J Gastrointest Surg (2014) 18:1231–1233 DOI 10.1007/s11605-014-2505-5
SSAT/ASCRS JOINT SYMPOSIUM
The Role of the Pathologist in the Diagnosis and Treatment of Dysplasia in Inflammatory Bowel Disease Mariana Berho & Daniela Allende
Received: 7 October 2013 / Accepted: 10 March 2014 / Published online: 27 March 2014 # 2014 The Society for Surgery of the Alimentary Tract
Keywords Inflammatory bowel disease . Dysplasia
1. Extent and duration of disease. 2. Early age of onset. 3. Primary sclerosing cholangitis occurring in a background of UC.
Introduction – It has been clearly demonstrated that patients suffering from long-standing inflammatory bowel disease (IBD) (ulcerative colitis and Crohn’s disease) are at increased risk of developing colorectal cancer (CRC). The exact magnitude of this risk is difficult to measure and ranges widely according to different reports. Several reasons could explain this variability including (1) selection bias: population based vs specialized centers; (2) practice patterns, different threshold among physicians to perform colectomies; (3) widespread use of medications that have been proven to reduce the risk of colorectal cancer (5ASA); and (4) rigorous endoscopic surveillance programs. In a meta-analysis of 116 studies that included almost 55,000 patients, Eaden at al1 demonstrated that the risk of developing CRC associated with IBD was 2, 8, and 18 % after 10, 20, and 30 years, respectively. Even when the variation in cancer risk among several institutions is considered, there appears to be a trend towards a decreased incidence in CRC in the most recent reports.
Risk Factors for the Development of CRC in IBD Several factors have been associated with an increased risk of CRC in IBD, these include the following2: M. Berho (*) : D. Allende Department of Pathology and Laboratory Medicine, Cleveland Clinic, Weston, FL, USA e-mail: [email protected]
The coexistence of primary sclerosing cholangitis (PSC) in patients with UC has been associated with a 4.8-fold increase in the incidence of CRC, especially in patients who receive liver transplants due to PSC.
4. Family history of CRC. –
A family history of CRC appears to increase the risk of CRC from 2 to 5-fold in a manner independent of other variables including PSC, surveillance, and drug therapy.
5. Severity of inflammation. –
The mediators and cellular effectors of inflammation are key components of the tumor microenvironment; furthermore, inflammatory conditions are present before a malignant change occurs. The “smouldering” inflammation unleashes many tumor-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, as well as subverts healthy immune responses. Understanding the molecular pathways of this cancer-related inflammation could lead in the identification of new target molecules that could dramatically impact diagnosis and treatment. As an example of the latter is Cox-2, a molecule shown to play a pivotal role in both inflammatory and neoplastic processes. We have recently studied the overexpression of Cox-2 in a group of patients with UC, dysplasia, and invasive cancer (unpublished results). Our
1232
J Gastrointest Surg (2014) 18:1231–1233
results showed that Cox-2 was found in all stages of neoplastic transformation, furthermore staining with Cox-2 was higher in neoplastic than in inflamed and non-inflamed mucosa in UC. In addition, in a few samples of actively inflamed, non-dysplastic mucosa did not show overexpression of this molecule indicating that Cox-2 overexpression reflects not only inflammation but also neoplastic transformation. Even though several other molecular and immunohistochemical markers have been studied in the setting of IBD dysplasia, including p53 1,2 and AMACR,3 none of them are used in clinical practice and their utility is limited.
Dysplasia in IBD Dysplasia has been traditionally defined as an unequivocal neoplastic transformation of the epithelium confined to the basement membrane. Based on this definition, the diagnosis of dysplasia has classically been linked to the histological examination of endoscopic biopsies. Dysplasia is further classified according to the degree of cytological and architectural atypia based on the Vienna Classification into “negative for dysplasia”, “indefinite”, “low grade”, and “high grade” (ref below). This classification has replaced the prior system developed by the IBD Dysplasia Morphology Study Group. In the past, treatment decisions have heavily relied on the histological impression, a typical and simplified example of an algorithm that would guide therapeutic intervention based on the pathologic diagnosis is shown in Fig. 1. The discovery of dysplasia in the background of IBD stratifies patients into groups with different risks for the development of CRC. The understanding that the development of CRC in IBD represents a continuum process that spans from normal mucosa–inflamed mucosa–dysplastic mucosa– invasive cancer is the basis of endoscopic surveillance
Treatment of dysplasia based on histopathological diagnosis
Indefinitive for dysplasia Close surveillance
Low grade dysplasia
High grade dysplasia Colectomy
Macroscopic classification of dysplastic lesions in IBD
Raised/elevated Adenoma-like
Irregular
Not detected endoscopically
DALM
Fig. 2 List of terminologies applied to describe dysplastic lesions in IBD
programs. It is important to recognize that the success of these surveillance programs relies on the collaborative effort of several individuals, endoscopist, patient, and pathologist, each of which carries various, inherent weaknesses that may compromise the value of the endoscopic surveillance of dysplasia. The role of the pathologist is critical and requires not only expertise in the field of dysplasia and IBD but also the willingness to communicate with the endoscopist in order to interpret the biopsies in the context of the endoscopic findings. Although the concept of dysplasia as a precursor of CRC is well accepted, the actual risk has been difficult to quantify, and studies estimating the rate of progression from dysplasia to cancer vary greatly. In a meta-analysis conducted by Thomas,3 low grade dysplasia (LGD) was associated with a 9-fold lifetime risk for developing CRC and a 12-time risk of evolving to high grade dysplasia HGD or cancer. These results, however, have not been uniformly validated, and several other publications have shown a much lower incidence of progression from LGD to HGD and carcinoma. The explanation for this discrepancy is likely multifactorial and encompasses diverse factors including inherent population differences as well as surveillance practices. The impact of inter- and intraobserver variability among pathologists in the diagnosis of dysplasia will logically influence significantly the natural history of dysplasia
Dysplastic lesion in IBD Isolated raised lesion, circumscribed completely excised Repeat endoscopy at 3 months with target bx around previous lesion No residual lesion
6 month surveillance if normal repeat annually
Fig. 1 Example of an algorithm that would guide therapeutic intervention based on the pathologic diagnosis
Flat
Isolated raised irregular lesion (DALM)
Multifocal flat dysplasia or flat dysplasia surrounding a raised lesion
Attempt to resect EMR
Unable to resect Proctocolectomy
Fig. 3 Algorithm for the treatment of dysplastic lesions in IBD
J Gastrointest Surg (2014) 18:1231–1233
progression and the development of CRC. Several studies have shown low agreement rates in the diagnosis of dysplasia among pathologists, especially between GI pathologists and general pathologists.4,5 This finding further supports the notion of having a specialized GI pathologist confirming a diagnosis of dysplasia in IBD. In general, the highest levels of agreement occur at the two ends of the spectrum: no dysplasia and high grade dysplasia, with the lowest kappa values obtained with the indefinite and low grade dysplasia categories. Although the latter mentioned findings may be discouraging, in our experience, the interobserver and intraobserver variability can reach optimal levels when stringent criteria are applied. In a study involving 158 patients, we were able to reach an overall kappa level of agreement of 0.82 (unpublished data). While polypoid (adenoma-like/DALM) dysplasia is easily recognized by the endoscopist, areas of flat dysplasia are more difficult to be identified and to manage. More recently, due in part to the introduction of more sensitive endoscopic techniques, it has become evident that most dysplastic lesions can be identified by a thorough endoscopic examination which results in targeted biopsies with a higher sensitivity in the diagnosis of dysplasia. Unfortunately, the lack of consensus in the terminology applied to describe dysplastic lesions in IBD has hampered communication among endoscopists and pathologists. A simplified list of terms is shown in Fig. 2. The combination of the endoscopic and histological findings enhances significantly the accuracy in the diagnosis of dysplasia and facilitates treatment decisions. Several studies have demonstrated that the ultimate choice of therapy relies, oftentimes, on the ability of the endoscopist to completely resect dysplastic lesions endoscopically. As an example, the discovery of a dysplastic lesion with an adenoma-like morphology with no other areas of dysplasia can safely be treated by endoscopic resection with no need of further surgical
1233
resection. A useful algorithm for the treatment of dysplastic lesions in IBD is shown in Fig. 3.
Conclusions It is essential that both endoscopists and pathologists get familiar with current recommendations for the diagnosis and treatment of dysplasia in IBD. Although interobserver variability in the pathological diagnosis of dysplasia remains a challenge, the application of strict and validated criteria leads to higher and more reliable levels of agreement among pathologists. The complexity associated with the diagnosis and treatment of dysplasia in IBD requires the involvement of a specialized team of GI pathologists and endoscopists that can effectively collaborate in implementing best treatment options.
References 1. Triantafillidis J, Nasioulas G, Kosmidi P.Colorectal Cancer and Inflammatory Bowel Disease: Epidemiology, Risk Factors, Mechanisms of Carcinogenesis and Prevention Strategies. Anticancer Res 2009; 29: 2727-2738 2. Lucas M. Inflammatory Bowel Disease as a Risk Factor for Colorectal Cancer. Dig Dis. 2010:619-624. 3. Thomas T, Abrams KA, Robinson RJ et al. Meta-analysis: Cancer risk of low grade dysplasia in chronic ulcerative colitis. Aliment Pharmacol Ther 2007;25:657-668. 4. Odze R, Goldblum J, Noffsinger A et al. Interobserver variability in the diagnosis of ulcerative colitis-associated dysplasia by telepathology. Mod Pathol 2002;379-386 5. Odze R, Tomaszewski J, Feldman M et al. Variability in the diagnosis of dysplasia in ulcerative colitis by dynamic telepathology. Oncol Rep 2006;16:1123-1129.
SSAT/ASCRS JOINT SYMPOSIUM
The Role of the Pathologist in the Diagnosis and Treatment of Dysplasia in Inflammatory Bowel Disease Mariana Berho & Daniela Allende
Received: 7 October 2013 / Accepted: 10 March 2014 / Published online: 27 March 2014 # 2014 The Society for Surgery of the Alimentary Tract
Keywords Inflammatory bowel disease . Dysplasia
1. Extent and duration of disease. 2. Early age of onset. 3. Primary sclerosing cholangitis occurring in a background of UC.
Introduction – It has been clearly demonstrated that patients suffering from long-standing inflammatory bowel disease (IBD) (ulcerative colitis and Crohn’s disease) are at increased risk of developing colorectal cancer (CRC). The exact magnitude of this risk is difficult to measure and ranges widely according to different reports. Several reasons could explain this variability including (1) selection bias: population based vs specialized centers; (2) practice patterns, different threshold among physicians to perform colectomies; (3) widespread use of medications that have been proven to reduce the risk of colorectal cancer (5ASA); and (4) rigorous endoscopic surveillance programs. In a meta-analysis of 116 studies that included almost 55,000 patients, Eaden at al1 demonstrated that the risk of developing CRC associated with IBD was 2, 8, and 18 % after 10, 20, and 30 years, respectively. Even when the variation in cancer risk among several institutions is considered, there appears to be a trend towards a decreased incidence in CRC in the most recent reports.
Risk Factors for the Development of CRC in IBD Several factors have been associated with an increased risk of CRC in IBD, these include the following2: M. Berho (*) : D. Allende Department of Pathology and Laboratory Medicine, Cleveland Clinic, Weston, FL, USA e-mail: [email protected]
The coexistence of primary sclerosing cholangitis (PSC) in patients with UC has been associated with a 4.8-fold increase in the incidence of CRC, especially in patients who receive liver transplants due to PSC.
4. Family history of CRC. –
A family history of CRC appears to increase the risk of CRC from 2 to 5-fold in a manner independent of other variables including PSC, surveillance, and drug therapy.
5. Severity of inflammation. –
The mediators and cellular effectors of inflammation are key components of the tumor microenvironment; furthermore, inflammatory conditions are present before a malignant change occurs. The “smouldering” inflammation unleashes many tumor-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, as well as subverts healthy immune responses. Understanding the molecular pathways of this cancer-related inflammation could lead in the identification of new target molecules that could dramatically impact diagnosis and treatment. As an example of the latter is Cox-2, a molecule shown to play a pivotal role in both inflammatory and neoplastic processes. We have recently studied the overexpression of Cox-2 in a group of patients with UC, dysplasia, and invasive cancer (unpublished results). Our
1232
J Gastrointest Surg (2014) 18:1231–1233
results showed that Cox-2 was found in all stages of neoplastic transformation, furthermore staining with Cox-2 was higher in neoplastic than in inflamed and non-inflamed mucosa in UC. In addition, in a few samples of actively inflamed, non-dysplastic mucosa did not show overexpression of this molecule indicating that Cox-2 overexpression reflects not only inflammation but also neoplastic transformation. Even though several other molecular and immunohistochemical markers have been studied in the setting of IBD dysplasia, including p53 1,2 and AMACR,3 none of them are used in clinical practice and their utility is limited.
Dysplasia in IBD Dysplasia has been traditionally defined as an unequivocal neoplastic transformation of the epithelium confined to the basement membrane. Based on this definition, the diagnosis of dysplasia has classically been linked to the histological examination of endoscopic biopsies. Dysplasia is further classified according to the degree of cytological and architectural atypia based on the Vienna Classification into “negative for dysplasia”, “indefinite”, “low grade”, and “high grade” (ref below). This classification has replaced the prior system developed by the IBD Dysplasia Morphology Study Group. In the past, treatment decisions have heavily relied on the histological impression, a typical and simplified example of an algorithm that would guide therapeutic intervention based on the pathologic diagnosis is shown in Fig. 1. The discovery of dysplasia in the background of IBD stratifies patients into groups with different risks for the development of CRC. The understanding that the development of CRC in IBD represents a continuum process that spans from normal mucosa–inflamed mucosa–dysplastic mucosa– invasive cancer is the basis of endoscopic surveillance
Treatment of dysplasia based on histopathological diagnosis
Indefinitive for dysplasia Close surveillance
Low grade dysplasia
High grade dysplasia Colectomy
Macroscopic classification of dysplastic lesions in IBD
Raised/elevated Adenoma-like
Irregular
Not detected endoscopically
DALM
Fig. 2 List of terminologies applied to describe dysplastic lesions in IBD
programs. It is important to recognize that the success of these surveillance programs relies on the collaborative effort of several individuals, endoscopist, patient, and pathologist, each of which carries various, inherent weaknesses that may compromise the value of the endoscopic surveillance of dysplasia. The role of the pathologist is critical and requires not only expertise in the field of dysplasia and IBD but also the willingness to communicate with the endoscopist in order to interpret the biopsies in the context of the endoscopic findings. Although the concept of dysplasia as a precursor of CRC is well accepted, the actual risk has been difficult to quantify, and studies estimating the rate of progression from dysplasia to cancer vary greatly. In a meta-analysis conducted by Thomas,3 low grade dysplasia (LGD) was associated with a 9-fold lifetime risk for developing CRC and a 12-time risk of evolving to high grade dysplasia HGD or cancer. These results, however, have not been uniformly validated, and several other publications have shown a much lower incidence of progression from LGD to HGD and carcinoma. The explanation for this discrepancy is likely multifactorial and encompasses diverse factors including inherent population differences as well as surveillance practices. The impact of inter- and intraobserver variability among pathologists in the diagnosis of dysplasia will logically influence significantly the natural history of dysplasia
Dysplastic lesion in IBD Isolated raised lesion, circumscribed completely excised Repeat endoscopy at 3 months with target bx around previous lesion No residual lesion
6 month surveillance if normal repeat annually
Fig. 1 Example of an algorithm that would guide therapeutic intervention based on the pathologic diagnosis
Flat
Isolated raised irregular lesion (DALM)
Multifocal flat dysplasia or flat dysplasia surrounding a raised lesion
Attempt to resect EMR
Unable to resect Proctocolectomy
Fig. 3 Algorithm for the treatment of dysplastic lesions in IBD
J Gastrointest Surg (2014) 18:1231–1233
progression and the development of CRC. Several studies have shown low agreement rates in the diagnosis of dysplasia among pathologists, especially between GI pathologists and general pathologists.4,5 This finding further supports the notion of having a specialized GI pathologist confirming a diagnosis of dysplasia in IBD. In general, the highest levels of agreement occur at the two ends of the spectrum: no dysplasia and high grade dysplasia, with the lowest kappa values obtained with the indefinite and low grade dysplasia categories. Although the latter mentioned findings may be discouraging, in our experience, the interobserver and intraobserver variability can reach optimal levels when stringent criteria are applied. In a study involving 158 patients, we were able to reach an overall kappa level of agreement of 0.82 (unpublished data). While polypoid (adenoma-like/DALM) dysplasia is easily recognized by the endoscopist, areas of flat dysplasia are more difficult to be identified and to manage. More recently, due in part to the introduction of more sensitive endoscopic techniques, it has become evident that most dysplastic lesions can be identified by a thorough endoscopic examination which results in targeted biopsies with a higher sensitivity in the diagnosis of dysplasia. Unfortunately, the lack of consensus in the terminology applied to describe dysplastic lesions in IBD has hampered communication among endoscopists and pathologists. A simplified list of terms is shown in Fig. 2. The combination of the endoscopic and histological findings enhances significantly the accuracy in the diagnosis of dysplasia and facilitates treatment decisions. Several studies have demonstrated that the ultimate choice of therapy relies, oftentimes, on the ability of the endoscopist to completely resect dysplastic lesions endoscopically. As an example, the discovery of a dysplastic lesion with an adenoma-like morphology with no other areas of dysplasia can safely be treated by endoscopic resection with no need of further surgical
1233
resection. A useful algorithm for the treatment of dysplastic lesions in IBD is shown in Fig. 3.
Conclusions It is essential that both endoscopists and pathologists get familiar with current recommendations for the diagnosis and treatment of dysplasia in IBD. Although interobserver variability in the pathological diagnosis of dysplasia remains a challenge, the application of strict and validated criteria leads to higher and more reliable levels of agreement among pathologists. The complexity associated with the diagnosis and treatment of dysplasia in IBD requires the involvement of a specialized team of GI pathologists and endoscopists that can effectively collaborate in implementing best treatment options.
References 1. Triantafillidis J, Nasioulas G, Kosmidi P.Colorectal Cancer and Inflammatory Bowel Disease: Epidemiology, Risk Factors, Mechanisms of Carcinogenesis and Prevention Strategies. Anticancer Res 2009; 29: 2727-2738 2. Lucas M. Inflammatory Bowel Disease as a Risk Factor for Colorectal Cancer. Dig Dis. 2010:619-624. 3. Thomas T, Abrams KA, Robinson RJ et al. Meta-analysis: Cancer risk of low grade dysplasia in chronic ulcerative colitis. Aliment Pharmacol Ther 2007;25:657-668. 4. Odze R, Goldblum J, Noffsinger A et al. Interobserver variability in the diagnosis of ulcerative colitis-associated dysplasia by telepathology. Mod Pathol 2002;379-386 5. Odze R, Tomaszewski J, Feldman M et al. Variability in the diagnosis of dysplasia in ulcerative colitis by dynamic telepathology. Oncol Rep 2006;16:1123-1129.
