The Bethesda system and evaluation of abnormal pap smears.

The Bethesda Pap Smear system and its 1991 revisions aim to simplify Papanicolaou (Pap) smear reporting and make it more reproducible. It redefines the Pap smear request as a medical consultation. The pathologist consultant is required not only to provide the smear reading but also its clinical recommendation. The Bethesda system insists on a detailed Pap smear report assessing specimen adequacy and types of epithelial changes. Squamous cell abnormalities are grouped according to their biologic potential. Both cervical intraepithelial neoplasia, grade I (CIN I) (mild dysplasia) and human papillomavirus (HPV) lesions are grouped together as low-grade squamous intraepithelial lesions (LGSIL), while moderate and severe dysplasia (CIN II and III) belong to the high-grade squamous intraepithelial lesion (HGSIL) category. Atypical squamous cells of undetermined significance (ASCUS) and atypical glandular cells of undetermined significance (AGCUS) need further qualification as to whether they favor either a reactive or neoplastic process. Guidelines for management of abnormal Pap smears are discussed in detail.

Chemotherapy of advanced and recurrent cervical carcinoma.

Chemotherapy is used primarily to treat advanced or recurrent cervical cancer. There are three major applications: primary therapy, as a radiation sensitizer, and neoadjuvant therapy. Primary chemotherapy is employed in advanced and disseminated cervical carcinoma (Stage VB). The four best single drugs with moderate activity against cervical cancer are: cisplatin, ifosfamide, dibromodulcitol (mitolactol), and Adriamycin (doxorubicin). Cisplatin and ifosfamide appear to be the best combination therapy: they provide an objective response rate of 33%. However, because the overall survival was not significantly improved with combination therapy, single-agent therapy with one of the above active drugs is acceptable. For stages IIB, III and IVA, the primary therapy is still radiation. Concomitant chemotherapy with hydroxyurea or a combination of cisplatin and 5-fluorouracil (5-FU) have been shown to enhance radiation response in several randomized trials. Hydroxyurea is the preferred radiation sensitizer because it offers less toxicity, ease of administration, and equivalent results. Chemotherapy in neoadjuvant setting produces promising results. Various cisplatin combinations of mitomycin C, 5-FU, vincristine, and bleomycin have been employed to shrink locally advanced cervical cancer and permit safe, radical excision. Early results with these combinations in small trials are encouraging but further studies are needed to fully evaluate their potential.

Advanced and recurrent carcinoma of the ovary treated with a combination of cyclophosphamide, doxorubicin, and cytosine arabinoside.

Twenty-six patients with advanced or recurrent epithelial ovarian carcinoma, FIGO Stages III and IV, were treated with combination chemotherapy using cyclophosphamide, doxorubicin, and cytosine arabinoside (CARA). In 17 cases, CARA was initiated following failure to single-agent chemotherapy, in all cases, melphalan. Nine patients with advanced cancer received CARA as their primary chemotherapy after maximum cytoreductive surgery. The overall response rate was 27%; however, in patients without prior chemotherapy the response rate was 44%. There were 6 complete responders, 1 partial responder, 13 patients with stable disease, and 6 who failed to respond to therapy. Four of six complete responders had remission durations greater than 10 months. The median progression free interval (PFI) of patients with residual tumor diameters less than 2 cm was significantly longer (P less than or equal to 0.04) than the PFI of patients with greater initial tumor burden. The median PFI of complete responders was significantly longer (P = 0.007) than PFI of patients with less than complete response. Previously untreated patients had longer median PFI than those who had failed previous chemotherapy (P = 0.07). The major dose-limiting toxicity of CARA was thrombocytopenia. Other myelosuppression was moderate and no cardiotoxicity was encountered.

Cervical carcinoma antigens in the diagnosis of human squamous cell carcinoma of the cervix.

The use of tumor-associated antigens (TAA) in the diagnosis of human squamous cell carcinoma of the cervix was evaluated by immunofluorescence staining of second cervical scrapes and touch preparations of normal and carcinomatous tissue. Rabbit antisera, prepared against human cervical squamous cell carcinoma homogenates and absorbed with normal human cervix and plasma, were used to stain 103 second cervical scrapes by indirect immunofluorescence. Of these specimens, 59 were positive by immunofluorescence, whereas the remaining 44 were negative. Compared with conventional cytologic diagnosis, positive immunofluorescence was detected in 100% (49/49) of the second scrapes from patients with cervical dysplasia or carcinoma (for a false-negative rate of zero). Of the second cervical scrapes from 57 patients negative by cytology, 13 were positive by immunofluorescence (for a false-positive rate of 22.8%). Indirect immunofluorescence tests on tumor touch preparations also revealed cervical TAA in other types of gynecologic tumors.

Treatment of advanced cervical cancer by combination of bleomycin and mitomycin-C.

A combination of bleomycin and mitomycin-C, reported as extraordinarily effective in a previous clinical trial, was used to treat 20 patients with advanced cervical cancer. Seven partial remissions (35%) and one complete remission (5%) were observed. Six of the partial remissions were of short duration (less than four months); the only patient with complete remission was still alive without evidence of disease ten months after initiation of chemotherapy. Nonresponders had a mean survival time of 6.6 months and responders 8.0 months. The treatment results confirm some efficacy of the drug regimen, although in our hands it did not live up to the high expectations raised by others.

Fine-needle aspiration cytology in gynecologic oncology. I. Diagnostic accuracy.

A prospective study was undertaken to determine the diagnostic accuracy of fine-needle aspiration (FNA) cytology in gynecology. A total of 77 aspirations were performed on 74 patients. In 34 instances the purpose was to rule out or confirm a diagnosis of primary disease, and in 43 cases the procedure was used for suspected metastatic disease or disease recurrent after surgery, radiation therapy, and/or chemotherapy. Excellent correlation was noted between the cytologic and subsequent histopathologic diagnoses of 58 aspirations from patients who also underwent surgical biopsy. Two specimens were false negatives as the result of sampling errors. The applicability of FNA cytology in the field of gynecolotic oncology is discussed.

Fine needle aspiration cytology in gynecologic oncology. II. Morphologic aspects.

This study was based on the evaluation of 140 fine-needle spirations from gynecologic lesion. Cytologic criteria for the diagnosis of benign and malignant lesions and cellular changes due to irradiation and chemotherapy are presented. For accurate evaluation of fine-needle aspiration specimens from the pelvis, the exact location of the sampling must be known, clinical data must be available, and the patholgist must have an intimate knowledge of anatomy, histology and pathology of benign and malignant lesions in this area. Fine-needle aspiration cytology provided a high degree of accuracy in the diagnosis of gynecologic lesions.

Fine needle aspiration cytology in gynecologic oncology. I. Clinical aspects.

One hundred forty fine needle aspirations were performed on 124 patients with a variety of gynecologic conditions. The primary goal of this study was to investigate the adequacy of this technique in the primary diagnosis of pelvic masses and in the detection of persistent or recurrent gynecologic malignancies following irradiation or chemotherapy. In this, the first of two articles, the clinical aspects of the procedure, including clinical indications and the different approaches and pelvic sites of fine needle aspiration, are discussed. The simplicity and lack of complications of the method, combined with a high degree of accuracy in predicting the histologic picture of various lesions, merit wider application of this technique as a reliable diagnostic tool in gynecologic oncology.

Invasive cancer of the cervix after cryosurgery. Pitfalls of conservative management.

Eight cases of invasive cervical carcinoma detected after cryotherapy for presumably noninvasive cervical lesions are reported. Three of these patients died from their disease less than 2 years following definitive therapy. The potential dangers of a less-than-optimal work-up of patients prior to freezing are analyzed and discussed in detail. Possible explanations for failures of cryotherapy are discussed, and guidelines for prevention of failures are presented.

Clear cell adenocarcinoma arising in endometriosis of the rectovaginal septum.

Malignant transformation in a focus of endometriosis is uncommon (less than 1%). The ovary is by far the most common site, followed in frequency by the rectovaginal septum. A case of clear cell adenocarcinoma arising in endometriosis of the rectovaginal septum is presented and its pathogenesis discussed.

Management of carcinoma in situ of the uterine cervix by selective local excision.

Local excision of severe dysplasia or carcinoma in situ of the uterine cervix by punch biopsies was the treatment in 366 cases. In 61%, cervical cytology reverted to negative or slight atypia. 153 patients have been followed from 1 to 7 years. Failures to remove the entire lesion were discovered within the first year of follow-up in all cases but 10. Complications were negligible and no patients have subsequently developed invasive cancer of the cervix. Selective local excision as an alternative to other minimally traumatic techniques, e.g. cryotherapy is discussed. Although the failure rate is slightly higher with local excision, an obvious advantage is the availability of all removed tissue for histopathologic diagnosis. Thus, the risk of overlooking microinvasive disease is reduced to a minimum.

Clear cell adenocarcinoma of the cervix and vagina. A clinicopathologic study of 21 cases with and without a history of maternal ingestion of estrogens.

Twenty-one cases of clear cell adenocarcinoma of the cervix and vagina have been reviewed. Fifteen cases occurred in females under 25 years of age and four in women over 45 years. In seven cases, a positive history of maternal ingestion of diethylstilbestrol (DES) was obtained. One mother gave a history of medication with conjugated estrogens and ethisterone. Of the 13 patients with a negative history, three were born during the time period when DES was commonly used to prevent abortion. Fifteen carcinomas were cervical in origin; seven of these also involved the vagina. In six cases the carcinoma was entirely vaginal. Vaginal involvement of the carcinomas was more common in the estrogen-related group. Two non-estrogen-related cases had coexisting congenital malformations with double uterus and vagina and unilateral renal agenesis. The histopathologic appearance was similar in both groups. In most cases, a mixture of papillary, microcystic, tubular, and solid features was seen. Vaginal adenosis was found in nine cases, six of which were estrogen-related. Surgical therapy was employed in most cases and was generally superior to radiation therapy. Five patients had lymphatic involvement. All died from carcinoma. The survival rate among sixteen patients followed for 2 years or more was 62.5%. The probable müllerian origin of clear cell adenocarcinoma is discussed. It is suggested that DES, by virtue of being an estrogen, interferes with the normal process of differentiation and degeneration of müllerian epithelium in the fetal vagina. The persistence of müllerian cells altered at the subcellular level could form the basis for development of carcinoma in later life. However, a similar sequence of events must also be accepted to occur "spontaneously" since clear cell adenocarcinoma can develop in women without a history of maternal estrogens.