Robert E. Petras

The diagnosis of low-grade dysplasia in Barrett's esophagus and its implications for disease progression

OBJECTIVE:The reported risk of progression from low-grade dysplasia (LGD) to high-grade dysplasia (HGD) or carcinoma (CA) in Barretts esophagus varies. However, the validity of a diagnosis of LGD may be questioned because of interobserver variability.METHODS:A search of the Cleveland Clinic Foundation surgical pathology files between 1986 and 1997 yielded biopsy specimens from 43 patients with Barretts esophagus diagnosed and coded as LGD. Patients with concurrent or prior diagnoses of HGD or carcinoma were excluded. The LGD cases were randomized and blindly reviewed by three gastrointestinal (GI) pathologists along with cases originally diagnosed as Barretts esophagus without dysplasia (ND; n = 28), indefinite for dysplasia (IND; n = 14), or HGD (n = 15). Each pathologist classified every biopsy specimen as ND, IND, LGD, or HGD, and interobserver agreements were determined by kappa statistics (K). Follow-up data were available on 25 patients originally diagnosed with LGD. Progression was defined as a subsequent diagnosis of HGD or CA on esophageal biopsy or resection specimens.RESULTS:Agreement between two GI pathologists for a diagnosis of LGD was fair (K = 0.28) and poor (K = 0.21 and −0.04). Individual GI pathologists agreed with the original diagnosis of LGD in 70%, 56%, and 16% of cases. The 25 patients with follow-up included 21 men and four women (mean age, 67 yr) with a mean follow-up of 26 months (range: 2–84 months). Seven patients (28%) with follow-up developed HGD (five patients) or CA (two patients), 2–43 months (median: 11 months) after a diagnosis of LGD. The individual GI pathologists’ diagnosis did not correlate with progression. However, when at least two GI pathologists agreed on LGD, there was a significant association with progression (seven of 17 patients, 41%, p= 0.04). When all three GI pathologists agreed on a diagnosis of LGD, four of five patients progressed (p= 0.012). In contrast, of the eight patients with follow-up and no agreement among GI pathologists for a diagnosis of LGD, none progressed.CONCLUSIONS:A high degree of interobserver variability is seen in the histological diagnosis of Barretts esophagus–related LGD. Although the number of observations is low, a consensus diagnosis of LGD among GI pathologists suggests an increased risk of progression from LGD to HGD or carcinoma.

Surveillance for colonic carcinoma in ulcerative colitis

To evaluate the efficacy of surveillance colonoscopy with biopsy for the detection of high-grade dysplasia (HGD) or colonic carcinoma in patients with chronic ulcerative colitis, we undertook a retrospective review of 248 patients who underwent 370 examinations (mean duration of disease 12 yr). High-grade dysplasia or carcinoma was found in 24 examinations in 16 patients, with a mean duration of disease of 16 yr. There were 15 patients with HGD. Nine patients had HGD alone, 6 had HGD and carcinoma, and 1 had carcinoma without HGD. The overall incidence of HGD was 6%. Dysplasia-associated lesions or mass were the most consistent indicators of carcinoma, the combination being present in four instances. Of the 7 patients with cancer, 6 were recognized by colonoscopy, and 1 patient with negative visual endoscopic findings was discovered using surveillance biopsies. The conclusions of this study are that dysplasia is a reliable histopathologic marker and correlates with the presence of cancer in chronic ulcerative colitis; the absence of dysplasia correlates with the absence of cancer. The presence of dysplasia-associated lesions or mass with HGD is the strongest indication for operation. This study supports the use of surveillance colonoscopy in managing high-risk ulcerative colitis patients.

Spectroscopic diagnosis of colonic dysplasia

Abstract— —We have developed a method for defining diagnostic algorithms for pathologic conditions based on fluorescence spectroscopy. We apply this method to human colon tissue and show that fluorescence can be used to diagnose the presence or absence of colonic adenoma. This method uses fluorescence excitation–emission matrices (EEM) to identify optimal excitation regions for obtaining fluorescence emission spectra which can be used to differentiate normal and pathologic tissues. In the case of normal and adenomatous colon tissue, these were found to be: 330, 370, and 430 nm ± 10 nm. At these excitation wavelengths, emission wavelengths for use in diagnostic algorithms are identified from average difference and ratio of the spectra from normal and pathologic tissues. In colon tissue, at 370 nm excitation, 404, 480, and 680 nm were found to be useful emission wavelengths for diagnosing the presence of adenoma in vitro. The basis of colon tissue autofluorescence was investigated using EEM of pure molecules and relevant excitation–emission maxima in the literature.

Observer variation in the diagnosis of superficial oesophageal adenocarcinoma

Background and aims: When to perform oesophagectomy for neoplastic progression in Barrett’s oesophagus is controversial. Some resect for high grade dysplasia whereas others defer treatment until intramucosal adenocarcinoma is diagnosed. Interobserver agreement for a diagnosis of high grade dysplasia or intramucosal adenocarcinoma remains unknown and may have therapeutic implications. Methods: Histological slides from 75 oesophagectomy specimens with high grade dysplasia or T1 adenocarcinoma were blindly reviewed by two gastrointestinal pathologists and one general surgical pathologist, and classified as high grade dysplasia, intramucosal adenocarcinoma, or submucosal adenocarcinoma. A subsequent re-review of all 75 cases by the same observers following establishment of uniform histological criteria was undertaken. Interobserver agreement was determined by kappa statistics. Coefficients <0.21, 0.21–0.40, 0.41–0.60, 0.61–0.80, and >0.80 were considered poor, fair, moderate, good, and very good agreement, respectively. Results: Interobserver agreement among all pathologists and between gastrointestinal pathologists when comparing high grade dysplasia with intramucosal adenocarcinoma was only fair (k=0.42; 0.56, respectively) and did not substantially improve on subsequent re-evaluation following establishment of uniform histological criteria (K=0.50; 0.61, respectively). Conclusions: When evaluating resection specimens and after implementation of uniform histological criteria, even experienced gastrointestinal pathologists frequently disagree on a diagnosis of high grade dysplasia versus intramucosal adenocarcinoma. Treatment strategies based on the histological distinction of high grade dysplasia from intramucosal adenocarcinoma using limited biopsy specimens should be re-evaluated.

Dysplasia of the anal transitional zone after ileal pouch-anal anastomosis: results of prospective evaluation after a minimum of ten years.

AbstractPURPOSE: Stapling of the ileal pouch-anal anastomosis with preservation of the anal transitional zone remains controversial because of concerns about the potential risk of dysplasia and cancer. The natural history and optimal treatment of anal transitional zone dysplasia ten or more years after surgery are unknown. This study establishes the risk of dysplasia in the anal transitional zone and the outcome of a conservative management policy for anal transitional zone dysplasia, with a minimum of ten years’ follow-up after ileal pouch-anal anastomosis. METHODS: A total of 289 patients undergoing anal transitional zone–sparing stapled ileal pouch-anal anastomosis for inflammatory bowel disease between 1986 and 1990 were studied. Patients undergoing anal transitional zone–sparing ileal pouch-anal anastomosis who were studied with serial anal transitional zone biopsies for at least ten years postoperatively were included (n = 178). Median follow-up was 130 (range, 120–157) months. RESULTS: Anal transitional zone dysplasia developed in 8 patients 4 to 123 (median, 9) months after surgery. There was no association with gender, age, preoperative disease duration, or extent of colitis, but the risk of anal transitional zone dysplasia was significantly associated with cancer or dysplasia as a preoperative diagnosis or in the proctocolectomy specimen. Dysplasia was high grade in two patients and low grade in six. Two patients with low-grade dysplasia on two or more occasions after detection of low-grade dysplasia underwent completion mucosectomy and perineal pouch advancement with neo–ileal pouch-anal anastomosis. One patient with high-grade dysplasia on two occasions was to undergo completion mucosectomy, but this was not technically feasible. Partial mucosectomy with vigorous anal transitional zone biopsy was performed with close postoperative surveillance. Biopsies were negative for dysplasia. The second recently diagnosed patient with high-grade dysplasia underwent examination under anesthesia with negative anal transitional zone biopsies and will be kept under close surveillance. No cancer in the anal transitional zone was found during the study period. The 4 other patients with low-grade dysplasia on 1 or 2 occasions were treated expectantly and have been dysplasia free for a median of 119 (range, 103–133) months. CONCLUSIONS: Anal transitional zone dysplasia after stapled ileal pouch-anal anastomosis is infrequent and is usually self-limiting. Anal transitional zone preservation did not lead to the development of cancer in the anal transitional zone with a minimum of ten years of follow-up. Long-term surveillance is recommended to monitor dysplasia. If repeat biopsy confirms persistent dysplasia, mucosectomy with perineal pouch advancement and neo–ileal pouch-anal anastomosis is recommended.

Management and outcome of patients with invasive carcinoma arising in colorectal polyps

BACKGROUND & AIMS Treatment for invasive adenocarcinoma in colorectal polyps (malignant polyps) is controversial. The aim of this study was to evaluate our institutional treatment strategy for malignant polyps. METHODS Malignant polyps were designated as having favorable histology (grade I or II carcinoma with at least a 2-mm free margin) or unfavorable histology (grade III invasive adenocarcinoma, invasive adenocarcinoma with an unassessable margin, or a margin of < 2 mm). Malignant polyps with favorable histology were considered treated adequately by endoscopic polypectomy, whereas further therapy was recommended for malignant polyps with unfavorable histology. Recurrence, residual adenocarcinoma in a follow-up resection specimen, or metastasis during follow-up were considered adverse outcomes. RESULTS Of the 47 patients identified, 17 (36%) had favorable histology. Sixteen patients (94%) were treated with polypectomy alone. None had an adverse outcome (median follow-up, 70 months). Thirty patients (64%) had unfavorable histology, and 21 patients (70%) underwent colectomy. Five patients underwent radiation therapy alone. Four patients underwent no additional therapy. Ten of 30 patients with unfavorable histology had adverse outcomes that differed significantly from the favorable histology group (P = 0.03). CONCLUSIONS Endoscopic polypectomy alone is adequate therapy for malignant polyps with favorable histology.

When is endoscopic polypectomy adequate therapy for colonic polyps containing invasive carcinoma

We correlated the histopathology with outcome for all patients with endoscopically removed colonic polyps containing invasive adenocarcinoma seen at our institution over a 10-yr period. Invasion was defined as infiltration of malignant cells into the submucosa. Of a total of 1523 adenomatous polyps, 41 polyps (2.7%) in 39 patients contained invasive adenocarcinoma. One patient was excluded from further analysis because of a synchronous colonic carcinoma. Fourteen patients (37%) had favorable histologic features (grade I or grade II carcinoma with free margin of resection and absence of lymphatic invasion), and none developed metastatic carcinoma during the follow-up period (mean 6.5 yr, range 4-10.6 yr). Twenty-four (63%) had unfavorable histologic features (grade III tumor with tumor at or near the margin of resection or lymphatic invasion), and 10 of these (42%) had either residual local or metastatic carcinoma in subsequent operations or during the follow-up period. This difference in outcome was statistically significant (p less than 0.05) when compared with the outcome of the group with favorable histology. We conclude that endoscopic polypectomy is adequate therapy for colonic polyps containing invasive carcinoma, provided that the favorable histologic features are present.

Detection of dysplasia at colonoscopy using laser-induced fluorescence: a blinded study

BACKGROUND Laser-induced fluorescence spectroscopy has the potential to detect colonic dysplasia in vivo. However, previous studies have limited their analyses to multivariate regression techniques and unblinded retrospective evaluation. The purpose of this study was to develop a probability-based algorithm to detect colonic dysplasia using laser-induced fluorescence spectroscopy and to evaluate it in a blinded manner. METHODS Fluorescence spectra were collected from normal mucosa and colonic polyps during colonoscopy using 370 nm excitation. Tissue was classified as normal, hyperplastic, or adenomatous by histologic examination. Preliminary data was used to devise an algorithm to differentiate tissue type based on probability distributions of the fluorescence intensity at 460 nm and the ratio of the intensity at 680 nm to that at 600 nm. The algorithm was then tested in a blinded fashion. RESULTS The algorithm correctly determined the tissue type in 88% of cases, equal to the agreement of independent pathologists. Sensitivity, specificity, and positive predictive value for the detection of dysplasia was 90%, 95%, and 90%, respectively. CONCLUSIONS Dysplasia was detected in vivo using fluorescence spectroscopy and a probability-based algorithm. This method may form the basis for a new surveillance technique for patients with increased risk for dysplastic transformation.

The safety of intraosseous infusions: Risks of fat and bone marrow emboli to the lungs

The technique of intraosseous infusion is a life-saving emergency alternative when IV access is impossible or will be critically delayed. Concerns about its safety remain, especially concerning the risk of bone marrow and fat emboli to the lungs. We examined autopsy pulmonary specimens on two children who had received intraosseous infusions during resuscitation attempts and found an average of 0.23 to 0.71 bone marrow and fat emboli per mm 2 of lung. We studied normotensive dogs with intraosseous infusions of emergency drugs and solutions into the distal femur. Three dogs were studied with each of the following emergency drugs or solutions: controls with normal saline (0.9% NaCl), epinephrine 0.01 mg/kg, NaHCO 3 1 mEq/kg, CaCl 10 mg/kg, atropine 0.01 mg/kg, hydroxyethyl starch 6% in normal saline 10 mL/kg, 50% dextrose in water 0.25 g/kg, and lidocaine 1 mg/kg. Four hours after infusion, the animals were killed, and representative sections of the lung were examined with oil red-0 and hematoxylin and eosin stains for the presence of fat and bone marrow emboli. Fat and bone marrow emboli were found in all lung sections, varying from 0.11 to 4.48 emboli/mm 2 lung (mean, 0.91 emboli/mm 2 lung) for the emergency drugs and solutions and 0.06 to 0.53 emboli/mm 2 (mean, 0.29 emboli/mm 2 lung) for the controls. Analysis of variance revealed no significant difference ( P = .07) in mean number of fat and bone marrow emboli per square millimeter of lung among the emergency drugs and compared with controls. The 95% confidence limits for estimating the proportion of the population to develop bone marrow and fat emboli after intraosseous infusions is 0.89 to 1.00. Despite the universal finding of fat and bone marrow emboli in patients and animals in which emergency drugs were administered by the intraosseous route, there were no significant alterations in Pao 2 or intrapulmonary shunt during the four-hour study period. This suggests that although fat and bone marrow emboli are a common occurrence after intraosseous drug administration, they are not of any immediate clinical importance, do not result in a pulmonary fat embolism syndrome or adult respiratory distress syndrome that might complicate resuscitation, and should not preclude the use of the intraosseous route for resuscitation drugs when IV access is delayed or impossible. However, the pulmonary fat embolism syndrome may complicate postresuscitation care, and bone marrow and fat emboli may be of clinical importance in patients with intracardiac right-to-left shunts because of the risk of cerebral emboli and emboli to other vital organs.

Incidence, risk factors, and treatment of dysplasia in the anal transitional zone after ileal pouch-anal anastomosis

Preservation of the anal transitional zone (ATZ) after restorative proctocolectomy and stapled ileal pouch-anal anastomosis (IPAA) for ulcerative colitis is controversial. PURPOSE: To evaluate the incidence, risk factors, and treatment options for dysplasia and/or cancer after restorative proctocolectomy and stapled IPAA. METHODS: We reviewed the records of all 254 patients operated on for ulcerative colitis who had a restorative proctocolectomy, stapled IPAA, and annual postoperative biopsies of ATZ. Follow-up studies included an annual questionnaire and physical examination. RESULTS: During a follow-up of 2.3±1.4 (mean ± standard deviation) years, low-grade dysplasia was found in eight patients (3.1 percent), 16 (median: range, 6–56) months after surgery. Repeated biopsies revealed dysplasia in only two of eight patients, and completion mucosectomy was performed. Dysplasia in ATZ was associated with a preoperative (P=0.02) or postoperative (P=0.04) pathologic diagnosis of ulcerative colitis with concurrent dysplasia or cancer. No association (P>0.05) was found between dysplasia and the following: age, sex, preoperative length of disease, use of a double-stapledversus single-stapled technique, or anastomotic distance from the dentate line. CONCLUSIONS: Incidence of low-grade dysplasia in ATZ was low. Restorative proctocolectomy with total mucosectomy of the anal canal and handsewn IPAA is recommended for patients with preoperative diagnosis of ulcerative colitis and concurrent cancer or dysplasia. Frequent follow-up with biopsies is recommended for patients with incidental finding of cancer or high-grade dysplasia after restorative proctocolectomy and stapled IPAA with preservation of ATZ. For persistent or recurrent low-grade dysplasia, we recommend a completion mucosectomy