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Reprint of: The natural history of adenomas
Best Practice & Research Clinical Gastroenterology 24 (2010) 397–406
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Best Practice & Research Clinical Gastroenterology
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Reprint of: The natural history of adenomasq Mauro Risio, Head of Department * Unit of Pathology, Institute for Cancer Research and Treatment (IRCC), Strada Provinciale 142, Km. 3,95, 10060 Candiolo, Torino, Italy
Keywords: Colorectal adenomas Cancerised adenoma Dysplasia Serrated polyps Tumour progression
It is well known that adenomas represent the morphologically categorised precursor of the vast majority of colorectal cancers. Only few adenomas actually develop invasive cancer (progressive adenomas), although every adenoma has the capacity of malignant evolution. Most adenomas stabilise their progression or even regress. Easily identifiable but widely ranged pathological features (size, architectural growth, type, grade and gross organisation of dysplasia) are predictive of their natural history in terms of potential of cancerisation and duration of the adenoma–carcinoma sequence. Knowledge of the biological machineries sustaining the progression rates and times could be crucial to refine the natural history assumptions in screening modelling. Ó 2010 Elsevier Ltd. All rights reserved.
The adenoma–carcinoma sequence: a stochastic model Every epithelial cancer, namely every carcinoma, including adenocarcinoma of the large bowel, is preceded by a pre-invasive stage of intra-epithelial neoplasia that lasts for years. The neoplastic process is therefore a single, indivisible continuum that begins and is confined within the epithelium (here the name ‘intra-epithelial neoplasia’) until invasion across the basement membrane occurs, at which time the term ‘carcinoma’ applies. From the morphological standpoint, the term ‘dysplasia’ is conventionally applied to the collection of changes in cellular morphology and tissue architecture that define intraepithelial neoplasia. The severity of intra-epithelial neoplasia is estimated from the degree of deviation from normal cellular morphology and differentiation pattern: the neoplastic process is thought to progress towards carcinoma through dysplasia of increasing severity. Intra-epithelial neoplasia is a monoclonal, multifocal, multistage process with heterogeneous phenotype generally arising within an epithelium affected by an extensive or diffuse field defect in q A publisher’s error resulted in this article appearing in the wrong issue. The article is reprinted here for the reader’s convenience and for the continuity of the special issue. For citation purposes, please use the original publication details; Best Practice; Research Clinical Gastroenterology, 24 (3) pp. 271–280. **DOI of original item: 10.1016/j.bpg.2010.04.005**. * Tel.: þ39 011 9933465; fax: þ39 011 9933480. E-mail address: [email protected]. 1521-6918/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2010.08.002
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several biological functions. A model exhaustively describing the natural history of intra-epithelial neoplasia is clonal evolution. According to this model, genetic instability, as manifested by gene mutations, gene amplifications, chromosomal structural rearrangements and defects, is the basis for the continuous production of genetically variant cells with selection and clonal expansion of those variants with phenotypical and growth advantages (i.e., neoplastic microdarwinism). Above all, intraepithelial neoplasia is a stochastic process in which each stage is probabilistically linked with different evolutive pathways (progression, regression and stabilisation) rather than deterministically associated with the onset of carcinoma [1]. As is the proposal of tumour progression, each stage is more likely to proceed to the next, but could also remain stable (probably fairly frequent), directly to proceed to develop a clone with malignant (invasive) phenotype or even regress. Whereas the magnitude of risk for progression parallels severity of dysplasia, regression is supposed to be likely along the course of early, pre-morphological changes. From aberrant crypts towards adenoma Several measurable indicators of cellular or molecular pre-morphological events associated with tumourigenesis in histologically normal colorectal mucosa have been detected in high-risk groups for colorectal cancer, as well as changes of genomic and epigenomic profiles [2]. Sound evidence exists that cell proliferation changes in histologically normal mucosa are early events, directly and closely associated with tumourigenesis [3]. In short, colorectal neoplasia is associated with complex changes in cell proliferation throughout the mucosa of the large intestine, which can be broken down into two elementary alterations, hyperproliferation and the upward shift of the proliferative compartment [4]. The cell proliferation profiles of the adenomatous crypt recapitulate, in accordance with the unifying model of ‘top-down morphogenesis’, such proliferative abnormalities: irrespective of the grade of dysplasia, in fact, the earliest stage in the genesis of an adenoma is an upward shift of the proliferative zone followed by retrograde migration of S-phase cells to the base of the crypt and hence the genesis of a single-crypt adenoma. From the morphological point of view, single-crypt adenoma is the basic, minimal lesion of colonic intra-epithelial neoplasia, being the morphological steps preceding single-crypt adenoma unknown in humans and identifiable in animal models only, using Western-style diets. In such a nutritionally induced model, the morphological changes that precede single-crypt adenoma (i.e., sub-crypt dysplasia) have been observed [5]. Subsequent cycles of crypt budding and fissions sustain the progressive expansion of dysplastic crypts through oligo-crypt adenomas (so called: aberrant crypt foci, ACF) to grossly evident adenomas or adenomatous polyps of the large bowel [6]. Clinical, epidemiological and biological evidences support the role of ACF in human colorectal tumourigenesis as a putative precursor to colorectal adenomas [7] even if their fast yearly turnover indicates the dynamic nature of the process, and impairs their use as a clinical intermediate biomarker [8].
Practice points Microadenomas represent the earliest morphological phase of human colorectal tumourigenesis. Instability of microadenomas inhibits their clinical application.
Progressive and non-progressive adenomas The adenoma–carcinoma sequence is a worthy model of tumour progression, according to which the accumulation of genetic alterations in the neoplastic clone leads to the emergence of tumoural subpopulations with progressively ingravescent phenotype. Adenomas with low- and high-grade dysplasia are intermediate steps, and carcinoma infiltrating the intestinal wall at various levels is the end point of the sequence. Adenomatous growth is progressive, and the increase in size parallels the grade of dysplasia. Although every adenoma has the capacity of malignant evolution, only few
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adenomas develop invasive cancer: a survey comparing adenoma prevalence and carcinoma incidence demonstrated that the percentage of transformation is about 0.25% per year [9]. Few adenomas can stabilise their volume or regress completely [10]. The potential of malignant evolution is correlated to size, growth pattern and grade of dysplasia. Adenoma size is relevant, considering that cancerisation occurs in 1% of less than 1-cm adenomas, in 10% of adenomas >1 cm and <2 cm, and in 50% of adenomas larger than 2 cm [11]. Since the three-dimensional subgroups made up the 60%, 23% and 17% of the above-mentioned series, respectively, the proportion of cancer arising in adenomas less than 1 cm in the general population is supposed to be very low (about 5%) [12]. Histological features that determine the malignant potential of an adenoma are the growth pattern and the grade of dysplasia. In adenomas mainly displaying a villous architectural configuration (tubulo-villous and villous), the risk of cancerisation rises to 17%, and pikes 37% in those with high-grade dysplasia [9]. It is well established that adenoma size is the major independent risk factor for the development of villous growth and highgrade dysplasia, and the grade of dysplasia, in turn, represents the most important determinant for the malignant transformation of adenomatous polyps [13]. The rate of clonal evolution is driven and concurrently accelerated by the rate of mutagenesis and cell proliferation of the neoplastic population. When direct clastogenic damage occurs, atypical mitoses are the morphological hallmark of genetic damage, indicating the loss of symmetry in cell division and the onset of DNA ploidy evolution. For this reason, the proportion of atypical mitoses closely reflects the potential of progression of adenomas, and a weak association of the malignancy potential was actually found with atypical mitoses [14]. Under these circumstances, apoptotic surveillance is activated, to delete the genetically abnormal cells. It is conceivable that the fall of apoptotic surveillance contributes to the clonal expansion of DNA-altered cells. Both mutagens and mitogens drive the rate of neoplastic progression, and Druckrey first quantitatively demonstrated an inverse relationship between the dose level of carcinogen and the length of the tumour latent period [1]. Although factors influencing mito–mutagenesis in the colon are not defined yet, the median times for malignant transformation of adenomas are known, ranging 7–11 in high-grade and low-grade dysplasia adenomas, respectively [15]. New biomarkers are required, to identify faster-progressing adenomas, with a shorter sojourn time (i.e., the duration between onset of a progressive adenoma and the identification of subsequent cancer), to be searched among morphological or molecular characteristics featuring muta and mitogenesis processes (e.g., atypical mitoses/apoptosis ratio). Although there are biological reasons to support dysplasia as the most predictive marker of cancerisation risk, the link between size and adenoma malignancy is greater than the one linking dysplasia and malignancy [12]. Furthermore, recent data from screening programmes [16] indicate only few subsets of subjects with high-grade dysplasia adenomas at risk for metachronous advanced neoplasia. A key role for a stage II promoter (a continuing weak promotion subsequent to a strong, initial conversion to promotability by a stage I promoter) could therefore be hypothesised (in accordance with the Berenblum model [1]), leading the growth of small or even diminutive low-grade dysplasia adenomas to advanced, large, villous and/or high-grade dysplasia, malignancy prone adenomas. The ‘snowplough’ pattern is supposed to represent the morphological counterpart of the twice-promoted clones bulking the dysplastic tissue [1]. Gene mutations sustaining stage II promotion could concern guanine– thymidine (G–T) transversions of Kirsten rat sarcoma virus genome (K-ras), which have been shown to be linked with aneuploidy and severe nuclear dysplasia [17],or Adenomatous Polyposis Coli (APC) somatic mutations in the critical sites of the beta-catenin degradation domain, that convey a selective advantage to the colonic adenomas by altering the apoptotic surveillance, which in turn increases the potential of malignant transformation [18]. Reasonably, research could also be focussed on the effect of derangement exerted by caspase2-mediated mitotic catastrophe on tumour progression [19].
Practice points The grade of dysplasia is highly predictive of the malignant transformation of adenomas. Adenoma size is the major risk factor for villous growth and high-grade dysplasia. The average time for malignant transformation is known.
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Research agenda Studies are required to identify the genetic events leading from small to advanced adenomas. Biomarkers for adenomas with a longer premalignant phase need to be defined. Regression of adenomas Among the dynamics of the natural history of the adenoma–carcinoma sequence, regression of adenomas has to be taken into account. Spontaneous regression of small (less than 5 mm) sporadic adenomatous polyps was demonstrated in short-term studies to frequently occur in the distal rectum [10], and has been hypothesised in long-term investigation to explain paradoxical changes in adenoma prevalence along the course of screening programmes [20]. Spontaneous regression of the residual adenomas after colectomy and ileo-rectal anastomosis was observed in patients with familial adenomatous polyposis, and induced by sulindac in the same patients [21]. The role of apoptosis in inducing regression was supposed even if apoptosis turned out not to be predictive of the response to the treatment [22]. Histologically, apoptosis activation, stromal lymphoid infiltration and microvessel thrombosis have been seen in regressing adenomas, suggesting the contribution of different mechanisms (programmed cell death, immune response and vascular failure). More recently [23] mechanisms involving the APC–beta-catenin–Wnt pathway have been suggested. Research is therefore needed to elucidate the biological mechanisms responsible for drug-induced regression. On the other hand, studies have denied the possibility of spontaneous regression for adenomas up to 9-mm in size [24]. Currently, regression is thought to be a dynamic process simultaneously involving both formation and regression of adenoma cohorts, likewise the cyclic fluctuation of ACF. This is worthy of being further investigated, considering its impact on the modelling and effectiveness of colorectal cancer screening programmes [25]. Non-polypoid neoplasia: flat and depressed adenomas Colon intra-epithelial neoplasia assumes different form of gross organisation. Polypoid adenoma (peduncolated or sessile), the most frequent one, is a circumscribed benign neoplasm composed of tubular and/or villous structures lined by dysplastic epithelium. Non-polypoid adenomas (slightly elevated, completely flat, slightly depressed) corresponding to type IIa, IIb, IIc of the endoscopically identified lesions in accordance to Paris Classification, can also occur. All these can lead, although with significant differences in duration, recurrence rate and elapsed time, to the development of one or more cancers in the large bowel, wherein evidence exists for a significantly higher risk of harbouring high-grade mucosal neoplasia or invasive carcinoma in non-polypoid with respect to polypoid adenomas [26] as a result of different molecular carcinogenetic pathways acting in the two subgroups [27]. High-grade dysplasia or invasive cancer can be found in 75% of depressed adenomas as compared with 14.3% and 8.3% of flat and polypoid adenomas, respectively. Furthermore, the average size of cancerised non-polypoid adenomas is smaller with respect to cancerised polyps (1.4 vs. 2.3 cm) [28]. Practice points Depressed adenomas have the highest risk to be cancerised at the time of diagnosis.
Research agenda Endoscopy–histology concordance needs to be perfected, to improve the identification of true non-polypoid adenomas.
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Serrated neoplasia and serrated adenomas Colonic epithelial serration, namely the saw-toothed outline derived from infolded epithelial tufts in the crypt and in the luminal surface, occurs in consequence of the undue accumulation of cells, following the loss of the homeostatic trophism. Transient serration associated with hyperproliferation can be found in reparative and regenerating colonic epithelium, whereas steady serration in the absence of hyperproliferation is displayed in the common hyperplastic polyps of the large bowel, in consequence of the inhibition of programmed cell death [29,30]: dysregulation of apoptotis is therefore the basic event triggering and sustaining serrated tumourigenesis (‘bottom-up morphogenesis’) [31,32]. Hyperplastic polyps are small-sized (0.2–0.5 cm) mucosal bumps of the sigmoid colon and rectum regarded as non-neoplastic lesions since no firm evidence has yet been presented of a greater likelihood of cancerisation of these polyps in comparison with the normal mucosa, and it is also well known that minimal changes of Lieberkhun crypts in the absence of dysplasia (so called ‘ACF, non-dysplastic type’) can lead to hyperplastic polyps. In effect, the absence of dysplasia, normal cell proliferation and cell hypermaturation are all characteristics supporting the non-neoplastic nature of hyperplastic polyps [33]. On the other hand, hyperplastic polyps are more frequent in colonic segments with carcinoma, share some phenotypic features with colorectal adenocarcinoma and are associated with lifestyle risk factors linked with neoplastic polyps [34]. Hyperplastic polyps are likely to be markers of the action of an environmental factor interacting in the initiation stage of colorectal tumourigenesis, but not influencing promotion: they are paraneoplastic rather than neoplastic lesions, even though the specific mechanisms that orientate the mucosa towards hyperplastic differentiation remain to be elucidated. Dysplasia can affect the serrated epithelium of hyperplastic polyps, featuring mainly right-sided colonic neoplastic polyps, the serrated adenomas, and providing the rationale for a new path of colonic dysplasia: the serrated neoplasia. It represents a unique precancerous morphogenetic pathway in that architectural abnormalities precede and are often uncoupled from nuclear and cytological dysplastic changes [35]. Sessile serrated adenomas (SSA) are right-sided, large-sized (>1 cm) sessile lesions displaying patchy or diffuse distortions of tissue organisation consistent with architectural dysplasia (i.e., branching of crypts; serration or foveolar cell phenotype at the base of the crypt; dilatation at the base of the crypt; and horizontal crypt growth). Intermingling and/or intermediate features of SSA and hyperplastic polyp can often be seen in the same histological section, above all in small polyps, impairing diagnostic reproducibility [36]. It has to be taken into account, however, that the prevalence of SSA in patient undergoing colonoscopy is 1.9%, and that they represent 7–15% of serrated polyps [37]. It has been estimated that only 8.3% of the polyps previously diagnosed as hyperplastic polyps would now be reclassified as SSA, and such a level of diagnostic accuracy is felt acceptable to support clinical decision making [36]. On the other hand, in traditional serrated adenomas (TSA) (serrated adenoma, polypoid type) nuclear (elongated, hyperchromatic, stratified nuclei) and cytological frankly dysplastic features are seen within the serrated epithelium, besides the architectural ones. A serrated dysplasia– carcinoma sequence exists, as a matter of fact, being histologically proven the transition to malignancy of serrated adenomas [38]. A tumourigenetic pathway parallels therefore the classical adenoma– carcinoma sequence of the large bowel, leading, through evolutive metaplasia of the colonic epithelium and progressive steps of architectural and nuclear dysplasia, to colorectal cancer. Mixed serrated polyps (MSP) include within a single lesion a serrated (dysplastic or non-dysplastic) and a conventional dysplastic component (tubular, tubulo-villous and villous adenoma) morphologically combining, in accordance with the recently proposed ‘fusion model’ [39], the two major routes of colorectal tumourigenesis, the adenoma–carcinoma sequence and the serrated pathway. The observation that most cancerised SSA display transition sectors of classical adenoma between SSA and invasive carcinoma [35] is also consistent with this interpretation. Such polyps, occurring in large number in hyperplastic polyposis [40], in attenuated familial adenomatous polyposis and in MUTYH gene-associated polyposis [41,42] are thought to be relatively aggressive, exploiting both hyperproliferation of adenomas and apoptosis inhibition of serrated neoplasia [39]. Taken together, these evidences indicate that a multistep progression exists, leading from serrated adenomas towards colorectal carcinoma through the transition from architectural to nuclear and cytologic dysplasia or the conversion to classical adenomatous dysplasia, the latter being even more common than evolution to advanced dysplasia [35].
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Methylation of CpG islands in the promoter regions of several genes is the genetic machinery sustaining the evolution of serrated neoplasia (CpG islands methylator phenotype, CIMP), involving at different rates p14, p16, oestrogen receptor, DNA repair genes hMLH1 and O-6-methylguanine-DNA methyltransferase (MGMT), Ras Association Domain Family 1A (RASSF1), APC, cyclooxygenase (COX)-2, E-cadherin gene (CDH1) and anonymous marker genes (methylated-in-tumor-1 (MINT1), MINT2, MINT31) [43]. CIMP drives serrated tumourigenesis by silencing pro-apoptotic (e.g., RASSF1, RASSF2) and cell-cycle inhibitory (p16, p14, p19, Rb) genes, whilst epigenetic suppression of DNA repair genes hMLH1 and MGMT, inducing high-level MSI, would represent the rate-limiting step for tumour progression [44]. BRAF-proto-oncogene serine/threonine protein kinase mutations are likely to represent the initiating event, unlinked with the action of the CIMP machinery, in the serrated tumourigenesis [45]. Acquisition of a BRAF mutation appears to be associated with the progression of hyperplastic polyps to SSA [46], whereas fusion pathways involving the sequential alterations of genes KRAS, APC, TP53 and O-6-methylguanine-DNA methyltransferase (MGMT) could lead from hyperplastic polyps to MSP and TSA [39]. Stochastic modelling is conceivable for serrated neoplasia, although the evolutive rates of the lesions are unknown at the present time. On the whole, 10–15% of colorectal cancers are expected to originate from serrated polyps [47]. The actual risk of malignant evolution in SSA is undefined, although a subset of these lesions appears to give rise to carcinoma often less than a few millimetres in size. A total of 37% of TSA show high-grade dysplasia, and 11% show intramucosal adenocarcinoma [48]. The evolutive speed is not completely known yet: roughly, the time elapsed from the diagnosis of SSA and the onset of advanced carcinoma is greater than three and five years in 90% and 55% of cases, respectively [49]. The overall association between serrated dysplasia and cancer (5.8%) [38] peaks 55% in cancers showing microsatellite instability [49,50] and 54–70% in hyperplastic (serrated) polyposis [51]. Based on the current knowledge, recommendations for treatment of serrated neoplasia should consider (1) location and size of the lesion, as critical issues for endoscopic removal; and (2) evidence of nuclear and cytologic dysplasia, featuring high-risk serrated polyps (TSA or MSP). Left-sided endoscopically removed SSA of any size is suitable to be followed-up as low-risk adenomatous polyps, and TSA and MSP as high-risk adenomatous polyps. It is advisable to follow-up as low-risk adenomatous polyps the small (<1 cm), right-sided, endoscopically completely removed SSA; incompletely removed, large (>1 cm) SSA should be repeatedly biopsied until the onset of cytologic dysplasia: then surgical excision and follow-up as high-risk adenomatous polyps. Major surgery and follow-up as high-risk adenomatous polyps are recommended for right-sided TSA and MSP [35].
Practice points SSAs have to be distinguished from hyperplastic polyps. SSAs are prevalently right-sided and large-sized sessile lesions. Management of serrated neoplasia is based on location, size and grade of nuclear dysplasia of the lesions.
Research agenda Investigations are needed to define the long-term natural history of SSAs and their actual risk of cancerisation.
Cancerised adenomas: the early metastatic phenotype Colorectal adenomas containing invasive carcinoma (ACIC) comprise a carcinoma invading the submucosa but not the muscular layer. ACIC are a key stage in the large bowel tumour sequence since they represent the earliest form of clinically relevant colorectal cancer in most patients. Because of the
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paucity of lymphatic vessels in the mucosa [52], polyps harbouring ‘in situ’ or intramucosal carcinoma are neither regarded nor treated as malignant polyps. Neoplastic invasion of the submucosa opens the way to metastasis via the lymphatic and blood vessels, and the choice between surveillance and major surgery will turn on the metastatic potential of ACIC. Easily identifiable but widely ranged morphological parameters alone (grade of the invasive carcinoma, lymphovascular invasion, state of the resection margin and width and depth of submucosal invasion) determine whether a low (7%) or high (35%) risk of metastasis exists [53]. The different histological risk factors can be further linked with distinct clinical outcomes: a positive resection margin is predictive of local disease, poorly differentiated carcinoma of haematogenous metastasis and cancer-related mortality and vascular invasion of lymph node metastasis [54]. More recently, a unique histologic feature, tumour budding (namely the presence of scattered isolated single cells or small cluster of cells at the advancing edge of the cancer), has been demonstrated to be a reliable marker of the metastatic potential of cancerised adenomas. Budding describes the biological behaviour of the tumour at the front of invasion in terms of epithelial– mesenchymal interactions [55] and its ability to predict metastases compared with the previously identified histologic factors has been proven [56,57]. On the whole, two distinct profiles are identifiable in the natural history of cancerised adenomas, in terms not only of lymph node metastases, but also of haematogenous spread, recurrence and mortality. This suggests the possibility that the malignant polyp represents the end point of two different, although morphologically indistinguishable, tumourigenic and genetic pathways, the former blocking the growth of early cancer, the latter allowing its fast progression towards advanced colorectal cancer [54]. When malignant transformation of colonic intra-epithelial neoplasia occurs, carcinoma has been thought to progress invariably, from invasion of the submucosa (i.e., ‘early colorectal cancer’, pT1 stage according to TNM system) through the extension to the deeper structures of the intestinal wall (i.e., ‘advanced colorectal cancer’, pT2–pT4 stages). The transition pT1–pT4 is thought to be a continuous, progressive, irreversible process, which parallels the metastatic ratio and the decreased survival of patients [58]. Several chromosome defects keep up with morphological evolution in colorectal tumour progression. Whilst 1p deletions represent an early event, numerical aberrations affecting chromosomes 7 and 18, 17p and 18q deletions were reported to be the most frequent late-stage events. A stochastic model has been hypothesised for colorectal carcinoma, in which the transition from early to advanced stages is probabilistically regulated by the loss of subtelomeric region in 17p [59]. Early colorectal cancer with loss of chromosome 17 actually represents the emergence from high-grade dysplasia adenomatous tissue of a cell clone with genotypically determined low proliferative levels, low DNA aneuploidy evolution rates and tendency to stabilise without further increase of the tumour stage. The opposite is true for colorectal cancers with 17p deletions, in which the invasion of the submucosa is likely to represent a fast transition towards the progressive invasion of cancer through the intestinal wall.
Practice points Cancerisation of colorectal adenomas requires the neoplastic invasion of the submucosa. Histological features (grade of carcinoma, lymphovascular invasion, resection margin and tumour budding) predict the clinical outcomes of cancerised adenomas.
Research agenda Studies are needed to assess the diagnostic reproducibility of tumour budding. Further research should define the biopathological features of non-progressive cancerised adenomas.
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Progression/stabilisation ratios along the natural history of colorectal adenomas could bias the effectiveness of screening programmes: Lead time bias. Diagnostic anticipation of preclinical phase uncoupled from changes in mortality. Removal of small, low-grade dysplasia adenomas with a low rate of neoplastic progression; Length bias. Identification and removal of adenomas uninvolved by the second-stage promoter and therefore likely for a long preclinical phase, more susceptible to screening detection than aggressive and rapidly evolving twice-promoted adenomas; and Identification bias. A subset of early cancers might be detected, which are genotypically determined to stabilisation. To summarise, in accordance with stochastic modelling of colorectal tumour progression, each step of the dysplasia–carcinoma sequence, from single-crypt dysplasia to cancerised adenoma, can be probabilistically profiled in terms of evolutive pathways (progression, regression and stabilisation). At present, dysplasia represents the mainstay of clinical decision making, assessing the potential of malignant evolution of adenomatous polyps. Nevertheless, new biomarkers are required for refining the identification of subsets of high-risk, high-grade dysplasic adenomas independently from the relationships with size, site and architecture of growth. This is also true for the duration and transition times of adenomas. Dysplasia can affect the serrated epithelium of hyperplastic polyps, featuring rightsided colonic neoplastic polyps, the serrated adenomas. Serrated adenomas are potentially evolutive neoplastic lesions, maximally presented in hyperplastic polyposis, to be histologically classified and appropriately managed. Regression of both micro and gross adenomas is well established, but it is likely to be conceived as a dynamic process, with overlapping phases of regression and growth of cancer precursors. Few, genotypically determined, cancerised adenomas are prone to stabilisation, instead of progressing towards advanced stages of colorectal cancer. These could represent an identification bias for screen-detected malignant polyps and impair the efficacy of the interventions. Conflict of interest None. References* [1] Boone CW, Kelloff GJ, Freedman SL. Intraepithelial and postinvasive neoplasia as a stochastic continuum of clonal evolution. J Cell Biochem 1993;17G:14–25. [2] Chen L-C, Hao C-Y, Chiu YSY, Wong P, Melnick JS, Brotman M, et al. Alteration of gene expression in normal-appearing colon mucosa of APCmin mice and human cancer patients. Cancer Res 2004;64:3694–700. [3] Akedo I, Ishikawa H, Ioka T, Kaji I, Narahara H, Ishiguro S, et al. Evaluation of epithelial cell proliferation rate in normal-appearing colonic mucosa as a high-risk marker for colorectal cancer. Cancer Epidemiol Biomarkers Prev 2001;10: 925–30. [4] Risio M, Lipkin M, Candelaresi GL, Bertone A, Coverlizza S, Rossini FP. Correlations between rectal mucosa cell proliferation and the clinical and pathological features of nonfamilial neoplasia of the large intestine. Cancer Res 1991;51: 1917–21. [5] Risio M, Lipkin M, Newmark H, Yang K, Rossini FP, Steele VE, et al. Apoptosis, cell replication, and western-style dietinduced tumorigenesis in colon. Cancer Res 1996;56:4910–6. *[6] Wong WM, Mandir N, Goodlad RA, Wong BC, Garcia SB, Lam SK, et al. Histogenesis of colorectal adenomas and hyperplastic polyps: the role of cell proliferation and crypt fission. Gut 2002;50:212–7. [7] Figueiredo P, Donato M, Urbano M, Goulao H, Sofia C, Leitao M, et al. Aberrant crypt foci: endoscopic assessment and cell kinetics characterization. Dis Colon Rectum 2009;24:441–50. [8] Schoen RE, Mutch M, Rall C, Dry SM, Seligson D, Umar A, et al. The natural history of aberrant crypt foci. Gastrointest Endosc 2008;67:1097–102. *[9] Eide TJ. Risk of colorectal cancer in adenoma-bearing individuals within a defined population. Int J Cancer 1986;15:173–6. [10] Hoff G, Foerster A, Vatn MH, Sanar J, Larson S. Epidemiology of polyps in the rectum and colon: recovery and evaluation of unresected polyps two years after detection. Scand J Gastroenterol 1986;21:853–62. *[11] Muto T, Bussey HJR, Morson BC. The evolution of cancer of the rectum. Cancer 1975;36:2251–70.
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Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008;299:1027–35. [27] Hiraoka S, Kato J, Tatsukawa M, Harada K, Fujita H, Morikawa T, et al. Laterally spreading type of colorectal adenoma exhibits a unique methylation phenotype and K-ras mutations. Gastroenterology 2006;131:379–89. *[28] Soetikno R, Friedland S, Kaltenbach T, Chayama K, Tanaka S. Nonpolypoid (flat and depressed) colorectal neoplasms. Gastroenterology 2006;130:566–76. [29] Risio M, Sarotto I, Rossini FP, Newmark H, Yang K, Lipkin M. Programmed cell death, proliferating cell nuclear antigen and p53 expression in mouse colon mucosa during diet/induced tumorigenesis. Anal Cell Pathol 2000;2:87–94. [30] Tateyama H, Li W, Takahashi E, Miura Y, Sugiura H, Eimoto T. Apoptosis index and apoptosis-related antigen expression in serrated adenoma of the colorectum. The saw-toothed structure may be related to inhibition of apoptosis. 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Sessile serrated adenoma. Challenging discrimination from other serrated colonic polyps. Am J Surg Pathol 2008;32:30–5. [37] Higuchi T, Sugihara K, Jass JR. Demographic and pathological characteristics of serrated polyps of colorectum. Histopathology 2005;47:32–40. [38] Makinen MJ. Colorectal serrated adenocarcinoma. Histopathology 2007;50:131–50. [39] Jass JR, Baker K, Zlobec I, Higuchi T, Barker M, Buchaman D, et al. Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a “fusion” pathway to colorectal cancer. Histopathology 2006;49:121–31. [40] Rozen P, Samuel Z, Brazowski E. A prospective study of the clinical, genetic, screening, and pathologic features of a family with hereditary mixed polyposis syndrome. Am J Gastroenterol 2003;98:2317–20. [41] Matsumoto T, Iida M, Kobori Y, Mizuno M, Nakamura S, Hizawa K, et al. Serrated adenomas in familial adenomatous polyposis: relation to germline APC gene mutation. 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Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
2
Reprint of: The natural history of adenomasq Mauro Risio, Head of Department * Unit of Pathology, Institute for Cancer Research and Treatment (IRCC), Strada Provinciale 142, Km. 3,95, 10060 Candiolo, Torino, Italy
Keywords: Colorectal adenomas Cancerised adenoma Dysplasia Serrated polyps Tumour progression
It is well known that adenomas represent the morphologically categorised precursor of the vast majority of colorectal cancers. Only few adenomas actually develop invasive cancer (progressive adenomas), although every adenoma has the capacity of malignant evolution. Most adenomas stabilise their progression or even regress. Easily identifiable but widely ranged pathological features (size, architectural growth, type, grade and gross organisation of dysplasia) are predictive of their natural history in terms of potential of cancerisation and duration of the adenoma–carcinoma sequence. Knowledge of the biological machineries sustaining the progression rates and times could be crucial to refine the natural history assumptions in screening modelling. Ó 2010 Elsevier Ltd. All rights reserved.
The adenoma–carcinoma sequence: a stochastic model Every epithelial cancer, namely every carcinoma, including adenocarcinoma of the large bowel, is preceded by a pre-invasive stage of intra-epithelial neoplasia that lasts for years. The neoplastic process is therefore a single, indivisible continuum that begins and is confined within the epithelium (here the name ‘intra-epithelial neoplasia’) until invasion across the basement membrane occurs, at which time the term ‘carcinoma’ applies. From the morphological standpoint, the term ‘dysplasia’ is conventionally applied to the collection of changes in cellular morphology and tissue architecture that define intraepithelial neoplasia. The severity of intra-epithelial neoplasia is estimated from the degree of deviation from normal cellular morphology and differentiation pattern: the neoplastic process is thought to progress towards carcinoma through dysplasia of increasing severity. Intra-epithelial neoplasia is a monoclonal, multifocal, multistage process with heterogeneous phenotype generally arising within an epithelium affected by an extensive or diffuse field defect in q A publisher’s error resulted in this article appearing in the wrong issue. The article is reprinted here for the reader’s convenience and for the continuity of the special issue. For citation purposes, please use the original publication details; Best Practice; Research Clinical Gastroenterology, 24 (3) pp. 271–280. **DOI of original item: 10.1016/j.bpg.2010.04.005**. * Tel.: þ39 011 9933465; fax: þ39 011 9933480. E-mail address: [email protected]. 1521-6918/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2010.08.002
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several biological functions. A model exhaustively describing the natural history of intra-epithelial neoplasia is clonal evolution. According to this model, genetic instability, as manifested by gene mutations, gene amplifications, chromosomal structural rearrangements and defects, is the basis for the continuous production of genetically variant cells with selection and clonal expansion of those variants with phenotypical and growth advantages (i.e., neoplastic microdarwinism). Above all, intraepithelial neoplasia is a stochastic process in which each stage is probabilistically linked with different evolutive pathways (progression, regression and stabilisation) rather than deterministically associated with the onset of carcinoma [1]. As is the proposal of tumour progression, each stage is more likely to proceed to the next, but could also remain stable (probably fairly frequent), directly to proceed to develop a clone with malignant (invasive) phenotype or even regress. Whereas the magnitude of risk for progression parallels severity of dysplasia, regression is supposed to be likely along the course of early, pre-morphological changes. From aberrant crypts towards adenoma Several measurable indicators of cellular or molecular pre-morphological events associated with tumourigenesis in histologically normal colorectal mucosa have been detected in high-risk groups for colorectal cancer, as well as changes of genomic and epigenomic profiles [2]. Sound evidence exists that cell proliferation changes in histologically normal mucosa are early events, directly and closely associated with tumourigenesis [3]. In short, colorectal neoplasia is associated with complex changes in cell proliferation throughout the mucosa of the large intestine, which can be broken down into two elementary alterations, hyperproliferation and the upward shift of the proliferative compartment [4]. The cell proliferation profiles of the adenomatous crypt recapitulate, in accordance with the unifying model of ‘top-down morphogenesis’, such proliferative abnormalities: irrespective of the grade of dysplasia, in fact, the earliest stage in the genesis of an adenoma is an upward shift of the proliferative zone followed by retrograde migration of S-phase cells to the base of the crypt and hence the genesis of a single-crypt adenoma. From the morphological point of view, single-crypt adenoma is the basic, minimal lesion of colonic intra-epithelial neoplasia, being the morphological steps preceding single-crypt adenoma unknown in humans and identifiable in animal models only, using Western-style diets. In such a nutritionally induced model, the morphological changes that precede single-crypt adenoma (i.e., sub-crypt dysplasia) have been observed [5]. Subsequent cycles of crypt budding and fissions sustain the progressive expansion of dysplastic crypts through oligo-crypt adenomas (so called: aberrant crypt foci, ACF) to grossly evident adenomas or adenomatous polyps of the large bowel [6]. Clinical, epidemiological and biological evidences support the role of ACF in human colorectal tumourigenesis as a putative precursor to colorectal adenomas [7] even if their fast yearly turnover indicates the dynamic nature of the process, and impairs their use as a clinical intermediate biomarker [8].
Practice points Microadenomas represent the earliest morphological phase of human colorectal tumourigenesis. Instability of microadenomas inhibits their clinical application.
Progressive and non-progressive adenomas The adenoma–carcinoma sequence is a worthy model of tumour progression, according to which the accumulation of genetic alterations in the neoplastic clone leads to the emergence of tumoural subpopulations with progressively ingravescent phenotype. Adenomas with low- and high-grade dysplasia are intermediate steps, and carcinoma infiltrating the intestinal wall at various levels is the end point of the sequence. Adenomatous growth is progressive, and the increase in size parallels the grade of dysplasia. Although every adenoma has the capacity of malignant evolution, only few
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adenomas develop invasive cancer: a survey comparing adenoma prevalence and carcinoma incidence demonstrated that the percentage of transformation is about 0.25% per year [9]. Few adenomas can stabilise their volume or regress completely [10]. The potential of malignant evolution is correlated to size, growth pattern and grade of dysplasia. Adenoma size is relevant, considering that cancerisation occurs in 1% of less than 1-cm adenomas, in 10% of adenomas >1 cm and <2 cm, and in 50% of adenomas larger than 2 cm [11]. Since the three-dimensional subgroups made up the 60%, 23% and 17% of the above-mentioned series, respectively, the proportion of cancer arising in adenomas less than 1 cm in the general population is supposed to be very low (about 5%) [12]. Histological features that determine the malignant potential of an adenoma are the growth pattern and the grade of dysplasia. In adenomas mainly displaying a villous architectural configuration (tubulo-villous and villous), the risk of cancerisation rises to 17%, and pikes 37% in those with high-grade dysplasia [9]. It is well established that adenoma size is the major independent risk factor for the development of villous growth and highgrade dysplasia, and the grade of dysplasia, in turn, represents the most important determinant for the malignant transformation of adenomatous polyps [13]. The rate of clonal evolution is driven and concurrently accelerated by the rate of mutagenesis and cell proliferation of the neoplastic population. When direct clastogenic damage occurs, atypical mitoses are the morphological hallmark of genetic damage, indicating the loss of symmetry in cell division and the onset of DNA ploidy evolution. For this reason, the proportion of atypical mitoses closely reflects the potential of progression of adenomas, and a weak association of the malignancy potential was actually found with atypical mitoses [14]. Under these circumstances, apoptotic surveillance is activated, to delete the genetically abnormal cells. It is conceivable that the fall of apoptotic surveillance contributes to the clonal expansion of DNA-altered cells. Both mutagens and mitogens drive the rate of neoplastic progression, and Druckrey first quantitatively demonstrated an inverse relationship between the dose level of carcinogen and the length of the tumour latent period [1]. Although factors influencing mito–mutagenesis in the colon are not defined yet, the median times for malignant transformation of adenomas are known, ranging 7–11 in high-grade and low-grade dysplasia adenomas, respectively [15]. New biomarkers are required, to identify faster-progressing adenomas, with a shorter sojourn time (i.e., the duration between onset of a progressive adenoma and the identification of subsequent cancer), to be searched among morphological or molecular characteristics featuring muta and mitogenesis processes (e.g., atypical mitoses/apoptosis ratio). Although there are biological reasons to support dysplasia as the most predictive marker of cancerisation risk, the link between size and adenoma malignancy is greater than the one linking dysplasia and malignancy [12]. Furthermore, recent data from screening programmes [16] indicate only few subsets of subjects with high-grade dysplasia adenomas at risk for metachronous advanced neoplasia. A key role for a stage II promoter (a continuing weak promotion subsequent to a strong, initial conversion to promotability by a stage I promoter) could therefore be hypothesised (in accordance with the Berenblum model [1]), leading the growth of small or even diminutive low-grade dysplasia adenomas to advanced, large, villous and/or high-grade dysplasia, malignancy prone adenomas. The ‘snowplough’ pattern is supposed to represent the morphological counterpart of the twice-promoted clones bulking the dysplastic tissue [1]. Gene mutations sustaining stage II promotion could concern guanine– thymidine (G–T) transversions of Kirsten rat sarcoma virus genome (K-ras), which have been shown to be linked with aneuploidy and severe nuclear dysplasia [17],or Adenomatous Polyposis Coli (APC) somatic mutations in the critical sites of the beta-catenin degradation domain, that convey a selective advantage to the colonic adenomas by altering the apoptotic surveillance, which in turn increases the potential of malignant transformation [18]. Reasonably, research could also be focussed on the effect of derangement exerted by caspase2-mediated mitotic catastrophe on tumour progression [19].
Practice points The grade of dysplasia is highly predictive of the malignant transformation of adenomas. Adenoma size is the major risk factor for villous growth and high-grade dysplasia. The average time for malignant transformation is known.
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Research agenda Studies are required to identify the genetic events leading from small to advanced adenomas. Biomarkers for adenomas with a longer premalignant phase need to be defined. Regression of adenomas Among the dynamics of the natural history of the adenoma–carcinoma sequence, regression of adenomas has to be taken into account. Spontaneous regression of small (less than 5 mm) sporadic adenomatous polyps was demonstrated in short-term studies to frequently occur in the distal rectum [10], and has been hypothesised in long-term investigation to explain paradoxical changes in adenoma prevalence along the course of screening programmes [20]. Spontaneous regression of the residual adenomas after colectomy and ileo-rectal anastomosis was observed in patients with familial adenomatous polyposis, and induced by sulindac in the same patients [21]. The role of apoptosis in inducing regression was supposed even if apoptosis turned out not to be predictive of the response to the treatment [22]. Histologically, apoptosis activation, stromal lymphoid infiltration and microvessel thrombosis have been seen in regressing adenomas, suggesting the contribution of different mechanisms (programmed cell death, immune response and vascular failure). More recently [23] mechanisms involving the APC–beta-catenin–Wnt pathway have been suggested. Research is therefore needed to elucidate the biological mechanisms responsible for drug-induced regression. On the other hand, studies have denied the possibility of spontaneous regression for adenomas up to 9-mm in size [24]. Currently, regression is thought to be a dynamic process simultaneously involving both formation and regression of adenoma cohorts, likewise the cyclic fluctuation of ACF. This is worthy of being further investigated, considering its impact on the modelling and effectiveness of colorectal cancer screening programmes [25]. Non-polypoid neoplasia: flat and depressed adenomas Colon intra-epithelial neoplasia assumes different form of gross organisation. Polypoid adenoma (peduncolated or sessile), the most frequent one, is a circumscribed benign neoplasm composed of tubular and/or villous structures lined by dysplastic epithelium. Non-polypoid adenomas (slightly elevated, completely flat, slightly depressed) corresponding to type IIa, IIb, IIc of the endoscopically identified lesions in accordance to Paris Classification, can also occur. All these can lead, although with significant differences in duration, recurrence rate and elapsed time, to the development of one or more cancers in the large bowel, wherein evidence exists for a significantly higher risk of harbouring high-grade mucosal neoplasia or invasive carcinoma in non-polypoid with respect to polypoid adenomas [26] as a result of different molecular carcinogenetic pathways acting in the two subgroups [27]. High-grade dysplasia or invasive cancer can be found in 75% of depressed adenomas as compared with 14.3% and 8.3% of flat and polypoid adenomas, respectively. Furthermore, the average size of cancerised non-polypoid adenomas is smaller with respect to cancerised polyps (1.4 vs. 2.3 cm) [28]. Practice points Depressed adenomas have the highest risk to be cancerised at the time of diagnosis.
Research agenda Endoscopy–histology concordance needs to be perfected, to improve the identification of true non-polypoid adenomas.
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Serrated neoplasia and serrated adenomas Colonic epithelial serration, namely the saw-toothed outline derived from infolded epithelial tufts in the crypt and in the luminal surface, occurs in consequence of the undue accumulation of cells, following the loss of the homeostatic trophism. Transient serration associated with hyperproliferation can be found in reparative and regenerating colonic epithelium, whereas steady serration in the absence of hyperproliferation is displayed in the common hyperplastic polyps of the large bowel, in consequence of the inhibition of programmed cell death [29,30]: dysregulation of apoptotis is therefore the basic event triggering and sustaining serrated tumourigenesis (‘bottom-up morphogenesis’) [31,32]. Hyperplastic polyps are small-sized (0.2–0.5 cm) mucosal bumps of the sigmoid colon and rectum regarded as non-neoplastic lesions since no firm evidence has yet been presented of a greater likelihood of cancerisation of these polyps in comparison with the normal mucosa, and it is also well known that minimal changes of Lieberkhun crypts in the absence of dysplasia (so called ‘ACF, non-dysplastic type’) can lead to hyperplastic polyps. In effect, the absence of dysplasia, normal cell proliferation and cell hypermaturation are all characteristics supporting the non-neoplastic nature of hyperplastic polyps [33]. On the other hand, hyperplastic polyps are more frequent in colonic segments with carcinoma, share some phenotypic features with colorectal adenocarcinoma and are associated with lifestyle risk factors linked with neoplastic polyps [34]. Hyperplastic polyps are likely to be markers of the action of an environmental factor interacting in the initiation stage of colorectal tumourigenesis, but not influencing promotion: they are paraneoplastic rather than neoplastic lesions, even though the specific mechanisms that orientate the mucosa towards hyperplastic differentiation remain to be elucidated. Dysplasia can affect the serrated epithelium of hyperplastic polyps, featuring mainly right-sided colonic neoplastic polyps, the serrated adenomas, and providing the rationale for a new path of colonic dysplasia: the serrated neoplasia. It represents a unique precancerous morphogenetic pathway in that architectural abnormalities precede and are often uncoupled from nuclear and cytological dysplastic changes [35]. Sessile serrated adenomas (SSA) are right-sided, large-sized (>1 cm) sessile lesions displaying patchy or diffuse distortions of tissue organisation consistent with architectural dysplasia (i.e., branching of crypts; serration or foveolar cell phenotype at the base of the crypt; dilatation at the base of the crypt; and horizontal crypt growth). Intermingling and/or intermediate features of SSA and hyperplastic polyp can often be seen in the same histological section, above all in small polyps, impairing diagnostic reproducibility [36]. It has to be taken into account, however, that the prevalence of SSA in patient undergoing colonoscopy is 1.9%, and that they represent 7–15% of serrated polyps [37]. It has been estimated that only 8.3% of the polyps previously diagnosed as hyperplastic polyps would now be reclassified as SSA, and such a level of diagnostic accuracy is felt acceptable to support clinical decision making [36]. On the other hand, in traditional serrated adenomas (TSA) (serrated adenoma, polypoid type) nuclear (elongated, hyperchromatic, stratified nuclei) and cytological frankly dysplastic features are seen within the serrated epithelium, besides the architectural ones. A serrated dysplasia– carcinoma sequence exists, as a matter of fact, being histologically proven the transition to malignancy of serrated adenomas [38]. A tumourigenetic pathway parallels therefore the classical adenoma– carcinoma sequence of the large bowel, leading, through evolutive metaplasia of the colonic epithelium and progressive steps of architectural and nuclear dysplasia, to colorectal cancer. Mixed serrated polyps (MSP) include within a single lesion a serrated (dysplastic or non-dysplastic) and a conventional dysplastic component (tubular, tubulo-villous and villous adenoma) morphologically combining, in accordance with the recently proposed ‘fusion model’ [39], the two major routes of colorectal tumourigenesis, the adenoma–carcinoma sequence and the serrated pathway. The observation that most cancerised SSA display transition sectors of classical adenoma between SSA and invasive carcinoma [35] is also consistent with this interpretation. Such polyps, occurring in large number in hyperplastic polyposis [40], in attenuated familial adenomatous polyposis and in MUTYH gene-associated polyposis [41,42] are thought to be relatively aggressive, exploiting both hyperproliferation of adenomas and apoptosis inhibition of serrated neoplasia [39]. Taken together, these evidences indicate that a multistep progression exists, leading from serrated adenomas towards colorectal carcinoma through the transition from architectural to nuclear and cytologic dysplasia or the conversion to classical adenomatous dysplasia, the latter being even more common than evolution to advanced dysplasia [35].
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Methylation of CpG islands in the promoter regions of several genes is the genetic machinery sustaining the evolution of serrated neoplasia (CpG islands methylator phenotype, CIMP), involving at different rates p14, p16, oestrogen receptor, DNA repair genes hMLH1 and O-6-methylguanine-DNA methyltransferase (MGMT), Ras Association Domain Family 1A (RASSF1), APC, cyclooxygenase (COX)-2, E-cadherin gene (CDH1) and anonymous marker genes (methylated-in-tumor-1 (MINT1), MINT2, MINT31) [43]. CIMP drives serrated tumourigenesis by silencing pro-apoptotic (e.g., RASSF1, RASSF2) and cell-cycle inhibitory (p16, p14, p19, Rb) genes, whilst epigenetic suppression of DNA repair genes hMLH1 and MGMT, inducing high-level MSI, would represent the rate-limiting step for tumour progression [44]. BRAF-proto-oncogene serine/threonine protein kinase mutations are likely to represent the initiating event, unlinked with the action of the CIMP machinery, in the serrated tumourigenesis [45]. Acquisition of a BRAF mutation appears to be associated with the progression of hyperplastic polyps to SSA [46], whereas fusion pathways involving the sequential alterations of genes KRAS, APC, TP53 and O-6-methylguanine-DNA methyltransferase (MGMT) could lead from hyperplastic polyps to MSP and TSA [39]. Stochastic modelling is conceivable for serrated neoplasia, although the evolutive rates of the lesions are unknown at the present time. On the whole, 10–15% of colorectal cancers are expected to originate from serrated polyps [47]. The actual risk of malignant evolution in SSA is undefined, although a subset of these lesions appears to give rise to carcinoma often less than a few millimetres in size. A total of 37% of TSA show high-grade dysplasia, and 11% show intramucosal adenocarcinoma [48]. The evolutive speed is not completely known yet: roughly, the time elapsed from the diagnosis of SSA and the onset of advanced carcinoma is greater than three and five years in 90% and 55% of cases, respectively [49]. The overall association between serrated dysplasia and cancer (5.8%) [38] peaks 55% in cancers showing microsatellite instability [49,50] and 54–70% in hyperplastic (serrated) polyposis [51]. Based on the current knowledge, recommendations for treatment of serrated neoplasia should consider (1) location and size of the lesion, as critical issues for endoscopic removal; and (2) evidence of nuclear and cytologic dysplasia, featuring high-risk serrated polyps (TSA or MSP). Left-sided endoscopically removed SSA of any size is suitable to be followed-up as low-risk adenomatous polyps, and TSA and MSP as high-risk adenomatous polyps. It is advisable to follow-up as low-risk adenomatous polyps the small (<1 cm), right-sided, endoscopically completely removed SSA; incompletely removed, large (>1 cm) SSA should be repeatedly biopsied until the onset of cytologic dysplasia: then surgical excision and follow-up as high-risk adenomatous polyps. Major surgery and follow-up as high-risk adenomatous polyps are recommended for right-sided TSA and MSP [35].
Practice points SSAs have to be distinguished from hyperplastic polyps. SSAs are prevalently right-sided and large-sized sessile lesions. Management of serrated neoplasia is based on location, size and grade of nuclear dysplasia of the lesions.
Research agenda Investigations are needed to define the long-term natural history of SSAs and their actual risk of cancerisation.
Cancerised adenomas: the early metastatic phenotype Colorectal adenomas containing invasive carcinoma (ACIC) comprise a carcinoma invading the submucosa but not the muscular layer. ACIC are a key stage in the large bowel tumour sequence since they represent the earliest form of clinically relevant colorectal cancer in most patients. Because of the
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paucity of lymphatic vessels in the mucosa [52], polyps harbouring ‘in situ’ or intramucosal carcinoma are neither regarded nor treated as malignant polyps. Neoplastic invasion of the submucosa opens the way to metastasis via the lymphatic and blood vessels, and the choice between surveillance and major surgery will turn on the metastatic potential of ACIC. Easily identifiable but widely ranged morphological parameters alone (grade of the invasive carcinoma, lymphovascular invasion, state of the resection margin and width and depth of submucosal invasion) determine whether a low (7%) or high (35%) risk of metastasis exists [53]. The different histological risk factors can be further linked with distinct clinical outcomes: a positive resection margin is predictive of local disease, poorly differentiated carcinoma of haematogenous metastasis and cancer-related mortality and vascular invasion of lymph node metastasis [54]. More recently, a unique histologic feature, tumour budding (namely the presence of scattered isolated single cells or small cluster of cells at the advancing edge of the cancer), has been demonstrated to be a reliable marker of the metastatic potential of cancerised adenomas. Budding describes the biological behaviour of the tumour at the front of invasion in terms of epithelial– mesenchymal interactions [55] and its ability to predict metastases compared with the previously identified histologic factors has been proven [56,57]. On the whole, two distinct profiles are identifiable in the natural history of cancerised adenomas, in terms not only of lymph node metastases, but also of haematogenous spread, recurrence and mortality. This suggests the possibility that the malignant polyp represents the end point of two different, although morphologically indistinguishable, tumourigenic and genetic pathways, the former blocking the growth of early cancer, the latter allowing its fast progression towards advanced colorectal cancer [54]. When malignant transformation of colonic intra-epithelial neoplasia occurs, carcinoma has been thought to progress invariably, from invasion of the submucosa (i.e., ‘early colorectal cancer’, pT1 stage according to TNM system) through the extension to the deeper structures of the intestinal wall (i.e., ‘advanced colorectal cancer’, pT2–pT4 stages). The transition pT1–pT4 is thought to be a continuous, progressive, irreversible process, which parallels the metastatic ratio and the decreased survival of patients [58]. Several chromosome defects keep up with morphological evolution in colorectal tumour progression. Whilst 1p deletions represent an early event, numerical aberrations affecting chromosomes 7 and 18, 17p and 18q deletions were reported to be the most frequent late-stage events. A stochastic model has been hypothesised for colorectal carcinoma, in which the transition from early to advanced stages is probabilistically regulated by the loss of subtelomeric region in 17p [59]. Early colorectal cancer with loss of chromosome 17 actually represents the emergence from high-grade dysplasia adenomatous tissue of a cell clone with genotypically determined low proliferative levels, low DNA aneuploidy evolution rates and tendency to stabilise without further increase of the tumour stage. The opposite is true for colorectal cancers with 17p deletions, in which the invasion of the submucosa is likely to represent a fast transition towards the progressive invasion of cancer through the intestinal wall.
Practice points Cancerisation of colorectal adenomas requires the neoplastic invasion of the submucosa. Histological features (grade of carcinoma, lymphovascular invasion, resection margin and tumour budding) predict the clinical outcomes of cancerised adenomas.
Research agenda Studies are needed to assess the diagnostic reproducibility of tumour budding. Further research should define the biopathological features of non-progressive cancerised adenomas.
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Progression/stabilisation ratios along the natural history of colorectal adenomas could bias the effectiveness of screening programmes: Lead time bias. Diagnostic anticipation of preclinical phase uncoupled from changes in mortality. Removal of small, low-grade dysplasia adenomas with a low rate of neoplastic progression; Length bias. Identification and removal of adenomas uninvolved by the second-stage promoter and therefore likely for a long preclinical phase, more susceptible to screening detection than aggressive and rapidly evolving twice-promoted adenomas; and Identification bias. A subset of early cancers might be detected, which are genotypically determined to stabilisation. To summarise, in accordance with stochastic modelling of colorectal tumour progression, each step of the dysplasia–carcinoma sequence, from single-crypt dysplasia to cancerised adenoma, can be probabilistically profiled in terms of evolutive pathways (progression, regression and stabilisation). At present, dysplasia represents the mainstay of clinical decision making, assessing the potential of malignant evolution of adenomatous polyps. Nevertheless, new biomarkers are required for refining the identification of subsets of high-risk, high-grade dysplasic adenomas independently from the relationships with size, site and architecture of growth. This is also true for the duration and transition times of adenomas. Dysplasia can affect the serrated epithelium of hyperplastic polyps, featuring rightsided colonic neoplastic polyps, the serrated adenomas. Serrated adenomas are potentially evolutive neoplastic lesions, maximally presented in hyperplastic polyposis, to be histologically classified and appropriately managed. Regression of both micro and gross adenomas is well established, but it is likely to be conceived as a dynamic process, with overlapping phases of regression and growth of cancer precursors. Few, genotypically determined, cancerised adenomas are prone to stabilisation, instead of progressing towards advanced stages of colorectal cancer. These could represent an identification bias for screen-detected malignant polyps and impair the efficacy of the interventions. Conflict of interest None. References* [1] Boone CW, Kelloff GJ, Freedman SL. Intraepithelial and postinvasive neoplasia as a stochastic continuum of clonal evolution. J Cell Biochem 1993;17G:14–25. [2] Chen L-C, Hao C-Y, Chiu YSY, Wong P, Melnick JS, Brotman M, et al. Alteration of gene expression in normal-appearing colon mucosa of APCmin mice and human cancer patients. Cancer Res 2004;64:3694–700. [3] Akedo I, Ishikawa H, Ioka T, Kaji I, Narahara H, Ishiguro S, et al. Evaluation of epithelial cell proliferation rate in normal-appearing colonic mucosa as a high-risk marker for colorectal cancer. Cancer Epidemiol Biomarkers Prev 2001;10: 925–30. [4] Risio M, Lipkin M, Candelaresi GL, Bertone A, Coverlizza S, Rossini FP. Correlations between rectal mucosa cell proliferation and the clinical and pathological features of nonfamilial neoplasia of the large intestine. Cancer Res 1991;51: 1917–21. [5] Risio M, Lipkin M, Newmark H, Yang K, Rossini FP, Steele VE, et al. Apoptosis, cell replication, and western-style dietinduced tumorigenesis in colon. Cancer Res 1996;56:4910–6. *[6] Wong WM, Mandir N, Goodlad RA, Wong BC, Garcia SB, Lam SK, et al. Histogenesis of colorectal adenomas and hyperplastic polyps: the role of cell proliferation and crypt fission. Gut 2002;50:212–7. [7] Figueiredo P, Donato M, Urbano M, Goulao H, Sofia C, Leitao M, et al. Aberrant crypt foci: endoscopic assessment and cell kinetics characterization. Dis Colon Rectum 2009;24:441–50. [8] Schoen RE, Mutch M, Rall C, Dry SM, Seligson D, Umar A, et al. The natural history of aberrant crypt foci. Gastrointest Endosc 2008;67:1097–102. *[9] Eide TJ. Risk of colorectal cancer in adenoma-bearing individuals within a defined population. Int J Cancer 1986;15:173–6. [10] Hoff G, Foerster A, Vatn MH, Sanar J, Larson S. Epidemiology of polyps in the rectum and colon: recovery and evaluation of unresected polyps two years after detection. Scand J Gastroenterol 1986;21:853–62. *[11] Muto T, Bussey HJR, Morson BC. The evolution of cancer of the rectum. Cancer 1975;36:2251–70.
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