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Background
The treatment of colon cancer represents a major triumph in the combination of surgical and chemotherapeutic approaches. Pathologists have helped to identify several prognostic markers that have led the way into understanding the biology of this cancer enabling the development of highly specific agents.
OUTLINE
PROGNOSIS CHARACTERIZATION GENERAL The pathologist must indicate the grade of differentiation as well as determine extent of invasion. The stage of the tumor is usually given as the Astler-Coller modification (see terms). About 40% of all colorectal cancers present with stage II (Dukes B2) Histologic features associated with lymph node metastasis in stage T1 and superficial T2 rectal adenocarcinomas in abdominoperineal resection specimens. Identifying a subset of patients for whom treatment with adjuvant therapy or completion abdominoperineal resection should be considered after local excision.
Goldstein NS, Hart J.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Am J Clin Pathol 1999 Jan;111(1):51-8 Abstract quote
Local excision of rectal adenocarcinomas that are confined to the submucosa is an accepted method of surgical excision. Adjuvant therapy and possibly completion abdominoperineal resection (APR) may be appropriate if lymph node (LN) metastases are present. Identifying the patients at high risk of having LN metastases would assist in disease management.
We retrospectively examined 73 APR resection specimens with T1 or superficial T2 adenocarcinomas. The leading edge of the tumor was evaluated for budding, microacinar structures, or isolated or small clusters of undifferentiated cells. The features were correlated with LN metastases. Eleven specimens had LN metastases. Extensive budding, microacinar structures, or undifferentiated cells, tumor grade 3, and small vessel vascular space invasion were associated with LN metastases.
Limiting the comparison to grade 1 and 2 adenocarcinomas showed association of extensive budding, microtubular architecture, and undifferentiated cells along the advancing edge with LN-metastases. If these histologic features are extensively present, the patient may be a candidate for adjuvant therapy or completion APR. The morphologic features of the advancing edge are independent of the tumor grade of the neoplastic glands within the body of the tumor; they can be incorporated into the evaluation of overall tumor grade.
AIB1
- Correlation of AIB1 overexpression with advanced clinical stage of human colorectal carcinoma.
Xie D, Sham JS, Zeng WF, Lin HL, Bi J, Che LH, Hu L, Zeng YX, Guan XY.
Cancer Center, Sun Yat-Sen University, Guangzhou 510275, China; Department of Pathology, Sun Yat-Sen University, Guangzhou 510275, China.
Hum Pathol. 2005 Jul;36(7):777-83. Abstract quote
AIB1, a member of the steroid receptor coactivator 1 family, has been cloned on 20q12 and is a candidate oncogene in human breast cancer. It is commonly amplified and overexpressed in several types of human cancers.
In this study, we examined the expression of AIB1, as related to clinicopathologic features, in 85 human colorectal cancers (CRCs). The status of the number of AIB1 copies, p53 expression, and DNA ploidy was also analyzed. The overexpression of AIB1 was detected in 35% of CRCs. Amplification of AIB1 was observed in 10% of CRCs. In addition, the overexpression of AIB1 was observed more frequently in CRCs in later clinical stages (T3 N1 M0/T3 N0 2M1), compared with that in T3 N0 M0 stage (P < .05).
These results suggest that overexpression of AIB1 might provide a selective advantage for the developmental growth and/or progression of subsets of CRCs. In addition, a significant correlation (P < .05) of overexpression of AIB1 with p53 overexpression as well as with aneuploid DNA content was observed in these CRCs. The overexpression of p53 was also correlated significantly with CRC DNA ploidy (P < .05). Furthermore, there was a substantial population of CRCs showing overexpression of both AIB1 and p53 protein and all had aneuploid DNA content; most of these were in the later clinical stage.
These findings suggest a possible convergence of AIB1 with a pathway involving p53, which might induce chromosomal instability and affect the clinical phenotype of a subset of CRCs.C-REACTIVE PROTEIN
C-reactive protein and the risk of incident colorectal cancer.
Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ.
Department of Medicine, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Md 21205, USA.
JAMA. 2004 Feb 4;291(5):585-90. Abstract quote
CONTEXT: Inflammation may play a role in the pathogenesis of colorectal cancer; however, epidemiological evidence supporting this hypothesis in average-risk persons is sparse.
OBJECTIVE: To determine the risk of incident colon and rectal cancer associated with elevated baseline plasma concentrations of C-reactive protein (CRP).
DESIGN, SETTING, AND PARTICIPANTS: Prospective, nested case-control study of a cohort of 22 887 adults (>18 years and Washington County, Maryland, residents) enrolled between May and October 1989 and followed up through December 2000. A total of 172 colorectal cancer cases were identified through linkage with the Washington County and Maryland State Cancer registries. Up to 2 controls (n = 342) were selected from the cohort for each case and matched by age, sex, race, and date of blood draw.
MAIN OUTCOME MEASURE: Odds ratio (OR) of incident colon and rectal cancer.
RESULTS: Plasma CRP concentrations were higher among all colorectal cases combined than controls (median CRP, 2.44 vs 1.94 mg/L; P =.01). The highest concentration was found in persons who subsequently developed colon cancer vs matched controls (median CRP, 2.69 vs 1.97 mg/L; P<.001). Among rectal cancer cases, CRP concentrations were not significantly different from controls (median CRP, 1.79 vs 1.81 mg/L; P =.32). The risk of colon cancer was higher in persons in the highest vs lowest quartile of CRP (OR, 2.55; 95% confidence interval [CI], 1.34-4.88; P for trend =.002). In nonsmokers, the corresponding association was stronger (OR, 3.51; 95% CI, 1.64-7.51; P for trend<.001). A 1-SD increase in log CRP (1.02 mg/L) was associated with an increased risk of colon cancer after adjusting for potential confounders and excluding cases occurring within 2 years of baseline (OR, 1.35; 95% CI, 1.05-1.74) or excluding those with late-stage colon cancer at the time of diagnosis (OR, 1.38; 95% CI, 0.99-1.91).
CONCLUSIONS: Plasma CRP concentrations are elevated among persons who subsequently develop colon cancer. These data support the hypothesis that inflammation is a risk factor for the development of colon cancer in average-risk individuals.CLAUDIN-1
- Claudin-1 is a strong prognostic indicator in stage II colonic cancer: a tissue microarray study.
Resnick MB, Konkin T, Routhier J, Sabo E, Pricolo VE.
1Department of Pathology, Rhode Island Hospital and Brown University School of Medicine, Providence, RI, USA.
Mod Pathol. 2005 Apr;18(4):511-8. Abstract quote
Tight junction associated proteins are key molecular components governing cellular adhesion, polarity and glandular differentiation. Tight junction proteins also play critical roles in cellular proliferation and neoplastic pathways via their functions as couplers of the extracellular milieu to intracellular signaling pathways and the cytoskeleton. Neoplastic cells frequently exhibit structural and functional deficiencies in the tight junction.
The purpose of this study was to determine the pattern of expression and prognostic value of four tight junction associated proteins, claudin-1, claudin-4, occludin and ZO-1 in a cohort of TNM stage II colon cancer using tissue microarray technology. In this study, we retrospectively analyzed, resected and otherwise untreated paraffin embedded specimens from 129 consecutive patients with TNM stage II colonic carcinomas for claudin-1, claudin-4, occludin and ZO-1 protein expression by immunohistochemistry. Seventy-five, 58, 56 and 44% of the tumors exhibited normal to elevated expression levels (+2 and +3 immunopositivity) of claudin-1, claudin-4, occludin and ZO-1 respectively. Low expression levels of claudin-1 and ZO-1 were directly associated with higher tumor grade (P=0.05 and 0.03 respectively). Multivariate analysis indicated that lymphovascular invasion (P=0.01) and low levels of claudin-1 (P=0.0001) expression were independent predictors of recurrence and that reduced claudin-1 expression (P=0.0001) was associated with poor survival.
This study is the first to comprehensively examine the expression of several tight junction associated proteins in colonic neoplasms and to correlate their expression with disease progression. Loss of claudin-1 expression proved to be a strong predictor of disease recurrence and poor patient survival in stage II colon cancer.CYCLIN E Expression of cyclin E and cyclin-dependent kinase 2 correlates with metastasis and prognosis in colorectal carcinoma
Jia-Qing Li, MD
Hiroshi Miki, MD, PhD
Masaki Ohmori, MD, PhD
Fei Wu, MD
Yasunobu Funamoto, MDHum Pathol 2001;32:949-953 Abstract quote
The expression of cyclin E and cyclin-dependent kinases 2 (CDK2) in metastatic foci, the relationship of their expression with some clinicopathologic characteristics, and the correlation of their expression with prognosis remain unclear.
To examine the roles of their expression in the progression of colorectal carcinoma, 21 normal mucosa, 9 hyperplastic polyps, 58 adenomas, 17 adenocarcinoma in adenomas, 203 primary cancers, 21 lymph node metastases, and 10 hepatic metastases were immunohistochemically stained with anti–cyclin E, anti-CDK2, and anti-Ki67 antibodies.
In the carcinogenic process, both cyclin E and CDK2 expressions increased significantly. From the primary to the lymph node–metastatic foci, cyclin E protein remained unchanged, but CDK2 increased significantly. From the primary to the liver-metastatic foci, cyclin E apparently decreased, and CDK2 was reduced almost to zero. In primary carcinomas, the reduction of cyclin E was significantly associated with large tumor size, mucinous type, venous invasion, deep infiltration, lymph nodal metastasis, peritoneal metastasis, advanced stage, and poor prognosis. Decreased CDK2 was obviously correlated with large tumor size, venous invasion, deep infiltration, hepatic metastasis, advanced stage, and poor prognosis. Increased cyclin E protein was related to elevated CDK2, which was further linked to higher Ki67.
Thus, CDK2 overexpression could facilitate lymph node metastasis. The overexpression of cyclin E and CDK2 may mainly promote the progression of early cancer. Anti–cyclin E or anti-CDK2 chemotherapy should be targeted to the cancers with such overexpression.
ENDOGLIN
Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in colorectal cancer.
Saad RS, Liu YL, Nathan G, Celebrezze J, Medich D, Silverman JF.
Department of Pathology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
Mod Pathol. 2004 Feb;17(2):197-203 Abstract quote.
Endoglin (CD105) has been shown to be a more useful marker to identify proliferating endothelium involved in tumor angiogenesis than panendothelial markers such as CD31.
We investigated endoglin and vascular endothelial growth factor expression as possible prognostic markers in colorectal cancer. Surgical specimens from 150 patients with resected colorectal carcinomas were immunostained for endoglin, CD31 and vascular endothelial growth factor. Colorectal carcinoma cases consisted of 50 cases without lymph node metastases, 50 cases with only lymph node metastases and 50 cases with liver metastases (38 cases also had positive lymph nodes). Positively stained microvessels were counted in densely vascular foci (hot spots) at x 400 fields in each specimen. For vascular endothelial growth factor, intensity of staining was scored on a three-tiered scale. Results were correlated with other prognostic parameters.
Endoglin demonstrated significantly more proliferating neoplastic microvessels than CD31 (31+/-10 vs 19+/-8/0.15 mm2 field, P<0.001). Low vascular endothelial growth factor expression within tumor cells was seen in 49 (33%) and high expression in 101 cases (67%). There was a positive correlation of endoglin, CD31 counts and vascular endothelial growth factor overexpression with the presence of angiolymphatic invasion and lymph node metastases (P<0.05). Only endoglin counts correlated significantly with liver metastases and positive vascular pedicle lymph nodes (P<0.05), while vascular endothelial growth factor showed significant correlation with the depth of invasion (P<0.01). Endoglin, by staining higher numbers of the proliferating vessels in colon carcinoma, is a more specific and sensitive marker for tumor angiogenesis than the commonly used panendothelial markers.
Endoglin staining also showed prognostic significance with positive correlation with angiolymphatic invasion and metastases to lymph nodes and liver.EPIDERMAL GROWTH FACTOR
- Expression of epidermal growth factor receptor in primary colorectal adenocarcinoma predicts expression in recurrent disease.
Khalifa MA, Rowsell CH, Gladdy RA, Ko YJ, Hanna S, Smith A, Law C.
Department of Pathology, Sunnybrook and Women's College Health, Sciences Center, Toronto, Canada.
Am J Clin Pathol. 2006 Feb;125(2):1-5. Abstract quote
We tested the usefulness of epidermal growth factor receptor (EGFR) immunostaining in primary colorectal adenocarcinoma as a predictor for EGFR status of tumor recurrences in 33 primary tumors and distant recurrences (July 1994 to June 2005). Representative primary and recurrent tumor sections were stained using mouse anti-EGFR antibodies, and only membranous staining of malignant cells was recorded. Results were reported as negative (no staining), 1+ (positivity in <50% of cells), or 2+ (positivity in >50% of cells). Of 33 cases, 19 (58%) showed the same extent of immunopositivity in primary and recurrent tumors.
Bivariate logistic regression analysis of primary tumors with 2+ vs those with negative or 1+ staining showed that the primary tumor status had a major predictive relationship with that of recurrence (odds ratio, of 45.99; confidence limit, 4.0-524.9; P = .0021). The difference between the median time to recurrence of primary tumors with the various degrees of staining was not statistically significant.
Our reporting method provides a useful correlation between the staining profiles of primary colorectal adenocarcinoma and recurrent disease. It is exceptionally reliable in predicting immunopositivity of a recurrence when more than 50% of cells of the primary tumor are immunoreactive.
- Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study.
Shia J, Klimstra DS, Li AR, Qin J, Saltz L, Teruya-Feldstein J, Akram M, Chung KY, Yao D, Paty PB, Gerald W, Chen B.
1Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA.
Mod Pathol. 2005 Oct;18(10):1350-6. Abstract quote
Recent data suggest that detection of epidermal growth factor receptor protein by immunohistochemistry (IHC) does not predict response to the antiepidermal growth factor receptor drug, cetuximab, in patients with colorectal carcinoma.
In searching for foundation for further investigation to optimize patient selection for cetuximab therapy, this study sought to exploit the tissue microarray and chromogenic in situ hybridization techniques to evaluate the status of epidermal growth factor receptor gene amplification in colorectal cancer and its relationship with protein expression by IHC.
The study included 158 primary or metastatic colorectal adenocarcinomas. Immunohistochemical results were scored as 0-3+ based on the intensity of membrane staining. The in situ hybridization signals were counted in 30 nuclei per tissue core. Overall, the rate of tissue loss was 7%, yielding 147 analyzable cases: 123 primary, 24 metastatic. Positive immunohistochemical staining of any intensity was detected in 85% (105/123) of primary and 79% (19/24) of metastatic tumors, whereas gene amplification (>5 gene copies/nucleus) was only seen in 12% (15/123) of primary and 8% (2/24) of metastatic tumors. Only 2/15 primary and 1/2 metastatic tumors that showed gene amplification were amplified at a high level (>10 gene copies/nucleus). Although a positive correlation was detected between the intensity of protein expression and the likelihood of gene amplification in both the primary (P=0.01) and the metastatic (P=0.05) tumors, IHC had a low specificity (17% in primary, 23% in metastatic) in predicting gene amplification. Conversely, all tumors that did not express the protein by IHC lacked gene amplification.
Thus, this study shows that only a small fraction of epidermal growth factor receptor- positive colorectal carcinomas detected by IHC are associated with gene amplification. Additional studies are needed to determine whether epidermal growth factor receptor gene amplification bears any informative value in predicting response to cetuximab-based therapy.Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system.
Goldstein NS, Armin M.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Cancer 2001 Sep 1;92(5):1331-46 Abstract quote
BACKGROUND: An epidermal growth factor receptor (EGFR) immunohistochemical detection system currently is being developed. The current study attempts to address background EGFR reactivity issues before determining the optimum EGFR scoring system.
METHODS: Tissue sections from 102 patients with T3N1-2M1 colon adenocarcinoma were stained with a prototype EGFR detection system. The number of cases, location, percentage, and intensity of reactive cells (0+ [none] to 3+ [strong]) were scored and compared with the length of survival.
RESULTS: Approximately 75.5% of the adenocarcinoma cases had EGFR reactivity; 31.4% of the tumors had 3+ reactivity in 10-50% of the neoplastic cells and 3.9% had 3+ reactivity in > 50% of cells. Increased numbers of reactive cells per case predominantly resulted from increased 3+ reactivity. The mean percentage of 2+ (moderate) and 3+ reactive cells per case increased in the regions of deepest invasion. The mean percentage of 3+ reactivity per case was significantly greater in the deepest tumor region compared with the superficial region (16.9% vs. 7.9%; P = 0.004). EGFR reactivity in metastases appeared to have the strongest correlation with reactivity in the deep regions of colon adenocarcinoma. An increasing percentage of 2+ and 3+ or 3+ only reactivity in the deep region was found to have the strongest correlation with decreased survival (P = 0.0252).
CONCLUSIONS: EGFR reactivity of 2+ and 3+ may provide a framework for a scoring system. It may be important to evaluate EGFR reactivity in the deepest region of tumor invasion because this region appears to contain the largest percentage of 3+ reactive cells and appears to have the strongest correlation with survival length and EGFR reactivity in lymph node and liver metastases.
EXTRAMURAL CANCER DEPOSITS
Department of Surgery, National Defense Medical College, Namiki, Tokorozawa, Saitama, Japan.
To establish an optimal categorization of cancer deposits without lymph node structure (extranodal cancer deposits [EX]) in a prognostic staging system, we analyzed 1,027 cases in which patients underwent potentially curative surgery for advanced colorectal adenocarcinoma. EX was classified as vascular invasion-type (VAS) or non-VAS.A total of 512 foci of EX were identified in 205 patients (20.0%), with VAS and non-VAS found in 68 and 182 patients, respectively. The hazard ratio for patients with nodal involvement was 3.6 and for patients with VAS and non-VAS, 2.5 and 4.7, respectively.
Based on multivariate analysis of these 3 parameters, only nodal involvement and non-VAS were significant prognosticators. By using the Akaike information criterion, N staging was capable of predicting survival outcome with the highest accuracy when both nodal involvement and non-VAS were treated together as an N factor and VAS was treated as a T factor ("new categorization").
The clinical significance of the TNM grading system for colorectal cancer would be enhanced if we treat EX as a new categorization.HISTOPATHOLOGY
- Impact of Colloid Response on Survival After Preoperative Radiotherapy in Locally Advanced Rectal Carcinoma.
Rullier A, Laurent C, Vendrely V, Bail BL, Bioulac-Sage P, Rullier E.
From the *Department of Pathology, Pellegrin Hospital, Bordeaux, France; and the Departments of daggerSurgery and double daggerRadiotherapy, Saint Andre Hospital, Bordeaux, France.
Am J Surg Pathol. 2005 May;29(5):602-606. Abstract quote
Neoadjuvant therapy for rectal carcinoma modifies morphology and natural history of the tumor. Colloid response defined by predominant colloid changes with or without residual tumor cells is a form of tumor response whose impact on survival is unknown.
This study evaluated influence of tumor histologic response, especially of colloid response, on survival in patients treated by long-course preoperative radiotherapy for rectal cancer. In 200 patients with uT3-T4 or N1 rectal carcinomas, influence of type of surgery, dose of radiotherapy, residual tumor size, surface tumor aspect, tumor response (downstaging vs. colloid or no response), tumor grade, vascular and neural invasion, circumferential margin, and postoperative chemotherapy on 5-year overall and disease-free survival were studied by univariate and multivariate analyses. A colloid response was observed in 20% of the cases. Tumor response, circumferential margin, and vascular invasion were independently associated with the disease-free survival.
Patients with downstaging had a better disease-free survival than patients without response (80% vs. 54%), whereas those with colloid response had an intermediate survival (64%). After colloid response, the rate of recurrence was similar to patients with downstaging for local recurrence (0%-3%) and to those with no response for distant recurrence (28%).
After preoperative radiotherapy for rectal cancer, survival and type of recurrence are influenced by the tumor response. The intermediate natural history of patients with colloid response suggests taking colloid response into account in postoperative tumor staging to optimize adjuvant therapy.
Analysis of pathological risk factors for lymph node metastasis of submucosal invasive colon cancer.
Egashira Y, Yoshida T, Hirata I, Hamamoto N, Akutagawa H, Takeshita A, Noda N, Kurisu Y, Shibayama Y.
Department of Pathology, Osaka Medical College, Takatsuki city, Osaka, Japan.
Mod Pathol. 2004 May;17(5):503-11. Abstract quote
There are currently no universally accepted indications and criteria for additional surgical resection of the colorectum after endoscopic resection of the submucosal invasive cancer.
The purpose of the present study is to establish accurate indications and criteria for additional surgical resection of the colorectum, based on the prediction of lymph node metastasis, after endoscopic resection of the submucosal invasive cancer.
We investigated 140 submucosal invasive colorectal cancers and analyzed the pathologic factors of lymph node metastasis. The tumors were evaluated for pathologic factors in the invasive area of the submucosal carcinoma and were compared between the cases with lymph node metastasis and those without lymph node metastasis. Lymph node metastasis was observed in 13 cases (9%). Univariate logistic regression analysis showed that the depth of invasion, cribriform-type structural atypia, absence of lymphoid infiltration, lymphatic permeation, and venous permeation were statistically significant as risk factors for lymph node metastasis.
Multivariate logistic regression analysis showed that the important risk factors included, in decreasing order, lymphatic permeation, absence of lymphoid infiltration, cribriform-type structural atypia, venous permeation, and depth of invasion. Submucosal invasion of 2 mm or more, and/or, depth of lymphatic permeation of 2 mm or more are risk factors for lymph node metastasis.
The pathologic criteria based on our results for additional colectomy enables greater accuracy selection of patients who will undergo further surgical treatment after endoscopic resection.Patterns of Morphologic Alteration in Residual Rectal Carcinoma Following Preoperative Chemoradiation and Their Association With Long-term Outcome
Shia, Jinru MD*; Guillem, Jose G MD†; Moore, Harvey G MD†; Tickoo, Satish K MD*; Qin, Jing PHD‡; Ruo, Leyo MD†; Suriawinata, Arief MD*; Paty, Philip B MD†; Minsky, Bruce D MD§; Weiser, Martin R MD†; Temple, Larissa K MD†; Wong, W Douglas MD†; Klimstra, David S MD*
From the Departments of *Pathology, †Surgery, ‡Biostatistics, and §Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY. Dr. Tickoo's current affiliation is: Department of Pathology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY. Dr. Suriawinata's current affiliation is: Department of Pathology, Mount Sinai Medical Center, New York, NY.
The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 215-223 Abstract quote Preoperative radiation (RT) and chemotherapy improve outcome in patients with locally advanced rectal adenocarcinoma and, therefore, have been used increasingly in patient management. The histopathologic alterations in postirradiated rectal adenocarcinoma and their prognostic significance have not been fully characterized. In this study, detailed analyses of morphologic alterations of stromal and tumor cells were performed in a series of 66 posttreatment rectal carcinomas, and the pathologic findings were correlated with long-term outcome. All tumors were locally advanced, with a bulky and/or tethered tumor or endorectal ultrasound or magnetic resonance imaging evidence of T 3-4 and / or N 1 disease. All patients were treated at one institution with preoperative RT to the pelvis (at least 4500 cGy) with or without concurrent 5-fluorouracil (5-FU)-based chemotherapy 4 to 7 weeks prior to surgical resection. Pathologic assessment showed some treatment response in all patients. Nine patients (13.4%) had complete response, and 8 (11.9%) had near-complete response (> 95% of the tumor replaced by fibroinflammatory tissue). Salient morphologic features included marked fibrosis with or without prominent inflammatory cells replacing neoplastic glands; lack of active tumor necrosis; increased mucin production and mucin pools; marked cytoplasmic eosinophilia, often in combination with marked nuclear atypia but without active mitoses in tumor cells showing treatment effect; endocrine tumor phenotype; and retention of mucosal adenoma in the presence of tumor regression within the bowel wall. With a median follow-up of 69 months, the estimated 5-year recurrence-free survival (RFS) for the entire group was 79%. By univariate analysis, the residual tumor stage ( P < 0.05) and reduction of pretreatment T stage ( P = 0.002) significantly correlated with RFS, as did pN stage ( P = 0.002) and lymphovascular invasion ( P = 0.008). The extent of treatment response did not correlate with RFS ( P = 0.4). However, patients with a treatment response = 95% seemed to fare better than those with a treatment response <95% (marginally significant difference in RFS, P = 0.057). Univariate and multivariate analyses identified the following morphologic patterns that were significantly associated with a reduced RFS independent of other risk factors: a fibrotic-type stromal response with minimal inflammatory infiltrates ( P = 0.001) and absence of surface ulceration ( P = 0.026). Our study represents the first detailed morphologic assessment of rectal carcinomas that have been subjected to long course preoperative RT and chemotherapy. Our results demonstrate distinct morphologic features in treated rectal carcinomas that are prognostically relevant.
There has been accumulating evidence to suggest that neoadjuvant therapy improves local control and survival in patients with rectal adenocarcinoma.4,5,26 Therefore, preoperative radiation (RT) with or without chemotherapy has been used increasingly in the management of this group of patients, and many rectal carcinoma specimens arrive at the laboratory already modified by chemoradiation. However, the morphologic alterations in these rectal carcinomas and their potential impact on outcome have not been fully characterized.
We22 and others12,18,27,29 have shown that preoperative long course RT (45-50.4 Gy in 25-28 fractions) with or without concurrent 5-fluorouracil (5-FU)-based chemotherapy frequently produces tumor regression by replacing neoplastic glands with fibrous or fibroinflammatory tissues. Several studies suggest that complete tumor response and tumor down-staging are associated with a better outcome.12,27,29 Whether or not the extent of tumor response has a significant impact on prognosis is an issue to be defined.12,22 We have also shown25 that tumor cells in postirradiated rectal cancer frequently show endocrine differentiation as demonstrated by endocrine morphology and positive immunoreactivity for chromogranin. The presence of endocrine cells was closely associated with a more advanced treatment response; however, its independent prognostic significance has not been determined.25
The histopathological parameters analyzed in the previous studies were focused on overall pathologic response, tumor and nodal staging, lymphovascular and perineural invasion,12,18,22,27,29 or endocrine differentiation in tumor cells without outcome analysis.25 In this study, our emphasis was on the morphologic aspect of treated rectal carcinomas, specifically on the following three categories: 1) stromal alteration and inflammatory cell infiltrate, 2) tumor cell morphology/cytology, and 3) changes in the overlying mucosa. Our purpose was to provide a detailed morphologic description of rectal carcinoma that has been subjected to long course RT with or without chemotherapy prior to surgery, and to identify patterns of morphologic alteration that bear prognostic significance.
INTEGRIN Integrin vß3 Expression in Colon Carcinoma Correlates with Survival
Alain Vonlaufen, M.D., Guido Wiedle, Ph.D., Bettina Borisch, M.D., Stefan Birrer, M.D., Peter Luder, M.D. and Beat A. Imhof, Ph.D.
Department of Pathology (AV, GW, BB, BAI), Centre Médical Universitaire, Geneva; Department of Surgery (SB), Tiefenauspital, Bern; and Department of Surgery (PL), Sonnenhofklinik, Bern, Switzerland
Mod Pathol 2001;14:1126-1132 Abstract quote
Integrin vß3 is expressed by newly formed blood vessels in diseased and neoplastic tissue and can therefore be used as a marker for angiogenesis.
We investigated its expression on the vasculature of 40 colon carcinomas using the anti-vß3-specific monoclonal antibody LM609. The average relapse-free interval and overall survival in patients suffering from colon carcinomas with high vascular expression of vß3 integrin was significantly reduced compared with that in patients with low vß3 integrin expressing tumor vasculature. Moreover, the expression level of vß3 integrin correlated with the presence of liver metastases.
In conclusion, we propose vascular expression of vß3 integrin as a prognostic indicator for colon carcinoma.
LYMPH NODES
Frances C. Wright, MD, FRCSC, Calvin H.L. Law, MD, MPH, FRCSC, Linda D. Last, CCRP, Rosalie Ritacco, Deepa Kumar, MD, FRCSC, Eugene Hsieh, MD, FRCPC, Mahmoud Khalifa, MD, PhD, FRCPC, and Andrew J. Smith, MD, MSc, FRCSC
Lymph node (LN) retrieval and assessment is critically important for accurate staging and treatment planning in colorectal cancer (CRC). Practicing pathologists in Ontario were identified and surveyed by phone to identify barriers to optimal retrieval and assessment. Of the pathologists surveyed, 57.9% were aware of guidelines for LN retrieval in CRC, but only 25.0% identified that a minimum of 12 LNs are necessary for accurate designation of node negativity.
An important role exists for an education strategy aimed at bridging the knowledge gap among practicing pathologists and surgeons regarding optimal LN assessment in CRC specimens.
Efficacy of manual dissection of lymph nodes in colon cancer resections.
Brown HG, Luckasevic TM, Medich DS, Celebrezze JP, Jones SM.
Deptartment of Pathology, Allegheny General Hospital, Pittsburgh, PA, USA.
Mod Pathol. 2004 Apr;17(4):402-6. Abstract quote
The adequacy of lymph node dissection of colonic resection specimens influences the clinical and pathologic staging, leading to important postsurgical treatment decisions. Although manual lymph node dissection is the current standard at most institutions, recent statistical studies indicate that all lymph nodes, including those measuring 1-2 mm, should be recovered to be assured of lymph node negative status.
Thus, we tested the efficacy of gross dissection by submitting the entire residual mesenteric fat. We analyzed 15 randomly chosen colonic resections (2 pT1, 1 pT2, 11 pT3, 1 pT4). After standard gross dissection of lymph nodes and submission of colonic material for diagnosis, the entire remaining mesenteric material was dehydrated over several days by serial washing in alcohol and acetone. All of the mesenteric tissue was submitted for histology. The average number of nodes found by original gross inspection was 20.8, while the average number of additional nodes found after clearing was 68.6. In all, 83% of the additional nodes were 2.0 mm or less in size. There were seven pN0 cases; one was upstaged by additional findings that may have been artifactual. There were four pN1 cases; three were upstaged to pN2 after submission of the mesenteric material. All four pN2 tumors had additional metastases identified. In all, 75% of all positive nodes were under 2.0 mm in size.
In this limited sample, standard gross dissection proved sufficient for most pN0 tumors to remain node negative. However, our findings within the pN1 group show that examination of all of the mesenteric material may be necessary to be assured of correct pN status.
Recommendations for a Minimum Number of Recovered Lymph Nodes Based on Predictive ProbabilitiesNeal S. Goldstein, M.D.
From the Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan, U.S.A.
Am J Surg Pathol 2002;26:179-189 Abstract quote This study investigates the relationship between the number of recovered lymph nodes and lymph node metastases in colorectal resection specimens.
All of the slides from 2427 pT3 colorectal resection specimens from patients operated on at William Beaumont Hospital during the 45 years from 1955 through 2000 were reviewed. Lymph node metastases were present in 333 of 1499 (22.2%) specimens with fewer than 15 recovered lymph nodes, compared with 789 of 928 (85.0%) specimens with 15 or greater recovered lymph nodes (p <0.01).
The proportion of lymph node metastases increased as a function of the number of recovered lymph nodes (p <0.01). Similarly, in patients without lymph node metastases, survival increased as a function of the number of recovered lymph nodes. Among these patients, the 5-year overall survival rate was 62.2% among patients with seven or fewer recovered lymph nodes and 75.8% among patients with 18 or more recovered lymph nodes (p = 0.018).
Statistical analysis found the predictive probability of identifying the single lymph node metastasis in a theoretical specimen with a single lymph node metastasis is 0.25 if 12 lymph nodes are recovered and 0.46 if 18 lymph nodes are recovered.
The predictive probability increased as the number of recovered lymph nodes increased, suggesting there is no minimum number that reliably or accurately stages all patients. Thus, all palpable lymph nodes should be recovered, including those that are 1 or 2 mm.
MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF)
Prognostic Values of Galectin-3 and the Macrophage Migration Inhibitory Factor (MIF) in Human Colorectal Cancers.Legendre H, Decaestecker C, Nagy N, Hendlisz A, Schuring MP, Salmon I, Gabius HJ, Pector JC, Kiss R.
Divisions of Digestive Surgery (HL, J-CP) and Gastroenterology (AH), Institut Bordet.
Mod Pathol 2003 May;16(5):491-504 Abstract quote This study aims to investigate whether the immunohistochemical levels of expression of galectin-3 and the macrophage migration inhibitory factor (MIF) are associated with prognostic values in human colorectal tumors.
This was performed on 99 specimens including 69 colorectal tumors (17 Dukes A, 19 Dukes B, 15 Dukes C and 18 metastatic tumors that we labeled as D), 10 hepatic metastases from colorectal cancers and 20 normal specimens (biopsies). The immunohistochemical levels of expression of MIF and galectin-3 were quantified on routine histological slides by means of computer-assisted microscopy. Separate analyses were performed on epithelial and connective tissue. The levels of expression of both MIF and galectin-3 were very significantly higher in epithelial tumor tissue when compared with normal epithelial specimens. A positive and significant correlation between MIF and galectin-3 expression was evidenced in connective tumor tissue, and in particular in the cases associated with short survival periods (less than 5 years).
In the case of the Dukes A or B tumors, we established two new prognostic groups (labeled I and II) on the basis of the levels of galectin-3 expression measured in the tumor epithelium. In the case of the Dukes C or D tumors, we established two other prognostic groups (labeled III and IV) on the basis of the levels of MIF expression measured in the connective tissue. Kaplan-Meyer analyses confirmed the additional prognostic values (as compared with conventional clinical staging) given by this new classification (groups I to IV). They show that the Dukes A or B tumors characterized by low levels of galectin-3 expression in the tumor epithelium are associated with significantly better prognoses than those characterized by high levels. In addition, the Dukes C or D tumors characterized by high levels of MIF expression in the connective tumor tissue are associated with significantly better prognoses than those characterized by low levels.
In conclusions, MIF and galectin-3 expression levels in colorectal tumors are related to their levels of biological aggressiveness. These markers could be used to identify patients at risk, for whom more aggressive adjuvant therapy seems to be indicated.MARGINS, RADIAL Circumferential Margin Involvement Is Still an Important Predictor of Local Recurrence in Rectal Carcinoma
Not One Millimeter but Two Millimeters Is the LimitIris D. Nagtegaal, M.D.; Corrie A. M. Marijnen, M.D.; Elma Klein Kranenbarg, M.SC.; Cornelis J. H. van de Velde, M.D., Ph.D.; J. Han J. M. van Krieken, M.D., Ph.D.; Pathology Review Committee* the Cooperative Clinical Investigators †
From the Departments of Pathology (I.D.N.), Surgery (I.D.N., C.A.M.M., E.K.K., C.J.H.V.), and Clinical Oncology (C.A.M.M.), Leiden University Medical Center, Leiden, and the Department of Pathology (I.D.N., J.H.J.M.K.), University Medical Center St. Radboud, Nijmegen, The Netherlands.
Am J Surg Pathol 2002;26:350-357 Abstract quote Despite improved surgical treatment strategies for rectal cancer, 5–15% of all patients will develop local recurrences. After conservative surgery, circumferential resection margin (CRM) involvement is a strong predictor of local recurrence. The consequences of a positive CRM after total mesorectal excision (TME) have not been evaluated in a large patient population.
In a nationwide randomized multicenter trial comparing preoperative radiotherapy and TME versus TME alone for rectal cancer, CRM involvement was determined according to trial protocol. In this study we analyze the criteria by which the CRM needs to be assessed to predict local recurrence for nonirradiated patients (n = 656, median follow-up 35 months). CRM involvement is a strong predictor for local recurrence after TME. A margin of 2 mm is associated with a local recurrence risk of 16% compared with 5.8% in patients with more mesorectal tissue surrounding the tumor (p <0.0001). In addition, patients with margins 1 mm have an increased risk for distant metastases (37.6% vs 12.7%, p <0.0001) as well as shorter survival.
The prognostic value of CRM involvement is independent of TNM classification. Accurate determination of CRM in rectal cancer is important for determination of local recurrence risk, which might subsequently be prevented by additional therapy. In contrast to earlier studies, we show that an increased risk is present when margins are 2 mm.
METASTASIS Regional lymph nodes
Liver, lungs, bones, and serosal membranes of the peritoneal cavity.Micrometastases and survival in stage II colorectal cancer.
Liefers GJ, Cleton-Jansen AM, van de Velde CJ, Hermans J, van Krieken JH, Cornelisse CJ, Tollenaar RA.
epartment of Surgery, Leiden University Medical Center, The Netherlands.
N Engl J Med 1998 Jul 23;339(4):223-8 Abstract quote
BACKGROUND: Standard treatment of colorectal cancer includes adjuvant chemotherapy for patients with stage III disease (defined by the presence of lymph-node metastases), but not for patients with stage II tumors (who have no lymph-node metastases). However, 20 percent of patients with stage II tumors die of recurrent disease. We investigated whether the detection of micrometastases can be used to identify patients with stage II disease who are at high risk for recurrence.
METHODS: We analyzed 192 lymph nodes from 26 consecutive patients with stage II colorectal cancer, using a carcinoembryonic antigen-specific nested reverse-transcriptase polymerase chain reaction. Five-year follow-up information was obtained on all patients. Observed and adjusted survival rates were assessed in the patients with and the patients without micrometastases.
RESULTS: Micrometastases were detected in one or more lymph nodes from 14 of 26 patients (54 percent). The adjusted five-year survival rate (for which only cancer-related deaths were considered) was 50 percent in this group, whereas in the 12 patients without micrometastases, the survival rate was 91 percent (P=0.02 by the log-rank test). The observed five-year survival rates were 36 percent and 75 percent, respectively (P=0.03). The groups were similar with respect to age, sex, tumor side (location in relation to the flexura lienalis), degree of tumor differentiation (grade), and diameter of the primary tumor.
CONCLUSIONS: Molecular detection of micrometastases is a prognostic tool in stage II colorectal cancer.
Pericolonic tumor deposits in patients with T3N+MO colon adenocarcinomas: markers of reduced disease free survival and intra-abdominal metastases and their implications for TNM classification.
Goldstein NS, Turner JR.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Cancer 2000 May 15;88(10):2228-38 Abstract quote
BACKGROUND: A pericolonic tumor deposit (PTD) is a grossly palpated adenocarcinomas within pericolonic adipose tissue not within a lymph node. The source and prognostic significance of PTDs has not been well defined.
METHODS: The authors studied 418 T3N+M0 colon adenocarcinomas to determine the frequency and significance of PTDs. They also step-sectioned 30 PTDs to determine their origin and assist in their optimum TNM classification. RESULTS: Seventy-one (18%) of 400 consecutively examined cases had PTDs. The actuarial 1-, 2-, and 5-year disease free survival rates were significantly lower among patients with a PTD. PTDs, regardless of size, significantly impacted disease free survival. Increasing numbers of PTDs was associated with shorter disease free survival. Adenocarcinoma grade, a PTD, increasing numbers of PTDs, and number of lymph node metastases were independently associated with shorter disease free survival. The likelihood of extrahepatic abdominal failure was proportionally greater with increasing numbers of PTDs. Adenocarcinoma was observed in perineural, peri-large vessel, or intravascular locations in step-sectioned PTDs.
CONCLUSIONS: A PTD is a perineural, perivascular, or intravascular tumor extension beyond the muscularis propria. They are distinct from lymph node metastases and should not be considered their prognostic equivalent. The disease free survival impact of even small PTDs was significant, suggesting that PTDs of all sizes should be considered a single entity. TNM classification of PTDs as lymph node metastases or discontinuous tumor extension is probably not accurate. The number and greatest dimension of PTDs should be reported separately from lymph node metastases.
MICROSATELLITE INSTABILITY
Microsatellite instability in colorectal carcinoma. The comparison of immunohistochemistry and molecular biology suggests a role for hMLH6 immunostaining.Rigau V, Sebbagh N, Olschwang S, Paraf F, Mourra N, Parc Y, Flejou JF.
Department of Pathology, AP-HP, Hopital Saint-Antoine, Paris, France.
Arch Pathol Lab Med 2003 Jun;127(6):694-700 Abstract quote CONTEXT: Microsatellite instability (MSI) due to defective mismatch repair (MMR) genes has been reported in the majority of colorectal tumors from patients with hereditary nonpolyposis colorectal cancer syndrome and in 10% to 15% of sporadic colorectal cancers. The identification of cancers associated with MSI requires classical molecular testing as the gold standard.
OBJECTIVE: The aim of this study was to evaluate the role of immunohistochemistry with antibodies directed against 4 MMR proteins as a screening tool for carcinomas with MSI.
METHODS: In this study, 204 formalin-fixed, paraffin-embedded colorectal carcinomas were examined for MMR protein expression (hMLH1, hMSH2, hMSH6, and hPMS2) and analyzed for MSI (MSI-H indicates at least 2 of 6 markers affected). These results were correlated with histopathologic parameters.
RESULTS: Immunohistochemical analysis revealed that loss of expression of at least 1 protein was present in 17% of cases. One hundred percent of carcinomas that showed high instability (MSI-H) showed loss of expression of hMLH1, hMSH2, or hMSH6. Loss of expression of 2 proteins was present in 59.4% of MSI-H cases, with only 2 combinations, namely, hMLH1/hPMS2 and hMSH2/hMSH6. Isolated loss of hMSH6 expression was present in 2 MSI-H cases.
CONCLUSIONS: These findings confirm that examination of MMR protein expression by immunohistochemistry is a simple method to diagnose colorectal cancer with MSI. Our data suggest that the study of hMSH6 may be useful, in addition to hMLH1 and hMSH2. Moreover, immunohistochemistry could represent a screening method with which to direct research on the mutations of MMR genes observed in hereditary nonpolyposis colorectal cancer syndrome.
Phenotype of microsatellite unstable colorectal carcinomas: well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability.Greenson JK, Bonner JD, Ben-Yzhak O, Cohen HI, Miselevich I, Resnick MB, Trougouboff P, Tomsho LD, Kim E, Low M, Almog R, Rennert G, Gruber SB.
Am J Surg Pathol 2003 May;27(5):563-70 Abstract quote The phenotypic markers of colorectal carcinomas with microsatellite instability have been widely studied and include mucinous or poor differentiation, prominent host response, a circumscribed growth pattern, histologic heterogeneity, and right-sided location.
As part of a population-based case-control study of colorectal cancer in northern Israel, we reviewed the pathology and microsatellite status of 528 consecutively diagnosed colorectal cancers. Phenotypic analysis was performed by one pathologist (J.K.G.) and included assessment of grade, mucinous histology (>50%, or focal), histologic heterogeneity, growth pattern, necrosis, and host response.
Microsatellite status was determined on microdissected portions of formalin-fixed, paraffin-embedded tissue using a panel of 5 NCI consensus primers. Fifty-two of 528 colorectal carcinomas were microsatellite unstable (9.85%). Multivariate analysis found that >2 tumor infiltrating lymphocytes per high power field (p <0.0001), the lack of dirty necrosis (p = 0.0054), a Crohn's-like host response (p = 0.0064), right-sided location (p = 0.032), well or poor differentiation (p = 0.037), and any mucinous differentiation (p = 0.039) were independent predictors of microsatellite instability. Tumor infiltrating lymphocytes were the single best histologic predictor of microsatellite instability.
The absence of dirty necrosis and the presence of well-differentiated tumors and tumors with only focal mucinous differentiation were also important markers for microsatellite instability that have not been emphasized previously. The combination of >2 tumor infiltrating lymphocytes per high power field and/or any mucinous differentiation and/or the absence of dirty necrosis identified all MSI-H tumors in this study.p53 p53 Nuclear Accumulation and Multiploidy Are Adverse Prognostic Factors in Surgically Resected Stage II Colorectal Cancers Independent of Fluorouracil-Based Adjuvant Therapy
Simonetta Buglioni, PhD
Igea D'Agnano, PhD
Stefania Vasselli, PhD
Raffaele Perrone Donnorso, MD
Carmen D'Angelo
Alessia Brenna
Maria Benevolo, PhD
Maurizio Cosimelli, MD
Gabriella Zupi, PhD
Marcella Mottolese, PhD
Am J Clin Pathol 2001;116:360-368 Abstract quote
To identify the prognostically highest risk patients, DNA content and p53 nuclear or cytoplasmic accumulation, evaluated by monoclonal antibody DO7 and polyclonal antibody CM1, were determined in 94 surgically resected stage II (Dukes B2) colorectal cancers, treated or not with adjuvant 5-fluorouracil–based chemotherapy.
Sixty-one (65%) of the tumors were aneuploid, 16 (17%) of which had a multiploid DNA content; 50 (53%) displayed DO7 nuclear p53 accumulation, and 44 (47%) showed cytoplasmic CM1 positivity. In multivariate analysis, only multiploidy and p53 nuclear positivity emerged as independent prognostic indicators of a poorer outcome. Positivity for p53 was associated with shorter survival in 5-fluorouracil–treated and untreated patients.
Therefore, in patients with Dukes B2 colorectal cancer, a biologic profile based on the combined evaluation of DNA multiploidy and p53 status can provide valuable prognostic information, identifying patients to be enrolled in alternative, more aggressive therapeutic trials.
pRb Aberrant expression of pRb and p16, alone or in combination, indicates poor outcome after resection in patients with colorectal carcinoma.
Cui X, Shirai Y, Wakai T, Yokoyama N, Hirano S, Hatakeyama K.
Hum Pathol. 2004 Oct;35(10):1189-95. Abstract quote
This study aimed to identify potential abnormalities of retinoblastoma protein (pRb) and p16(INK4a) (p16) expression in resectable colorectal carcinomas (CRCs) and to assess the prognostic significance of pRb and p16 levels in patients with CRC. From July 1990 through December 1993, 117 consecutive patients with CRC underwent curative resection with radical lymphadenectomy. The resected specimens were examined immunohistochemically using monoclonal antibodies to identify abnormalities of pRb and p16 expression.
The association of pRb and p16 expression status with clinicopathologic features was analyzed retrospectively. The Cox proportional hazards model was used to identify factors independently affecting survival after resection. The median follow-up period was 62 months. Aberrant expression of pRb and p16 was identified in 82 (70%) and 87 (74%) patients, respectively. Coincident abnormalities of these proteins occurred in 61 (52%) patients. Loss of pRb expression correlated with tumor site (P = 0.0119), whereas p16 overexpression correlated with tumor size (P = 0.0034). Coincident abnormalities of pRb and p16 were associated with TNM tumor stage (P = 0.011). The outcome after resection was worse in patients with aberrant expression of pRb and/or p16 than in patients with normally expressed pRb and p16 (for pRb, P = 0.0151; for p16, P = 0.0247).
Coincident abnormalities of pRb and p16 indicated the worst patient survival (P = 0.0310). Aberrant expression of pRb and p16 independently affected postresection survival (relative risk = 6.312, P <0.0001; relative risk = 5.994, P <0.0001, respectively). Most CRCs demonstrate aberrant expression of pRb and/or p16 at resectable stages. Aberrant expression of pRb and p16, alone and in combination, heralds poor prognosis in patients with CRC.PERITONEAL INVOLVEMENT
Peritoneal involvement in stage II colon cancer.Lennon AM, Mulcahy HE, Hyland JM, Lowry C, White A, Fennelly D, Murphy JJ, O'Donoghue DP, Sheahan K.
Center for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland.
Am J Clin Pathol 2003 Jan;119(1):108-13 Abstract quote A pathologist (K.S.) reviewed histologic slides for peritoneal involvement by tumor cells for 118 patients with stage II colon cancer. Patients were followed up for a median of 6 years. Tumor cells were found free in the peritoneal space in 16 cases (13.6%).
The presence of cancer cells free in the peritoneal space was associated with lymphovascular invasion (P = .001) and neural invasion (P < .001). The overall 5-year survival was 80% in the patient population, but was 39% and 86% for those with and without tumor cells free in the peritoneal space, respectively (P < .0001). Multivariate analysis confirmed that free tumor cells within the peritoneal space (P < .0001) and lymphovascular invasion (P = .007) were related independently to outcome.
Peritoneal involvement with tumor cells free in the peritoneal space in stage II colon cancer is a powerful indicator of outcome; patients have a survival similar to that for patients with stage III disease.
SIGMOIDOSCOPY
Results of repeat sigmoidoscopy 3 years after a negative examination.Schoen RE, Pinsky PF, Weissfeld JL, Bresalier RS, Church T, Prorok P, Gohagan JK; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Group.
Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
JAMA. 2003 Jul 2;290(1):41-8 Abstract quote CONTEXT: The necessary frequency of endoscopic colorectal cancer screening after a negative examination is uncertain. OBJECTIVE: To examine the yield of adenomas and cancer in the distal colon found by repeat flexible sigmoidoscopy (FSG) 3 years after a negative examination.
DESIGN, SETTING, AND PARTICIPANTS: Participants were drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), a randomized, controlled community-based study of cancer screening. The mean (SD) age was 65.7 (4.0) years at study entry (1993-1995) and 61.6% were men. Individuals underwent screening FSG at baseline and at 3 years as part of the protocol and were referred to their personal physicians for further evaluation of screen-detected abnormalities. Results from subsequent diagnostic evaluations were tracked in a standardized fashion. Of 11 583 eligible for repeat screening FSG 3 years after an initial negative examination, 9317 (80.4%) returned.
MAIN OUTCOME MEASURES: Polyp or mass detection in distal colon at year 3 repeat FSG; incidence of adenoma or cancer in distal colon at year 3 examination; determination of reason for detection (increased depth of insertion or improved preparation at the year 3 examination or detection in a previously examined area).
RESULTS: A total of 1292 returning participants (13.9%) had a polyp or mass detected by FSG 3 years after the initial examination. In the distal colon, 3.1% (292/9317) were found to have an adenoma or cancer. The incidence of advanced adenoma (n = 72) or cancer (n = 6) in the distal colon was 78 (0.8%) of 9317. Of individuals with advanced distal adenomas detected at the year 3 examination, 80.6% (58/72) had lesions found in a portion of the colon that had been adequately examined at the initial sigmoidoscopy.
CONCLUSIONS: Repeat FSG 3 years after a negative examination will detect advanced adenomas and distal colon cancer. Although the overall percentage with detected abnormalities is modest, these data raise concern about the impact of a prolonged screening interval after a negative examination.TELOMERASE REVERSE TRANSCRIPTASE
Immunohistochemical detection of telomerase reverse transcriptase in colorectal adenocarcinoma and benign colonic mucosa.Wei R, Younes M.
Department of Pathology, Baylor College of Medicine and Methodist Hospital, Houston, TX.
Hum Pathol 2002 Jul;33(7):693-6 Abstract quote Telomerase activity (TA) is increased in human cancers and cell lines and is thought to contribute to their immortality. High TA has been found to correlate with aggressive tumor behavior.
The aim of this study was to determine whether increased TA in colorectal carcinoma (CRC) correlates with survival. Formalin-fixed and paraffin-embedded tissue sections from 82 CRC and 6 cases of benign colon with diverticulosis were immunohistochemically stained for telomerase reverse transcriptase (TRT) using the immunoperoxidase method. The percentage of positive nuclei was determined for each case. Survival analysis was performed using the Kaplan-Meier method. TRT immunoreactivity was always nuclear. In normal colonic mucosa, TRT immunoreactivity was detected in the bottom of crypts. However, in normal colon adjacent to CRC, telomerase immunoreactivity was detected throughout the length of the crypts, including the upper third, and frequently in the surface epithelium. Telomerase immunoreactivity in more than 25% of the cancer cell nuclei was associated with significantly poorer patient survival (P = 0.0081).
We conclude that increased TA in CRC, as demonstrated by TRT immunostaining, is associated with poorer survival, and that TA is present in normal colonic mucosa and is increased in colonic mucosa near CRC. Additional studies with larger patient samples and multivariate analysis are needed to determine whether TRT expression is an independent prognostic factor in CRC.
TOPOISOMERASE I PROTEIN
Topoisomerase I protein expression in primary colorectal cancer and lymph node metastases.Boonsong A, Curran S, McKay JA, Cassidy J, Murray GI, McLeod HL.
Departments of Medicine & Therapeutics and Pathology, University of Aberdeen Institute of Medical Sciences, Aberdeen, Scotland, UK.
Hum Pathol 2002 Nov;33(11):1114-9 Abstract quote Topoisomerase I (topo I) is an important target for the treatment of malignant disease, especially colorectal cancer. Because there is little information on the expression of topo I in colorectal tumors, this study evaluated and characterized topo I protein expression in primary colorectal cancer and lymph node metastases and studied the association between topo I protein expression and clinicopathologic data, p53 status, and proliferating cell nuclear antigen (PCNA) status.
Immunohistochemistry assay was performed for topo I protein expression in 249 primary human colorectal cancer and 42 paired lymph node metastasis samples. Topo I expression was described as the percentage of cells staining positive for topo I, along with the intensity and localization of the staining.
Clinicopathologic data (sex, age, Dukes' stage, differentiation grade, survival status), p53 status, and PCNA status were statistically analyzed for association with topo I protein expression. Topo I expression in paired primary lymph node metastases were studied for concordance. Topo I protein expression was detected in 127 (51%) samples, including 24.4% with >50% positive tumor cells. The majority had nuclear (70.1%) or nuclear and cytoplasmic staining (17.3%). A higher percentage of cells expressing topo I in primary colorectal cancer was significantly associated with advanced age (P =.040). Patients with rectal cancer had greater topo I expression than those with colon tumors (P =.029). No significant correlation was found between topo I protein expression and sex, Dukes' stage, differentiation grade, survival status, p53 status, and PCNA status. Concordance in topo I staining between primary and lymph node metastases was observed in 33 of 42 cases (P =.029).
This suggests that the activity of topo I inhibitors will not differ across various tumor stages, pathology, and patient gender. p53 and PCNA status do not appear to influence topo I expression, and topo I has no apparent association with the acquisition of a metastatic phenotype.
Topo I expression now needs to be evaluated in patients undergoing topo I-inhibitor therapy, to better define the role of this protein as a predictive marker.
Circadian Variation of Topoisomerase II-alpha in Human Rectal Crypt Epithelium: Implications for Reduction of Toxicity of Chemotherapy.
Clayton F, Tessnow KA, Fang JC, Holden JA, Moore JG.
Department of Pathology (FC) and Gastroenterology Division (JGM), Salt Lake Veterans Administration Hospital, Salt Lake City, Utah, and Gastroenterology Division (KAT, JCF, JGM) and Pathology Department (FC, JAH), University of Utah.
Mod Pathol 2002 Nov;15(11):1191-6 Abstract quote Topoisomerase II-alpha is a target of common chemotherapeutic agents such as doxorubicin and etoposide, which induce DNA damage by altering the activity of this enzyme.
We took rectal biopsies at 4-hour intervals over a 24-hour period (seven total) from each of 10 healthy volunteers and examined immunoperoxidase-stained coded anti-topoisomerase II-alpha-stained sections. A significant circadian periodicity was seen in the number of rectal crypt epithelial cell nuclei that were stained (P =.01). Mean peak staining was at 7:23 a.m. +/- 45 minutes, and the mean rate of change (difference between peak and trough expression) was 40%.
Topoisomerase II-alpha expression in rectal epithelium has a significant circadian variation similar to that of tritiated thymidine incorporation. Although direct confirmation is needed, giving topoisomerase II-targeted chemotherapeutic agents at the proper time of day might reduce their mucositis side effects.
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