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The eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual attempts to address ambiguity in the pT category assignment for colon cancer from prior editions. Despite modifications, the distinction between the pT3 and pT4a categories continues to be a source of diagnostic confusion. In this study, we assessed interobserver agreement among pathologists from different institutions in the application of AJCC eighth edition criteria for categorizing deeply invasive colonic adenocarcinomas. We identified morphologic patterns that produce diagnostic confusion. We assessed 47 colon cancers that closely approached the serosal surface. Six pathologists with interest in gastrointestinal pathology and 4 focused in other subspecialties classified each case as pT3 or pT4a, based on examination of low-magnification and high-magnification images of the most deeply invasive area. Interobserver agreement was assessed using Fleiss' κ. Cases displayed 3 morphologic patterns at the advancing tumor edge, namely, (1) continuous invasion through an inflammatory focus, (2) pushing border, and (3) infiltrative glands and cell clusters with serosal reaction. Gastrointestinal pathologists achieved slight (κ=0.21) or moderate (κ=0.46) and (κ=0.51) agreement in each category, whereas agreement among nongastrointestinal pathologist was fair (0.31) and (0.39), or moderate (0.57) for each category, respectively. In 10 (21%) cases, the distinction between pT3 and pT4a would have changed the overall clinical stage. We conclude that histologic criteria for serosal penetration is a persistent source of diagnostic ambiguity for gastrointestinal and general pathologists in the pT categorization of colon cancers. Clarification of these criteria will help ensure uniform reporting of pathologic and clinical stage.

Goblet cell carcinoid tumors are amphicrine tumors whose biological behavior ranges from indolent to highly aggressive, depending on tumor grade. Current grading systems for these tumors are based on identifying an adenocarcinoma arising in the setting of a goblet cell carcinoid tumor, which distinguishes this tumor from other gastrointestinal tract adenocarcinomas. Because goblet cell tumors are predominantly tumors of mucin secreting cells, we propose that they be classified as goblet cell adenocarcinomas, and graded using a methodology that has parallels in colorectal adenocarcinoma grading. We graded a large series of goblet cell adenocarcinomas by assessing the proportion of the tumor that demonstrates tubular or clustered growth. Histologic grade correlated with overall survival independent of stage, with median overall survival of 204, 86, and 29 months for low-grade, intermediate-grade, and high-grade goblet cell adenocarcinomas, respectively. Tumor stage also correlated with overall survival. We also graded the tumors according to previously proposed grading systems, and found that these systems are valid, in that they segregate patients according to prognosis.

Cancer involvement of the colonic serosa is designated pT4a by the American Joint Committee on Cancer Staging Manual, 7th edition. The manual defines criteria for pT4a as either tumor penetration of the serosa or comingling of cancer cells and mesothelial cells in histologic sections. Unfortunately, the pT4a grouping is inconsistently applied, because these guidelines are overly limited: fibroinflammatory changes near the serosa may be associated with peritoneal metastases even in the absence of overt peritoneal penetration. Thus, reliable ancillary techniques for detecting serosal penetration by the tumor and accurate criteria for stage assessment are needed. We evaluated the utility of cytologic preparations in determining tumor stage by comparing results of serosal scrape cytology with histologic stage assessment of 120 colon cancer resection specimens. We correlated our findings with the presence and type of inflammatory changes near the serosa to determine which, if any, are reliable indicators of peritoneal penetration. Cytologic smears from all pT1 and pT2 tumors were negative for carcinoma. However, 13 (19%) pT3 tumors showed cancer in cytologic smears, all of which were deeply invasive. In fact, 46% of pT3 cancers present ≤1 mm from a serosal tissue reaction were associated with cancer in cytologic preparations from the serosa, which was comparable to pT4a tumors (55%). We conclude that cytologic smears improve detection of peritoneal penetration among pT3 tumors compared with histology alone. Tumors close (≤1 mm) to a fibroinflammatory tissue reaction on the serosa are likely associated with peritoneal involvement by cancer. Peritumoral abscesses that communicate with the serosa and hemorrhage or fibrin on the serosa also predict cancer involvement of the peritoneum. The presence of these findings among deeply invasive cancers should prompt their classification as pT4a lesions.

We have recently shown that a study population of patients with at least 1 sessile serrated adenoma (SSA) are 4 times more likely to harbor synchronous serrated polyps [SSAs, traditional serrated adenomas (TSAs) and right sided hyperplastic polyps] than a unselected population of patients. However, 35% of the polyps in the study patients were conventional adenomas (CAds). We hypothesized that the CAds in these study patients would have histologic and molecular differences compared with CAds from a control population without sessile serrated adenomas. To this end, 104 study and 79 control CAds were analyzed according to 9 histologic criteria. A subset of these polyps was also screened for BRAF mutations, KRAS mutations, CpG island methylation, and MUC6 expression. A total of 31 study CAds and 2 control CAds had atypical histologic features (bright cytoplasmic eosinophilia +/- focal serrations and crypt dilatation). None of the adenomas tested had mutations in BRAF or KRAS. Evidence of low levels of CpG island methylation was seen in 35% of the atypical CAds and in only 4.5% of the typical CAds. In addition, these atypical CAds were more likely to express MUC6. Thus, the presence of cytoplasmic eosinophilia with or without focal serrations and crypt dilatation identifies a subset of CAds with characteristics of the serrated neoplasia pathway. These atypical CAds occur more commonly in patients predisposed to developing SSAs and suggest the presence of a mucosal field defect in these patients.

The classification of primary malignant lymphomas of the gastrointestinal tract by their cell of origin has been a subject of great controversy in recent years, with the proportion of histologic subtypes varying substantially in different published series. Much of this controversy was initially due to the widely recognized inherent difficulty of classifying lymphomas based on routine histologic sections alone. However, the advent of immunohistochemical techniques has also yielded disparate results. Particularly contentious has been the notion of true histiocytic lymphomas, which some investigators have claimed to be relatively frequent in the gastrointestinal tract, whereas others doubt whether they exist at all. We present here a classification of 25 gastrointestinal lymphomas seen in the surgical pathology services of UCLA Hospital and Stanford University Medical Center. Unlike all previously reported series, we have utilized frozen tissue sections for the performance of immunohistochemical studies, which we and others have found to be far more reliable than the use of formalin-fixed, paraffin-embedded tissues, particularly in detecting monoclonal surface staining of immunoglobulin light- and heavy-chain markers. We find that this technique lessens the likelihood of overinterpreting the stains for histiocyte markers (alpha 1-antitrypsin and lysozyme), which are often difficult to read owing to strong positive staining of benign reactive histiocytes within the tumor. Utilizing these techniques, we have been able to classify definitely 21 of our 25 lymphomas (84%) as of B-cell origin, whereas none appeared to be histiocytic. We conclude that true histiocytic lymphomas of the gastrointestinal tract must be very rare, and we recommend the routine use of frozen tissue sections for more accurate classification of these interesting lesions.