI: http://dx.doi.org/10.5772/intechopen.102364*

**Figure 3.** *Crypt architectural distortion and hypocellular stroma in quiescent disease.*

#### **5. Histologic disease activity**

Assessment of disease activity is essential for developing and determining appropriate therapy in patients with UC. Disease activity and treatment response can be assessed using symptoms, biomarkers, endoscopy, and histology. Currently, clinical decision-making is predominantly based on clinical and endoscopic measures. Recently, histology has been recognized as an important prognostic factor and potential treatment target in patients with UC [31]. Both, epithelial damage in association with neutrophils and basal plasmacytosis have been proposed as markers of disease activity and the prediction of relapse. A recent meta-analysis revealed that histological remission was associated with lower rates of clinical relapse compared with those with histological activity and was a superior predictor of clinical relapse compared with endoscopic and clinical remission [32]. Furthermore, the presence of mucosal inflammation during follow-up in patients with UC was associated with a greater risk of subsequent colorectal neoplasia than in those with mucosal healing [33].

Histologically, the level of activity and the stage of the disease (e.g., flaring vs. quiescent UC) can be assessed by different scoring systems. Although more than 30 histological scoring systems in UC have been described, three have undergone extensive validation—the GS, Nancy Index, and Robarts Histopathologic Index [31, 34]. Recently a new consensus-based scoring index has been proposed, intended for both clinical practice and clinical trials that still needs to be validated [10]. Although these are not applied routinely, the pathology report should include some information on the level of activity in the biopsies to assess the effect of therapy and the risk of relapse. Pai [31] recommends that pathologists classify UC biopsies into 1 of 5 categories: normal colonic mucosa, quiescent chronic colitis without basal plasmacytosis, quiescent chronic colitis with basal plasmacytosis, chronic active colitis without basal plasmacytosis, or chronic active colitis with basal plasmacytosis. If present, active inflammation should be graded. Assessing the degree of activity should be carried out on the worst affected biopsy sample [10].

#### **5.1 Fulminant UC**

Fulminant colitis is a term used for clinically acute severe colitis, usually involving the entire large bowel, often associated with systemic illness and sometimes accompanied by colonic dilatation (toxic megacolon). It is a well-recognized mode of presentation of UC that typically requires surgical resection [35]. In fulminant UC resections show mainly acute features (**Figure 4**), while chronic changes are rarely present. With the absence of the part of classical histological changes characteristic of UC both, identification and subclassification of inflammatory bowel disease can be very difficult.

In fulminant colitis, the macroscopic appearance of the mucosa is not sufficiently distinct to differentiate UC from Crohn's disease and serositis may be observed [27, 36]. In parallel, fulminant colitis caused by UC may show Crohn's-like histological features, such as deep ulcers, transmural inflammation, and rectal sparing. There may

#### **Figure 4.**

*Surgical resection of the colon from a patient with fulminant UC. Sharp demarcation from macroscopically normal terminal ileum is apparent (arrow).*

*Histomorphological Diagnosis of Ulcerative Colitis and Associated Conditions DOI: http://dx.doi.org/10.5772/intechopen.102364*

be deep ulcerations, typically eroding down to muscularis propria in a broad-based fashion. The transmural inflammation in this setting is typically more active and diffuse, lacking discrete lymphoid aggregates. This finding does not preclude a diagnosis of UC. In a study by Swan, the two most specific predictors of a final diagnosis of Crohn's disease were granulomas and transmural lymphoid aggregates, macroscopic features were unhelpful [27]. Apparent rectal sparing is also recognized in fulminant UC, where inflammation of the transverse colon is so severe as to make the rectum look comparatively spared [37].

#### **6. Histological mimickers of UC**

The main histological feature of UC is chronic active inflammation. In addition to Crohn's disease, many conditions can mimic UC on mucosal biopsies. Besides being familiar with histological features of a wide range of diseases and conditions that can be included in the differential diagnosis, a knowledge of the clinical, endoscopic, and in some cases even imaging features is required for the pathologist to come to the right conclusion. It is, therefore, recommended that the pathologist has access to the endoscopy report and possibly also radiological and microbiological investigations [21, 22]. Some more common mimickers are addressed in the following section.

#### **6.1 Crohn's disease**

Although Crohn's and UC are frequently discussed together under the term chronic inflammatory bowel disease, distinguishing UC from Crohn's is nevertheless important. One of the reasons is that only patients with UC are considered for ileal pouch formation, because of the high risk of complications after this procedure in patients with Crohn's disease. The most common macroscopic and microscopic features distinguishing UC from colonic Crohn's disease are listed in **Table 1**. Although non-caseating epithelioid granulomas are considered a classical feature of Crohn's disease, the presence of granulomas associated with cryptolysis are now well recognized in UC and their presence should not exclude the possibility of UC [21, 38] (**Figure 2**). Rectal sparing, cecal patch, and ileal disease, all features of UC that might suggest the diagnosis of Crohn's disease were discussed in one of the previous sections. Treatment of UC can also result in patchy disease, that is, a change from continuous to discontinuous inflammation and should not lead to reclassification to Crohn's disease [26]. Transmural inflammation, another classical feature of Crohn's disease may be encountered in fulminant UC [27]. Compared to surgical resection samples, the confident distinction of UC from Crohn's disease is even more challenging in endoscopic biopsy samples where only mucosal and limited submucosal tissue is sampled. When convincing features of chronic inflammatory bowel disease are evident, but further classification is not possible, the diagnostic term inflammatory bowel disease, unclassified (IBDU) is used [5, 22].

#### **6.2 Infective colitis**

Infective colitis is one of the most important differential diagnoses of chronic inflammatory bowel disease including UC since the steroid therapy used for treating inflammatory bowel disease can have adverse results in patients with infective colitis.


#### **Table 1.**

*Classical microscopic and macroscopic characteristics of ulcerative colitis and Crohn's disease.*

One of the most common inflammatory patterns in enteric infections is the so-called nonspecific acute self-limited colitis that characteristically features intact crypt architecture with neutrophilic infiltrates of the surface epithelium. Basal plasmacytosis should not be seen as this is a marker of chronicity [39]. However, crypt abscesses and cryptitis may be present in the acute phase. As patients often do not come to endoscopy until several weeks after onset of symptoms, pathologists frequently do not see the classic histological features of acute infectious-type colitis. The protracted course of colitis, which may be seen for example in Campylobacter infections or shigellosis is more challenging to diagnose histologically as the development of "chronic" features such as crypt destruction and architectural disturbance may resemble inflammatory bowel disease including UC [40]. Extensive involvement of the surface mucosa by neutrophils is not often seen in inflammatory bowel disease and should alert the pathologist to the possibility of infection or toxin-induced injury [40]. In contrast, basal plasmacytosis, one of the earliest features of UC, crypt distortion, and irregular mucosal surface favor inflammatory bowel disease over infection [16, 19, 41]. However, in patients with early-onset UC (within 10 days of symptoms) structural changes may not yet be present [5, 42].

Lymphogranuloma venereum (LGV) and syphilis are sexually transmitted diseases caused by Chlamydia trachomatis and Treponema pallidum, respectively.

#### *Histomorphological Diagnosis of Ulcerative Colitis and Associated Conditions DOI: http://dx.doi.org/10.5772/intechopen.102364*

LGV and syphilitic proctitis are usually reported in men who have sex with men and can clinically mimic UC [43]. Histologically, both infections are characterized by an intense lymphohistiocytic infiltrate associated with prominent plasma cells within the mucosa and submucosa but minimal basal plasmacytosis. Characteristically, the associated acute inflammation with cryptitis and crypt abscesses is only mild to moderate. Crypt distortion and granulomas are minimal as well and Paneth cell metaplasia is rare [19, 43, 44]. Specific antibodies for T. pallidum are available that work well on paraffin-embedded tissue, however, real-time polymerase chain reaction on rectal swab specimens is the most reliable diagnostic test [43].

In addition to infections mimicking UC, in treated patients with clinical deterioration, superimposed infection, particularly CMV and Clostridium difficile should be considered [45, 46].

In some cases, diagnosis of infectious colitis is not possible on histological grounds alone. It is, therefore, vital to exclude infection by stool culture. In addition, a detailed clinical history addressing intestinal and extraintestinal symptoms, travel history, sexual history, and conditions influencing immune status should be collected [41].

#### **6.3 Drug-induced colitis**

Drug-induced colitis can show several histological patterns, one of them being a UC-like pattern with diffuse inflammation and ulceration. Histological features that favor drug-induced etiology include significant eosinophilic infiltrate, epithelial apoptosis, melanosis, cytoplasmic vacuolation, and increased intraepithelial lymphocytes [39].

Recently several monoclonal antibodies targeting immune checkpoint molecules became available for the treatment of advanced neoplasms. These immune checkpoint inhibitors (ICIs) induce immune activation and robust antitumor T-cell activity and can greatly improve survival. Following the administration of ICIs, immune-mediated adverse events including enterocolitis that can be severe are common [41, 47]. Microscopic features of ICI colitis include mixed inflammation of the lamina propria, cryptitis, crypt abscesses, crypt destruction, and granulomas [48] (**Figure 5**). In cases of distal distribution or pancolitis they may suggest UC. In ICI colitis crypt distortion, if present, is usually mild. Atrophic crypts often show marked attenuation of crypt epithelium and contain luminal apoptotic debris admixed with inflammatory cells [49]. If ICI colitis recurs, there may be chronic features such as basal lymphoplasmacytosis, crypt architectural irregularity, and Paneth cell metaplasia. Apoptosis and lymphocyte-mediated epithelial damage at the base of crypts favor ICI colitis, whereas severe inflammation, severe crypt distortion, and basal plasmacytosis favor UC [41, 50].

#### **6.4 Segmental colitis associated with diverticulosis**

Segmental colitis associated with diverticulosis (SCAD) is chronic colitis that is confined to the colonic segment containing diverticula [51]. By definition, the rectum and proximal colon are spared from inflammation [51]. SCAD is histologically characterized by a transmucosal chronic inflammation associated with crypt distortion, cryptitis, crypt abscesses, goblet cell depletion, basal plasmacytosis, or granulomas (UC-like or Crohn's disease-like pattern)[52]. However, these features are exclusively distributed in the sigmoid tract with sparing of the rectal and distal colonic mucosa [52–54]. Thus, for a correct diagnosis, it is fundamental to know the exact biopsy site

*Ulcerative Colitis - Etiology, Diagnosis, Diet, Special Populations, and the Role of Interventional…*

#### **Figure 5.**

*Colitis associated with ICIs showing diffuse chronic inflammation with cryptitis and crypt abscesses without crypt distortion and basal plasmacytosis.*

and to compare the morphology of the sigma and rectum in the differential diagnosis with IBD. In addition, patients with SCAD tend to be older compared to inflammatory bowel disease patients.

### **7. Associated conditions with ulcerative colitis**

#### **7.1 UC with primary sclerosing cholangitis**

Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease, characterized by the inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts, leading to the formation of multifocal bile duct strictures [55]. It is frequently associated with other diseases and a classic extraintestinal manifestation of IBD. The diagnosis of PSC may precede diagnosing the patient with IBD but can present even after colectomy in IBD patients [56]. The course of UC differs significantly when PSC is present; the most notable differences are the presence of more extensive but colitis showing lower activity. It is also more often associated with rectal sparing and socalled backwash ileitis compared with patients with UC without primary sclerosing cholangitis [56]. Another important issue is the higher incidence of carcinomas in the PSC-UC patients [56, 57].

#### **7.2 Histological evaluation after previous surgery**

Absolute indications for surgery in UC patients include uncontrolled hemorrhage, perforation, and colorectal carcinoma or dysplastic lesions not amenable

#### *Histomorphological Diagnosis of Ulcerative Colitis and Associated Conditions DOI: http://dx.doi.org/10.5772/intechopen.102364*

to endoscopic removal. Surgery is also indicated in refractory acute severe UC or medically refractory disease [1]. The most commonly performed surgery for UC is restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) [58].

Adaptive changes of the pouch mucosa ("colonic metaplasia") are present several months after surgery in up to 87% of biopsies and consist of villous atrophy, crypt hyperplasia, and infiltration of the lamina propria by mononuclear cells, eosinophils, and histiocytes. In addition, mild ischemic changes can be observed in a few patients, while others may show features of mucosal prolapse. These changes should not be regarded as evidence of pouchitis. True pouchitis is associated with increased villous atrophy, acute and/or chronic inflammatory infiltrates, cryptitis, crypt abscesses, and ulceration [20, 59]. Based on the etiology pouchitis can be subdivided into idiopathic and secondary. Secondary pouchitis can occur in up to 30% of cases and can be classified as infectious (CMV, candida), ischemic, nonsteroidal antiinflammatory drugsinduced, collagenous, autoimmune-associated, or Crohn's disease [59]. Histology has a limited role in the evaluation of pouchitis; the main purpose for histology evaluation of the pouch is the exclusion of secondary pouchitis and dysplasia [60]. The diagnosis and differential diagnosis of pouchitis should be based on a combination of clinical, endoscopic, and histological findings [61].

When pouch biopsies show severe inflammation with neutrophils within the lamina propria and epithelium associated with erosions and ulcerations this should not lead to the reclassification into Crohn's disease. Even deep submucosal lymphoid aggregates and fistulous tracts were found in pouches excised from UC patients. A diagnosis of Crohn's disese after IPAA surgery should only be made when reexamination of the previous histological specimens shows typical pathologic features of Crohn's disese [62].

Pouchitis should be distinguished from cuffitis, which is inflammation in the columnar cuff mucosa distal to the pouch. After the IPAA procedure patients might often have residual rectal tissue, referred to as a rectal cuff, at the anastomosis between the ileum and anal canal. This area can become inflamed due to an exacerbation of UC leading to cuffitis [8, 60].

#### **7.3 Cytomegalovirus infection and UC**

In patients with UC, the risk for reactivation of latent cytomegalovirus (CMV) infection is a common complication, particularly in those with steroid-resistant disease [45]. On routine H&E stained slides, CMV typically presents as large cells, two- to four-fold larger than normal, with large amphophilic intranuclear inclusions, surrounded by a clear halo, and smaller cytoplasmic inclusions. However, CMV colitis in IBD patients tends to present with atypical, small viral inclusions, often lacking the characteristic owl-eye appearance, and it mostly affects endothelial cells in granulation tissue in ulcers [45, 63]. Therefore, CMV reactivation should be actively sought in all patients with severe colitis refractory to immunosuppressive therapy and on biopsies with prominent granulation tissue associated with large ulcers. Because the infected cells are usually scarce on limited biopsy material and morphologically less characteristic they may be missed on routine H&E stains. Immunohistochemistry, using monoclonal antibodies directed against CMV immediate early antigen, increases the diagnostic yield in comparison with H&E staining. Semiquantitative immunohistochemistry, reporting the number of infected cells and/or the number of CMV positive biopsy fragments, may have a predictive value [64].

#### **7.4 Colitis cystica profunda**

Colitis cystica profunda (CCP) is a rare benign condition characterized by cystic dilatation and misplacement of mature crypts through the muscularis mucosae into the submucosa and/or deeper layers of the bowel wall. It is a complication of various conditions including inflammatory bowel diseases, more commonly UC [65]. The condition usually affects the rectum and sigmoid colon, though it may diffusely involve the entire large bowel. It is believed to be the result of misplacement and entrapment of regenerating glands during healing. With gland formation extending deep into the bowel wall, it can be easily misdiagnosed as adenocarcinoma, particularly in endoscopic biopsies. Features favoring the diagnosis of CCP over cancer include multiple lesions, intact mucosa on the surface and no atypia on histology. Special care must be taken not to over-diagnose regenerative atypia as a well-differentiated adenocarcinoma [66].

#### **7.5 Mucosal dysplasia and colon cancer**

It has long been known that the risk of colorectal carcinoma in patients with colonic IBD is greater than in the general population [67, 68]. Recent populationbased cohort studies indicate that current treatment approaches and surveillance measures have markedly reduced the risk making it more comparable to that of the general population [69]. Colorectal cancer risk, however, remains elevated in certain populations, such as those with young age at onset, long duration of disease, extensive and uncontrolled inflammation, and those with primary sclerosing cholangitis or family history of colorectal cancer [70].

Mucosal dysplasia is the best and most reliable marker of an increased risk of malignancy in patients with UC [70, 71]. Dysplasia should be distinguished into low and high degrees, using the architectural and cytological criteria of the World Health Organization [72]. In low-grade dysplasia, crypt architecture shows minimal distortion. Cytologically, the nuclei have slight hyperchromasia and the nuclear membrane has irregular edges. High-grade dysplasia is characterized by greater architectural complexity and marked nuclear pleomorphism, irregular nuclear membranes, and macronucleoli. There is more nuclear crowding and overlapping, and consequently greater nuclear stratification. Cytoarchitectural alterations not meeting the above-mentioned criteria that can also not be attributed to regeneration secondary to inflammation or medical procedure are considered "indefinite for dysplasia."

Dysplasia related to UC develops in areas with chronic inflammation and is often multifocal. Dysplasia and neoplastic lesions in UC can often be non-polypoid, flat, or ill-defined. Flat dysplasia is not endoscopically visible and can be detected microscopically in random biopsies from unremarkable mucosa. For that reason, many biopsies are performed in patients at risk to increase detection of neoplasia. The interobserver variability for dysplasia is high among pathologists, particularly for low-grade and indefinite dysplasia, making this field one of the most challenging in gastrointestinal pathology [73]. Therefore, confirmation of dysplasia by a pathologist with expertise in gastrointestinal pathology has been recommended [22]. Although discussed in past recommendations [22], recent recommendations do not encourage the use of p53 immunohistochemistry for detecting and discriminating dysplasia (**Figure 6**) [6, 8, 11].

*Histomorphological Diagnosis of Ulcerative Colitis and Associated Conditions DOI: http://dx.doi.org/10.5772/intechopen.102364*

**Figure 6.** *Low-grade dysplasia in a patient with longstanding active UC (left) showing p53 positivity (right).*

#### **8. Conclusion**

UC is a complex disease that requires a multidisciplinary approach. Histological evaluation of biopsies and resection specimens from the gastrointestinal tract plays a vital part in the management of UC patients. Despite the evolution of advanced endoscopic procedures that help in a detailed assessment of mucosa recent studies have confirmed the value of histology in predicting clinical outcomes.

#### **Conflict of interest**

The author declares no conflict of interest.

*Ulcerative Colitis - Etiology, Diagnosis, Diet, Special Populations, and the Role of Interventional…*

### **Author details**

Jera Jeruc Faculty of Medicine, Institute of Pathology, University of Ljubljana, Ljubljana, Slovenia

\*Address all correspondence to: jera.jeruc@mf.uni-lj.si

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Histomorphological Diagnosis of Ulcerative Colitis and Associated Conditions DOI: http://dx.doi.org/10.5772/intechopen.102364*

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#### **Chapter 5**

### The Role of the Pathologist in Ulcerative Colitis

*Gayana Mahendra and Janaki Hewavisenthi*

#### **Abstract**

Pathologists have an essential and wide role in the management of patients with ulcerative colitis (UC) which is a chronic inflammatory disorder of the bowel with remissions and relapses. The initial diagnosis of UC itself is challenging as the histological features vary widely with the clinical phase of the disease. Differentiating UC from other types of acute and chronic colitis, especially Crohn's disease is crucial in the management. Understanding the characteristic morphological features of UC as well as unusual morphological features of the disease are important in this task. The histological disease activity has now been identified as important in therapeutic decisions. There are several histological activity indices in UC and currently, the Nancy histological index has been recommended to be used in daily clinical practice. Identifying dysplasia associated with UC and its grading is a challenging task for the pathologist and it is a crucial step in the surveillance and management of this chronic disease.

**Keywords:** ulcerative colitis, histological features, diagnostic pitfalls, histological disease activity, dysplasia in ulcerative colitis

#### **1. Introduction**

Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon characterized by remissions and relapses. The disease almost always begins in the rectum and extends proximally to involve the colon. In some patients, the disease is confined to the rectum (ulcerative proctitis) and in others, the inflammation extends to a variable distance along the colon in a continuous manner. The entire colon is involved in some patients (pancolitis). The clinical presentation and the disease course vary widely amongst patients. Majority of the patients present with an acute episode that clinically mimics any of the acute colitis. The patients on surveillance could show minimal clinical symptoms and minimal histological changes during the periods of remission. Some patients have continuous low activity while some may have an initial episode of active disease followed by long periods of quiescence where the accuracy of the initial diagnosis becomes questionable [1]. Some patients present with the fulminant disease either as the first attack or in an acute exacerbation and this may lead to resection of the colon as an emergency measure.

The pathologist plays a major role in the diagnosis and the management of this chronic relapsing disease. The differing clinical presentations, the chronic relapsing and remitting nature of the disease resulting in recurrent mucosal damage and healing, and the iatrogenic interventions both medical and surgical lead to a variable pathological picture (both macroscopic and microscopic) making the pathologists task a difficult one. Therefore, the diagnosis of UC should always be a combined effort of the clinician, endoscopist, and pathologist. The pathologist should be provided with information regarding clinical symptoms, their duration, the clinical course of the disease, the treatment received by the patient, and the endoscopic appearance of the bowel.

The pathologists are called upon to play various roles during the management of UC. These include the initial diagnosis of the disease and its differentiation from the other forms of colitis and in the classification of inflammatory bowel disease (IBD) in differentiating it from Crohn disease (CD). The morphological differential diagnosis of UC is wide and depends on whether the biopsies are performed during an acute relapse, in remission, or while on treatment.

Assessment of disease activity in UC is another responsibility of the pathologist. There are various clinical and endoscopic activity indices; however, histology is considered to be the gold standard in assessing the disease activity in UC [2]. There are various activity indices used by pathologists. The selection of the activity index that is used in practice is largely determined by the preference of the reporting pathologist and the responsible clinicians [3].

Pathologists are also required to identify dysplasia associated with UC. Dysplasia is an indicator of poor prognosis in UC patients, with a high risk of evolution towards invasive colorectal adenocarcinoma in the absence of treatment. Diagnosis and classification of dysplasia in UC is a challenge to the pathologist and it is a crucial step in the surveillance and management of the patients.

Basic knowledge of the histopathology of this disease is important for clinicians managing UC to interpret and act on the information provided in the pathology report. Here, the morphological features of UC are reviewed, with an emphasis on typical features as well as atypical features that could cause diagnostic pitfalls. The challenges the pathologist faces when examining the diagnostic material at different stages of the disease are highlighted. Further, the use of histological indices for the evaluation of disease activity, identification, and grading of dysplasia associated with UC are also discussed.

#### **2. Macroscopic appearance of ulcerative colitis**

UC is characterized by diffuse, continuous inflammation without skip lesions, restricted to the rectal and colonic mucosa. The bowel is characteristically filled with blood-stained dark fluid mixed with mucus. At the onset of the disease, the mucosa shows diffuse granularity, oedema, and erythema justifying the term 'red velvety' appearance. With the progression of the disease, the mucosa becomes friable with the appearance of punctate ulcers followed by irregular broad-based ulcers of various sizes. Ulceration may undermine the mucosa creating mucosal bridges. Ulcers distributed along the long axis of the colon extending down to muscularis propria are seen in UC but not the serpentine ulcers that are characteristic of CD. These mucosal changes involve the rectum and variable lengths of the proximal colon in continuity. The distal colon is more severely diseased than the proximal colon. The margin between the inflamed and normal mucosa is distinct and abrupt.

*The Role of the Pathologist in Ulcerative Colitis DOI: http://dx.doi.org/10.5772/intechopen.102072*

#### **Figure 1.**

*Macroscopic appearance of the colon in UC showing involvement of the entire colon with ulceration and pseudopolyp formation.*

Against a backdrop of mucosal ulceration, there are islands of non-ulcerated residual and regenerating mucosa, bulging into the lumen creating inflammatory pseudopolyps which are usually small, multiple, and bizarre in shape. Sometimes these pseudopolyps could be large and may mimic malignancy (**Figure 1**) [4].

The mucosa is atrophic and smooth with the absence of mucosal folds in longstanding UC. In the quiescent stage of UC, the mucosa may appear normal or exhibit diffuse granularity and inflammatory pseudopolyps.

The extent of UC is classified according to the Montreal classification as follows [5];


#### **3. Microscopy appearance of ulcerative colitis**

For the optimum assessment of the microscopy, the pathologist should be supplied with adequate and good-quality colonoscopic biopsies. The endoscopist should obtain samples from the ileum, at least four colonic sites, and the rectum, with a minimum of two biopsies from each site [6].

Biopsies from each colonic segment should be submitted in separate containers for each colonic segment, which should be accurately labeled. This is of paramount importance as the pathologist has no means of identifying the separate colonic segments/sites based on histology. This in turn will hinder the pathologists' attempts at mapping the pattern and distribution of disease activity throughout the colon.

Samples should be fixed immediately by immersion in buffered formalin solution before transport and should be accompanied by clinical information, including endoscopic findings, duration of disease, and current treatment. It is important to sample both endoscopically normal as well as abnormal mucosa as there could be histological activity identified in even endoscopically normal mucosa [7, 8]. Proper orientation of the biopsy during tissue embedding is important as tangentially sectioned biopsies hinder the assessment of the crypt architecture. Serial sectioning is also vital as certain focal features like granulomas may appear at different levels. However, the ideal number of sections is not defined and varies with the laboratory. At least two tissue levels, and preferably three, are advisable [2]. Some laboratories produce step-sections on two slides, but this may incur extra costs. Routine staining with hematoxylin and eosin is appropriate. Special stains and immunohistochemistry are not routinely necessary for the diagnosis or classification of IBD [2].

#### **3.1 Main histological characteristics of ulcerative colitis**

The knowledge of the normal histology of the gastrointestinal mucosa is essential for the optimal interpretation of biopsy specimens in IBD. Four main histological characteristics are assessed in the diagnostic process of IBD.

#### *3.1.1 Crypt architectural abnormalities*

Normal colonic crypts are straight, parallel, and extend from the surface, up to the muscularis mucosae. The crypt architecture is assessed based on the crypt size, crypt branching, crypt shortening, and variability in inter-crypt spacing. The crypt architectural distortion observed in UC is characterized by irregularly arranged, dilated, branched, fused, and shortened crypts. The crypt size and spacing could vary. This is a manifestation of ongoing inflammation and regeneration [9]. However, the crypts in the anorectal junction and ileocaecal junction can show minor abnormalities resembling architectural distortion due to regional variations. Another point to remember is that the crypt architecture should not be assessed close to lymphoid aggregates as these could result in distortion.

#### *3.1.2 Cellularity in the lamina propria*

Lymphocytes and plasma cells are always found in the colorectal lamina propria (LP). Normally, these chronic inflammatory cells are most dense in the upper third of the mucosa and their density decreases towards the base, resulting in the 'plasma cell gradient'. The absence of the plasma cell gradient is accepted as normal in the caecum and ascending colon. The cellularity in the LP varies depending on the anatomical site of the colon. In general, the caecum and the right colon are most cellular with a progressive decrease in the cellularity from the right to the left side. Dense lymphoid tissue may be found in the normal large bowel, particularly in the rectum. The abundance of eosinophil granulocytes varies a lot between normal individuals and is found to have a seasonal and geographic variation and is more in the right colon and the ileum than the left colon [2, 10].

Abnormal cellularity of the LP refers both to increased and altered distribution of cell types that are normally present. Basal plasmacytosis or plasma cells extending below crypt endings in more than two foci in a biopsy is considered to denote an increase in chronic inflammation (**Figure 2**).

#### **Figure 2.**

*Main histological features of UC. (A) Basal plasmacytosis and mucin depletion. (B) Villiform surface, variation in size and shape and branching of crypts. (C) Surface ulceration, diffuse heavy inflammatory cell infiltrate in the lamina propria and crypt abscess formation ((A–C): H&E ×200).*

#### *3.1.3 Neutrophil granulocytes in the lamina propria*

Normal colonic mucosa does not contain neutrophils except a few scattered neutrophils, that may occur as a result of bowel preparation [11]. Neutrophils are the hallmark of activity in IBD/UC. These are found in the LP or they can infiltrate the crypt surface epithelium (termed cryptitis) or enter the lumen of crypts forming crypt abscesses (**Figure 2**).

#### *3.1.4 Epithelial abnormalities*

These include mucin depletion, surface epithelial damage, and metaplastic changes. Mucin depletion can be defined as a decreased number of goblet cells or decreased amount of intracellular mucin. Focal epithelial cell loss, flattening, erosions, and ulcers denote epithelial damage and reflect the activity of the disease. Metaplastic changes are seen in the form of Paneth cell or pyloric gland metaplasia. None of these findings is disease-specific and might be observed in UC, CD, and other types of colitis.

Working definitions of some of the microscopic features of IBD/UC are given in **Table 1** [11].

#### **3.2 Typical histological features of ulcerative colitis**

The histologic findings in UC vary depending on the clinical phase of the disease and the grade of inflammatory activity. The histological features that define chronicity are crypt architectural distortion, crypt atrophy, diffuse mixed lamina propria inflammation, basal plasmacytosis, basally located lymphoid aggregates, and Paneth cell metaplasia [9]. Inflammatory activity is defined by the presence of neutrophils. Neutrophilic cryptitis, crypt abscesses, hemorrhage, erosions, ulceration, and necrosis are features of active inflammation.

It is convenient to divide the histologic appearances into those seen inactive disease, resolving disease, and disease in remission.

#### *3.2.1 Active ulcerative colitis*

The characteristic features of acute UC include architectural distortion which is more in the distal colon than the proximal bowel, diffuse chronic inflammatory cell infiltrates



#### **Table 1.**

*Working definitions of histological features seen in UC/IBD.*

extending up to the muscularis mucosae, and neutrophil infiltration. The neutrophils seem to migrate directly from capillaries into the crypt epithelium (cryptitis) and often form crypt abscesses. Ulcers covered with granulation tissue and regenerative epithelium could be seen. The surface epithelium may take an undulating or low villiform appearance. The inflammation may extend into the superficial submucosa but the muscularis propria and serosa remain free of inflammation, except in fulminant colitis.

Neutrophils are predominant within the lumina of the crypts in UC and comparatively small numbers are seen migrating between the epithelial cells. Crypt abscesses are the precursors of mucosal ulceration and inflammatory polyp formation. In severe active UC, crypt abscesses burst into the loose submucosal tissues and there is a tendency to spread beneath the mucosal membrane, which sloughs off leaving an ulcer. The remaining mucosa is relatively raised from the ulcerated area and forms 'inflammatory pseudopolyps'.

The inflammatory damage to the crypts produces a variety of degenerative and regenerative changes in the crypt epithelium. There is loss of mucin from goblet cells, often with enlargement and hyperchromatism of nuclei of the absorptive cells. Such changes must not be mistaken for dysplasia. In the presence of attenuated or restituting superficial epithelium, the changes in the crypts are almost certainly reactive [1].

There is a heavy diffuse infiltrate of inflammatory cells in the LP. These include neutrophils, lymphocytes, plasma cells, eosinophils, and mast cells. The presence of deep plasma cells is characteristic of longstanding UC. Many eosinophils may be seen in the LP in some of the biopsies but the role of eosinophils in UC is uncertain and has been subject to many studies [10]. Lymphoid aggregates, that may show germinal centres, are common in UC. These are situated basally between crypt bases and the muscularis mucosae (**Figure 3**). Epithelioid granulomas, which are a hallmark of CD, are not identified in UC, where only foreign body granulomas evolved as a response to mucin from ruptured crypts (termed cryptolytic granulomas) are observed.

#### *3.2.2 Resolving ulcerative colitis*

With the resolution of disease, the numbers of inflammatory cells of all types show a variable density, therefore, the LP could be either hyper or hypocellular. Further, the distribution of inflammatory cells becomes uneven. The goblet cell population returns to normal. The crypt architecture will show variable evidence of distortion, depending on the severity of the attack. The crypts may appear short and branched, the changes invariably being more marked distally. The resolution may occur at different rates in different parts of the colon, and this may give rise to the false impression of segmental disease (**Figure 4**).

#### **Figure 3.**

*Histological appearances of active UC. (A) Depletion of mucin in the epithelium, cryptitis, heavy infiltrate of lymphocytes, plasma cells, and eosinophils in the LP (H&E ×400). (B) Marked crypt distortion and crypt abscess formation. (C) Surface ulceration. (D) A lymphoid aggregate with the germinal centre formation in the LP ((B–D): H&E ×200).*

#### **Figure 4.**

*Resolving UC; a mild crypt architectural distortion, normal mucin content in the glands, hypocellular LP, no activity (H&E ×100).*

#### *3.2.3 Quiescent ulcerative colitis*

Varying degrees of crypt atrophy and distortion are the hallmarks of the quiescent disease. Active inflammation is absent. The muscularis mucosa is thickened and a characteristic finding in UC, especially in rectal biopsies, is the double muscularis mucosae [1]. Paneth cell metaplasia in the left colon and pyloric-type metaplasia in any location of the colon are also features of chronic disease [1].

*The Role of the Pathologist in Ulcerative Colitis DOI: http://dx.doi.org/10.5772/intechopen.102072*

Although most UC patients have some residual changes of previous damage, such as crypt distortion, atrophy, and Paneth cell metaplasia, it has become increasingly recognized that a group of UC patients may show complete resolution with no evidence of previous disease [12, 13]. This must always raise the question of whether the original diagnosis is UC or infective colitis. In such situations, a careful review of the previous clinical records including the initial biopsies and ancillary investigations may be of help [1].

#### **4. Unusual morphological patterns of ulcerative colitis**

There are some exceptions to the classic morphological patterns described above, that may lead to diagnostic confusion. A summary of the unusual morphologic patterns of disease in UC is noted in **Table 2**. Pathologists need to recognize these patterns to avoid falling into a diagnostic trap.

#### **4.1 Morphological features of treated ulcerative colitis**

Endoscopically or histologically discontinuous disease may be observed in the setting of medically treated UC. This occurs as a result of uneven healing [6]. The same process may also lead to absolute or relative rectal sparing in 30–40% of patients [9]. As patchiness of the disease and rectal sparing mimicking CD is commonly seen in treated UC, evaluation of disease distribution to subtype IBD should not be attempted in this setting. This emphasizes the importance of pre-treatment histology and the value of communication between the clinician and the pathologist.

#### **4.2 Appendiceal 'skip' lesions and the 'caecal patch' in ulcerative colitis**

Appendiceal involvement is demonstrated in about 75% of the total colectomies performed for UC. This may be continuous with extensive colitis or may represent a 'skip lesion' of UC with involvement of the more distal colon only [9]. Such a skip lesion may raise the suspicion of CD and be erroneously considered as a contraindication for pouch surgery. The mucosal inflammation in the appendix may extend to the appendiceal orifice and contiguous large bowel as a periappendiceal patch.

Similar to the appendiceal skip lesion, there could be isolated involvement of the caecum and/or ascending colon, which is discontinuous with the left-sided colitis. It is shown that patchy right-sided inflammation in patients with left-sided colitis has


little clinical significance but should be recognized by pathologists to prevent a false diagnosis of CD in this setting [14].

It is also interesting that in appendices removed for possible acute appendicitis, inflammation confined to the mucosa with associated crypt distortion should raise the possibility of an appendiceal involvement in UC.

#### **4.3 Involvement of the ileum**

Ileitis is found in about 10% of patients with UC, the extent of involvement varying from 50–250 mm [1]. The mucosal changes are similar to those seen in the colon and are always in continuity with the disease in the large bowel. The involvement of the ileum is associated with an open dilated and incompetent ileocaecal valve. Although the term 'backwash ileitis' is in common use for this condition, it is not necessarily accurate as evidence for such a mechanism is not yet proven [1]. This condition should not be confused with CD of the terminal ileum which typically shows longer lengths of involvement and is normally associated with chronic active inflammation, and other features of CD. Unfortunately, strict histopathologic criteria for backwash ileitis have not been defined [15].

#### **4.4 Rectal sparing**

According to traditional belief, UC is a diffuse continuous disease that begins in the rectum and extends proximally, without skip areas. The term 'absolute rectal sparing' refers to the rectum with a normal endoscopic appearance and normal histology. Another term sometimes used is 'relative rectal sparing', in which the rectum has inflammation that is less severe than the more proximal colon [16]. Rectal sparing and patchiness of inflammation are seen in medically treated UC, especially with therapeutic steroid enemas. This too emphasizes the importance of the provision of clinical details to the pathologist. The pathologists should also be vigilant not to interpret these findings as definite evidence of CD.

#### **4.5 Ulcerative colitis in pediatric populations**

Pediatric-onset of IBD can show fewer characteristic symptoms and histological findings than adult-onset IBD. In general, diagnostic biopsies from children with UC often show less severe inflammation, fewer architectural abnormalities, and less epithelial injury despite extensive disease [2, 6, 17, 18].

The available evidence strongly suggests that UC in children is typically a pancolitis with variable degrees of inflammation on histology [16]. In a subset of pediatric patients, relative rectal sparing and patchy inflammation both endoscopically and histologically may occur at the pre-treatment stage of UC. These features are also observed in treated pediatric patients presumably similar to adults. In a minority, absolute rectal sparing occurs [16]. It is prudent not to preclude the diagnosis of UC in children when these atypical features are present. The precise reason why pre-treatment stage pediatric patients have a higher prevalence of rectal sparing compared to adults is unclear. Younger age (<10 years) at presentation and shorter duration between the symptoms and endoscopy are proposed explanations [19].

#### **4.6 Fulminant ulcerative colitis**

Fulminant colitis is defined as severe, acute inflammation of the colon with associated systemic toxicity. Most cases (89%) of fulminant colitis represent IBD, with the remainder relating to ischemia or infection, amongst other aetiologies [20].

In fulminant UC, the inflammatory cell infiltrate extends beyond the mucosa with thinning of the wall. There is separation and oedema of the muscle layer known as myocytolysis. There is diffuse haemorrhagic necrosis of the mucosa, deep fissuring ulcers, and transmural polymorphous inflammation. Unlike in classical UC where the serosa is shiny and intact, there is a purulent or seropurulent exudate seen on the peritoneal surface in many cases of fulminant colitis. The bowel wall is also markedly thinned out and dilated and this usually occurs in the region of the transverse colon. Macroscopic features, such as dilation, skip lesions, rectal sparing, linear ulcers, terminal ileal disease, pseudopolyps, and creeping fat, are poor discriminators of UC and CD, in the setting of fulminant colitis.

#### **5. Histological differential diagnosis of ulcerative colitis and diagnostic pitfalls**

#### **5.1 Infective colitis**

Infective colitis may clinically mimic acute UC. However, most cases of infectious colitis demonstrate a histological pattern of acute colitis, which may be diffuse, patchy, or focal, without evidence of architectural distortion. Less commonly, chronic infectious colitis may produce a histological pattern of chronic active colitis resembling IBD. Most of these cases have no specific diagnostic features on histological examination and in such cases, knowledge of the clinical history and correlation with serologic studies or stool cultures are required for diagnosis.

Some features help in differentiating acute self-limiting colitis from UC in the acute stage. In acute self-limiting colitis, the neutrophils are plentiful in the LP and are more superficially arranged. In UC, the neutrophils are predominant within the lumina of the crypts and comparatively small numbers are seen migrating between the epithelial cells [1]. Chronic changes, such as crypt distortion in UC, take about 4–6 weeks to develop and this could, therefore, cause a diagnostic difficulty in the early stages of the disease.

In amoebic colitis, presenting as chronic active colitis, there could be trophozoites of *Entamoeba histolytica* in biopsy material and identifying the trophozoites becomes crucial because, if immunosuppressive therapy is started for presumed IBD in these patients, it can result in perforation due to fulminant amoebic colitis. Superimposed infection with many organisms can occur with established UC and cytomegalovirus (CMV), campylobacter and *Clostridium difficile* are some of the important secondary infections to be considered when UC presents with an acute exacerbation [21].

#### **5.2 Chronic ischaemic colitis**

Chronic ischemia may produce a pattern of chronic active colitis and can present a difficult differential diagnosis. Chronic or recurrent ischemia may cause

significant crypt distortion, Paneth cell metaplasia, and chronic active inflammation, all features which mimic UC. However, atrophic and regenerative changes in the epithelium, hyalinization of the LP, and the presence of microthrombi in the adjacent mucosa should suggest ischemia [21]. Overall, in ischemia, the chronic active inflammation is mild relative to the degree of epithelial injury [21]. Further confounding this differential diagnosis, UC has been reported to cause a hypercoagulable state, particularly in genetically predisposed patients. In this setting, a superimposed arterial and venous thrombosis may occur, leading to severe steroidrefractory colitis [21].

#### **5.3 Diverticular disease-associated colitis (DAC)**

Chronic active colitis resembling UC may be seen in the setting of diverticulosis. In addition, diverticulosis is a relatively common disease of the elderly and, thus, both diverticulosis and IBD (either CD or UC) may coexist in the same patient. Unlike chronic active colitis of UC, DAC is confined to segments involved by diverticular disease, most commonly the sigmoid colon, and, by definition, spares the rectum. However, UC and diverticular colitis may in some cases represent overlapping entities, as a small subset of diverticular colitis patients has progressed to typical rectosigmoid UC and DAC may respond to medical therapy utilized for IBD [21].

#### **5.4 Drug-induced colitis**

Some forms of medication-induced colitis may demonstrate chronic active colitis, which may enter the differential diagnosis of UC. Nonsteroidal anti-inflammatory drugs (NSAIDs) may result in the reactivation of UC. However, in some patients, this group of drugs has also been implicated in initiating UC [1].

The most useful histological feature in distinguishing NSAID-related colitis from UC is an increase in apoptotic bodies in the crypt epithelium and lymphocytes and mononuclear cells of the superficial LP. The morphological changes that occur with NSAIDs include a generalized increase in chronic inflammatory cells in the LP, a prominent eosinophil infiltrate, increased intra-epithelial T lymphocytes and thickening of the subepithelial collagen plate may resemble eosinophilic colitis, lymphocytic colitis, and collagenous colitis, respectively [1].

#### **5.5 Diversion colitis**

Diversion colitis develops in segments of the bowel that have been excluded from the fecal stream, such as in a Hartmann's pouch. This chronic inflammatory condition usually develops within a few months to several years following surgical diversion, and typically regresses completely within 3–6 months of re-establishment of the fecal stream [22]. The disease may mimic IBD on biopsy samples and may show crypt atrophy, distortion, and lymphoid hyperplasia, involving the mucosa and/or submucosa. Symptomatic patients can show superimposed cryptitis, crypt abscesses, and superficial aphthous-type erosions or frank ulceration.

This warrants the importance of obtaining a biopsy of the segment at the time of the surgery to get a baseline analysis and review of the clinical, radiological, and endoscopic information prior to diagnosis.

#### **5.6 Crohn disease (CD)**

In most instances, UC and CD may be readily distinguished from each other pathologically, particularly when each exhibits classic histological features assisted by clinical data and other ancillary investigations. There are several circumstances in which the 'classic' morphological features that help to distinguish UC from CD are altered or absent. When these atypical morphological features are present, they may mimic CD (**Tables 3** and **4**). Most of these atypical features have already been discussed in Section 3.

#### *5.6.1 Granulomas in UC*

Approximately 30–40% of CD cases contain either mucosal or mural, nonnecrotic granulomas [22]. When present, it is a helpful feature to confidently diagnose CD, especially in mucosal biopsies. Granulomas in CD are composed of loose collections of CD 68 immunostain positive epithelioid histiocytes. When there is rupture of a crypt or extravasated mucin in UC, there could be the formation of a granuloma which is termed a 'cryptolytic granuloma' that could be difficult to


#### **Table 3.**

*Classic morphological features helpful in differentiating UC from CD [13].*


#### **Table 4.**

*Unusual morphological patterns of UC that may mimic CD.*

**Figure 5.**

*(A) Cryptolytic granuloma following a rupture of a crypt in UC. Extravasated mucin, multinucleated giant cells, and inflammatory cells are seen. (B) Epithelioid cell granuloma formed by histiocytic cells in CD ((A and B) H&E ×400).*

distinguish from granulomas of CD (**Figure 5**). Examination of multiple tissue levels that will demonstrate the relationship between granulomas and the crypt epithelium is a helpful measure in this situation. Cryptolytic granulomas often contain an admixture of neutrophils and lymphocytes, in addition to foamy macrophages and multinucleated foreign body-type giant cells and these are not usually seen in CD-related granulomas [22].

#### *5.6.2 Transmural inflammation in UC*

In CD, transmural lymphoid aggregates are seen randomly in the wall of the bowel. In fulminant UC when superficial fissuring ulcers that extend into the deep submucosa or superficial muscularis propria are present and in toxic megacolon when myocyte necrosis and serosal inflammation are prominent, there could be mural mononuclear inflammation. However, in contrast to CD, these do not form typical discrete lymphoid aggregates and are usually seen underlying the areas of severe ulceration [22]. Thus, lymphoid aggregates in areas under intact mucosa are not a feature of UC and, in fact, favor a diagnosis of CD.

#### *5.6.3 CD with UC-like features*

Typical features of CD such as granulomas, fissuring ulcers, and transmural lymphoid aggregates are seen less commonly in the colon compared to the small intestine [15]. Therefore, some cases of colonic CD may mimic UC by demonstrating only superficial mucosal involvement without inflammatory changes in the submucosa or muscularis propria, diffuse and continuous disease, and even pancolitis. Nearly 20% of CD patients develop colitis without the involvement of the upper GI tract [22]. In these cases, careful evaluation of colonic and ileal biopsies for granulomas, identifying focal or patchy inflammation and activity within the LP, identifying transmural lymphoid aggregates in resections, correlation with a detailed clinical history and imaging will be of help in differentiating UC from CD.

#### **6. Indeterminate colitis (IC) and inflammatory bowel disease unclassified (IBDU)**

In up to 5% of IBD cases, an exact classification of IBD into UC or CD proves difficult due to either the overlapping histological features of the two diseases or to the fact that UC and CD represent two ends of the spectrum of a single disease [1, 6].

Several different terms have been used to refer to this condition, including 'indeterminate colitis' (IC), 'inflammatory bowel disease unclassified' (IBDU), 'chronic inflammatory bowel disease unclassified', and 'chronic idiopathic inflammatory bowel disease not otherwise specified'. The European Crohn's and Colitis Organization (ECCO) and the European Society of Pathology (ESP) jointly addressed the ambiguous usage of this terminology, in their consensus report in 2013 [6]. Accordingly, the term IBDU could be used for patients with chronic colitis who have IBD based on the clinical history, but endoscopy and histology of the biopsies show no definitive features of either UC or CD [6]. This term is reserved for biopsy examination as the post-operative examination of resections of such IBDU cases usually provides definitive evidence of UC or CD.

The entity of IBDU is more common in the pediatric population. The possible reasons for this being more colitis than ileitis occurs in CD in early cases and the presence of rectal sparing in UC in the pediatric population [6]. Upper GI biopsies are particularly helpful in these cases.

The pathological diagnosis of IC is made only on resected specimens with the presence of overlapping features or the absence of a clear diagnostic pattern to distinguish CD from UC.

Usually, macroscopically IC shows diffuse disease with involvement of transverse and right colon and less severe inflammation in the distal colon. There is extensive ulceration. Microscopy confirms extensive ulceration with a sharp transition to normal adjacent mucosa and multiple V-shaped ulcers lacking surrounding inflammation. The overlapping histological features of IC are given in **Table 5**.

It makes no difference whether the large bowel resection is called 'UC' or 'IC', but CD needs to be excluded conclusively since an ileal pouch-anal anastomosis (IPAA)/'pouch' procedure is generally contradicted in CD.


#### **Table 5.**

*Overlapping histological features in indeterminate colitis (IC).*

#### **7. Measuring the disease activity in ulcerative colitis**

The complete assessment of disease activity in UC involves symptomatic evaluation, physical examination, measurement of laboratory indices, endoscopic visualization, and the histological assessment of the mucosal inflammation [3]. However, measuring disease activity using all these different parameters is cumbersome and time-consuming in practice and will delay therapy. In routine clinical practice, the disease activity and subsequent medical treatment are usually assessed largely by the clinical symptomatology. Histological assessment of the degree of inflammation is the gold standard for evaluating the true disease activity but its conventional use is limited owing to its inconvenience, invasiveness, and cost [3].

Traditionally, clinical and endoscopic remission were the two main therapeutic targets for UC. However, up to 40% of patients in clinical and endoscopic remission show persistent histological activity [2]. Furthermore, histological activity predicts the worst outcome and histological inflammation represents a significant risk factor for the subsequent development of UC-related colorectal neoplasia. Therefore, histological remission is now increasingly regarded as an important therapeutic target for UC [2].

There are about 30 histological activity indices in IBD, that have been introduced over the last few decades [23]. These systems use different stepwise grading scales for the assessment of inflammation which is used as the basis of grading the disease activity. These scales have four to seven steps and quantitatively assess the following features—architectural changes in the mucosa, chronic inflammatory cell infiltrate, amount and location of neutrophils within the mucosa, crypt abscess formation, erosion, and ulcers.

Of these scores, the 'Geboes score' developed in 2000 has been the most widely used and can serve as an independent risk factor for disease progression in UC [24, 25]. The more recent 'Nancy histological index' (NHI) and 'Robarts histopathological index' (RHI) both from 2016 have proven feasible, easy to use, and are the most extensively validated [26, 27]. There is currently no general agreement on which index should be used. The 2020 ECCO position paper concluded that the NHI can be recommended for daily clinical practice and for clinical trials both the NHI and RHI are feasible [2].

RHI requires assessment of four features which include ulceration/erosion, neutrophils in the epithelium, neutrophils in the LP, and the chronic inflammatory cell infiltrate. Each of the features is subdivided on a scale of 0–3 to calculate the ultimate disease activity score. This may reduce its clinical usefulness and probably is more useful for clinical trials and in research. In NHI, three main histological characteristics which include ulceration, the acute inflammatory cell infiltrate and the chronic inflammatory cell infiltrate are assessed. The NHI is defined by a 5-level classification ranging from grade-0 (absence of significant histological disease activity) to grade-4 (severely active disease) (**Table 6**) [27].

In the NHI, chronic inflammation includes lymphocytes, plasma cells, and eosinophils and it is assessed without quantification. Furthermore, if neutrophilic inflammation is present, regardless of extent, the degree of chronic inflammation is not assessed.

It has been shown that both NHI and RHI have a similar degree of inter and intraobserver agreement and share equivalent feasibility in terms of time taken for scoring the biopsies [28].


#### **Table 6.**

*Nancy histological index (NHI).*

Despite the development and validation of novel histologic scoring systems, there are no agreed definitions for histologic healing and remission. Histologic healing is the ultimate goal of the treatment and could be defined as complete normalization of the mucosa [7]. What constitutes complete normalization needs to be precisely defined. Rare architecturally distorted crypts should not be overinterpreted as evidence of persistent architectural abnormalities. A rare, branched crypt can be seen even in a normal colon. Furthermore, the crypts in a normal rectum often do not extend to the muscularis mucosae [7].

The best definition of histologic remission in UC is also unclear. Traditionally, this has been regarded as persistent architectural abnormalities without neutrophilic (active) inflammation, with varying degrees of lymphoplasmacytic inflammation. The presence of mucosal eosinophils is allowed [7]. Ideally, remission includes clinical, endoscopic, and histological resolution, which is called complete remission.

#### **8. Dysplasia andv malignancy in ulcerative colitis**

The risk of colorectal carcinoma (CRC) is increased in patients with long-term UC compared to the general population. Carcinogenesis in UC is inflammation-driven and has a different pathway than usual colorectal carcinogenesis. Epithelial cells acquire early mutations of TP53 and KRAS genes and no mutations of APC genes, while in non-inflammatory carcinogenesis of the colon, APC mutation is the earliest event [7].

Epithelial dysplasia is the precursor lesion of UC-associated CRC. The features associated with increased risk of dysplasia/CRC in UC include the duration of the disease, the anatomical extent of the disease, early age of onset, concomitant sclerosing

cholangitis, family history of CRC, and endoscopic/histological activity of the disease [29]. The prognosis of CRC in IBD may be worse than CRC in the general population and shows higher mortality [9].

#### **8.1 Colorectal dysplasia in ulcerative colitis**

The presence of dysplasia in endoscopic biopsies is the most reliable marker of cancer risk. There are no specific clinical features related to dysplasia in UC. Most cases of dysplasia occur in the left/distal colon, and this mirrors the higher incidence of UC-associated colorectal carcinoma (CRC) in the rectosigmoid region. The endoscopic appearance of dysplasia is categorized according to the SCENIC classification and includes visible and invisible lesions. The visible lesions are subdivided into polypoidal (either pedunculated or sessile) and non-polypoidal (superficial, flat, depressed [29].

Dysplasia of the colorectum is defined as an unequivocal epithelial alteration that remains confined within the basement membrane within which it originated. The microscopic features of dysplasia in UC are based on a combination of cytoarchitectural features of the crypt epithelium that remains confined to the mucosa and are identical to those used in the general assessment of dysplasia elsewhere [9]. Dysplasia is classified according to either the Riddell or the Vienna system [30, 31]. In the Riddell system, there are four categories for dysplasia, which are negative, indefinite, low grade, and high grade. The Vienna system has five categories with the addition of invasive carcinoma.

The most common histological subtypes of dysplasia include intestinal (adenomatous) and serrated types [29]. Regardless of these subtypes, dysplasia is divided into low grade and high grade according to the cytoarchitectural features. In low-grade dysplasia (LGD) the crypts may be tubular and/or villous or serrated and they show either no or only mild crypt budding or crowding. The dysplastic cells show enlarged, hyperchromatic nuclei with a high nuclear/cytoplasmic ratio, nuclear stratification limited to the basal half of the cytoplasm, and clumped chromatin or multiple small nucleoli. In serrated dysplasia, the dysplastic cells may show hypereosinophilic, mucin depleted cytoplasm, or a microvesicular epithelium that is similar to the sporadic sessile serrated adenomas. These atypical nuclear features usually involve both the crypt and surface epithelium.

High-grade dysplasia (HGD) exhibits enlarged nuclei with marked nuclear hyperchromasia, pleomorphism, stratification involving the full thickness of the cytoplasm, increased mitoses, and loss of nuclear polarity. It shows complex glandular architecture with crowding, cribriforming, complex branching, and budding [29].

The category indefinite for dysplasia refers to ambiguous epithelial alterations that cannot with certainty be classified either as negative or positive for dysplasia. Some of the settings in which indefinite for dysplasia is considered are shown in **Table 7**.

#### **8.2 Some issues in histopathological reporting in UC-associated dysplasia**



#### **Table 7.**

*Some settings where indefinite for dysplasia are considered.*

atypical nuclear changes, such as enlargement, hyperchromasia, stratification, and brisk mitoses. Careful observation for surface maturation, which is a feature in reactive conditions helps to solve this problem. Another good practice is to perform colonoscopic surveillance during a period of remission of UC.


#### **Figure 6.**

*Dysplasia in UC. (A) Flat low-grade dysplasia with villous configuration. There is no significant pleomorphism or loss of polarity (H&E ×100). (B) High-grade dysplasia with crowding glandular proliferation (H&E ×100). Reprinted by ([21], pp. 178-192). Published by Oxford University press and digestive science publishing Co Limited.*

epithelium [32]. Perhaps the most helpful feature is that the 'pseudo-dysplasia' induced by cyclosporin is strikingly diffuse, with many, and sometimes all, crypts showing similar changes, a pattern not usually seen in UC associated dysplasia. Therefore, the clinician needs to alert the pathologist to the fact that the patient has been on cyclosporin and that the pathologist in turn should be cautious when diagnosis dysplasia in this situation (**Figure 6**).

#### **8.3 The demise of the term 'DALM' in ulcerative colitis**

A diagnosis of dysplasia is made on biopsy material taken from a polyp or a mass evident on endoscopy was historically termed 'dysplasia associated lesion or mass' (DALM) and was considered as an indication for colectomy to rule out the possibility of invasive malignancy. In 2015 SCENIC international consensus statement on the surveillance and management of dysplasia in IBD, abandoned the term DALM and replaced it with endoscopically visible and non-visible lesions [33]. With advancements in endoscopic polypectomy and endoscopic mucosal resections (EMR), the concept of DALM is now outdated because most lesions that are noninvasive can be removed using these techniques [1].

#### **8.4 Carcinoma in ulcerative colitis**

Carcinomas arising in UC are mostly similar to their counterpart in non-colitis patients except for the background colitis. However, there are some features that are more frequent in UC-associated carcinomas. The tumors could be multiple and often are flat lesions with ill-defined edges, therefore, these tumors are easily felt than seen. Histologically there is a higher incidence of high-grade tumors and mucinous subtypes [1].

#### **9. Conclusions**

The pathologist plays a vital role in the diagnosis and follows up of patients with UC. The histological features in the biopsies vary widely depending on the stage of this chronic relapsing and remitting disease, making the differential diagnosis lengthy and challenging. The final diagnosis should be ideally concluded at a clinicopathological meeting. Understanding the typical and atypical histological features of UC is vital in the task of differentiating UC from other types of colitis, mainly CD. Histological disease activity and identifying histological remission are increasingly considered important therapeutic targets. Identifying dysplasia associated with UC and its grading is a crucial step in the surveillance and management of this chronic disease.

#### **Acknowledgements**

The authors gratefully thank Dr. D.T.T. Jayasinghe and Dr. R.D.K. Medonza, Postgraduate trainee in Histopathology, Faculty of Medicine, University of Kelaniya, for their assistance in photomicrography.

*The Role of the Pathologist in Ulcerative Colitis DOI: http://dx.doi.org/10.5772/intechopen.102072*

#### **Author details**

Gayana Mahendra\* and Janaki Hewavisenthi Faculty of Medicine, Department of Pathology, University of Kelaniya, Sri Lanka

\*Address all correspondence to: baggmahendra@yahoo.co.uk

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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