Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers.

Molecular analysis of hereditary nonpolyposis colorectal carcinomas (HNPCC) has identified DNA mismatch repair deficiencies with resulting microsatellite instability (MSI) as a pathway of carcinogenesis that appears to be relevant for prognosis, treatment, and possibly prevention. In this study, expression of cell cycle proteins and other known prognostic markers is correlated with the microsatellite status of colorectal cancers (CRC). One hundred consecutive cases from the CRC Registry at Thomas Jefferson University were analyzed for MSI. Immunohistochemistry was performed for the mismatch repair proteins hMLH1 and hMSH2, tumor suppressor p53, apoptosis inhibitor bcl-2, cell cycle proteins p21(WAF1/CIP1), and p27 and the proliferation markers Ki-67 and topoisomerase II. High MSI (MSI-H) is significantly correlated with loss of either hMLH1 or hMSH2, presence of bcl-2, and absence of p53. p21(WAF1/CIP1) is positive in all tumors with MSI-H. Previous findings of a lower proliferation rate were confirmed with a topoisomerase II stain. Microsatellite stable (MSS) tumors generally express both MSH2 and MLH1. Other highly significant differences are positive p53 in 56% of MSS cases and negative bcl-2 in 98% of MSS cases. p27 expression is found in approximately 50% of all CRCs irrespective of the microsatellite status. MSI-H tumors follow the mutator pathway, with loss of expression of one mismatch repair protein, wild-type p53, lower proliferation, and positivity for p21(WAF1/CIP1). MSS tumors follow the suppressor pathway, characterized by p53 overexpression, higher proliferation, and absence of bcl-2 expression; p21(WAF1/CIP1) expression can be variable. These data provide a molecular basis for the clinical observation that patients with HNPCC appear to have a more favorable prognosis. HUM PATHOL 31:1506-1514.

The role of p53, p21WAF1/C1PI, and bcl-2 in radioresistant colorectal carcinoma.

Genetic alterations in the p53 tumor suppressor gene are common in human colorectal cancers, occurring in approximately 70% of tumors. In vitro studies have shown that wild-type p53 is involved in controlling cell cycle checkpoint functions and apoptosis involved in the cytotoxic response induced by ionizing radiation and several anticancer chemotherapeutic agents. Wild-type p53 protein can transcriptionally activate the WAF gene, which encodes a cyclin-dependent kinase inhibitory protein, p21WAF1/C1PI protein, and transcriptionally repress the bcl-2 gene, which encodes an inhibitor of apoptosis. To learn more about the in vivo relationship between p53 protein and the expression of p21WAF1/C1PI and bcl-2 proteins in human colorectal cancers treated with radiation therapy, we examined the expression of these proteins by immunohistochemistry in pre-irradiated biopsy specimens and surgical specimens with residual tumor of 27 patients with colorectal carcinoma. Cell proliferation was measured using Ki-67 expression in the tumor cells. The p53 protein was not detected in normal colorectal mucosa, but it was expressed in 21 of 27 (78%) of pre-irradiated tumor samples and in 19 of 27 (70%) of post-irradiated tumors. Expression of the bcl-2 protein in normal colorectal mucosa was confined to the basal epithelial cells of the crypts. Diffuse bcl-2 staining was detected in tumor cells in 13 of 27 (48%) of pre-irradiated samples and in 14 of 27 (52%) of post-irradiated samples. p21WAF1/C1PI expression was detected in 14 of 27 (52%) of pre-irradiated samples but only in 7 of 27 (26%) of post-irradiated samples. No inverse relationship between expression of p53 protein and abnormal bcl-2 expression was apparent. p21WAF1/C1PI was expressed in most nonproliferating Ki-67-negative epithelial cells at the apical tips of the crypts in normal colorectal mucosa, but not in proliferating Ki-67-positive cells of adjacent adenomatous mucosa. An inverse relationship between Ki-67 and p21WAF1/C1PI expression was observed in normal colorectal mucosa and adjacent adenomatous mucosa. After radiation therapy, p53 protein accumulation did not change among residual tumors in 18 cases (three of which were initially negative and remained negative); in four cases there was a significant increase, and five cases had a substantial decrease of p53 expression. Aberrant bcl-2 expression is not correlated with expression of p53 and does not increase significantly in post-irradiated tumor cells. p21WAF1/C1PI expression is markedly reduced in tumor cells that survive radiation therapy.

Vasovenous fistula after vasectomy.

PIP: Reported is the first known case in which vasovenous fistula occurred as a complication of vasectomy. A 44-year-old US man, who had undergone a routine vasectomy 3 months earlier, presented with hematospermia and gross hematuria. Cytoscopy revealed blood emanating from the left ejaculatory duct. Left scrotal exploration demonstrated a vein transversing into the area of the vas deferens where previously placed clips were present. Histopathological examination revealed multiple vascular structures, abnormal in number and caliber, which were adherent to the vas deferens. It is postulated that, in this case, the hematoma occurred as a result of bleeding from a vein adjacent to the surgical clip. The inflammatory response to the clip may then have involved the neighboring injured vein, resulting in fistula formation. This rare complication can be averted through efforts not to injure vascular structures during vasectomy.^ieng

Detection of human papillomavirus in verrucous carcinoma from HIV-seropositive patients.

Anogenital squamous cell carcinoma has been noted with increased frequency in HIV-seropositive patients. Verrucous carcinoma is a variant of squamous cell carcinoma that tends to be locally invasive and non-metastasizing. Although human papillomavirus (HPV) has been strongly implicated in other squamous neoplasms, it has been variably associated with verrucous carcinoma and has not been examined in these lesions in the HIV-positive population. The aim of this study was to examine the association of HPV with anal verrucous carcinoma in patients with the human immunodeficiency virus (HIV). HPV DNA in situ hybridization for HPV Types 6/11, 16/18, and 31/33/35 was performed on formalin-fixed, paraffin-embedded tissue from six cases of verrucous carcinoma and four cases of condyloma acuminatum in perianal specimens from HIV-seropositive patients. HPV DNA sequences were identified in five of six cases of verrucous carcinoma and in all cases of condyloma acuminatum. Of the five verrucous carcinomas that harbored detectable HPV DNA, four contained HPV 6/11 and two contained HPV 16/18. One contained both HPV 6/11 and HPV 16/18. All four cases of condyloma acuminatum were positive for HPV 6/11. One patient included in this series had three chronologically separate verrucous carcinomas. The initial lesion was negative for HPV DNA. Subsequent verrucous carcinomas were positive for HPV type 6/11 and type 16/18, respectively. The data presented support the concept that verrucous carcinoma in the HIV-seropositive population is associated with HPV, which may indeed play an important role in its pathogenesis.