Years ago, as I was preparing a review on the incidence of rare cancers in different parts of the world, I came across a series of studies suggesting that adenocarcinoma of the gallbladder was unusually common in one coastal region of Western Japan. In an attempt to get some insider’s information on these findings, I asked a Japanese pathologist who was on sabbatical in my laboratory about the possible causes for this incidence peak in the very region where the most prolific authors of studies on gallbladder cancer were located. Initially hesitant, the usually prudent young man burst out just one word, “criteria,” before retreating rapidly. The following morning, he presented me with a well-referenced essay he had spent the night writing. The piece stated several times that not even remotely did he intend to imply that a certain famous professor in that area was using loose criteria, which, of course, was exactly what his glib answer meant: criteria are major determinants of the frequency of a diagnosis.
Serrated polyps with no dysplastic features used to be banal hyperplastic polyps until about 20 years ago, when Fenoglio-Preisler, Torlakovic, Snover, and Jass, later followed by other insightful pathologists, recognized that the larger and more complex among them, particularly those with a flat endoscopic appearance, were precursors of a distinct pathway to colon cancer, both more rapid and more ominous than the pathway followed by traditional adenomas.1–4 These lesions were first called sessile serrated adenomas (SSA), then sessile serrated polyps (SSP), and eventually sessile serrate polyp/adenoma (SSP/A), which is currently the favorite term. The elemental morphologic unit of the SSP/A is a jagged often horizontally branching crypt with a flat base. Most of these polyps are located in the ascending colon, an area where the excision of a large flat lesion in a single piece is technically challenging.5,6 Thus, often removed piecemeal, right-sided flat polyps come to the pathologist in many fragments that most histology laboratories make no attempt to orientate. As the identification of jagged, broad-based crypts is difficult in poorly oriented specimens, many of these polyps remain unrecognized and are either dismissed as hyperplastic polyps or classified as undetermined serrated polyps, a nonactionable diagnosis guaranteed to irk the clinician. Another hurdle is the existence of two main types of criteria: the World Health Organization (WHO) (3 architecturally distorted branching flattened crypts)7 and the guidelines issued as an expert panel consensus review known as the CM-2012 (a single such crypt).8 Intuitively, a pathologist who receives mostly poorly oriented fragments and follows the WHO criteria will diagnose fewer serrated polyps than a colleague who applies the CM-2012 criteria to well-oriented specimens. However, as not all that is intuitive happens, Kolb et al9 carried out a well-designed study to test this hypothesis. Not surprisingly, their results confirmed that better orientation and broader criteria yield diagnoses that are both more consistent and more precise. Still, pathologists’ agreement remained far from optimal.
The gold standard for ethnographic studies once included the use of a participant observer. An anthropologist would live in the community to be studied, adopt local customs, and record behaviors. Only when the seminal work of Margaret Mead in Samoa was critically revisited did it clearly emerge that in many instances informants give answers they believe the researcher wants to hear, elaborate less than accurately on certain facts, hide unsavory behaviors, and sometimes simply lie. The lesson from this is that any external element in a system, no matter how apparently unobtrusive (a person, a set of questions or instructions, an incentive to participate), introduces unmeasurable bias. Kolb and colleagues must be commended for their serious attempt to reproduce the real world as closely as possible: they sent glass slides (rather than pictures biased by the photographer’s preferences) to community pathologists not specialized in gastrointestinal pathology and did not disclose to them the aims of the study. However, participants were personally known to at least one of the authors, received copies of the diagnostic criteria for SSP/A with detailed instructions, and were given a $75 token of appreciation for their efforts. It is difficult to believe that these cosseted pathologists did not guess the purpose of the exercise and examined the 100 study slides in the same spirit with which they would have approached their daily load of colonic polyps.
Despite the limitations posed by the not-so-blinded pathologists (in my view a bias that is almost impossible to avoid in any prospective study involving the review of histologic slides), I believe that this study makes two important contributions. The most immediate is an advancement in our understanding of the process leading to a diagnosis of SSP/A, with the confirmation of the hypothesis that simple and less restrictive guidelines combined with the preparation of optimally oriented sections make pathologists more consistent and less likely to generate equivocal reports. However, the truly important message of this study is that even clear criteria and impeccably oriented specimens do not ensure perfect agreement among pathologists. Should these results make clinicians diffident of their pathologists? Certainly not, but it should help make them more engaged in the histopathologic process.
Most readers of this journal are gastroenterologists. Therefore, as a pathologist who has spent the last 20 years unsuccessfully recommending that gastric biopsy specimens should be placed in two separate topographically identified jars (one for specimens from the antrum and one for those from the corpus), I cannot resist taking advantage of this pulpit to make another delenda Carthago exhortation to my clinical colleagues. Kolb’s method for the orientation of polyps is simple, clever, and clearly effective. Spend the few extra seconds needed to implement it in the endoscopy suite and you will reduce the number of those nebulous diagnoses that you find so frustrating because they are not actionable. Not enough? Make your pathologists aware of the evolving criteria for new entities that, unless they specialize in gastrointestinal pathology, they may not have yet fully appreciated. Know your bearings in the gastrointestinal tract, sit across the microscope and review cases, discuss and try to understand discrepancies between endoscopic and microscopic findings.
Cato was persistent and Carthage was eventually destroyed. Perhaps one day gastrointestinal mucosal biopsies will reach the microscope properly oriented. By then, we may even have developed better criteria. And gastroenterologist-pathologist teams will reach the perfect diagnosis together.
1. Longacre TA, Fenoglio-Preiser CM. Mixed hyperplastic adenomatous polyps/serrated adenomas. A distinct form of colorectal neoplasia. Am J Surg Pathol. 1990;14:524–537.
2. Torlakovic E, Snover DC. Serrated adenomatous polyposis in humans. Gastroenterology. 1996;110:748–755.
3. Jass JR. Serrated adenoma and colorectal cancer. J Pathol. 1999;187:499–502.
4. Jass JR, Biden KG, Cummings MC, et al.. Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways. J Clin Pathol. 1999;52:455–460.
5. Lash RH, Genta RM, Schuler CM. Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients. J Clin Pathol. 2010;63:681–686.
6. Yang JF, Tang SJ, Lash RH, et al.. Anatomic distribution of sessile serrated adenoma/polyp with and without cytologic dysplasia. Arch Pathol Lab Med. 2015;139:388–393.
7. Snover DC, Ahnen DJ, Burt RW, et al.Bosman FT, Carneiro F, Hruban RH, Theise ND. Serrated polyps of the colon and rectum and serrated polyposis. World Health Organization Classification of Tumors of the Digestive System. Lyon: IARC; 2010:160–165.
8. Rex DK, Ahnen DJ, Baron JA, et al.. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol. 2012;107:1315–1329. Quiz 4, 30.
9. Kolb JM, Morales SJ, Rouse NA, et al.. Does better specimen orientation and a simplified grading system promote more reliable histologic interpretation of serrated colon polyps in the community practice setting? Results of a nation-wide study. J Clin Gastroenterol. 2016;50:233–238.