Molecular Pathogenesis of Gastrointestinal Neoplasia
Moderators: Dr. Wataru Yasui and Dr. Jeremy Jass
Section 4 -
Alternative Pathways of Colorectal Tumorigenesis
Michael J O'Brien and Shi Yang
Boston University School of Medicine
The Serrated Polyp Neoplasia Pathway
The serrated polyp neoplasia pathway comprises a morphologically distinct group of colorectal
neoplasms and represents, as proposed by Jass et al. , an alternative molecular pathway to colorectal
cancer. The sequence begins in a hyperplastic polyp (or precursor aberrant crypt focus(ACF) and
progresses via an atypical hyperplastic polyp variant to a serrated adenoma and ultimately to carcinoma.
The predominant carcinomas of this pathway, accounting for up to 10 – 15% of all colorectal
carcinomas(CRC), are adenocarcinomas that show defective DNA mismatch repair(MMR) resulting in
microsatellite instability(MSI-High), but they also include some proportion of carcinomas that are
microsatellite stable(MSS) or MSI-Low(MSI-L).
Serrated Carcinoma Characteristics
Most if not all sporadic MSI carcinomas have a serrated histogenesis. 
They tend to occur in the proximal colon, have an epidemiological association with cigarette smoking but
are, nonetheless, typically encountered in elderly females.  MSI carcinomas of the serrated pathway
show a polyclonal or polymorphous histological pattern  that includes well differentiated, often cystic
and papillary glands, areas of mucinous differentiation and poorly differentiated, insular, trabecular or
undifferentiated (medullary) architectural patterns. A lymphocytic response is apt to be prominent but
less so than in HNPCC.  Nuclei of these tumors tend to be round and vesicular with nucleoli contrasting
with the irregularity and hyperchromaticity of those of conventional CRC. Significantly, when a residual
adenoma is present it is likely to be a serrated adenoma differing also in that respect from CRC in HNPCC
which develops in a traditional adenoma.
Molecular Genetic Profiles
Adenomas (or aberrant crypt foci) of the traditional adenoma-carcinoma sequence are instigated by
mutations of the APC or b-catenin gene that lead to disruption of the Wnt
signaling pathway; the end-point carcinomas are characterized by chromosomal instability as distinct from
microsatellite instability.  Inactivation of suppressor genes that govern the progress to malignancy in
these neoplasms is due, primarily, to chromosomal deletions (loss of heterozygosity).
 The initiating
or significant early event of the serrated polyp neoplasia pathway, by contrast, appears to be activation
of the RAS-RAF-MAP-Kinase signaling pathway, most frequently by mutations of the BRAF oncogene. 
CpG-island methylation of promoter regions of key suppressor and mutator genes rather than chromosomal
deletion is the main engine of progression in the serrated pathway. 
In the case of BRAF(V600E)
mutated precursors, in particular, it can ultimately silence both alleles of the hMLH1 gene
resulting in MSI.  An activating mutation of KRAS2 appears to play an occasional role in both
pathways,  but is more frequently associated with the traditional adenoma-carcinoma sequence where such
mutations often appear in the intermediate stages of adenoma progression. 
The penultimate stage in the progression to carcinoma in this pathway is likely to be a serrated
adenoma,  although some have proposed that the atypical hyperplastic polyp variant serrated polyp with abnormal proliferation (syn.s: sessile serrated adenoma;
sessile serrated polyp)
may proceed directly to carcinoma.
Serrated adenomas, which represent
less than 1% of all adenomas, were first categorized as a distinct histological entity by Longacre and
Fenoglio-Preiser in 1990.  They have a serrated crypt architecture resembling that of a hyperplastic
polyp but exhibit dysplasia throughout, as in traditional adenomas. On one end of the morphologic
spectrum, these lesions may be difficult to distinguish from the HP variant SPAP
(syn: SSA; SSP), while on the opposite end of the spectrum SAs may resemble traditional
adenomas. Some have emphasized the presence of a predominant eosinophilic columnar cell phenotype in
addition to uniformly distributed dysplasia to distinguish SA from SPAP.  Varying proportions of SAs
may show a phenotype that closely resembles traditional adenoma or show a predominant goblet cell rather
than an eosinophilic columnar cell phenotype. A traditional adenoma-like pattern seen contiguous to
early MSI-H adenocarcinomas may represent a phenotypic variant of high grade dysplasia in SAs and SPAPs.
Goldstein  has suggested that this resemblance to traditional adenomas is spurious because a careful
examination of nuclear detail can reveal a basilar and cuboidal and finely granular appearance that
differs from the pencillate pseudostratified nuclei with coarsely granular chromatin of traditional (APC
Torlakovic and Snover,  in a study of a series of 6 patients with the hyperplastic polyposis
syndrome, including 4 with associated adenocarcinoma, first drew attention to an HP variant that was
prone to occur proximally in the colon and to show patterns of disordered growth very similar to that of
SA, although it lacked definite adenomatous or dysplastic changes. These polyps tended to be sessile and
the authors proposed the term sessile serrated adenoma(SSA) for this form of
HP. Taking a different approach, Goldstein et al.  also drew attention to the prevalence of HPs of
this type in the proximal colon in patients who later developed sporadic MSI cancer. Informed by their
earlier study of HPs in hyperplastic polyposis, Torlakovic et al.  applied a statistical analysis
method called cluster analysis, generally used for the analysis of microchip gene expression patterns, to
a panel of 24 different morphologic parameters in 289 sporadic HPs. The analysis identified 3 major
histologic sub-types of HPs, or serrated polyps: Goblet Cell Serrated Polyp (GCSP), Serrated Polyp with
Microvesicular Mucin (MVSP) and Serrated Polyp with Abnormal Proliferation (SPAP; syns: SSA;SPP).
Briefly, GCSPs are characterized by surface papillation and prominence of goblet cells; MVSPs are
distinguished by the predominance of microvesicular cells over goblet cells and serration extending to
mid crypt; SPAPs (syn.s: SSAs;SSPs) are identified by the abnormal architecture of the crypt bases with
branching, dilatation, papillary infolding, irregular shapes and long axes parallel to the bowel lumen;
other features include dystrophic goblet cells and mature cells with gastric foveolar phenotype in the
crypt base (inverted crypts).
Since then, molecular studies have validated this classification by demonstrating associations
between the 3 main subtypes and specific molecular genetic profiles.  Such studies also demonstrate
that HPs are in fact neoplasms, in that they represent clonal proliferations of genetically altered
epithelial cells of the colorectal mucosa. Furthermore, as Jass has suggested, their potential
importance may be that they represent "sanctuary neoplasms," that is, lesions that permit the
accumulation of genetic changes that in a normal crypt cell would activate apoptosis.  Although the
vast majority of HPs probably succumb to apoptosis, this protection may in some instances result in the
cumulative acquisition of mutations or epigenetic alterations of the genome that can result in further
neoplastic proliferation and ultimately invasive adenocarcinoma. Some of the genetic factors that govern
such outcomes may yield to studies of an autosomal dom inantly inherited predisposition to serrated
neoplasia, distinct from hyperplastic polyposis, recently described by Young et al.  The MVSP variant
in particular, which is the prototypical HP, is appropriately labeled an early neoplasm in that it
appears to have the potential, particularly if located proximally, to transition to a more advanced
lesion, namely SPAP(syn: SSA;SSP) and SA. The GCSP variant on the other hand, representing the common
HP of the distal rectosigmoid appears to be self limited and has not been shown to have a capacity to
progress further. 
Separate Pathways to Distinct Colorectal Carcinoma Endpoints
The presentation will include data from a recently completed study of BRAF and KRAS, CIMP and MSI status in multiple cases of each of the histological
categories, including end-point carcinomas with residual adenoma, of the serrated polyp neoplasia pathway
and the traditional adenoma-carcinoma sequence.  The findings of the study indicate that a
BRAF(V600E) mutation is a specific marker for a serrated polyp pathway that has its origin in
a hyperplastic polyp (MVSP) and a potential endpoint as MSI carcinoma. CIMP-H develops early in this
sequence and MSI-H develops late. The data provided a less complete picture of a second serrated
pathway, identified by a KRAS2 mutation in serrated adenomas, but show that the progressive stages of
both iterations of the serrated neoplasia pathway are separate and distinct from those of the traditional
The serrated polyp neoplasia pathway is an important alternative model of carcinogenesis in the colon
that invites numerous basic and clinical research questions. Among the former are the specific molecular
pathways that favor HP persistence over apoptosis, that account for the key transitions in the serrated
pathway such from MVSP to SPAP or from SPAP to SA, that clarify the role of KRAS or the nature of the
specificity of BRAF(V600E) for MSI endpoints. This model will also provide a framework for
studies of the phenomenon of CPG island methylation and the role of genetic predisposition. Clinical
studies are needed that can elucidate a time-frame of the progress of serrated neoplasia and provide
evidence-based guidance for developing recommendations for risk assessment and surveillance of
individuals with the precursor lesions of the serrated pathway.
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