Dataset for Pathology Reporting of Colorectal Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

OBJECTIVE: The aim of this study to describe a new international dataset for pathology reporting of colorectal cancer surgical specimens, produced under the auspices of the International Collaboration on Cancer Reporting (ICCR). BACKGROUND: Quality of pathology reporting and mutual understanding between colorectal surgeon, pathologist and oncologist are vital to patient management. Some pathology parameters are prone to variable interpretation, resulting in differing positions adopted by existing national datasets. METHODS: The ICCR, a global alliance of major pathology institutions with links to international cancer organizations, has developed and ratified a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Here we describe the production of a dataset for colorectal cancer resection specimens by a multidisciplinary panel of internationally recognized experts. RESULTS: The agreed dataset comprises eighteen core (essential) and seven non-core (recommended) elements identified from a review of current evidence. Areas of contention are addressed, some highly relevant to surgical practice, with the aim of standardizing multidisciplinary discussion. The summation of all core elements is considered to be the minimum reporting standard for individual cases. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or non-core. CONCLUSIONS: This first internationally agreed dataset for colorectal cancer pathology reporting promotes standardization of pathology reporting and enhanced clinicopathological communication. Widespread adoption will facilitate international comparisons, multinational clinical trials and help to improve the management of colorectal cancer globally.

Sessile Serrated Adenoma With Dysplasia of the Colon.

OBJECTIVES: Sessile serrated adenomas with dysplasia (SSADs) of the colon are transitional lesions between sessile serrated adenomas (SSAs) and a subset of colorectal adenocarcinomas. We wished to gain insight into the relative percentages and significance of SSAD subtypes. METHODS: Retrospective (2007-2012) clinicopathologic review of colorectal polyps initially regarded as having mixed serrated and dysplastic elements. SSADs were subdivided into those with cap-like adenomatous dysplasia (ad1), non-cap-like adenomatous dysplasia (ad2), serrated dysplasia (ser), minimal dysplasia (min), and dysplasia not otherwise specified (nos). MLH1 immunostaining was performed on many. RESULTS: SSADser (7.7%) had a greater propensity for right colon, women, and MLH1 loss vs the entire cohort. SSAad1 (11.6%) had the least female preponderance, was least likely to have MLH1 loss, and was most likely to affect the left colorectum. SSAD with MLH1 loss was associated with an increased burden of SSAs in the background colon (P = .0003) but not tubular adenomas or hyperplastic polyps. Most SSADs (ad2 and nos groups, 80% combined) showed difficult-to-classify dysplasia, intermediate MLH1 loss rates, and intermediate clinical features. CONCLUSIONS: While some trends exist, morphologically subclassifying SSADs is probably not justified in routine clinical practice. MLH1 loss portends a greater burden of SSAs in the background colon.

Diagnostic challenges of focal nodular hyperplasia: interobserver variability, accuracy, and the utility of glutamine synthetase immunohistochemistry.

AIMS: The diagnosis of focal nodular hyperplasia (FNH) and the interpretation of glutamine synthetase (GS) staining can be challenging on biopsies. We aimed to evaluate the reproducibility of needle biopsy diagnosis of FNH, the effect of GS immunohistochemistry on FNH diagnosis, and which histological features are most useful for the diagnosis of FNH. METHODS AND RESULTS: The study included virtual needle biopsies generated from 75 resection specimens (30 FNHs, 15 hepatocellular adenomas, 15 hepatocellular carcinomas, and 15 non-lesional liver specimens). Pathologists were reasonably accurate (83.1%) in the diagnosis of FNH with haematoxylin and eosin alone. Ductular reaction and nodularity had the highest sensitivity for a diagnosis of FNH (88.1% and 82.2%, respectively), whereas central scar was the most specific feature (90.6%). The presence of two or more of the classic histological features had 89.6% sensitivity and 86.2% specificity for a diagnosis of FNH. Diagnostic accuracy was significantly higher with the addition of a GS stain. A map-like GS staining pattern was highly specific (99.3%) for FNH. However, GS staining was interpreted as non-map-like in 14.4% of reviews of true FNH cases, and overall interobserver agreement for interpretation of the GS staining pattern was only moderate (kappa = 0.42). CONCLUSIONS: Pathologists are reasonably accurate in the diagnosis of FNH on virtual biopsies, and GS staining improves accuracy. However, a subset of FNH cases remain challenging. Steatosis and a pseudo-map-like GS staining pattern were associated with increased difficulty. Therefore, although a map-like GS staining pattern is useful for confirmation of a diagnosis, the lack of a map-like GS staining pattern on needle biopsy does not necessarily exclude a diagnosis of FNH.

Characterization of Novel Injectable Lifting Agents Used in Colonic Polyp Removal: An Emerging Amyloid Mimic.

Colon polypectomy can require an injection of a submucosal lifting agent to fully visualize and completely remove the polyp. To the best of our knowledge, this is the largest morphologic series on the novel lifting agents Eleview and Orise. The study consisted of 1 polypectomy and 8 colon resections from 9 patients: 6 women, 3 men (mean age=64 y); Orise=6, Eleview=3; the median time interval between injection and resection=16 weeks. Pathologic diagnoses of the polyps included tubular adenoma (n=4), tubulovillous adenoma (n=4), and sessile serrated adenoma/polyp (n=1). We report that a histologically processed Orise aliquot from the manufacturer showed similar histology to that seen in the specimens from patients with confirmed Orise injection. The morphology of the agents in the patient specimens changed with time status postinjection: immediate resection of the lifting agent showed basophilic, amorphous, and bubbly-extracellular material with prominent hemorrhage, and resection ∼3 months after lifting agent injection showed prominent hyalinized, pink-amorphous ribbons and globules with a foreign body giant cell reaction and fibrosis. The epicenter of the lifting agents was in the submucosa, and the agents were neither refractile nor polarizable. Because of the morphologic overlap with amyloid, 5 cases were stained with Congo Red, and all cases were negative. In conclusion, awareness of the morphology of these new lifting agents is important for accurate diagnosis and to avoid the diagnostic pitfall of amyloid. These lesions can be definitively distinguished from amyloid by their nonreactivity on a Congo Red and familiarity with their characteristic clinicopathologic presentation.

Tumor histopathology predicts outcomes after resection of colorectal cancer liver metastases treated with and without pre-operative chemotherapy.

BACKGROUND AND OBJECTIVES: Study objectives, included determination of: (i) associations between radiologic and pathologic responses of colorectal cancer liver metastases (CRCLM) to chemotherapy; and (ii) whether CRCLM histopathology is associated with recurrence free survival (RFS) after resection among patients not treated with pre-operative chemotherapy (untreated). METHODS: Demographics, clinicopathologic characteristics, and outcomes among patients who underwent CRCLM resection from 2007 to 2014 were reviewed. Tumor regression grade (TRG) of 1-2 and 4-5 depict low and high proportions of viable tumor relative to fibrosis, respectively. RESULTS: Of 138 patients, 84 (60.9%) were treated with pre-operative chemotherapy. In these patients, there was no difference in proportions with TRG 1-2 among those with verses without radiologic response (26.9% vs. 18.8%, P = 0.393). TRG 1-2 was associated with superior RFS on univariable (median 15 vs. 6 months, P < 0.001) and multivariable (P = 0.005) analyses. Radiologic response was not associated with RFS. Among untreated patients (n = 54), TRG 4-5 was associated with poor RFS on univariable (median 44 vs. 15 months, P = 0.011) and multivariable (P = 0.012) analyses. CONCLUSIONS: High proportions of CRCLM fibrosis occur in 20% of patients without radiologic response to chemotherapy. Among untreated patients, high proportion of viable tumor relative to fibrosis is associated with poor RFS after resection. J. Surg. Oncol. 2016;113:456-462. © 2016 Wiley Periodicals, Inc.

Imaging Surveillance of Hypervascular Liver Lesions in Non-Cirrhotic Patients.

A consensus surveillance protocol is lacking for non-cirrhotic patients with hypervascular liver lesions presumed to represent hepatocellular adenomas. Patients with hypervascular liver lesions <5 cm not meeting criteria for focal nodular hyperplasia or hepatocellular carcinoma underwent surveillance with contrast-enhanced magnetic resonance imaging (MRI) 6, 12, and 24 months after baseline imaging. If lesions remained stable or decreased in size, then surveillance imaging was discontinued. Between 2011 and 2014, 116 patients with hypervascular liver lesions were evaluated. Seventy-nine patients were eligible for the surveillance protocol. Median follow-up was 24 months (range, 1-144 months). One patient (1 %) continued oral contraceptive pill (OCP) use and presented with hemorrhage requiring embolization 5 months after initial diagnosis. Ten patients (13 %) underwent elective embolization or surgical resection for size ≥5 cm. The remaining 68 patients (86 %) continued surveillance without hemorrhage or malignant transformation. Risk factors for requiring intervention during the surveillance period included younger age, larger lesion size, and estrogen use (all p < 0.05). Patients with hepatocellular adenomas <5 cm can safely be observed after discontinuing OCP with serial imaging 6, 12, and 24 months after diagnosis. If lesions remain stable or decrease in size, then longer-term surveillance is unlikely to identify patients at risk for complications.

CT colonography for the detection of nonpolypoid adenomas: sensitivity assessed with restricted national CT colonography trial criteria.

OBJECTIVE: The purpose of this study was to determine the prevalence of nonpolypoid adenomas and the sensitivity of CT colonography (CTC) in their detection by use of the restricted criteria of height-to-width ratio<50% and height elevation≤3 mm. MATERIALS AND METHODS: In the National CT Colonography Trial (American College of Radiology Imaging Network protocol 6664), a cohort of 2531 participants without symptoms underwent CTC and screening colonoscopy. The CTC examinations were interpreted with both 2D and 3D techniques. Nonpolypoid adenomatous polyps identified with CTC or colonoscopy were retrospectively reviewed to determine which polyps met the restricted criteria. The prevalence of nonpolypoid adenomas and the prospective sensitivity of CTC were determined. Descriptive statistics were used to report the prevalence, size, and histologic features. The sensitivities (with 95% CIs) for nonpolypoid and polypoid lesions were compared by two-sided Z test for independent binomial proportions. RESULTS: The retrospective review confirmed 21 nonpolypoid adenomas, yielding a prevalence of 0.83% (21 of 2531 participants). Eight (38.1%) were advanced adenomas, many (50% [4/8]) only because of large size (≥10 mm). The overall per polyp sensitivity of CTC (combined 2D and 3D interpretation) for detecting nonpolypoid adenomas≥5 mm (n=21) was 0.76; ≥6 mm (n=16), 0.75; and ≥10 mm (n=5), 0.80. These values were not statistically different from the sensitivity of detecting polypoid adenomas (p>0.37). CONCLUSION: In this large screening population, nonpolypoid adenomas had a very low prevalence (<1%), and advanced pathologic features were uncommon in polyps<10 mm in diameter. Most nonpolypoid adenomas are technically visible at CTC. The prospective sensitivity is similar to that for polypoid adenomas when the interpretation combines both 2D and 3D review.

The National CT Colonography Trial: assessment of accuracy in participants 65 years of age and older.

PURPOSE: To conduct post-hoc analysis of National CT Colonography Trial data and compare the sensitivity and specificity of computed tomographic (CT) colonography in participants younger than 65 years with those in participants aged 65 years and older. MATERIALS AND METHODS: Of 2600 asymptomatic participants recruited at 15 centers for the trial, 497 were 65 years of age or older. Approval of this HIPAA-compliant study was obtained from the institutional review board of each site, and informed consent was obtained from each subject. Radiologists certified in CT colonography reported lesions 5 mm in diameter or larger. Screening detection of large (≥10-mm) histologically confirmed colorectal neoplasia was the primary end point; screening detection of smaller (6-9-mm) colorectal neoplasia was a secondary end point. The differences in sensitivity and specificity of CT colonography in the two age cohorts (age < 65 years and age ≥ 65 years) were estimated with bootstrap confidence intervals (CIs). RESULTS: Complete data were available for 477 participants 65 years of age or older (among 2531 evaluable participants). Prevalence of adenomas 1 cm or larger for the older participants versus the younger participants was 6.9% (33 of 477) versus 3.7% (76 of 2054) (P < .004). For large neoplasms, mean estimates for CT colonography sensitivity and specificity among the older cohort were 0.82 (95% CI: 0.644, 0.944) and 0.83 (95% CI: 0.779, 0.883), respectively. For large neoplasms in the younger group, CT colonography sensitivity and specificity were 0.92 (95% CI: 0.837, 0.967) and 0.86 (95% CI: 0.816, 0.899), respectively. Per-polyp sensitivity for large neoplasms for the older and younger populations was 0.75 (95% CI: 0.578, 0.869) and 0.84 (95% CI: 0.717, 0.924), respectively. For the older and younger groups, per-participant sensitivity was 0.72 (95% CI: 0.565, 0.854) and 0.81 (95% CI: 0.745, 0.882) for detecting adenomas 6 mm in diameter or larger. CONCLUSION: For most measures of diagnostic performance and in most subsets, the difference between senior-aged participants and those younger than 65 years was not statistically significant.

Meta-analysis of histopathological features of primary colorectal cancers that predict lymph node metastases.

BACKGROUND: Treatment decisions for colorectal cancer vary based on lymph node status. While some histopathological features of the primary tumor correlate with lymph node spread, the relative influences of these risk factors are not well quantified. OBJECTIVE: This study aims to systematically review published studies relating histopathological features of primary colorectal cancer to the presence of lymph node metastases and to determine how reliable certain factors might be at predicting nodal metastasis when only the primary lesion is available for study. DATA SOURCES: Inclusive literature search using EMBASE and Ovid MEDLINE databases plus manual reference checks of all articles correlating lymphatic spread with colorectal cancer (any T stage) from 1984 to mid-2008 was performed. STUDY SELECTION: This search generated two levels of screening utilized on 602 citations, yielding 123 articles for full review. Data reported from 76 articles were chosen. MAIN OUTCOME MEASURES: The relative influence of each histopathological feature on the likelihood of lymphatic metastases was determined. Fixed-effects meta-analysis was performed, and results were reported as Mantel-Haenszel odds ratios (OR). RESULTS: Of 42 histopathological features analyzed, only 40.4% were reported in >2 articles. The positive predictive values for the top quartile of most frequently reported risk factors were 25.5-86.4%. Among the commonly reported histopathological findings, lymphatic invasion (OR, 8.62) significantly outperformed tumor depth (T2 vs. T1; OR, 2.62) and overall differentiation (OR, 2.38) in predicting nodal spread. For the rectal cancer subset, risk factors differed from the overall colorectal group in predictive ability; poor differentiation at the invasive front (OR, 6.08) and tumor budding (OR, 5.82) were the most predictive. LIMITATIONS: This literature search is limited by the small number of studies examining only rectal cancers and the potential changes in histological and/or surgical techniques over the study period. CONCLUSIONS: No single histopathological feature of colorectal cancer reliably predicted lymph node metastases. Several risk factors that correlate highly with nodal disease are not routine components of standard pathology reports. Until further research establishes histopathological or molecular patterns for predicting lymph node spread, caution should be exercised when basing treatment decisions solely on these factors.

Chromosomal abnormalities determined by comparative genomic hybridization are helpful in the diagnosis of atypical hepatocellular neoplasms.

AIMS: To explore the utility of cytogenetic abnormalities in the distinction of hepatic adenoma (HA) and well-differentiated hepatocellular carcinoma (HCC). METHODS AND RESULTS: Array-based comparative genomic hybridization (CGH) was used to determine chromosomal abnormalities in 39 hepatocellular neoplasms: 12 HA, 15 atypical hepatocellular neoplasms (AHN) and 12 well-differentiated HCC. The designation of AHN was used in two situations: (i) adenoma-like neoplasms (n = 8) in male patients (any age) and women >50 years and <15 years old; (ii) adenoma-like neoplasms with focal atypical features (n = 7). CGH abnormalities were seen in none of the HAs (0/12), eight (53%) AHNs and 11 (92%) HCCs. The number and nature of abnormalities in AHN was similar to HCC with gains in 1q, 8q and 7q being the most common. Although follow-up information was limited, recurrence and/or metastasis were observed in three AHNs (two with abnormal, one with normal CGH). CONCLUSIONS: Adenoma-like neoplasms with focal atypical morphological features or unusual clinical settings such as male gender or women outside the 15-50 year age group can show chromosomal abnormalities similar to well-differentiated HCC. Even though these tumours morphologically mimic adenoma, they can recur and metastasize. Determination of chromosomal abnormalities can be useful in the diagnosis of AHN.

Chromosomal changes in fibrolamellar hepatocellular carcinoma detected by array comparative genomic hybridization.

Fibrolamellar hepatocellular carcinoma is a rare subtype of hepatocellular carcinoma with distinct clinical and histological features, and better survival compared with conventional hepatocellular carcinoma in some but not all series. We performed a comparative genomic hybridization analysis on 11 fibrolamellar carcinomas and correlated the findings with clinicopathologic features and survival. Chromosomal imbalances were identified in six cases (55%), whereas the other five (45%) yielded normal results. The mean number of aberrations per case was 3.9 for all cases and 7.2 in abnormal cases. Among the six abnormal cases, gains or losses were observed at 3 loci in two cases, 7 loci in one case, 8 loci in two cases and 14 loci in one case. The most common abnormalities were observed in chromosomes 7, 8 and 18, with 7q gain in five cases and 7p gain in four cases. Aberrations associated with intermediate or advanced conventional hepatocellular carcinomas, including losses at 3q, 4q and 13q were identified in 17-33% of fibrolamellar carcinomas. There was no correlation of chromosomal changes with age, gender and tumor size. The 5-year survival among the six patients with no chromosomal abnormalities was 80% (4/5) compared with 33% (2/6) in patients with chromosomal abnormalities (P=0.1). In conclusion, fibrolamellar carcinomas show fewer chromosomal abnormalities compared with those reported in literature for conventional hepatocellular carcinoma. The most common abnormalities occur in chromosomes 7 and 8. Fibrolamellar carcinomas with chromosomal changes appear to behave more aggressively compared with cases with no cytogenetic abnormalities. The favorable outcome in some fibrolamellar carcinomas may be due to absent or low number of cytogenetic aberrations.