Colposcopy.

Though in the 1980s, colposcopically-directed biopsy excluded over 90% of CIN 3 and cancer (CIN 3+), recent reviews found sensitivity of colposcopically-directed biopsy for CIN 3+ of 50-65%. Studies from China showed that the sensitivity of colposcopically-directed biopsy for CIN 3+ is higher for large CIN 3+ than for small CIN 3+ and higher for associated high-grade cervical cytology than for low-grade cervical cytology. Colposcopically-directed biopsy excluded over 90% of CIN 3+ in the 1980s because colposcopy clinics in the 1980s evaluated women with high-grade cytology that had large CIN 3+; it no longer excludes CIN 3+ well because current colposcopy clinics evaluate women with low-grade cytology that have small CIN 3+. When colposcopically-directed biopsy is used to exclude CIN 3+ our understanding of the natural history of CIN is skewed, errors occur in defining appropriate screening practice, and inaccurate diagnosis results in incorrect treatment. The impression that CIN is more common on the anterior lip of the cervix is an artifact introduced by the inaccuracy of colposcopy. An unjustified enthusiasm for screening with acetic acid aided visual inspection (VIA) occurred when the sensitivity of VIA for CIN 3+ was inflated by screening studies using colposcopically-directed biopsy as the gold-standard for CIN 3+. To limit the harm of inaccurate diagnosis associated with colposcopically-directed biopsy, at colposcopy we advise random biopsies at the squamocolumnar junction in cervical quadrants without visible lesions and, unless the woman is pregnant, endocervical curettage (ECC). As the diagnosis of CIN 3+ solely by ECC is uncommon in women under age 25, the ECC may be omitted in women under age 25 years. If multiple cervical biopsies are performed, to limit discomfort, a bronchoscopy biopsy instrument which obtains 2-mm biopsies should be used.

Shanxi Province cervical cancer screening study II: self-sampling for high-risk human papillomavirus compared to direct sampling for human papillomavirus and liquid based cervical cytology.

The objective of this study was to compare the sensitivity and specificity of a new method for self-sampling for high risk human papillomavirus (HPV) with direct sampling and liquid based cervical cytology. In Shanxi Province, China, 8,497 women (ages 27-56) underwent a self-sample for HPV using a conical-shaped brush placed into the upper vagina and rotated. Three to sixteen months later the women were screened with liquid-based cytology and direct HPV tests. Subjects with any abnormal test underwent colposcopy and multiple biopsies. Mean age was 40.9 years. 4.4 percent of subjects had >or=CIN II, 26% a positive self-sample and 24% a positive direct test for HPV. The sensitivity for detection of >or=CIN II was 87.5% for self-sampling, and 96.8% for the direct test (P < 0.001). The specificity was 77.2% for the self-sample and 79.7% for the direct test. With an abnormal Pap defined as ASCUS or greater the sensitivity of the Pap for the detection of >CIN II was 88.3% and the specificity was 81.2%. We conclude that self-sampling for HPV is less sensitive for >CIN II than the direct test, but similar to liquid based cytology.

The colposcopic impression. Is it influenced by the colposcopist's knowledge of the findings on the referral Papanicolaou smear?

OBJECTIVE: To determine whether the colposcopic impression is influenced by the colposcopist's knowledge of the referral Papanicolaou smear. STUDY DESIGN: Using a community hospital database, the accuracy of the colposcopic impression (accuracy = proportion of women with histology greater than cervical intraepithelial neoplasia [CIN] 2 that have colposcopic impressions of greater than CIN 2) when referral smears were atypical squamous cells of uncertain significance (ASCUS), atypical glandular cells of uncertain significance (AGUS) or low grade squamous intraepithelial lesion (LSIL) was compared to that when smears showed high grade squamous intraepithelial lesion (HSIL) or cancer. The analysis was repeated with a screening study database in which colposcopic impression was assigned without knowledge of the Papanicolaou smear. Univariate and logistic regression analysis of the second database determined the relative importance of size and grade of lesion and Papanicolaou result to the accuracy of the colposcopic impression. RESULTS: In the community database, colposcopic accuracy was 60/510 (12%) when smears were ASCUS, AGUS or LSIL and 77/132 (58%) when smears were HSIL or cancer (P < .001); in the second database, it was 2/19 (11%) when smears subsequently were reported as negative, ASCUS, AGUS or LSIL and 33/65 (54%) when smears were HSIL or cancer (P < .005). An accurate colposcopic impression was seen in 5/39 (13%) women with one-quadrant lesions, 8/18 (44%) with two-quadrant lesions and 23/27 (85%) with three- or four-quadrant lesions (P < .005). None of 19 women with smears reported as negative, ASCUS, AGUS or LSIL had lesions involving three or four quadrants of the cervix, while 27/65 (42%) women with smears reported as HSIL or cancer had such lesions (P < .005). With logistic regression, the more quadrants of the cervix involved, the more accurate the colposcopic impression. Once controlled for lesion size, there was no improvement when worst histologic grade or Papanicolaou smear result was considered. CONCLUSION: Through lesions greater than CIN 2 were more often overlooked when referral smears were negative, ASCUS, AGUS or LSIL than when they were HSIL or cancer, the real reason that the lesions were not detected by colposcopy was that they were small.

Cervical cancer screening by simple visual inspection after acetic acid.

OBJECTIVE: To estimate the sensitivity and specificity of visual inspection using acetic acid as a primary screen for cervical intraepithelial neoplasia (CIN). METHODS: Visual inspection was done on 1997 women aged 35-45 years in a screening trial in rural China. Each women had colposcopy and at least five cervical biopsies (directed biopsy of lesions, one biopsy at 2, 4, 8, or 10 o'clock at the squamocolumnar junction in each normal quadrant, and an endocervical curettage). RESULTS: Forty-three women had biopsy-proven CIN II, 31 had CIN III, and 12 had invasive cancer. In two women only the endocervix was positive (one with CIN II and one with CIN III). Visual inspection yielded normal results in 1445 women (72%), low-grade intraepithelial neoplasia in 525 (26%), high-grade in 21 (1%), and cancer in six (0.3%). With abnormal visual inspection defined as low-grade intraepithelial neoplasia or worse, the sensitivity for detecting biopsy proven CIN II or worse was 71% (61 of 86, 95% confidence interval [CI] 60%, 80%); the specificity was 74% (1420 of 1911, 95% CI 72%, 76%); the sensitivity was 65% for smaller lesions (37 of 57, 95% CI 51%, 77%), and 89% for larger lesions (24 of 27, 95% CI 71%, 98%) (P =.03). CONCLUSION: The sensitivity of visual inspection equaled or exceeded reported rates for conventional cervical cytology. Visual inspection and colposcopy have similar specificity profiles for CIN II and greater. The benefit of an inexpensive point-of-care diagnosis and treatment algorithm will be a powerful incentive to pursue visual inspection for cervical cancer screening in developing countries.

Invasive cervical cancer following cryotherapy for cervical intraepithelial neoplasia or human papillomavirus infection.

OBJECTIVE: To determine the following: 1) the causes for the failure of cervical cryotherapy to prevent cervical cancer, and 2) whether cervical cryotherapy is associated with the development of cervical adenocarcinoma rather than squamous carcinoma. METHODS: We reviewed the medical charts of 327 women with cervical cancer. One hundred forty-seven for whom pertinent history was missing were contacted by telephone or at clinic visits. History obtained verbally was confirmed by outside medical records. Cervical biopsies (N = 16) and endocervical curettages (ECCs) (N = 15) performed before cryotherapy and biopsies at the diagnosis of cancer (N = 21) were reviewed. RESULTS: Twenty-one women with cervical cancer had a history of cryotherapy for cervical intraepithelial neoplasia (CIN) or human papillomavirus infection (HPV). The interval between cryotherapy and cancer was more than 2 years in 19 and more than 5 years in ten. Several categories of pre-treatment errors were identified. Evaluation before cryotherapy was appropriate in only nine cases. Interpretive errors were noted in three of 16 cervical biopsies and ten of 15 ECCs. After cryotherapy, 12% of women had appropriate follow-up. Of the invasive cancers that developed, 24% in the cryotherapy group and 21% in the non-cryotherapy group were adenocarcinomas. CONCLUSIONS: Careful evaluation before cryotherapy, accurate pathology reports, and consistent long-term follow-up are necessary if cryotherapy is to be used to treat CIN or HPV. We found no evidence that cryotherapy is associated with the development of cervical adenocarcinoma.

Clinical stage I adenocarcinoma of the endometrium--analysis of recurrences and the potential benefit of staging lymphadenectomy.

Two hundred forty-eight consecutive patients with clinical Stage I adenocarcinoma of the endometrium were seen between 8/77 and 8/88. Twenty-one were medically not operable and eleven others had papillary serous tumors. The remaining 216 were managed by a consistent operative protocol except that routine preoperative cesium was discontinued after 12/83. Patients received postoperative pelvic radiation on the basis of the depth of invasion, extrauterine pelvic disease, and/or cervix involvement. No patient underwent a pelvic lymphadenectomy. Only palpably suspicious nodes were removed. Twenty-one of these two hundred sixteen patients developed a recurrence. These 21 cases are analyzed for the probability of a staging lymphadenectomy having prevented their recurrence. Median follow-up of all 216 patients is 61 months with a mean time to recurrence of 26.5 months. No patient was lost to follow-up. Patients who recurred are analyzed by grade, depth of invasion, surgical stage, time to recurrence, site of recurrence, survival, protocol breaks, and frozen section discrepancies. No patient recurred on the pelvic side-wall. All patients found to have positive para-aortic nodes have died. No patient who received vaginal and/or pelvic radiation recurred in the pelvis. We conclude that staging lymphadenectomy would not have improved the outcome for these patients.

A randomized trial of three methods of obtaining Papanicolaou smears.

The relationship between technique of obtaining Papanicolaou smears, presence of endocervical cells, and rate of cervical neoplasia was studied by comparing an endocervical and ectocervical nylon brush (Bayne brush), Ayre spatula plus endocervical brush, and spatula plus cotton-tipped swab in a randomized, prospective trial involving 11,061 patients. Eligible patients had a cervix and were not pregnant. Clinic records of patients with abnormal cytology were reviewed to determine the pathologic diagnosis. Whether pathology was defined as including condyloma, dysplasia, and cancer; dysplasia and cancer; moderate dysplasia, severe dysplasia, and cancer; or just severe dysplasia and cancer, no significant difference was found in the rates of pathology between the three techniques. Endocervical cells were identified in 89.5% of smears obtained with the Bayne brush, in 91.5% with the spatula plus endocervical brush, and in 71.1% with the spatula plus cotton-tipped swab (P less than .001). Among smears obtained with the spatula plus swab, the rate of any pathology was higher in smears that contained endocervical cells than in smears in which endocervical cells were absent (2.0 versus 0.6%; P = .009). After correction for the influence of age, there remained predictive value with the presence of endocervical cells. Once corrected for the influence of age, the rate of pathology and abnormal cytology in smears obtained with the spatula plus brush or the Bayne brush was not dependent upon the presence of endocervical cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Management of massive ovarian tumors.

Two patients with massive ovarian tumors, one with a 51 kilogram Stage IC mucinous cystadenocarcinoma and the other with a 34 kilogram mucinous cystadenoma, are presented. Problems associated with resection of massive ovarian tumors, including respiratory failure, intraoperative fluid shifts, adequate exposure, orthostatic hypotension and adynamic intestine, are identified. Guidelines for avoiding these pitfalls by the use of appropriate monitoring, controlled drainage of the cyst and transverse elliptic incision with abdominoplasty are suggested.

Utilization of a murine model to optimize volume and dwell time of intraperitoneal cisplatin.

The pharmacokinetics of intraperitoneal (ip) cisplatin were investigated in a murine model. Groups of six animals were studied at initial cisplatin concentrations (Ci) of 50, 100, 200, and 400 micrograms/ml, and at injection volumes (V) of 0.5, 1, 2, and 4 ml. For each Ci and V, four dwell times (Dt) between 1.5 and 120 min were studied. At 180 min mice were killed and five tissues (heart, kidney, liver, bowel, and peritoneum) were obtained for platinum measurement. Platinum recovered from the peritoneal cavity at the end of the dwell time and platinum tissue levels were determined by a radioactive tracer assay using Pt 195m-labeled cisplatin. A total of 384 mice were studied. The permeability times the effective surface area product (pS) was found to be independent of Ci, V, and Dt. Platinum tissue levels were proportional to absorbed dose. As the ratio of platinum tissue level to absorbed dose is constant, it is not possible to change Ci, V, nor Dt to minimize toxicity from a given absorbed dose. This study suggests that the therapeutic index of an individual intraperitoneal cisplatin treatment will not be changed by modifying Ci, V, nor Dt.

Intraperitoneal cis-platinum as salvage therapy for refractory epithelial ovarian cancer.

Eighteen patients with residual epithelial ovarian cancer at second-look laparotomy were treated with a combined total of 210 cycles of intraperitoneal cis-platinum. Sixteen patients had previously received cis-platinum containing combination chemotherapy systemically. Seven patients had microscopic residual disease at the start of intraperitoneal therapy, eight had macroscopic disease of 5 mm in diameter or less, and three had disease of 6-10 mm in diameter. The drug was administered weekly in 2 L of Ringer's lactate solution via an indwelling Tenckhoff catheter, and the dose ranged from 30-270 mg per cycle (median 120 mg). The dwell time was 20 minutes. After 12 cycles, response was assessed by open laparoscopy (six patients), laparotomy (eight patients), or peritoneal cytology (three patients). One patient developed distant metastases. Local and systemic toxicity was mild. Delays of therapy were necessary for eight of the 210 cycles because of hematologic toxicity. Of the 15 patients available for pathologic evaluation, four (26.6%) had a complete response and two (13.3%) had a partial response. Results of this pilot study suggest a possible role for intraperitoneal cis-platinum in the management of carefully selected patients with epithelial ovarian cancer.

False-negative peritoneal cytology in metastatic ovarian carcinoma.

Seventy-nine laparotomies for disseminated intraperitoneal ovarian carcinoma were reviewed to determine the frequency and possible causes of false-negative peritoneal cytology. Negative peritoneal cytology (defined as any reading other than positive) was found in 16 of 79 cases (20%). False-negative cytology occurred more frequently with peritoneal washings (48%) than with ascites (6%; P less than .001); with second-look surgery (50%) than at primary surgery (12%; P = .004); with peritoneal metastasis less than 0.5 cm (50%) than with metastasis greater than 0.5 cm (16%; P = .02); and with bloody cytology specimens (25%) rather than specimens without blood (0%; P = .06). Volume of peritoneal specimen, architectural grade, cytologic grade, and stage of disease (III versus IV), did not affect the frequency of false-negative cytology. The high prevalence of negative cytology associated with peritoneal washings, small tumor size, and second-look surgery suggests that negative cytology is a result of poor distribution of peritoneal washings and infrequent exfoliation of malignant cells rather than misinterpretation of malignant cells present in cytology specimens.

Hexamethylmelamine, methotrexate, 5-fluorouracil as second line chemotherapy after platinum for epithelial ovarian malignancies.

Thirty-three patients were treated with HexAF after previous treatment with cyclophosphamide (C), Adriamycin (A), and cisplatin (P). The patients had either progressed on CAP, had persistent disease after CAP, or recurred after a negative second look. Treatment schedule was hexamethylmelamine (Hex) 150 mg po qd days 1-14, methotrexate (A) 40 mg/m2 IV days 1 and 8, and 5-fluorouracil (F) 600 mg/m2 IV days 1 and 8. Courses were repeated every 4 weeks. Thirty-one of 33 patients were evaluable for response. Three of 31 patients had partial responses, 7 of 31 had stable disease, and 21 of 31 progressed. Median survival of the responders (n = 3) was 23 months and the nonresponders (n = 28) was 6 months (p = 0.027). Patients with less than 1 cm disease (n = 12) had a median survival of 20 months, and those with greater than 1 cm (n = 21) had a median survival of 6 months (p = 0.004). Toxicity was mild. Even with a statistically significant survival advantage for HexAF responders, we consider a response rate of less than 10% unacceptable.

Stage I carcinoma of the endometrium: a 5-year experience utilizing preoperative cesium.

A treatment protocol for the management of stage I endometrial carcinoma utilizing preoperative cesium is evaluated. One hundred and twelve consecutive patients were treated according to this protocol over a 5-year period. Based on this experience and a literature review a new protocol is recommended. The significant changes include primary surgery without preoperative cesium, primary treatment based on grade without regard to uterine size, modified radical hysterectomy for G3 tumors, pelvic radiotherapy for clear cell carcinoma confined to the pelvis regardless of depth of invasion, cytoxan, adriamycin, and cis-platinum for papillary serous tumors, and postoperative vaginal cuff cesium for G2 and G3 tumors not requiring pelvic radiotherapy.

Treatment of vulvar carcinoma in situ with the CO2 laser.

Between January 1960 and December 1982, 142 patients with carcinoma in situ of the vulva were treated at Cedars-Sinai Medical Center and UCLA Medical Center. Primary treatment consisted of wide excision in 45 patients; vulvectomy in 23 patients; topical chemotherapy in 9 patients; and CO2 laser therapy in 42 patients. Twenty-three patients were also treated with the CO2 laser for recurrent disease. Multifocal disease was present in 59% of the cases. Lesions involving the posterior vulva recurred most commonly, for both initial and recurrent disease. Results utilizing the CO2 are compared with the other methods of treating carcinoma in situ of the vulva. The CO2 laser is well suited for treatment of both multifocal and unifocal vulvar lesions, as it allows for maximal retention of vulvar integrity with no decrease in therapeutic efficacy.

Pharmacokinetics of Ip cisplatin in refractory ovarian carcinoma.

Four patients with small residual ovarian carcinoma following treatment with cisplatin, doxorubicin, and cyclophosphamide have subsequently received 57 courses of ip cisplatin. Cisplatin (120-270 mg in 2 L of Ringer's lactate) was administered via Tenckhoff catheter, with a dwell time of 15-20 mins. Courses were given weekly for 12 weeks, with response documented by laparoscopy or laparotomy prior to and following the trial. With a dwell time of 20 mins, 75% +/- 5% (mean +/- SD) of platinum was recovered. With 120 mg of cisplatin and a dwell time of 20 mins, total plasma platinum peaked at 1.23 +/- 0.42 microgram/ml and by 8 hrs decreased to 0.67 +/- 0.12 microgram/ml. Filterable (non-protein-bound) platinum peaked at 0.73 +/- 0.21 microgram/ml and by 8 hrs fell to 0.03 microgram/ml. Excretion rate paralleled the filterable plasma curve, peaking at 40 mins; 30% +/- 7% of absorbed drug was recovered in urine within 24 hrs. Renal clearance of filterable platinum was 106 +/- 20 ml/min. Creatinine clearance was 76 +/- 7 ml/min. Three responses, one complete and two partial, were noted. Zero to two episodes of vomiting occurred in each course. One patient had a creatinine clearance decrease to 40 ml/min, one had two episodes of thrombocytopenia, and one had mild abdominal pain with a cisplatin dose of greater than or equal to 210 mg. No neurotoxicity, catheter infection, or peritonitis was encountered.

Comparison of the iv and ip routes of administration of cisplatin in dogs.

Cisplatin at a dose of 3 mg/kg was administered to dogs either iv or ip. Cisplatin concentrations in serum, urine, and tissues were measured with a radioisotope tracer method employing 195mPt cisplatin. Systemic toxicity was monitored by serial BUN, creatinine, and wbc and platelet counts. The mode of administration did not affect systemic toxicity since the changes in renal and bone marrow functions were identical in the two groups. Serum cisplatin levels following iv administration peaked at 13.5 micrograms/ml at 5 minutes and were biphasic with rapid initial decline and a prolonged elimination phase. In contrast, levels following ip administration increased rapidly to 1.5 micrograms/ml at 4 hours and then decreased with the iv levels. The amount of drug recovered in the urine was similar regardless of method of administration, with approximately 50% of the injected dose excreted by Day 4. The drug levels within the tissues on Days 4 and 8 were similar, with the exception of the tissues lining the peritoneal cavity. On Day 4 the tissues lining the peritoneal cavity had 2.5-8 times higher levels of drug after ip administration, and this difference was statistically significant (P less than 0.01). Local toxic effects encountered with ip administration consisted of bloody ascites on Day 4 (four of none dogs) and filmy adhesions on Day 8 (one of four dogs). It is concluded that ip cisplatin chemotherapy may increase the therapeutic index for small tumors which are confined to the peritoneal cavity.

The metabolism of cis-dichlorodiammineplatinum (II): distribution, clearance, and toxicity.

The distribution and toxicity of 195mPt-labeled cis-platinum were studied in two groups of dogs. Serum and tissue levels, renal and marrow toxicities, and urinary excretion were compared in dogs given cis-platinum, 3 mg/kg, intravenously with a group treated by intraperitoneal administration. Peak serum levels occurred immediately after intravenous administration and 8 hours after intraperitoneal instillation, at which time the two were identical and declined at similar rates. Mean levels of cis-platinum measured in peritoneal tissues on day 4 were higher in the intraperitoneal group. Blood urea nitrogen, creatinine, and white blood cell and platelet counts were similar in both groups. Bloody ascites and adhesion formation occurred in 37.5% of dogs treated by intraperitoneal administration. The intraperitoneal route of chemotherapy administration results in higher drug levels in target peritoneal tissues without a corresponding increase in systemic toxicity.