Appendiceal mucinous neoplasms (AMNs), characterized by expansile or "pushing" growth of neoplastic epithelium through the appendix wall, are sometimes accompanied by peritoneal involvement, the ...extent and grade of which largely determine clinical presentation and long-term outcomes. However, the prognosis of tumors entirely confined to the appendix is still debated and confusion remains regarding their biologic behavior and, consequently, their clinical management and even diagnostic nomenclature. We evaluated AMNs limited to the appendix from 337 patients (median age: 58 years, interquartile range (IQR): 47-67), 194 (57.6%) of whom were women and 143 (42.4%) men. The most common clinical indication for surgery was mass or mucocele, in 163 (48.4%) cases. Most cases (N = 322, 95.5%) comprised low-grade epithelium, but there were also 15 (4.5%) cases with high-grade dysplasia. Lymph nodes had been harvested in 102 (30.3%) cases with a median 6.5 lymph nodes (IQR: 2-14) per specimen for a total of 910 lymph nodes examined, all of which were negative for metastatic disease. Histologic slide review in 279 cases revealed 77 (27.6%) tumors extending to the mucosa, 101 (36.2%) to submucosa, 33 (11.8%) to muscularis propria, and 68 (24.4%) to subserosal tissues. In multivariate analysis, deeper tumor extension was associated with older age (p = 0.032; odds ratio (OR): 1.02, 95% confidence intervals (CI): 1.00-1.03), indication of mass/mucocele (p < 0.001; OR: 2.09, CI: 1.41-3.11), and wider appendiceal diameter, grossly (p < 0.001; OR: 1.61, CI: 1.28-2.02). Importantly, among 194 cases with at least 6 months of follow-up (median: 56.1 months, IQR: 24.4-98.5), including 9 high-grade, there was no disease recurrence/progression, peritoneal involvement (pseudomyxoma peritonei), or disease-specific mortality. These data reinforce the conclusion that AMNs confined to the appendix are characterized by benign biologic behavior and excellent clinical prognosis and accordingly suggest that revisions to their nomenclature and staging would be appropriate, including reverting to the diagnostic term mucinous adenoma in order to accurately describe a subset of them.
The precise contributions of histopathologic features in the determination of stage and prognosis in small intestinal neuroendocrine tumors (NETs) are still under debate, particularly as they pertain ...to primary tumor size, mesenteric tumor deposits (TDs), and number of regional lymph nodes with metastatic disease. This single-institution series reviewed 162 patients with small bowel NETs (84 females, mean age: 60.3±12.0 y). All cases examined (100%) were immunoreactive for both chromogranin A and synaptophysin. Primary tumor size >1 cm (P=0.048; odds ratio OR=3.06, 95% confidence interval CI: 1.01-9.24) and lymphovascular invasion (P=0.007; OR=4.85, 95% CI: 1.53-15.40) were associated with the presence of lymph node metastasis. Conversely, TDs (P=0.041; OR=2.73, 95% CI: 1.04-7.17) and higher pT stage (P=0.006; OR=4.33, 95% CI: 1.53-12.28) were associated with the presence of distant metastasis (pM). A cutoff of ≥7 positive lymph nodes was associated with pM (P=0.041), and a thusly defined modified pN stage (pNmod) significantly predicted pM (P=0.024), compared with the prototypical pN (cutoff of ≥12 positive lymph nodes), which did not. Over a median follow-up of 35.7 months, higher pNmod (P=0.014; OR=2.15, 95% CI: 1.16-3.96) and pM (P<0.001; OR=11.00, 95% CI: 4.14-29.20) were associated with disease progression. Proportional hazards regression showed that higher pNmod (P=0.020; hazard ratio=1.51, 95% CI: 1.07-2.15) and pM (P<0.001; hazard ratio=5.48, 95% CI: 2.90-10.37) were associated with worse progression-free survival. Finally, Kaplan-Meier survival analysis demonstrated that higher pNmod (P=0.003), pM (P<0.001), and overall stage group (P<0.001) were associated with worse progression-free survival, while higher pM also predicted worse disease-specific survival (P=0.025). These data support requiring either chromogranin or synaptophysin, but not both, for small bowel NET diagnosis, the current inclusion of a 1 cm cutoff in primary tumor size and the presence of TDs in staging guidelines, and would further suggest lowering the cutoff number of positive lymph nodes qualifying for pN2 to 7 (from 12).
Aims
To examine the clinicopathological characteristics of granulomatous gastritis (GG) among different aetiologies, particularly Crohn disease (CD), and determine the contribution of Helicobacter ...pylori and the clinical significance of isolated GG.
Methods and results
We identified 269 GG cases overall (0.19% prevalence): 220 had an underlying granulomatous disease (CD, sarcoidosis, tuberculosis) and only eight of these (3.6%) had H. pylori, fewer than the 10.3% rate among non‐GG biopsies (P < 0.001). Conversely, among 49 GG cases without known cause (foreign body, undetermined, idiopathic), 13 (26.5%) had H. pylori more than background (P = 0.001). Most patients (n = 185/68.8%) had CD and these were more probably male (P < 0.001), younger (P < 0.001), white (P < 0.001) and had single (P = 0.010), smaller (P = 0.005) and antral (P = 0.027) granulomas amid inflammation (P = 0.005) compared to non‐CD GG cases; younger age was independently associated with CD P = 0.003; odds ratio (OR) = 1.13, 95% confidence interval (CI) = 1.04–1.22. Among CD patients, younger age (P = 0.003; OR = 1.04, 95% CI = 1.01–1.07) and upper gastrointestinal (GI) symptoms (P = 0.017; OR = 2.53, 95% CI = 1.18–5.43) were associated with new (versus established) diagnosis, whereas multiple gastric granulomas (P = 0.003; OR = 4.67, 95% CI = 1.67–13.04) and lack of upper GI symptoms (P < 0.001; OR = 6.75, 95% CI = 2.94–15.49) were associated with lower GI granulomas. Of 86 isolated GG cases (i.e. no prior diagnosis or lower GI granulomas), 51 (59.3%) were eventually diagnosed with CD, and this was independently associated with younger age (P = 0.014; OR = 1.11, 95% CI = 1.02–1.21) and upper GI symptoms (P = 0.033; OR = 19.27, 95% CI = 1.27–293.31). The positive predictive value of finding isolated GG towards a CD diagnosis in patients aged <30 years was 91%, increasing in males (93%), with single (94%), antral (97%) granulomas or upper GI symptoms (94%).
Conclusions
GG does not correlate with H. pylori in patients with granulomatous disease, but may be associated with the organism when such diagnosis is lacking. In CD patients with GG, younger age and upper GI symptoms are associated with a new CD diagnosis, whereas multiple gastric granulomas and lack of upper GI symptoms correlate with lower GI granulomas. GG, including in isolated cases with no prior clinical history or granuloma, probably signifies CD, particularly in younger, male patients or those with single, antral granulomas or upper GI symptoms.
Pyloric gland metaplasia (PGM) is a histopathologic change usually seen after inflammatory injury and, although described in association with inflammatory bowel disease (IBD) and particularly Crohn ...disease (CD), its significance is still debated. We evaluated long-term correlates of PGM in a large cohort of 601 intestinal specimens, 227 (37.8%) biopsies, and 374 (62.2%) resections, from 567 different patients, 328 (57.8%) male and 239 (42.2%) female, with a mean age of 43.4±15.8 years. During mean clinical follow-up of 83.5±48.1 months, 511 (90.1%) patients were diagnosed with IBD, 457 (89.4%) with CD, and 53 (10.4%) with ulcerative colitis. In multivariate analysis, IBD patients with PGM were younger (P<0.001) and more often had severely active inflammation (P=0.002) compared with non-IBD patients, whereas, among IBD patients, those with ulcerative colitis were more likely to have PGM in a biopsy (P<0.001) or in the colorectum (P=0.009), compared with CD patients. Kaplan-Meier analyses showed that incidental PGM in a biopsy was more likely to predict IBD in patients younger than 50 years (P<0.001) and those without a history of bowel surgery (P<0.001) and also more likely to signify CD in patients younger than 50 years (P=0.004), those without a history of bowel surgery (P=0.020), and when identified in the small intestine (P=0.032). In conclusion, intestinal PGM warrants a high suspicion for IBD and specifically CD, however, it should be interpreted with caution, especially in older patients or those with a history of prior intestinal surgery and in colorectal biopsies or specimens lacking severely active inflammation.
Extramural venous invasion (EMVI) is an established independent prognostic factor in colorectal carcinoma where it is linked to hematogenous spread (i.e., liver metastases), influencing the decision ...for adjuvant chemotherapy. However, its prognostic significance in small intestinal neuroendocrine tumors (NETs) has not been studied, nor is it routinely assessed or reported. We reviewed primary small bowel NETs (14 jejunum, 82 ileum, 8 not specified) from 104 patients (52 women; median age 60.5, range: 24–84). EMVI was identified in 58 cases (55.8%), including in 13 of 21 equivocal cases using an elastin stain. In univariate analysis, EMVI was associated with lymphovascular and perineural invasion, tumor stage, and lymph node and distant metastases, whereas in multivariate analysis, only distant metastases remained significant (p < 0.001). Liver metastases were present in 55 cases (52.9%) and were significantly associated in univariate analysis with lymphovascular and perineural invasion, tumor stage, lymph node metastases, and EMVI, whereas in multivariate analysis, only EMVI remained significant (p < 0.001; odds ratio (OR) = 59.42). Eight patients developed metachronous liver metastases during follow-up (mean 22.9 ± 22.0 months, range: 4.7–73.2) and all (100%) were positive for EMVI. In contrast, of 49 patients who never developed liver metastases over significantly longer follow-up (mean 71.0 ± 32.4 months, range: 6.6–150.4; p < 0.001), only 7 (14.3%) had EMVI (p < 0.001). In Kaplan–Meier analysis, 8 of 15 patients with EMVI (53.3%) developed metachronous liver metastases, compared with 0 of 42 patients without EMVI (p < 0.001). In contrast, nonhepatic distant metastases, seen in 26 (25.0%) patients, were not associated with EMVI in multivariate or Kaplan–Meier analyses. Our data demonstrate that EMVI is common in small bowel NETs and strongly correlates with development of liver metastases. Therefore, its evaluation is critical and should be assessed in combination with adjuvant techniques such as elastin staining, if necessary. Moreover, inclusion of EMVI in pathology reporting guidelines should be considered.
Depth of invasion through the intestinal wall, categorized as primary tumor stage (pT), is an important prognostic factor in colorectal cancer. However, additional variables that may affect clinical ...behavior among tumors involving the muscularis propria (pT2) have not been examined at length. We evaluated 109 patients with pT2 colonic adenocarcinomas (median age: 71 y, interquartile range: 59 to 79 y) along various clinicopathologic parameters, including invasion depth, regional lymph node involvement, and disease progression after resection. Tumors extending to the outer muscularis propria (termed pT2b) were associated in multivariate analysis with older patient age ( P =0.04), larger tumor size ( P <0.001), higher likelihood of lymphovascular invasion (LVI; P =0.03) and higher lymph node stage (pN; P =0.04), compared with tumors limited to the inner muscle layer (pT2a), and LVI was the single most important variable predicting regional lymph node metastasis at resection in these tumors ( P =0.001). The Kaplan-Meier analysis during a median clinical follow-up of 59.7 months (interquartile range: 31.5 to 91.2) revealed that disease progression was more likely in pT2 tumors that exhibited, at the time of staging: size >2.5 cm ( P =0.039), perineural invasion (PNI; P =0.047), high-grade tumor budding ( P =0.036), higher pN stage ( P =0.002), and distant metastasis ( P <0.001). Proportional hazards (Cox) regression identified high-grade tumor budding ( P =0.02) as independently predicting shorter progression-free survival in pT2 tumors. Finally, among cases that would not ordinarily be candidates for adjuvant treatment (ie, pT2N0M0), the presence of high-grade tumor budding was significantly associated with disease progression ( P =0.04). These data suggest that, during the diagnosis of pT2 tumors, pathologists may wish to pay particular attention and ensure adequate reporting of certain variables such as tumor size, depth of invasion within the muscularis propria (ie, pT2a vs. pT2b), LVI, PNI, and, especially, tumor budding, as these may affect clinical treatment decisions and proper patient prognostication.
The SMAD4 tumor suppressor gene product inhibits transforming growth factor-β-mediated signaling and is mutated in ~10% of colorectal carcinomas. The prognostic significance of SMAD4 mutations has ...been controversial. We studied the pathological and clinical characteristics of SMAD4-mutated intestinal adenocarcinomas using a retrospective case-control study design. Cases and controls were identified among 443 primary adenocarcinomas that had undergone next generation DNA sequencing (NGS) with the Ion AmpliSeq Cancer Hotspot Panel v2, which evaluates 50 cancer-related genes. Twenty-eight SMAD4-mutated (SMAD4m) patients were matched 1:2 with 56 consecutive SMAD4 wild-type (SMAD4wt) control patients from the same analysis stream. Compared with the SMAD4wt controls, the SMAD4m tumors were of higher stage (P = 0.026) and were more likely to feature mucinous differentiation (P = 0.0000), to occur in the setting of Crohn's disease (P = 0.0041), and to harbor concurrent RAS mutations (P = 0.0178). Tumor mucin content was significantly correlated with mutations involving the MH2 domain of the SMAD4 protein (P = 0.0338). Correspondence between mutation sites and morphology was demonstrated directly in a mixed adenocarcinoma and neuroendocrine tumor where SMAD4 mutations involving different protein domains were found in histologically disparate tumor regions despite both containing identical KRAS and TP53 mutations.
Peutz-Jeghers polyps (PJPs) are hamartomatous polyps that may define patients with Peutz-Jeghers syndrome (PJS), a rare inherited polyposis syndrome with high cancer risk. However, the clinical ...significance of 1–2 sporadic PJPs (without other PJS stigmata) regarding malignant potential and identification of new PJS probands is still unclear. We identified 112 patients with 524 histologically confirmed PJPs and categorized them based on polyp number into syndromic (n = 38) if ≥3 PJPs or diagnosed PJS, solitary (1 PJP, n = 61), and intermediate (2 PJPs, n = 13). Clinicopathologic features, including presence of dysplasia in the polyp and development of neoplasia in the patient, were compared on a per-patient and per-polyp basis. Whereas patients with solitary and intermediate PJPs were not different from each other, patients with syndromic PJPs were, in multivariate analysis, younger (P = .001) and more likely to develop neoplasia (P = .02) over a 62.6-months median follow-up than patients with sporadic PJPs. On an individual polyp basis, syndromic PJPs were more likely, in multivariate analysis, to occur in the small intestine (P < .001), but less likely to harbor metaplasia (P = .03) or dysplasia (P = .001), than sporadic PJPs. Dysplasia and metaplasia were more likely in larger PJPs, by multivariate analysis (P = .007 and P < .001, respectively). These data suggest that strict criteria for PJS (including ≥3 PJPs), as currently used, stratify patients into distinct groups with significant differences in clinicopathologic parameters, particularly regarding risk of neoplasia. However, sporadic PJPs exhibit characteristics such as dysplasia and are thus important to recognize and diagnose but perhaps as heralding only a forme fruste PJS.
•Accepted criteria for the diagnosis of Peutz-Jeghers syndrome (PJS) vary, particularly as they pertain to a sufficient number of Peutz-Jeghers polyps (PJPs) required.•This study compared patients in an intermediate category (2 PJPs, but with no other stigmata of PJS) and found them more similar to patients with solitary (n = 1) PJPs and, together, significantly different from PJS patients, in terms of age and risk of neoplasia.•Syndromic PJPs were more likely to be found in the small intestine, but less likely to harbor metaplasia or dysplasia than sporadic PJPs (n = 1 or 2).•While sporadic PJPs are important to identify, given the risk of dysplasia, they occur in patients that are clinicopathologically distinct from patients with PJS, as strictly defined.
Primary tumor stage (pT) is an important prognostic indicator in colonic adenocarcinomas; however, cases that have no muscle fibers beyond the advancing tumor edge but also show no extension beyond ...the apparent outer border of the muscularis propria (termed pT2int) have not been previously studied.
To address the clinicopathologic characteristics and prognosis of pT2int tumors.
We recharacterized 168 colon carcinomas and compared pT2int cases to bona fide pT2 and pT3 tumors.
In side-by-side analysis, 21 pT2int cases diverged from 29 pT2 tumors only in terms of larger size (P = .03), but they were less likely to show high-grade (P = .03), lymphovascular (P < .001), and extramural venous invasion (P = .04); discontinuous tumor deposits (P = .02); lymph node involvement (P = .001); and advanced stage (P = .001) compared with 118 pT3 tumors. Combining pT2int with pT2 cases (versus pT3) was a better independent predictor of negative lymph nodes in multivariate analysis (P = .04; odds ratio OR, 3.96; CI, 1.09-14.42) and absent distant metastasis in univariate analysis (P = .04) compared with sorting pT2int with pT3 cases (versus pT2). Proportional hazards regression showed that pT2 and pT2int cases together were associated with better disease-free survival compared with pT3 tumors (P = .04; OR, 3.65; CI, 1.05-12.70). Kaplan-Meier analysis demonstrated that when pT2int were grouped with pT2 tumors, they were significantly less likely to show disease progression compared with pT3 (P = .002; log-rank test) and showed a trend toward better disease-specific survival (P = .06) during a mean patient follow-up of 44.9 months.
These data support the conclusion that pT2int carcinomas have clinicopathologic characteristics and are associated with patient outcomes more closely aligned with pT2 rather than pT3 tumors.
Inflammatory polyps (IPs) in inflammatory bowel disease may have been associated in the past with increased neoplasia risk. Additionally, colonic mucosa in filiform polyposis and giant inflammatory ...polyposis may be difficult to visualize during endoscopic surveillance, perhaps contributing to early colectomy in these patients.
To examine the clinicopathologic characteristics and significance of IPs and inflammatory polyposis in inflammatory bowel disease.
We identified 336 resections from inflammatory bowel disease patients (212 63.1% male; mean age, 40.3 years; 175 52.1% with ulcerative colitis), including 78 with rare/few (<10) IPs, 141 with multiple (≥10) IPs, and 117 with inflammatory polyposis (including 30 with filiform polyposis/giant inflammatory polyposis) and compared them with 100 controls without IPs along various parameters, including overall and occult (unexpected) dysplasia.
There was no increased neoplasia in resections with IPs compared with controls, given similar age, disease duration, degree of inflammation, anatomical extent of colitis, prevalence of primary sclerosing cholangitis, and tissue sampling. Increasing numbers of IPs and inflammatory polyposis were significantly associated in multivariate analysis with ulcerative and indeterminate colitis (P = .003) and shorter disease duration (P = .01), but also, and independently, with lower rates of dysplasia overall, including all grades (P = .001) and advanced neoplasia (P = .04). There were no instances of occult dysplasia (any grade) among inflammatory polyposis cases.
These findings support the conclusion that the presence of IPs per se, and inflammatory polyposis in particular (including filiform polyposis and giant inflammatory polyposis), should not be considered an independent risk factor for the development of neoplasia in inflammatory bowel disease patients, outside the context of disease duration and inflammatory burden.
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