Criteria for Pathologic Sampling of Gallbladder Specimens

OpenAlex · İngilizce

To the Editor The article by Renshaw and Gould1 brings up a question that not only is challenging for our field but also is an issue with far-reaching implications on how sampling of specimens will be performed in the cost containment era with upcoming health care changes in the United States and the world. The authors advocate that, in the pathologic sampling of gallbladder (GB) specimens, taking additional sections to rule out a neoplastic process may not be justifiable. We believe that the authors have a valid point, but this approach reflects only one side of this challenging equation. Let us take this approach to the extreme: annually, approximately 1 million cholecystectomies are performed in the United States, with an estimated 9,000 gallbladder cancer (GBC) diagnoses.2 Therefore, even if we stopped examining GBs pathologically altogether, our “miss” rate of a GBC would be only 0.04%, which some may consider negligible and may even regard as a reasonable health care policy considering the upcoming finances. We suspect, however, that those patients with GBC may have another stance on this issue and may question the justification for the hundreds of billions of dollars that continue to be spent on identifying clinically silent prostate cancer with minimal or no impact on survival from the global health care perspective.3,4 Accountable care issues and health care policies aside, in a discussion about sampling of GBs, one thing that needs to be kept in the forefront is the fact that GBC is highly insidious, notorious for being “inapparent” both clinically and at the macroscopic level. In fact, even in experts’ hands that perform careful macroscopic and complete microscopic evaluation of the GBs, more than one-third of the advanced GBCs (pT2 and above) are missed during gross examination,5–7 and this number is significantly higher, about 70%, for cases of early GBC (Tis/T1).5 This leads to frequent misdiagnoses as well as common and serious understaging of the carcinomas identified, which we witness routinely in both our consultation and our in-house cases in North America. In fact, the significantly lower survival rates recorded for early stage GBCs in the low-incidence regions such as Europe and North America (35% five-year survival rate of T1b cancers) as compared with the 90% ten-year survival rates documented in the high-incidence regions (Chile and Asia) are attributable exactly to this undersampling → understaging phenomenon. This undersampling phenomenon is even a bigger challenge in those rare patients who have received neoadjuvant therapy. These observations bring up the importance of the it depends angle in establishing the guidelines for pathologic sampling of specimens. Although Renshaw and Gould’s experience may have substantial validity and practicality for the low-risk populations, in contrast, the pathologists working with high-risk populations have had to develop an entirely different approach. For example, authors in Chile, where the GBC incidence is as high as 18 per 100,000 population and GBC is the leading cause of death among women older than 40 years, have established the following sampling protocol as routine practice for GBs with no grossly visible pathology.8 Initially, a full-thickness slice from the top of the fundus all the way to the cystic duct margin is obtained, and if any microscopic neoplastic lesion is identified in these sections, then the entire GB is submitted according to an established mapping protocol. With this approach, countless numbers of invasive cancers not evident grossly or undetected in the initial set of slides are discovered in these subsequent sections, in addition to a higher number of superficial cancers, which do have a good prognosis but still about a 10% recurrence rate. Along the lines of the it depends approach, in our practice in the United States, we advocate the following: carefully examine the specimen, including the wall and the contents, and take 1 random section similar to the one described above. We routinely take the cystic duct margin unopened en face, which comes handy in those rare cases with microscopic neoplastic pathology. We then try to employ the following rules of thumb depending on what we find in the initial sections. Pyloric gland metaplasia or mucinous pyloric gland nodules less than 3 mm: no additional sections. In our experience, pyloric gland metaplasia is very common, and even nodular pyloric gland lesions are highly innocuous and do not require specific attention.9 Intestinal metaplasia: 2 additional cassettes. In our experience, intestinal metaplasia often occurs in association with dysplasia/carcinoma.9 Focal epithelial atypia in intact and unremarkable epithelium: 2 additional cassettes (each with multiple strips). The purpose of this is to rule out a higher grade atypia (true high-grade dysplasia or carcinoma in situ [HGD/CIS]).10 Especially those with basal atypia and maturation toward the surface often prove to be insignificant. In our experience, true HGD/CIS usually has a wild-fire phenomenon (it is often spread widely in the mucosa by the time of diagnosis) and is thus detectable in this sampling. If true HGD is detected, then 12 additional cassettes are examined to rule out invasive carcinoma and stage it accurately. Nodular pyloric gland lesion greater than 3 mm: reexamine the specimen container. Adenomatous and mass-forming preinvasive lesions (what we refer to as intracholecystic papillary tubular neoplasm)11 often detach from the surface and get dismissed by the gross prosectors as “debris.” Focal severe epithelial atypia in injured/inflamed GB with denuded epithelium: 4 additional cassettes. Convincing HGD: 12 cassettes. As discussed previously, once HGD develops, it usually spreads to a large zone of mucosa by the time of diagnosis and is readily evident10; the purpose here is to determine RAS involvement (which, in our opinion, requires additional surgery) and, more importantly, rule out a subtle pT2 carcinoma. Established hyalinizing cholecystitis (incomplete porcelain GB): 12 cassettes; if HGD, which is often the denuding/clinging type, or intramural glands with atypia are detected, total sampling. In our experience, full-blown hyalinizing cholecystitis (with minimal or no calcifications) has a close association with adenocarcinoma, and the carcinomas arising in this setting can be very subtle.12 Evolving hyalinizing cholecystitis (with some preserved muscle): 4 additional cassettes. In our experience, these are much less likely to harbor carcinoma than those with fully developed hyalinizing cholecystitis.12 Intracholecystic papillary tubular neoplasms (adenoma, polypoid/papillary dysplasia of any size): submit the entire lesion and take at least 5 additional sections from seemingly uninvolved GB, since HGD is common in the uninvolved mucosa, and invasive carcinoma can be away from the main lesion. Polyps of any kind: submit the entire lesion. In our experience, even cholesterol polyps greater than 1 cm can show dysplastic changes. Smaller polyps can typically be examined in 1 cassette as a part of the routine evaluation and do not necessitate any additional sections unless dysplasia is detected in the polyp. Invasive carcinoma, extensive: 7 cassettes composed of tumor to serosa, tumor to hepatic bed, tumor to cystic duct margin, tumor to normal, 2 of seemingly uninvolved GB, and lymph nodes, of which there are usually a few, if any, and typically fit into 1 cassette. Invasive carcinoma, limited/undetermined depth: 12 cassettes, as above, and 5 additional sections of suspicious-appearing areas to establish the depth of invasion (stage) accurately, which is often difficult by gross examination alone. History of sclerosing cholangitis, hyperimmunoglobulin M syndrome, or anomalous union of pancreatobiliary ducts: minimum of 3 cassettes. In summary, the analysis by Renshaw and Gould1 highlights the fact that most GB specimens in North America yield no significant neoplastic pathology. However, in developing a reasonable approach to the sampling of GBs in a given practice, it is necessary to incorporate the risk of the population, especially since neoplastic lesions of the GB are often very subtle grossly. For this reason, it is also important to appreciate the associations of different epithelial lesions and pathologic processes and their relative risk of occurrence with neoplasms, as well as develop a sampling protocol accordingly. 2013 We thank Drs Adsay et al for taking the time to reply to our article. It is a pleasure to note that their very detailed protocol does not include blindly submitting the entire gallbladder in most cases of carcinoma, which was the main point of our article. However, their statement that we advocate that “taking additional sections to rule out a neoplastic process may not be justifiable” is not what we said in our article. What we advocate is evidence-based practice, and the evidence we presented advocates taking a limited number of additional sections but not submitting the entire gallbladder, since this does not materially change the diagnosis. Despite the many references they cite, from their letter it is unclear whether the submission protocol these authors propose is evidence-based or simply what they do in their own institutions. Since their protocol submits more material than we suggest is necessary, it would seem a relatively easy study for them to compare the 2 protocols to see if those additional sections result in differences in either diagnosis or patient management. If there is an added benefit to additional sections, we have no problem changing our practice. Until then, however, we will continue to recommend evidence-based submission protocols.