A GCIG international survey: clinical practice patterns of sentinel lymph node biopsies in cervical cancer.

PURPOSE: To evaluate the practice patterns among centers and physicians worldwide regarding sentinel lymph node biopsies (SLNB) in cervical cancer (CC) patients. METHOD: A validated 35-item questionnaire regarding SLNB in CC supported by the Gynecologic Cancer Intergroup (GCIG), and sponsored by the North-Eastern German Society of Gynaecologic-Oncology (NOGGO) was sent to all major gynecological cancer societies across the globe for further distribution from October 2015 and continued for a period of 7 months. RESULTS: One hundred and sixty-one institutions from around the world participated. One hundred and six (66%) of the participants were from university centers and 111 (69%) were gynecologic oncologists. One hundred and fifty-two (97%) performed lymphadenectomy (LNE) and 147 (94%) did so systematically; 97 (60%) used SLNB, due to lower morbidity (73%), reliability (55%) and time-saving (27%). In cases of positive SLNB (pN+), 39% of respondents stopped the operation and sent the patient for chemoradiation (CRT), 45% completed pelvic and paraaortic LNE, whereas 26% went on to perform a radical hysterectomy (RH) and systematic pelvic and paraaortic LNE. In case of negative SLNB (pN0), 39% of institutions still performed a systematic pelvic and paraaortic LNE. CONCLUSION: In this survey worldwide, SLNB adoption is an encouraging 60%, yet ample differences exist regarding strategy, and to a lower extent the techniques used. Lack of experience is the most common reason SLNB is not performed. Efforts to increase surgical education on SLNB technique and multicenter prospective trials providing evidence-based guidelines are warranted.

Protein interaction of retinoblastoma gene product pRb110 with M(r) 73,000 heat shock cognate protein.

Both the tumor suppressor gene products, the retinoblastoma sensitivity gene product pRb110 and p53, are found in oligomer complexes with the oncogene products of the DNA tumor viruses. It has been demonstrated that p53 binds to the M(r) 70,000 heat shock protein family. However, the protein association of pRb110 with the M(r) 70,000 heat shock protein family is not yet known. We analyzed the immunoprecipitates made with TYK-nu human ovarial carcinoma cell lysate and anti-pRb110 or anti-heat shock protein monoclonal antibodies. In this paper, we demonstrate that pRb110 is associated with the M(r) 73,000 heat shock cognate protein, but not with the M(r) 72,000 heat shock protein. This selective protein association was also detected in HeLa cervical carcinoma cells. Furthermore, the protein complexes of the M(r) 73,000 heat shock cognate protein and pRb110 were dissociated with the presence of ATP, but not with ADP and the nonhydrolyzable ATP analogue, ATP gamma S. This indicates that the dissociation is dependent on the ATP hydrolysis. These data may suggest an as yet undefined important role of M(r) 73,000 heat shock cognate protein in the cell growth control in collaboration with pRb110.

Fine-scale deletion mapping of the distal long arm of chromosome 6 in 70 human ovarian cancers.

To define a small region on chromosome 6q containing a putative tumor suppressor gene for ovarian cancer, we examined loss of heterozygosity in 70 ovarian tumors of three histological types with nine restriction fragment length polymorphism markers located at 6q24-27. Among 33 cancers of serous type that were informative at one or more loci, 17 showed allelic loss at a few or all loci examined, whereas only 1 of 15 mucinous-type tumors and 2 of 12 clear-cell tumors revealed loss of heterozygosity. This result supported our earlier suggestion that alteration of a gene on chromosome 6q may play an important role during development of serous ovarian tumors (Sato et al., Cancer Res., 51: 5118-5122, 1991). Frequent losses were observed between loci defined by CI6-119 (D6S195) at 6q26 and CI6-49 (D6S161) at 6q27. A detailed deletion map indicated a commonly deleted region between loci defined by CI6-111 (D6S193) and CI6-24 (D6S149); these two markers are estimated to be 1.9 cM apart on the basis of linkage analysis. Our results further define a region containing a tumor suppressor gene involved in ovarian carcinoma within an approximately 2-megabase-long segment of chromosome 6q.

Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region.

Matrix metalloproteinases (MMPs), a family of closely related enzymes that degrade the extracellular matrix, are likely to be involved in invasion and metastasis of tumor cells. A guanine (G) insertion/deletion polymorphism within the promoter region of MMP-1 influences the transcription of this gene; i.e., the 2G (insertion-type) promoter possesses greater transcriptional activity than the 1G (deletion-type) promoter. To investigate whether this feature contributes to cancer development and/or progression, we genotyped 163 ovarian cancer patients for the polymorphism and then analyzed levels of expression of the MMP-1 gene in their tumors. The proportion of patients who were either heterozygotes or homozygotes for the 2G allele was significantly higher than that observed among 150 individuals without cancer (P = 0.028). Moreover, the levels of MMP-1 expression in cancer tissues among the patients carrying 2G alleles were elevated significantly in comparison with 1G homozygotes (P = 0.0038). By stimulating degradation of extracellular matrix, an excess of MMP-1 production may enhance development and/or rapid progression of ovarian cancers.

Detailed deletion mapping of chromosome 17q in ovarian and breast cancers: 2-cM region on 17q21.3 often and commonly deleted in tumors.

Using 11 restriction fragment length polymorphism markers, we examined loss of heterozygosity on the long arm of chromosome 17, where one or more genes responsible for hereditary breast and ovarian cancers may be present, in sporadic forms of 94 ovarian and 246 breast cancers. Loss of heterozygosity was observed in 33 of 84 (39.3%) ovarian and in 88 of 214 (41.1%) breast cancers that were informative with at least one marker. Detailed deletion mapping of chromosome 17q in these cancers identified two distinct, commonly deleted regions. One was located between 17q12 and 17q21.3 and the other between 17q25.1 and 17q25.3. In breast cancers, the proximal commonly deleted region was between two loci defined by markers CI17-701 and CI17-730 at 17q21.3, which are 2.4 cM apart. This segment overlaps the region that includes the putative gene for hereditary breast and ovarian carcinomas. The results suggest that at least two tumor suppressor genes associated with sporadic ovarian and breast cancers are present on chromosome 17q and that one of them may be the same gene that is responsible for the hereditary form.

Definition of a commonly deleted region in ovarian cancers to a 300-kb segment of chromosome 6q27.

Allelic deletions of chromosome 6q that occur frequently in ovarian cancers imply the presence of a putative tumor suppressor gene in this chromosomal vicinity. We analyzed DNA from 32 patients with ovarian carcinomas for loss of heterozygosity at loci on the distal portion of chromosome 6q and constructed a detailed deletion map. The map indicated a commonly deleted region between loci D6S149 (defined by CI6-24) and A2, which are estimated to be 300 kb apart on the basis of our cosmid contig map. By means of exon trapping, we found that the human AF-6 gene, which is disrupted in acute myeloid leukemia cells that carry a (6;11)(q27;q23) translocation, is located within the commonly deleted region. Subsequent screening of the AF-6 gene in ovarian carcinomas revealed no mutations. However, our mapping results, which narrowed the region containing the putative tumor suppressor gene to a 300-kb segment of 6q27, will facilitate further efforts to identify a gene associated with ovarian cancer.

Demonstration of selective protein complexes of p53 with 73 kDa heat shock cognate protein, but not with 72 kDa heat shock protein in human tumor cells.

It has been demonstrated that p53, especially, mutant p53 (mp53), makes protein complexes with major heat shock proteins hsp72/hsc73. However, there is no direct evidence showing whether hsp72 or hsc73 could bind preferentially to p53. In the present study, using TYKnu human ovarial carcinoma cells and monoclonal antibodies reacting specifically to hsp72/hsc73, we were able to find the selective protein complex formation with p53, presumably mp53, and hsc73, but not in the case of p53 and hsp72. The p53-hsc73 protein complexes dissociate with the addition of ATP, indicating that the dissociation is dependent upon the ATP-hydrolysis. These data suggest that hsc73 rather than hsp72 plays an important role in the yet undefined mechanism of disregulated cell growth control by mp53.

Telomerase activity in malignant ovarian tumors with deregulation of cell cycle regulatory proteins.

Using a semiquantitative telomeric repeat amplification protocol assay, telomerase-positive frequencies and enzyme levels were measured. Out of 95% of 49 human ovarian tumors, the highest level of telomerase activity was observed in malignant tumors. Furthermore, by immunohistochemical staining of cell cycle regulatory proteins (pRB, p16, cyclin D1, cyclin E and p53) at the G1 checkpoint, we evaluated the relation between each protein alterations and the levels of telomerase activity. We could not demonstrate a clear relation with each molecule except for cyclin E, but suggesting that aberrant accumulation of these proteins was considered as a reason for telomerase deregulation, which may play an essential role in the pathway of telomerase regulation.

Peritoneal cytology of ovarian cancer patients receiving intraperitoneal therapy: quantitation of malignant cells and response.

An analysis was performed of malignant and host cells found in peritoneal fluids obtained during intraperitoneal chemotherapy and immunotherapy in patients with ovarian cancer. The concentration of malignant cells and the surgically documented response to the intraperitoneal treatment were correlated. Twenty-three patients were treated with intraperitoneal cisplatin or alpha-2 interferon (rIFN-alpha 2) after persistent carcinoma was documented at second-look laparotomy. Six patients (26%) had a complete response to therapy, and all of these patients had a malignant cell concentration of less than 10(2)cells/cm2/dL. No responses were seen in patients whose initial malignant cell concentration was greater than 10(3)cells/cm2/dL. Among patients treated with intraperitoneal alpha-interferon, five of 11 whose initial concentration of malignant cells was less than 10(2) cells/cm2/dL responded to therapy, whereas none of the patients whose malignant cell concentration was 10(2) cells/cm2/dL or greater responded. In patients treated with intraperitoneal cisplatin, the initial concentration of malignant cells associated with any surgically documented response was less than 10(3)cells/cm2/dL. A host mesothelial reaction was prominent after intraperitoneal alpha-interferon, but not observed in women treated with intraperitoneal cis-platin. The fluctuating pattern of peritoneal white blood cells documented during therapy did not correlate with response. THe evaluation of peritoneal cytology specimens during intraperitoneal chemotherapy should include a quantitative assessment of malignant cells and reactive mesothelial cells in order to reflect more accurately the histologically documented findings. Initial quantitative cytology appears to correlate with the likelihood of a surgically documented response to intraperitoneal therapy.

Multiple primary malignancies in patients with gynecologic cancer.

A retrospective analysis was made of 1044 patients with gynecologic malignancies treated in our department over a 12-year period, in order to review the frequency and types of multiple primary neoplasms. Multiple primary neoplasms were detected in 45 (4.3%) cases, including 16 (2.1%) out of 733 cervical cancers, 14 (8.2%) out of 166 endometrial cancers, three (15%) out of 20 vaginal cancers and 12 (9.8%) out of 123 ovarian cancers. Fifteen cases were synchronous and the remaining 24 cases were heterochronous, with an average 4.9-year interval. The most frequent other site of neoplasm was the breast, particularly in patients with endometrial or ovarian cancer. We conclude that gynecologic malignancies are often associated with primary cancers elsewhere, especially in the breast, stomach, colon and thyroid. A patient presenting with a gynecologic malignancy should be thoroughly examined for a second cancer, as should patients being followed-up after treatment for genital tract cancer.

Minimal-deviation adenocarcinoma (adenoma malignum) of the uterine cervix; four case reports.

Four cases of minimal-deviation adenocarcinoma (adenoma malignum) of the uterine cervix are analysed in this clinicopathological study. Four patients, one Ib, two IIb and one IIIb stage, showed poor prognosis, which included three patients who died within 36 months, because of diagnostic delays of 5 years, 6 months and 1 year due to cytohistologically benign appearances. Cytologically, the nuclei were somewhat more irregular in size and shape than those of normal columnar epitherial cells. Slightly multilayered cell clusters were arranged as honeycombs, palisades or sheets with glandular openings. The characteristic histological features were the presence of sharp points projecting from the glands and marked variation in the size and shape of the glands. Ultrastructurally, intestinal metaplastic cells containing both microvilli with core filaments and rootlets, and secretary granules in the same cell were present in the specimens of two evaluable patients. These features indicate a disorder of differentiation. In order to diagnose this tumor accurately, comprehensive analysis should be required concerning the clinical features, cytohistological findings and ultrastructural findings.

Genetic analysis of familial and multiple malignancies of endometrial cancer.

The presence of the positive replication errors (RER) phenotype in familial and multiple primary malignancies of endometrial cancer, and its association with a poor prognosis was examined. We analyzed 40 endometrial cancers for RER. Eight endometrial cancers with the RER(+) phenotype at multiple microsatellite loci were detected. The presence of the RER(+) phenotype was higher than in non-familial malignancies. None of the eight cases with the RER(+) phenotype involved multiple primary malignancies; however these patients had shorter survival times. In this study, we suggest that RER examination in endometrial cancer may be useful for establishing a diagnosis of a familial malignancy, and for predicting a poor prognosis.

The cytological features and DNA content of cervical adenocarcinoma.

The relationship among cytological features, DNA content, and degree of histological differentiation of cervical adenocarcinoma was investigated in an attempt to discover a more accurate means of screening for this cancer. In highly differentiated adenocarcinoma (so-called adenoma malignum), the nuclei were only somewhat more irregular in size and shape than those of normal columnar epithelial cells. The cells were arranged in slightly multilayered clusters. The cells of well-differentiated adenocarcinoma were usually columnar in shape, and they exfoliated side by side in clusters. In moderately differentiated adenocarcinoma, solitary cells with markedly atypical nuclei were combined with multilayered cell clusters. The cells from poorly differentiated adenocarcinoma were roundish, occurred as solitary cells or irregularly overlapping cell clusters, and showed markedly atypical nuclei. As the degree of histological differentiation decreased, as determined by measurement of the DNA content of the cells, the DNA distribution covered a wider range in terms of ploidy, and the number of cells exceeding tetraploid DNA content increased.

Morphology of adenocarcinoma in situ and microinvasive adenocarcinoma of the uterine cervix. A cytologic and ultrastructural study.

Adenocarcinoma in situ (AIS) and microinvasive adenocarcinoma of the uterine cervix and normal endocervical columnar epithelium were studied by cytology, morphometry and electron microscopy to identify differentiating features and to ascertain the cellular origin of cervical adenocarcinoma. Smears from AIS showed the characteristic cytology, consisting of glandular rosettes, palisading and crowded sheets; most nuclei had a relatively uniform oval shape. Smears from microinvasive adenocarcinoma showed more crowded sheets, with enlarged, round and irregular-shaped nuclei and prominent oval nucleoli. These nuclear features were confirmed by the morphometric results. Ultrastructurally, reserve cells in the normal tissues contained tonofibers and secretory granules and showed squamous and adenomatous features. The ultrastructural features of microinvasive adenocarcinoma were similar to those of well-differentiated invasive adenocarcinoma. The cells from both contained tonofibers and secretory granules. These findings suggested that the reserve cell is the cell of origin for cervical adenocarcinoma.

Cervicovaginal and endometrial cytology in ovarian cancer.

The clinical significance of cytologic examination was studied in 114 patients with ovarian cancer who had received preoperative cytologic examinations. The overall positive rate of the cytologic examinations was 26.3% (30 of 114): 22 (19.3%) of the 114 cases had positive cervicovaginal smears while 13 of 31 endometrial aspiration smears (41.9%) were positive. The positive rate was not related to the volume of ascites but rather to its presence or absence. Thus, if ascites was observed, the positive rate was about 2.1 times higher than if it was absent. In two of four cases of ovarian cancer with no endometrial invasion but a positive cytologic examination of ascitic fluid, fallopian tube specimens contained cancer cells; this suggests that ovarian cancer cells may reach the cervix and/or vagina by passing through the fallopian tube, particularly if ascites is present. Since cytologic examination, especially of endometrial aspiration smears, shows a high positive rate if ovarian cancer cells are observed in the abdominal cavity, cytology should be used as an important ancillary method for the assessment of ovarian cancer.

Peritoneal washing cytology at second-look laparotomy in cisplatin-treated ovarian cancer patients.

The use of peritoneal washing cytology during second-look laparotomy in 58 cisplatin-treated ovarian cancer patients was evaluated. Washing was performed for the 41 patients who showed no gross evidence of persistent disease. Peritoneal washing cytology was positive in 8 of 18 cases with histologically identified residual disease and in 4 of 23 cases without residual disease. However, three of the four cytologically positive patients without other evidence of disease later died of recurrences. The five-year survival rate of the 23 patients who showed no residual carcinomas macroscopically was 60.9%; when their washing cytologies were negative, there was a 73.7% five-year survival rate. These findings indicate that, despite its limitations, a peritoneal washing cytology at the time of second-look laparotomy is important to assess the response to treatment and to evaluate the prognosis of patients with ovarian cancer.

[Treatment of recurrent ovarian cancer].

Significant prolongation of survival time among the patients with advanced ovarian cancer has been brought under the development of surgery and chemotherapy, but even those with clinical remission shows sometimes recurrence. For the recurrent ovarian cancer patients at present there are no definite strategy to treat the recurrent cases. Under these circumstance, we have reviewed the current treatment of cytoreductive surgery and chemotherapy for the recurrent cases. 1) surgical treatment Generally, in the cases of recurrent ovarian cancer, cytoreductive surgery is required to minimize the residual tumour in the abdomen. But sometimes we can find the distant metastasis including liver, lung, and lymph node. This means that surgery is not sufficient for control of recurrent tumor. Further adjuvant chemotherapy will be required to control metastatic tumors. 2) chemotherapy After the detail assessment of the initial treatment of cases, at first we should think about retreatment with CDDP-based regimen and secondly about dose-intensification of CDDP or CBDCA for the CDDP-resistant cases. And as combination regimens, topoisomerase inhibitors, etoposide or CPT-11 are also preferable to use, alkylating agents such as ifosfamide, 5-fluorouracil, and some current trials with new drug, taxol are effective for recurrent cases. In conclusion, further active chemotherapy using platinum compounds, topoisomerase inhibitors, taxol will be achieved for the control of the recurrent cases of ovarian cancer.

[Recent progress in epidemiologic research of uterine cancer].

Although the mortality and incidence of cervical cancer have been decreasing, those of uterine-body, or endometrial, cancer have been increasing. The proportion of endometrial cancer was reported to have become 33.6% of primary uterine cancers in 1995. Infection with certain types of human papilloma virus (HPV) is considered to be etiologically important for the occurrence of cervical cancer. Because HPV is sexually transmitted, some risk factors for cervical cancer are associated with certain kinds of sexual behavior such as a young age at first intercourse, multiple partners, and infrequent use of barrier-type contraceptives such as condoms. Frequent conceptions and deliveries and histories of sexually transmitted diseases like infection with herpes simplex virus type 2 or chlamydia also have been suggested to be associated with the risk of cervical cancer. Smoking habits and infrequent intake of vegetables and fruits may be related to the increased risk of cervical cancer by supporting persistent infection of HPV through impaired immunological function. Although host factors such as a variant of a tumor suppressor gene like p53 have been assessed in terms of the risk of cervical cancer, these are not yet clearly elucidated. Estrogen stimulation of the endometrium unopposed by progesterone stimulation, namely, unopposed estrogen stimulation, is thought to be involved in the etiology of endometrial cancer. Frequent intake of animal fat, obesity or being overweight, infertility, and histories of diabetes mellitus, hypertension, and polycystic ovary syndrome have been reported to be risk factors for endometrial cancer, and they are thought to increase unopposed estrogen stimulation. Estrogen replacement therapy for postmenopausal symptoms, tamoxifen therapy for breast cancer, and taking sequential-type oral contraceptives have been shown to be exogenous risk factors for endometrial cancer in that they increase unopposed estrogen stimulation to endometrium.

[Ovarian cancer].

Age-adjusted ovarian cancer deaths and mortality rates have increased annually in Japan from 1968 to 1995, with the absolute number of deaths increasing 4-fold during these years. Internationally, the mortality rates are high in North America or northern Europe, but their incidences have gradually decreased. However, the incidences of ovarian cancer have increased in France, Spain, and Japan. Risk factors for epithelial ovarian cancer include older age, being northern European or North American, family history of ovarian cancer, nulliparity, infertility, and obesity, and preventive factors include oral contraceptive use, gravidity, lactation, tubal ligation, and hysterectomy.

[Feasibility, activity, and change in the level of blood paclitaxel concentration after weekly paclitaxel therapy for a patient with recurrent ovarian cancer].

The patient was a 59-year-old woman with recurrent ovarian cancer. A CT scan of the abdomen showed enlargement of abdominal para-aortic lymph nodes (PAN) after the primary operation and 8 cycles of the combination chemotherapy with paclitaxel (TXL) and carboplatinum (CBDCA). As a second line chemotherapy for the patient, weekly administration of TXL (60 mg/m2/week x 3 weeks) was given. The toxicity was acceptable and less pronounced than with the standard TXL + CBDCA therapy. Peak blood TXL concentration, about 90 ng/ml, was achieved 4 hours after the administration of TXL. The blood TXL concentration was below the detectable limit 48 h after the administration of TXL. An almost 50% shrinkage in the size of the PAN was obtained after 2 cycles of treatment. Good QOL is being maintained without any repeated aggravation of the tumor.