Grading of Total Mesorectal Excision Specimens: Assessment of Interrater Agreement.

BACKGROUND: Total mesorectal excision is the standard of care for patients with rectal cancer. Pathological evaluation of the quality of the total mesorectal excision specimen is an important prognostic factor that correlates with local recurrence, but is potentially subjective. OBJECTIVE: This study aimed to determine the degree of variation in grading, both between assessors and between fresh and formalin-fixed specimens. DESIGN: Raters included surgeons, pathologists, pathology residents, pathologists' assistants, and pathologists' assistant trainees. Specimens were assessed by up to 6 raters in the fresh state and by 2 raters postfixation. Four parameters were evaluated: mesorectal bulk, surface regularity, defects, and coning. Interrater agreement was measured using ordinal α-values. SETTING: The study was conducted at a single academic center. MAIN OUTCOME MEASURES: The primary outcome was agreement between individuals when grading total mesorectal excision specimens. RESULTS: A total of 37 total mesorectal excision specimens were assessed. Reliability between all raters for fresh specimens for mesorectal bulk, surface regularity, defects, coning, and overall grade were 0.85, 0.85, 0.92, 0.84, and 0.91. When compared with all raters, pathologists and residents had higher agreement and pathologists and surgeons had lower agreement. Ordinal α-values comparing pathologist and pathologist's assistant agreement for overall grade were similar pre- and postfixation (0.78 vs 0.80), but agreement for assessing defects decreased postfixation. Among pathologists' assistants, agreement was higher when grading specimens postfixation than when grading fresh specimens. LIMITATIONS: Assessment bias may have occurred because of the greater number of pathologists' assistants participating than the number of residents and pathologists. CONCLUSIONS: The results indicate good interrater agreement for the assessment of overall grade, with defects showing the best interrater agreement in fresh specimens. Although total mesorectal excision specimens may be consistently graded postfixation, the assessment of defects postfixation may be less reliable. This study highlights the need for additional knowledge-transfer activities to ensure consistency and accurate grading of total mesorectal excision specimens. See Video Abstract at http://links.lww.com/DCR/A497.

The impact of knowledge transfer on the detection of venous invasion in colorectal cancer.

Venous invasion (VI) is an independent predictor of hematogenous metastasis and mortality in colorectal cancer (CRC) yet remains widely underreported. Its detection may require recognition of subtle morphologic clues, which at times are only unmasked with an elastin stain. This study evaluates the impact of a knowledge transfer initiative (KTI) on VI detection in a "real-world" pathology practice setting. Following participation in an interobserver variability study of VI detection (Kirsch et al, 2013), 12 participants received educational materials highlighting key issues in VI detection. Eighteen months later, participants were invited to submit pathology reports from all CRC resections signed out 18 months prior to and 18 months following the KTI (n = 266 and n = 244, respectively). Nine pathologists participated. Reports were reviewed for VI and other established prognostic factors. Numbers of elastin stains and tumor-containing blocks were also recorded. Comparative analyses were adjusted for baseline differences in tumor, lymph node, and metastasis stage; tumor location; use of neoadjuvant therapy; and number of tumor-containing blocks. VI detection increased significantly post-KTI versus pre-KTI (39.3% versus 18.4%, adjusted odds ratio [OR] 2.86 [1.91-4.28], P < .001). Increased VI detection post-KTI was observed in both stage II (31.8% versus 12.5%, adjusted OR 3.27 [1.45-7.42], P = .004) and stage III CRC (62.4% versus 28.2%, adjusted OR 4.23 [2.37-7.55], P < .001). All pathologists demonstrated increased VI detection post-KTI. Use of elastin stains was significantly higher post-KTI versus pre-KTI (61.5% versus 5.3% of cases respectively, P < .001). This study demonstrates the effectiveness of knowledge transfer in increasing VI detection in routine pathology practice.

Venous invasion in colorectal cancer: impact of an elastin stain on detection and interobserver agreement among gastrointestinal and nongastrointestinal pathologists.

Venous invasion (VI) is an independent prognostic indicator in colorectal cancer and may prompt consideration for adjuvant chemotherapy in patients with stage II tumors. Recent evidence suggests that VI is underreported in colorectal cancer and that detection may be enhanced by an elastin stain. This study aimed (1) to determine the impact of an elastin stain on VI detection and on interobserver agreement between gastrointestinal (GI) and non-GI pathologists, and (2) to identify factors associated with increased VI detection. Forty hematoxylin and eosin (H&E)-stained slides were circulated to 6 GI and 6 non-GI pathologists who independently assessed the VI status as positive, negative, or equivocal. Six weeks later, 40 corresponding Movat-stained slides were recirculated together with the original H&E slides and reassessed for VI status. Detection of VI was >2-fold higher with a Movat stain compared with an H&E stain alone (46.4% vs. 19.6%, P=0.001). GI pathologists detected VI more frequently than non-GI pathologists on both H&E (30.0% vs. 9.2%, P=0.029) and Movat (58.3% vs. 34.6%, P=0.018) stains. There was higher interobserver agreement in the case of a Movat stain, particularly for extramural VI (H&E: κ=0.23 vs. Movat: κ=0.41). A poststudy survey indicated that GI pathologists and non-GI pathologists applied similar diagnostic criteria but that GI pathologists more frequently applied "orphan arteriole" and "protruding tongue" signs as diagnostic clues to VI. This study confirms that VI is underdetected on H&E and highlights the role of elastin staining in improving VI detection and interobserver agreement. Strategies to improve VI detection are warranted.

Sessile serrated adenoma (SSA) vs. traditional serrated adenoma (TSA).

The morphologic distinction between various serrated polyps of the colorectum may be challenging. The distinction between sessile serrated adenoma (SSA) and traditional serrated adenoma (TSA) may be difficult using currently available criteria mostly based on cytologic characteristics. We have evaluated 66 serrated polyps including 29 SSA, 18 TSA, and 19 hyperplastic polyps for overall shape of the polyps, architectural features of individual crypts, the presence of eosinophilic cytoplasm, size and distribution of the proliferation and maturation zones, as well as Ki-67 and CK20 expression. The extent of the expression of CK20 and Ki-67 could not distinguish between the 3 types of serrated polyps, but the distribution of their expression was very helpful and differences were statistically significant. The distribution of Ki-67+ cells was the single most helpful distinguishing feature of the serrated polyp type (P<0.0001, chi test). Hyperplastic polyps had regular, symmetric, and increased Ki-67 expression. SSA had irregular, asymmetric, and highly variable expression of Ki-67. TSA had low Ki-67 expression, which was limited to "ectopic crypts" and admixed tubular adenomalike areas. In serrated polyps, ectopic crypt formation (ECF) defined by the presence of ectopic crypts with their bases not seated adjacent to the muscularis mucosae was nearly exclusive to TSA and was found in all cases, while the presence of cytologic atypia and eosinophilia of the cytoplasm were characteristic, but not limited to TSA. No evidence of ECF, but nevertheless abnormal distribution of proliferation zone was characteristic of SSA, whereas HP had neither. The presence of the ECF defines TSA in a more rigorous fashion than previous diagnostic criteria and also explains the biologic basis of exuberant protuberant growth associated with TSA and the lack of such growth in SSA. Recognition of this phenomenon may also help in exploring the genetic and molecular basis for differences between SSA and TSA, because these architectural abnormalities may well be a reflection of abnormalities in genetically programmed mucosal development.

Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence.

Milan and University of California at San Francisco (UCSF) criteria are used to select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT). Recurrent HCC is a significant cause of death. There is no widely accepted pathological assessment strategy to predict recurrent HCC after transplantation. This study compares the pathology of patients meeting Milan and UCSF criteria and develops a pathological score and nomogram to assess the risk of recurrent HCC after transplantation. All explanted livers with HCC from our center over the 18-yr period 1985 to 2003 were assessed for multiple pathological features and relevant clinical data were recorded; multivariate analysis was performed to determine features associated with recurrent HCC. Using pathological variables that independently predicted recurrent HCC, a pathological score and nomogram were developed to determine the probability of recurrent HCC. Of 75 cases analyzed, 50 (67%) met Milan criteria, 9 (12%) met only UCSF criteria and 16 (21%) met neither criteria based on explant pathology. There were 20 cases of recurrent HCC and the mean follow-up was 8 yr. Recurrent HCC was more common (67 vs. 12%; P < 0.001) and survival was lower (15 vs. 83% at 5 yr; 15 vs. 55% at 8 yr; P < 0.001) with those who met only UCSF criteria, compared to those who met Milan criteria. Cryptogenic cirrhosis (25 vs. 5%; P = 0.015), preoperative AFP >1,000 ng/mL (20 vs. 0%; P < 0.001) and postoperative OKT3 use (40 vs. 15%; P = 0.017) were more common among patients with recurrent HCC. While microvascular invasion was the strongest pathological predictor of recurrent HCC, tumor size >or=3 cm (P = 0.004; odds ratio [OR] = 7.42), nuclear grade (P = 0.044; OR = 3.25), microsatellitosis (P = 0.020; OR = 4.82), and giant/bizarre cells (P = 0.028; OR = 4.78) also predicted recurrent HCC independently from vascular invasion. The score and nomogram stratified the risk of recurrent HCC into 3 tiers: low (<5%), intermediate (40-65%), and high (>95%). In conclusion, compared to patients meeting Milan criteria, patients who meet only UCSF criteria have a worse survival and an increased rate of recurrent HCC with long-term follow-up, as well as more frequent occurrence of adverse histopathological features, such as microvascular invasion. Application of a pathological score and nomogram could help identify patients at increased risk for tumor recurrence, who may benefit from increased surveillance or adjuvant therapy.

Comparison of ThinPrep and conventional smears in salivary gland fine-needle aspiration biopsies.

BACKGROUND: ThinPrep (TP) cytology for evaluation of nongynecological specimens is being increasingly used. There are few studies comparing TP with conventional smears (CS) in salivary gland (SG) fine-needle aspiration biopsies (FNAB). This study compares diagnostic accuracy and morphology of TP and CS in SG FNABs. METHODS: The authors retrospectively reviewed 98 satisfactory SG FNABs with both TP and CS. All cases had surgical resection. CS and TP slides were assessed for multiple morphological parameters, as well as the ability to make the diagnosis. Chi-square analysis was performed to compare CS and TP. RESULTS: An accurate diagnosis was rendered more commonly with CS compared with TP (57% versus 42%; P = .032), whereas the unsatisfactory rate was greater with TP compared with CS (19% versus 9%; P = .041). The error (4%) and indeterminate (35%) rates for TP were similar to CS. The diagnostic yield was greater for cellular cases, which were more frequent with CS compared with TP, than for cases of low cellularity; the diagnostic yield of cellular TP cases and cellular CS cases was similar. Artifacts (crush, air drying, obscuring blood) were more frequent (12%, 13%, and 27% versus 2%, 0%, and 1%; P

Survivin and hedgehog protein expression in serrated colorectal polyps: an immunohistochemical study.

Sessile serrated adenomas and traditional serrated adenomas are pathogenetically related to inhibition of apoptosis. Survivin and hedgehog proteins, including sonic hedgehog, patched, and smoothened, inhibit apoptosis, with hedgehog proteins forming a signal transduction cascade implicated in digestive cancers. This study compares survivin and hedgehog protein expression in serrated polyps and tubulovillous adenomas. Biopsies of sessile serrated adenomas (48) and traditional serrated adenomas (10) diagnosed during 2005 were retrieved from our files. Biopsies of normal mucosa (10), hyperplastic polyps (14), and tubulovillous adenomas (22) were used for comparison. Immunohistochemistry for survivin, sonic hedgehog, patched, and smoothened was graded as high or low grade. chi(2) tests were used to evaluate correlation between polyp type and survivin and hedgehog expression. Traditional serrated adenomas were also compared to sessile serrated adenomas with foci of cytological dysplasia (11 cases) with respect to MLH1 and p53 expression. Sessile serrated adenomas showed high-grade nuclear and cytoplasmic expression of survivin at the bottom of crypts more frequently than tubulovillous adenomas (60% versus 18%, P = .001 [nuclear]; 54% versus 18%, P = .005 [cytoplasm]), the latter showing a top-heavy pattern of staining. Survivin expression in hyperplastic polyps was similar to sessile serrated adenomas, being bottom-heavy, whereas traditional serrated adenomas showed diffuse staining throughout crypts. Although traditional serrated adenomas showed high-grade expression of sonic hedgehog more frequently than tubulovillous adenomas (90% versus 18%; P < .001), sonic hedgehog, patched, and smoothened expression was low grade among normal mucosa, hyperplastic polyps, and sessile serrated adenomas. All cytological dysplasias showed increased p53 expression within dysplastic foci, and MLH1 was also lost within dysplastic foci in 4 cases; traditional serrated adenomas showed intact MLH1 expression and minimal p53 expression throughout. Survivin expression is localized to the bottom of crypts in sessile serrated adenomas and hyperplastic polyps, whereas tubulovillous adenomas show top-heavy expression. Traditional serrated adenomas express survivin throughout crypts, suggesting intersection between the serrated and conventional adenoma-cancer pathways. Sonic hedgehog up-regulation is characteristic of traditional serrated adenomas, distinguishing this entity from other colorectal polyps.

The total mesorectal excision specimen for rectal cancer: a review of its pathological assessment.

Total mesorectal excision (TME) refers to the surgical removal of the complete perirectal soft tissue envelope, using sharp instruments under direct vision, and has become the contemporary standard of care for patients with rectal cancer. Pathologists play a key role in the evaluation of these specimens, including the quality assurance of surgical performance, as well as evaluation of the circumferential radial margin (CRM). While the latter is the most significant predictor of local recurrence, the quality of the excised mesorectum is another important factor in assessing the risk of local recurrence in patients with a negative CRM. Since proper pathological assessment of the TME specimen provides important prognostic information, as well as critical feedback to surgeons regarding technical performance, it is important to have adequate guidelines for the macroscopic handling of these specimens. The CLASSICC study of the Medical Research Council in the United Kingdom, as well as the Dutch TME trial have introduced a new standard for the pathological assessment of TME specimens, including an approach that involves assessment in both the fresh and fixed states, at least 48 hours of fixation of an intact specimen, with observations made on both the external appearance and cross-sectional slices. This article reviews the pathological assessment of the TME specimen, including basic definitions, current international guidelines, an approach to evaluating the mesorectum and a discussion of special issues relating to margins, lymph node retrieval and effects of neoadjuvant therapy.

Gastrointestinal stromal tumors: a contemporary review.

The literature on gastrointestinal stromal tumors (GISTs) has rapidly expanded and has demonstrated how scientific advancements in diagnosis can revolutionize the understanding of disease, while paving the way for effective treatment. While KIT (CD117) immunohistochemistry has established our definition of GISTs, molecular genetics continue to refine it. Elucidation of the aberrant receptor tyrosine kinase (RTK) model of GIST pathogenesis through mutations in c-kit and platelet-derived growth factor alpha PDGFRalpha proto-oncogenes has been prerequisite to the use of imatinib mesylate (STI571, Gleevec; Novartis, Switzerland), a molecular inhibitor of several tyrosine kinases, in the treatment of GISTs. In addition to providing a means for effective treatment, clarification of the molecular pathology of GISTs may potentially offer a new classification of these tumors by correlating genotype with histological, immunohistochemical, and clinical phenotype. This article seeks to review current knowledge of GISTs, offering a practical guide to their diagnosis and describing current epidemiological, molecular biological, and therapeutic aspects.

Malignant neoplasm of perivascular epithelioid cells of the liver.

Neoplasms of perivascular epithelioid cells (PEComas) have in common the coexpression of muscle and melanocytic immunohistochemical markers. Although this group includes entities with distinct clinical features, such as angiomyolipoma, clear cell sugar tumor of the lung, and lymphangioleiomyomatosis, similar tumors have been documented in an increasing diversity of locations. The term PEComa is now generally used in reference to these lesions that are not angiomyolipomas, clear cell sugar tumors, or lymphangioleiomyomatoses. While most reported PEComas have behaved in a benign fashion, malignant PEComas have occasionally been documented. We present a case of hepatic PEComa with benign histologic features, which nonetheless presented with metastases to multiple sites nearly 9 years later. This case represents the second documented malignant PEComa of the liver, as well as the longest follow-up of a surviving patient with a malignant PEComa, emphasizing both the need for criteria that more accurately predict the behavior of PEComas and the necessity of long-term follow-up of patients with PEComas.

Primary PEComa of the bladder treated with primary excision and adjuvant interferon-alpha immunotherapy: a case report.

BACKGROUND: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms of uncertain malignant potential, which have in common the co-expression of muscle and melanocytic immunohistochemical markers. CASE PRESENTATION: A 48-year-old man presented with dysuria, passage of urinary sediment and lower abdominal discomfort. A three centimeter mass was identified by cystoscopy in the posterior midline of the bladder. Computerized tomography suggested an enterovesical fistula. The patient underwent laparotomy, partial cystectomy and partial small bowel resection. Pathological examination revealed PEComa of the bladder. The patient underwent adjuvant interferon-alpha immunotherapy. Subsequent follow-up procedures, including cystoscopy and imaging, have not revealed evidence of recurrence. The patient is clinically free of disease 48 months after surgery. CONCLUSION: This case represents the second documented PEComa of bladder and demonstrates that adjuvant therapies, including anti-angiogenic and immunotherapy, may be considered for patients with locally advanced or metastatic genitourinary PEComa.

Increasing incidence of adenocarcinoma of the gastroesophageal junction and distal stomach in Canada -- an epidemiological study from 1964-2002.

BACKGROUND: The increasing incidence of esophageal and proximal gastric (cardia) adenocarcinoma and the decreasing incidence of distal gastric (antropyloric) adenocarcinoma has been documented in several populations. The aim of the present study was to examine incidence trends of these neoplasms in Ontario, Canada's most populous province, over a 39-year period. METHODS: Analyses were based on data obtained from the Ontario Cancer Registry of Cancer Care Ontario. Number of cases and rates per 100,000 age-adjusted to the 1996 Canadian standard, were obtained for all esophageal and gastric carcinoma cases reported between 1964 and 2002. Rates were grouped into five-year periods to analyze trends over the 39-year period. Point and 95% CI estimates of average annual percentage change in incidence rates were calculated with a log-linear regression model. RESULTS: The incidence of adenocarcinoma of the distal esophagus increased in men and women (average annual increase of 9.5% in men; 4.3% in women). The incidence of adenocarcinoma of the cardia increased in men and women (average annual increase of 7.3% in men; 5.8% in women). The incidence of antropyloric adenocarcinoma increased in men and women (average annual increase of 4.4% in men; 5.3% in women). The incidence of esophageal squamous cell carcinoma remained stable. CONCLUSIONS: There has been a significant increase in the incidence of adenocarcinoma around the gastroesophageal junction in men over the 39-year study period. The increase in incidence of distal gastric adenocarcinoma is unexpected and may relate to a reclassification phenomenon, immigration trends in Ontario and a rising incidence of diffuse/signet ring cell adenocarcinoma.

Eosinophilic esophagitis in adults: distinguishing features from gastroesophageal reflux disease: a study of 41 patients.

Eosinophilic esophagitis in adults is a recently described entity occurring in young males with dysphagia, in whom esophageal biopsies show eosinophilic infiltration. This study defines the clinical and histological features of patients with eosinophilic esophagitis, distinguishing it from gastroesophageal reflux disease. Esophageal biopsies from patients with dysphagia or esophagitis were reviewed blindly, and assessed for: epithelial eosinophil counts, presence of eosinophilic microabscesses, edema, basal zone hyperplasia, lamina propria papillae elongation, eosinophils and fibrosis. Clinical and endoscopic findings were obtained. Eosinophilic esophagitis was diagnosed with epithelial eosinophils > or = 15 in > or = 2 high-power fields (hpfs) or > or = 25 in any hpf. Analysis was performed with Mann-Whitney, chi2 and ANOVA tests. Of 157 cases, 41 had eosinophilic esophagitis. Male gender (81%) and age < or = 45 (54%) were commoner in patients with eosinophilic esophagitis (P = 0.001, 0.010, respectively). Dysphagia was more common in eosinophilic esophagitis patients (63%, P < 0.001); heartburn was more common in noneosinophilic esophagitis patients (53%, P < 0.001). Endoscopic rings were more common in eosinophilic esophagitis patients (27%, P = 0.023); hiatus hernia was more common in noneosinophilic esophagitis patients (11%, P = 0.022). Eosinophils were more numerous in eosinophilic esophagitis biopsies (mean 39/hpf, P < or = 0.001). Only eosinophilic esophagitis biopsies had eosinophilic microabscesses (42%, P < or = 0.001). Edema, basal zone hyperplasia, lamina propria papillae elongation and lamina propria eosinophils were commoner in eosinophilic esophagitis (P < or = 0.001-0.002), while lamina propria fibrosis was specific for eosinophilic esophagitis (39%, P < 0.001). Eosinophilic esophagitis is a disease with a predilection for young males with dysphagia and rings on endoscopy. Biopsies in eosinophilic esophagitis have high epithelial eosinophil counts, averaging nearly 40/hpf. Increased awareness of eosinophilic esophagitis is necessary, since treatment with allergen elimination or anti-inflammatory therapy may be more effective than acid suppression.

In-situ and invasive carcinoma within a phyllodes tumor associated with lymph node metastases.

BACKGROUND: Phyllodes tumors (cystosarcoma phyllodes) are uncommon lesions in the female breast. Rarely, the occurrence of carcinoma within a phyllodes tumor has been reported in the literature, but has never been associated with lymph node metastases. CASE PRESENTATION: A 26-year-old woman presented with a firm, mobile, non-tender mass in the left breast and palpable lymph nodes in the left axilla. The excised lesion appeared well circumscribed and lobulated, with variable fleshy and firm areas. Microscopic examination showed a circumscribed fibroepithelial lesion with a well developed leaf-like architecture, in keeping with a benign phyllodes tumor. The epithelial component showed extensive high grade ductal carcinoma in-situ (DCIS) and invasive carcinoma of no special type, located entirely within the phyllodes tumor. Subsequent axillary lymph node dissection revealed metastatic carcinoma in four lymph nodes. CONCLUSIONS: Although rare, phyllodes tumors may harbor DCIS and invasive carcinoma, with potential for lymph node metastasis.