Krukenberg tumors: can management be improved?

OBJECTIVE: The Montefiore Medical Center experience with women with gastrointestinal (GI) cancer was reviewed to: (1) evaluate clinical parameters in patients with Krukenberg tumor (GI cancer metastatic to the ovaries) and (2) evaluate oophorectomy in GI cancer patients. METHODS: (1) Charts of all female patients admitted between 1985 and 1996 with gastric or colon cancer were reviewed. RESULTS: The frequency of Krukenberg tumor was 7/1,021 (0.7%). The median age at presentation was 39.5 years (range 35-80); 5 were premenopausal, 2 of whom were postpartum. Krukenberg tumor was significantly more common in the premenopausal patients with gastric cancer (p = 0.002), colon cancer (p = 0.001), and in both sites combined (p < 0.001). Our rate of pregnancy-associated Krukenberg tumors (28.6%) was significantly higher (p < 0.05) than that found in 4 of 5 large studies. The average survival of our 7 patients was 12.3 months (range 4 days to 26 months), with secondary debulking and chemotherapy offering 1 patient the longest longevity. Only 19/788 (2.4%) women had oophorectomy during their colon cancer surgery revealing 2 (10.5%) Krukenberg tumors, 6 (31.6%) benign solid or cystic ovarian tumors, and 11 (57.9%) normal or atrophic ovaries. CONCLUSIONS: Krukenberg tumors are rare. There is no uniformity of data reported in the literature. Krukenberg tumors were more common in premenopausal women with gastric or colon cancer compared to postmenopausal women. Our rate of pregnancy-associated Krukenberg tumors appeared to be higher compared to other studies. Prophylactic oophorectomy in pre- and postmenopausal women should be considered at the time of GI cancer surgery, and requires further study. A national registry combined with prospective, multisite studies are needed to gather data and evaluate treatment.

Biologic characteristics of specific human papillomavirus types predicted from morphology of cervical lesions.

Human papillomavirus (HPV) DNA was detected by Southern blot hybridization in cervicovaginal lavage samples from 199 of 329 (60.5%) women attending a municipal hospital colposcopy clinic. Human papillomavirus was identified in 195 of 264 (73.9%) patients with a squamous intraepithelial lesion or cancer on biopsy or Papanicolaou smear (Bethesda system) compared with 11 of 65 (16.9%) without squamous intraepithelial lesion (P < .0001). The most common HPV type identified was HPV 16 (20.6% of positive samples), and 36.7% of isolates contained uncharacterized HPVs. Of women with cervical intraepithelial neoplasia (CIN) grade III or cancer, 23.4% were infected with HPV 16 compared with less than 4% with any other single HPV type. Based on biopsy diagnosis in patients infected with specific HPV types, HPVs 6 and 11 had low oncogenic potential; HPVs 18, 31, 35, and 45 had intermediate oncogenic potential; and HPVs 16 and 33 had high oncogenic potential. Hyperchromatic, unusually enlarged nuclei ("meganuclei"), and/or abnormal mitoses were found significantly more often in lesions infected with HPVs 16, 33, and 35 than in those infected with HPVs 6, 11, 18, 31, and 45, even in low-grade lesions, and may represent a histologic marker for HPVs with significant oncogenic potential. Human papillomavirus capsid protein was detected significantly less often by immunocytochemical staining in CIN I and CIN II lesions infected with HPVs 16 and 33 (8.3%) than in those infected with HPVs 6, 11, 18, and 31 (60%; P = .007), suggesting early abnormalities in cellular differentiation in lesions infected with highly oncogenic HPVs.

Type-specific and cross-reactive epitopes in human papillomavirus type 16 capsid proteins.

Genital human papillomavirus (HPV) 16 infection is frequently associated with cancer of the uterine cervix, as well as with precancerous lesions. In order to generate serologic reagents which might be useful in the diagnosis of HPV 16 infection, rabbit polyclonal and mouse monoclonal antisera were raised to carboxy terminal peptides from the HPV 16 L1 and L2 open reading frames (ORFs). Anti-L1 and -L2 peptide sera recognized HPV 16 L1 and L2 fusion proteins in Western blots and by immunoprecipitation. In Western blot analysis of L1 proteins from different HPV types, antisera to the L1 peptide reacted only with HPV 16, thus identifying an HPV 16 type-specific linear epitope. Anti-L2 peptide sera reacted with L2 fusion proteins from HPVs 6 and 16, but not from BPV, thus identifying a partially cross-reactive epitope in the HPV 16 L2. Computer analysis of carboxy terminal amino acid sequences of the L1 and L2 ORFs of multiple HPV types supported the Western blot findings. Despite the HPV 16 type specificity found in Western blots, anti-L1 peptide sera identified nuclear antigen by immunocytochemistry in cervical biopsies infected with HPV 16, as well as other genital HPV types. Anti-L2 peptide sera failed to recognize antigen in infected tissue.

Comparison of Cytobrush and cervicovaginal lavage sampling methods for the detection of genital human papillomavirus.

The development of an accurate method for the detection and typing of genital human papillomavirus is of substantial clinical importance. This virus has been implicated as an etiologic agent in the development of cervical neoplasia. To detect human papillomavirus infection with maximum sensitivity, cells must be collected and assayed for human papillomavirus deoxyribonucleic acid. We compared two noninvasive methods of sampling exfoliated cervical cells--cervicovaginal lavage and scrape-Cytobrush. Seventy-four patients newly referred to the colposcopy clinic were divided randomly for cell sampling by either cervicovaginal lavage followed by scrape-Cytobrush or, conversely, scrape-Cytobrush followed by cervicovaginal lavage. Restriction analysis and Southern blot hybridization were used to test all the samples thus obtained for human papillomavirus. Overall, test results from 42 patients (56.8%) were positive for human papillomavirus deoxyribonucleic acid. Twenty-six (31.1%) tested positive for human papillomavirus by both sampling methods, and 32 (43.2%) tested negative for human papillomavirus by both methods. One (1.4%) tested positive with scrape-Cytobrush sampling but negative with cervicovaginal lavage, while 15 (20.3%) tested negative with scrape-Cytobrush but positive with cervicovaginal lavage (p less than 0.001, McNemar's test). These data, combined with previous work from our group, suggest that, of the available methods, cervicovaginal lavage, coupled with human papillomavirus deoxyribonucleic acid hybridization, is the most sensitive noninvasive method for harvesting cells for molecular identification of human papillomavirus in the female lower genital tract.

Molecular diagnosis of genital human papillomavirus infection: comparison of two methods used to collect exfoliated cervical cells.

Human papillomavirus infection is implicated as an etiologic agent in the development of neoplasia and invasive carcinoma of the cervix. To detect human papillomavirus infection of the cervix, cells must be collected and assayed for human papillomavirus-related deoxyribonucleic acid sequences. Gynecologists and other clinical investigators generally use an exocervical spatula scrape and an endocervical swab for cell collection, analogous to Papanicolaou smear collection. However, inadequate cell recovery is common. To overcome this problem, we have developed the cervicovaginal lavage method for human papillomavirus detection. In the present study we compared the cervicovaginal lavage method with the widely used scrape-swab method in 48 women referred for colposcopic examination. After a Papanicolaou test, two samples were obtained from each woman, either with cervicovaginal lavage followed by scrape-swab or with the scrape-swab followed by cervicovaginal lavage. Human papillomavirus types were assessed by restriction analysis and Southern blot hybridization. In 21 women (44%) test results were positive for human papillomavirus with both the scrape-swab and cervicovaginal lavage cell collection methods; in nine women (19%) test results were positive only with the cervicovaginal lavage method; and in 18 women (38%) results were negative for human papillomavirus with both techniques. None of the women had human papillomavirus detected by scrape-swab without also having it detected with cervicovaginal lavage. The human papillomavirus deoxyribonucleic acid types identified were concordant in the 21 women whose infections were detected with both sampling methods, although the second virus type was detected only with cervicovaginal lavage in one woman who had a mixed genital tract infection. We concluded that cervicovaginal lavage is a more sensitive cell collection method than the scrape-swab technique for assessing human papillomavirus infection of the cervix.

Detection of human papillomavirus deoxyribonucleic acid in exfoliated cervicovaginal cells as a predictor of cervical neoplasia in a high-risk population.

Specific types of human papillomavirus are currently implicated as etiologic agents of precancerous and cancerous lesions of the cervix. We have previously described the use of cervicovaginal lavage and molecular hybridization to detect human papillomavirus infections of the cervix. We report here the predictive value of this method of human papillomavirus detection to identify women with biopsy proved dysplastic and cancerous lesions of the cervix. One hundred ninety-one women from a city hospital colposcopy clinic underwent concurrent Papanicolaou smear, cervicovaginal lavage, and coloposcopically directed cervical biopsy. Human papillomavirus deoxyribonucleic acid was detected in 114 (59.7%) of these women. Of the positive results, human papillomavirus type 16 accounted for 23.7%, human papillomavirus type 18 for 10.5%, human papillomavirus type six or 11 for 6.2%, related human papillomavirus types for 52.6%, and 7.0% contained more than one type. The distribution of human papillomavirus types was similar in both women younger than 40 years of age and in older women. Eighty-nine of 128 (69.5%) women less than 40 years old with cervical lesions had positive findings of human papillomavirus, and 18 of 29 (62.1%) older women with cervical lesions had positive findings of human papillomavirus. Detection of human papillomavirus types 16 and 18 identified only 35 of 157 (22.3%) women with cervical lesions. The sensitivity of detecting all types of human papillomavirus as a predictor of a biopsy proved lesion (68.0%) was comparable with the sensitivity of cytologic examination alone (74.0%). However, human papillomavirus detection combined with the Papanicolaou smear provided an increased overall sensitivity of 89.3% (p less than 0.01). In fact, women either positive for human papillomavirus or having abnormal cytologic findings were 11.8 times more likely to have a biopsy proved cervical lesion than human papillomavirus-negative women with negative cytologic results (95% confidence interval for odds ratio: 5.3 to 26.6). We conclude that the sensitivity of cytologic examination plus human papillomavirus detection is superior to the use of either cytologic studies or human papillomavirus detection alone in identifying patients with cervical lesions.

Head and neck squamous cell carcinomas associated with human papillomaviruses and an increased incidence of cervical pathology.

Human papillomaviruses (HPVs) have been identified in benign and cancerous epithelial lesions of the female genital tract. They have also been identified in papillomata and cancers of the upper aerodigestive tract. This study investigates the hypothesis that lesions of the cervicovaginal area are more common in women with cancers of the head and neck region. The presence of HPV in lesions of both regions is examined. Seven female patients with cancer of the upper aerodigestive tract had DNA analysis of their carcinoma specimens. HPV type 16 was found in two of the seven (28%). Fourteen female patients with upper aerodigestive tract cancers had Papanicolaou smears to search for cytologic evidence of HPV infection, and cervicovaginal lavages to analyze DNA from exfoliated cervical cells. Five of thirteen (38%) Papanicolaou smears revealed koilocytotic atypia and three of these patients had HPV DNA types 16 or 18 identified in the cervical lavage. The incidence of cervical atypia noted is 13-fold greater than average. One patient had HPV type 16 in both her supraglottic cancer and in her cervicovaginal lavage. Evidence of HPV infection at two separate anatomic sites suggests a systemic susceptibility to HPV infection.