Theodore J. Saclarides

Neuroendocrine cancers of the colon and rectum

PURPOSE: Our goal was to define the incidence of neuroendocrine carcinomas of the colon and rectum, the patterns of neuroendocrine expression, and the cellular subtype within neuroendocrine tumors. We attempted to determine whether differences in neuroendocrine expression or specific cell type influenced survival. METHODS: Over a ten-year period, 988 patients had resections for colorectal cancer. Using immunohistochemical staining methods specific for neuroendocrine markers, 39 (3.9 percent) neuroendocrine cancers were identified retrospectively. Tumors were also stained with monoclonal antibody A-80 which is specific for exocrine differentiation. In this way we were able to determine the extent of neuroendocrine differentiation such as pure neuroendocrine, predominant neuroendocrine, and equal neuroendocrine-exocrine expression. RESULTS: Average patient age was 65.5 (range, 28–89) years; there were 25 males and 14 females. Nineteen tumors were located in the right colon, 11 in the left, and 9 were in the rectum. Three histopathologic patterns were identified: pure neuroendocrine (n=11), predominantly neuroendocrine (n=17), and cancers with equal exocrine and neuroendocrine differentiation (n=7). Three cellular subtypes were seen: small-cell (n=15), intermediate-cell (n=15), and well-differentiated neuroendocrine cancers (n=5). There was one Dukes A cancer, 7 Dukes B, 16 Dukes C, and 15 patients had metastases to distant sites at the time of diagnosis. As a group, neuroendocrine tumors have a poor prognosis: six-month survival was 58 percent, three-year survival was 15 percent, and five-year survival was 6 percent. Survival statistically correlated with tumor stage (P=0.01) but not with age, sex, tumor location, histopathologic pattern, or neuroendocrine subtypes. Median survival for pure neuroendocrine carcinomas was seven months and for predominantly neuroendocrine carcinomas was five months. Tumors with equal neuroendocrine and exocrine differentiation had a median survival of 22 months (P=0.3). Small-cell neuroendocrine carcinomas had a median survival of five months, intermediate-cell had 11 months, and well-differentiated had a median survival of 22 months (P=0.1). CONCLUSIONS: Neuroendocrine differentiation is found in at least 3.9 percent of colon and rectal cancers. Many of these tumors were initially diagnosed as “carcinoids,” the diagnosis was changed to “neuroendocrine carcinoma” after immunohistochemical staining. Overall survival is poor especially for small-cell and pure neuroendocrine carcinomas.

Predicting lymph node metastases in rectal cancer.

For properly selected rectal cancers, local excision is a sphincter-saving alternative to abdominoperineal resection. If histologic assessment of a locally excised tumor reveals ominous features, further treatment with radical resection or irradiation may be necessary to treat potential lymph node metastases. PURPOSE: We wished to determine which features, if any, were predictors of nodal metastases. METHODS: Nine histologic and morphologic features of 62 radically excised rectal cancers were reviewed to determine which factors, if any, were associated with nodal disease. RESULTS: Using a chi-squared analysis, we found worsening differentiation (P=0.0001), increasing depth of penetration (P=0.026), a microtubular configuration of 20 percent or more (P=0.023), and the presence of venous (P=0.001) or perineural invasion (P=0.002) to significantly influence nodal disease. Lymphatic invasion was witnessed too infrequently to determine significance but, when present, was associated with nodal metastases in every case. Exophytic tumor morphology, mitotic count, and tumor size were not significant predictors. An analysis of variables determined that, of all factors or combination of factors examined, Broders classification was the strongest predictor of nodal disease. CONCLUSIONS: If a rectal cancer is accessible and of small size to facilitate local excision, an in-depth histologic assessment is needed to determine if nodal metastases are likely on a statistical basis.

Tumor angiogenesis in primary and metastatic colorectal cancers.

PURPOSE: Angiogenesis is needed to sustain growth of both primary and metastatic lesions; however, comparisons in microvessel density between a primary tumor and its metastases have not been widely performed. We studied microvessel density in primary colorectal cancers and their liver metastases. METHODS: Sections from 32 primary lesions and 53 hepatic metastases were immunostained with a monoclonal antibody for von Willebrands factor, an endothelial cell marker. Blood vessels were quantified under X 100 magnification using both conventional light microscopy and computer-assisted image analysis. Primary and metastatic angiogenesis scores (AS),i.e.,vessel counts, were analyzed with respect to tumor size, hepatic multicentricity, synchronicity, resectability, and patient survival. Using computer-assisted calculations, the same analyses were performed using blood vessel to tumor surface area ratios, vessel wall thickness, and intensity of immunostaining. RESULTS: Angiogenesis scores were significantly lower in metastatic lesions compared with their primary tumors (P<0.0001). Primary AS did not correlate with metastatic tumor size, resectability, multicentricity, or patient survival. Metastatic AS strongly predicted patient survival (P<0.0009) but with a negative coefficient,i.e.,higher scores were associated with improved survival. Metastatic AS were higher in resectable than in nonresectable metastases and in solitary than in multiple metastases; however, these trends were not statistically significant. Metachronous liver lesions had significantly higher angiogenesis scores than synchronous metastases (P<0.04). Similar trends were seen using computer-assisted image analysis. CONCLUSIONS: These results indicate that in presence of an established metastasis, there is a weak angiogenic relationship between a primary tumor and its metastasis. Heterogeneity in metastatic lesions cannot be explained solely by studying angiogenesis in primary tumors. Microvessel density in a primary tumor may not be useful as an independent prognostic indicator in late stages of disease. In such cases, assessment of microvessel density in a metastatic tumor whenever possible may be an indicator of prognosis.

Laparoscopic removal of a large colonic lipoma

A 72-year-old white male was found to have a 6-cm submucosal mass at 35 cm on screening sigmoidoscopy. The lesion had all the characteristics of a submucosal lipoma. Instead of performing a laparotomy with its potential morbidity, the lesion was removed laparoscopically in its entirety without untoward operative sequelae. Laparoscopic techniques have had a profound impact on the treatment of patients with surgical disorders. This new technology can be applied to selected patients with colorectal diseases.

Hormone receptor studies in axillary metastases from occult breast cancers

The authors describe 11 patients with occult breast carcinoma, who initially presented with axillary nodal metastases of unknown origin. In all 11 cases, physical examination and mammography results were normal. Steroid hormone receptor studies were done on tissue from all 11 axillary masses and 2 masses underwent lactalbumin staining as well. In 8 of the 11 patients these studies were positive, suggesting breast as the primary tumor site. Estrogen (30 to 445 fmol/g) or progesterone (30 to 1059 fmol/g) receptors, or both, were positive in seven cases. Although a breast carcinoma was subsequently found in all 11 patients, receptor studies on the primary tumor could not be done in every instance. The authors conclude that performing steroid hormone receptor assays on axillary metastases from occult tumors not only may provide information regarding the identity of the primary tumor but also may be the sole opportunity to determine its hormone receptor status. Cancer 59:1170‐1172, 1987.

WR-1065 and Radioprotection of Vascular Endothelial Cells. II. Morphology

Although the aminothiol WR-1065 protects normal tissues, its direct effect on the damage and restoration of the vascular endothelium is not clear. In endothelial cells, WR-1065 attenuates both the DNA damage and the G1-phase arrest induced by radiation. After the destruction of nearby endothelial cells, the survivors rearrange their cytoskeleton, migrate and replicate. To determine the effect of radiation on morphology and migration, portions of bovine aortic endothelial cell cultures were denuded with a pipette tip and irradiated (137Cs gamma rays). The following observations were noted after 5 Gy: within 10 min, there was increased formation of protein-mixed disulfides including actin-mixed disulfide; after 30-min, alpha 5 beta 1, the integrin receptor for fibronectin, was up-regulated on the apical membrane surface. Within 5 h, actin-containing stress fibers reorganized, although there was no change in the total filamentous (F-)actin content within the cells. Compared to controls after 24 h, the irradiated cells had migrated 15% farther (P < 0.01), and at the leading edge covered twice the surface area (P < 0.0001). The addition of 2 mM WR-1065 for 2 h before 5 Gy inhibited the increased expression of alpha 5 beta 1, promoted retention of stress fibers and prevented the enhanced cell migration and spreading. These results indicate that WR-1065 prevents radiation-induced morphological responses. This effect appears to be mediated by an impact on both adhesion molecule expression and cytoskeletal reorganization.

TRANSANAL ENDOSCOPIC MICROSURGERY

Transanal endoscopic microsurgery has become an established method of transanally excising rectal tumors. It uses a closed, airtight system that provides constant rectal distension, improved visibility, and longer reach than conventional instrumentation. Virtually any rectal adenoma and properly selected cancers can be removed with this technique. Transanal endoscopic microsurgery excision of cancers requires that strict selection criteria be satisfied and is best suited for T1 cancers. Transanal endoscopic microsurgery should not replace low anterior resection or abdominoperineal resection for those cancers that have either deep penetration into the rectal wall or lymph node metastases. This procedure is safe, is associated with minimal complications, and most patients can be treated on an outpatient basis. Complications include bleeding, urinary retention, temporary soilage, and inadvertent entry into the peritoneal cavity. Once transanal endoscopic microsurgery has been mastered, it may become the technique of choice for locally excising rectal neoplasms.

RADIATION INJURIES OF THE GASTROINTESTINAL TRACT

Although radiation has proven itself valuable in the treatment of a variety of pelvic malignancies, it is not without serious morbidity. This article has outlined the incidence of acute and chronic injury, ways to prevent the occurrence of complications, and the use of new medical and surgical treatments.

ANGIOGENESIS IN COLORECTAL CANCER

Angiogenesis is a complicated multistep process involving the breakdown of the endothelial cell basement membrane, digestion of the extracellular matrix, proliferation and migration of endothelial cells toward the angiogenic stimulus, and formation of functioning capillaries. This neovascular network not only provides nutrients for an expanding tumor mass but also a means of dissemination to sites far removed from the primary tumor site. The entire process is mediated by cytokines or growth factors released either by the tumor cells themselves or by endogenous cells within the microenvironment surrounding the tumor. The literature has conclusively shown that those lesions with high angiogenesis scores or microvessel densities are associated with a higher risk of metastases, recurrence, and early patient death. This is especially so for colorectal cancer. Antiangiogenesis therapy holds promise for the future and, in the adjuvant setting, has many theoretical advantages over conventional cytotoxic chemotherapy.

Immunohistochemical detection of mutant P53 protein and human papillomavirus-related E6 protein in anal cancers.

PURPOSE: The wild-type P53 protein, a product of theP53gene, is a normal growth controlling protein. Mutation of theP53gene generates a mutant P53 protein which promotes tumor formation through loss of growth suppression. Some of the agents responsible forP53gene mutation are known, one of which may be tumorigenic human papillomavirus (HPV) infection. Anal cancers are demonstrating a changing trend in the affected population, from older females in the older reported series to younger males more recently. This may be a reflection of infection with tumorigenic HPV types 16 and 18. The E6 oncoprotein of these viruses inactivates the growth-controlling wild-type P53 protein. In this study, our purpose was to determine the incidence of mutant P53 and HPV-16 and 18-related E6 protein and their coexpression in anal cancers. METHODS: We examined 29 anal cancers immunohistochemically for mutant P53 protein, HPV 16 and 18 E6 protein, and coexpression of the two. RESULTS: Mutant P53 protein was present in 58.6 percent of anal cancers overall and in 85.7 percent of anal adenocarcinomas. E6 oncoprotein was present in five cases (17.2 percent), all of which were squamous-cell carcinomas. Coexpression of both mutant P53 and E6 proteins was seen in only three cases (10.3 percent). CONCLUSION: Although tumorigenic HPV may be an important cause forP53gene mutation in anal cancers, perhaps other mutagenic factors play a predominant role.