Does immunostaining effectively upstage colorectal cancer by identifying micrometastatic nodal disease?
ABSTRACT Measure the association between the incidence of primary tumor staining and the identification of mediastinal lymph node (MLN) using cytokeratins, NM23, DCC-positive tumors, and vascular endothelial growth factor (VEGF) expression in T(2) and T(3)/N(0) colorectal cancers. The impact of MLN on both recurrence and survival was assessed.
There were 153 CORC patients (T(2), T(3)/N(0)) selected from a prospectively accrued database. All patients had been staged by routine histopathology after a curative resection and no patients received adjuvant chemotherapy. The primary tumors (PT) were assessed with a panel of immunohistochemical stains (cytokeratin, DCC, Nm23, and VEGF). If the PT was positive, the regional nodes were assessed with that marker(s). For any positive tumor marker, all lymph nodes (LNs, mean of 12.6+/-4.2) were stained for this marker.
Patient age ranged from 38 to 86 years with a mean age of 61.56+/-25.56 years. Mean follow-up was 72.1+/-32.4 months. Recurrence rate of the whole group was 19/153 (12.4%) and the mean time to recurrence was 37.6+/-23.6 months (15 to 77 months). Crude mortality was 39.9%, while the cancer specific mortality was 11.2% after the whole follow-up period. The relationship between PT staining and MLNs was: cytokeratin-PT 143 (93.5%)/MLN 9 (6.3%); NM23-PT 51 (33.3%)/MLN 3 (5.9%); DCC-PT 79 (53%)/MLN 3 (3.8%); and VEGF-PT 72 (47%)/MLN 4 (5.6%). Nineteen (12.4%) patients experienced tumor recurrence. No correlation exist between PT and/or MLN staining and either recurrence or survival. No patient with MLN with any stain experienced a recurrence. There was no advantage to using an individual stain or all four stains.
Immunohistochemical stains for PT and focused analysis of regional nodes did not improve prediction of survival or recurrence. Sentinel LN evaluation and the provision of adjuvant chemotherapy in node-negative patients should be questioned and not be utilized outside of a research protocol.
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ABSTRACT: Recent studies have suggested that vascular endothelial growth factor (VEGF), in addition to its proangiogenic properties, also functions as a survival factor for endothelial cells. The authors hypothesized that inhibition of VEGF activity by blockade of VEGF receptor-2 (R-2) function prevents angiogenesis and decreases tumor growth in colon carcinoma liver metastases. Spleens of mice were injected with human colon carcinoma cells producing liver metastases. After 7 days of tumor growth, groups of mice received either antibody to VEGFR-2 (DC101) or phosphate-buffered saline (control). In a follow-up experiment, a similar treatment regimen was followed except that mice were sacrificed at 1-week intervals to assess the time course of endothelial cell and tumor cell apoptosis. After 21 days of therapy, the authors observed a significant decrease in vessel counts in liver metastases from human colon carcinoma in nude mice after therapy with VEGFR-2 antibody. Tumor cell apoptosis was increased significantly in the tumors of mice receiving DC101. Temporal studies with immunofluorescent double staining for the microvasculature and apoptotic cells revealed an increase in endothelial cell apoptosis that preceded an increase in tumor cell apoptosis. In vitro, treatment of human umbilical vein endothelial cells with antibody to VEGFR-2 produced a > 2.5-fold increase in endothelial cell apoptosis. Therapy targeting the VEGFR-2 inhibited tumor growth in a murine model of colon carcinoma liver metastasis. Surprisingly, this therapy did not only inhibit angiogenesis but also led to endothelial cell death. These findings suggest that VEGF, via VEGFR-2 signaling, functions as a survival factor for tumor endothelial cells in liver metastases from colon carcinoma.Cancer 08/2000; 89(3):488-99. · 5.20 Impact Factor
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ABSTRACT: Allelic deletions involving chromosome 18q occur in more than 70 percent of colorectal cancers. Such deletions are thought to signal the existence of a tumor suppressor gene in the affected region, but until now a candidate suppressor gene on this chromosomal arm had not been identified. A contiguous stretch of DNA comprising 370 kilobase pairs (kb) has now been cloned from a region of chromosome 18q suspected to reside near this gene. Potential exons in the 370-kb region were defined by human-rodent sequence identities, and the expression of potential exons was assessed by an "exon-connection" strategy based on the polymerase chain reaction. Expressed exons were used as probes for cDNA screening to obtain clones that encoded a portion of a gene termed DCC; this cDNA was encoded by at least eight exons within the 370-kb genomic region. The predicted amino acid sequence of the cDNA specified a protein with sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested. Somatic mutations within the DCC gene observed in colorectal cancers included a homozygous deletion of the 5' end of the gene, a point mutation within one of the introns, and ten examples of DNA insertions within a 0.17-kb fragment immediately downstream of one of the exons. The DCC gene may play a role in the pathogenesis of human colorectal neoplasia, perhaps through alteration of the normal cell-cell interactions controlling growth.Science 02/1990; 247(4938):49-56. · 31.03 Impact Factor
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ABSTRACT: Patients with transmurally invasive, lymph node negative colorectal carcinoma (Dukes' B) have a 5-year survival rate ranging from 53.9% to 84.9%. The authors postulate that patients with Dukes' B colon cancer who die of their disease have occult micrometastases in their pericolic lymph nodes at the time of original diagnosis. In an attempt to identify these occult micrometastases, pericolic lymph nodes from Dukes' B colon cancer resections were stained retrospectively with antibodies against cytokeratin (anti-keratin AE1/AE3, Boehringer Mannheim, Indianapolis, IN) and CC49 (a second-generation monoclonal antibody directed against TAG-72. The authors reviewed all Dukes' B (transmurally invasive, lymph node negative) primary colorectal carcinoma resection specimens from the surgical pathology files of the Ohio State University Hospitals between 1984 and 1987. Survival data were obtained from the Tumor Registry of the Arthur G. James Cancer Hospital and Research Institute, Columbus, Ohio. The results were analyzed by univariate and multivariate analysis. Fifty cases with 568 lymph nodes (11.3 per case) were examined with each antibody using standard immunoperoxidase techniques. Positive staining for cytokeratin was seen in 14 patients (33 lymph nodes), 6 of whom died of colon cancer within 66 months (43%). Only 1 of the 36 patients with cytokeratin-negative lymph nodes died of colon cancer over the same time period (3%, P = 0.0009 univariate, P = 0.0013 multivariate). There was no significant difference in survival between the CC49-positive and CC49-negative groups. Immunoperoxidase techniques are capable of identifying micrometastatic disease in lymph nodes missed by routine hematoxylin and eosin staining. Further, the presence of cytokeratin-positive cells within lymph nodes correlated with a significantly poorer prognosis. Therefore, cytokeratin staining of pericolic lymph nodes in patients with Dukes' B colorectal cancer is recommended. Larger multicenter studies are needed, however, to confirm these results and to evaluate the appropriateness of adjuvant chemotherapy in patients whose disease is upstaged by immunohistochemical staining.Cancer 03/1994; 73(3):563-9. · 5.20 Impact Factor