Robert J. Kurman

The behavior of endometrial hyperplasia. A long‐term study of “untreated” hyperplasia in 170 patients

Endometrial curettings from 170 patients with all grades of endometrial hyperplasia, who did not undergo a hysterectomy for at least 1 year were evaluated in order to correlate the histopathologic features with behavior. Follow‐up ranged from 1 to 26.7 years (mean, 13.4 years). Cytologic and architectural alterations were analyzed separately in order to assess their respective roles in predicting the likelihood of progression to carcinoma. Classification of proligerative lesions based solely on the presence of cytologic atypia revealed that atypia was a discriminant factor. Proliferations lacking cytologic atypia were designated hyperplasia and those displaying atypia were designated atypical hyperplasia. Only 2 (1.6%) of 122 patients with hyperplasia progressed to carcinoma compared with 11 (23%) of women with atypical hyperplasia (P = 0.001). Subclassification of the two forms of hyperplasia (those with cytologic atypia and those without) was performed using the degree of architectural abnormalities. Hyperplasia and atypical hyperplasia displaying marked glandular complexity and crowding producing a back‐to‐back appearance were designated complex hyperplasia (CH) and complex atypical hyperplasia (CAH), respectively. Hyperplasia and atypical hyperplasia with lesser degrees of glandular complexity and crowding were designated simple hyperplasia (SH) and simple atypical hyperplasia (SAH), respectively. Progression to carcinoma occurred in 1 (1%) of 93 patients with SH, in 1 (3%) of 29 patients with CH, in 1 (8%) of the patients with SAH, and in 10 (29%) of the patients with CAH. The differences between the four subgroups suggest a trend but are not statistically significant. The findings in this study provide a rationale for classifying noninvasive endometrial proliferations primarily on the basis of cytologic atypia since this is the most useful criterion in predicting the likelihood of progression to carcinoma. In addition, the presence of concommitant architectural alterations appears to identify a particularly high‐risk subgroup.

Evaluation of criteria for distinguishing atypical endometrial hyperplasia from well‐differentiated carcinoma

Endometrial curettings from 204 patients containing severe forms of atypical hyperplasia, carcinoma in situ, and well‐differentiated carcinoma were compared with subsequent hysterectomy specimens to evaluate and identify the most useful histologic criteria for predicting the presence of invasive carcinoma. Endometrial stromal invasion, increased degrees of nuclear atypism, mitotic activity, cellular stratification, and epithelial necrosis in curettings were associated with a greater likelihood of carcinoma in the uterus. Of these, stromal invasion was the most significant feature. When stromal invasion was absent, carcinoma was present in the uterus in only 17%, and the carcinomas were well differentiated and confined to the endometrium or only superficially invasive. When stromal invasion was present in curettings, residual carcinoma was present in the uterus in half, and of these, one third were moderately or poorly differentiated and a quarter invaded deeply into the myometrium. The criteria for invasion are 1) an irregular infiltration of glands associated with an altered fibroblastic stroma or desmoplastic response; 2) a confluent glandular pattern in which individual glands are uninterrupted by stroma and merge to form a cribriform pattern of stromal replacement; 3) an extensive papillary pattern; and 4) replacement of stroma by masses of squamous epithelium. To qualify as invasion, items 2, 3, and 4 must occupy at least one half (2.1 mm) a low power field 4.2 mm in diameter. Because of the important role of stromal invasion in predicting prognosis, future classifications of endometrial neoplasia should utilize this feature in distinguishing atypical hyperplasia from well differentiated adenocarcinoma.

Analysis of individual cervical human papillomavirus types in neolasia: A possible role for type 18 in rapid progression

Histologic and molecular analyses of 214 cervical biopsy specimens were performed to test the hypothesis that certain individual human papillomavirus types that are usually grouped together are differentially distributed in various grades of cervical intraepithelial neoplasia and invasive squamous carcinoma. Specifically, types 16 and 18, which are commonly grouped together, were analyzed separately and compared. Biopsies obtained from three different geographic sites in the United States and Brazil were analyzed by Southern blot hybridization and correlated with the histologic diagnosis from the same tissue sample. There was a highly significant correlation between papillomavirus type and histologic grade comparing all grades of cervical intraepithelial neoplasia with invasive cancer ( p p

Doxorubicin as an adjuvant following surgery and radiation therapy in patients with high-risk endometrial carcinoma, stage I and occult stage II: A Gynecologic Oncology Group study

The Gynecologic Oncology Group studied the use of adjuvant doxorubicin after surgery and radiation therapy for endometrial carcinoma in a randomized, prospective manner. The study population consisted of patients clinically stage I or II (occult) who, after surgical-pathologic evaluation, had one or more risk factors for recurrence: greater than 50% myometrial invasion, pelvic or aortic node metastasis, cervical involvement, or adnexal metastases. All patients without aortic node metastasis received 5000 rads to the whole pelvis at 160-180 rads per day. If aortic node metastasis was documented, aortic field radiation to the top of T12 was offered. The aortic target dose was 4500 rads at 150 rads per day. After completion of radiation therapy, the patients were randomized to receive doxorubicin bolus therapy (60 mg/m2 starting dose) to a maximum cumulative dose of 500 mg/m2. Between November 1977 and July 1986, 92 patients were entered into the doxorubicin (DOX) treatment arm, and 89 patients entered the no-DOX arm. There was no statistically significant difference in survival or progression-free interval of the two arms. The 5-year survival rates for patients with deep myometrial invasion, cervical involvement, and pelvic node metastases were similar (63-70%), whereas the rate for patients with aortic node metastases was 26%. There was no significant difference in the recurrence pattern between the two treatment arms. There were no cases of grade 3 or 4 cardiac toxicity. Twelve patients (6.9%) developed small bowel obstruction after radiation therapy. There were three treatment-related deaths in the DOX arm and two in the radiation therapy-only arm. We conclude that, because of protocol violations, small sample size, and the number of patients lost to follow-up, this study was unable to determine what effect use of doxorubicin as adjuvant therapy had on recurrence, progression, and survival of the endometrial cancer study population. The combination of surgical staging and postoperative radiation as used in this study appears to increase the risk of bowel complications.

Papillomavirus infection of the cervix. II. Relationship to intraepithelial neoplasia based on the presence of specific viral structural proteins

Three hundred twenty-two cases of cervical dysplasia (mild, moderate, and severe) and carcinoma in situ (CIS) were examined for the presence of papillomavirus structural antigens with a peroxidase-antiperoxidase method on formalin-fixed, paraffin-embedded tissue. The primary antiserum, prepared from purified, detergent-disrupted bovine papillomavirus type 1 virions, is broadly reactive against the genus-specific (common) antigen(s) of the papillomaviruses. Using the peroxidase-antiperoxidase technique on cervical tissue obtained from biopsy, conization and hysterectomy specimens, papillomavirus structural proteins were identified in association with mild dysplasia in 65 of 152 (43%) cases, with moderate dysplasia in 12 of 82 (15%) cases, with severe dysplasia in eight of 47 (17%) cases, and with CIS in four of 41 (10%) cases. Papillomavirus antigens were found directly within the lesion in all the cases of mild and moderate dysplasia but in only two instances of severe dysplasia and in none of the examples of CIS. In the remaining 10 cases of severe dysplasia and CIS associated with the presence of papillomavirus antigens, cells containing papillomavirus structural proteins were present in areas of moderate dysplasia immediately adjacent to the high-grade lesions in seven instances and in areas of mild or moderate dysplasia not directly in contact with the high-grade lesions in three. Among the 12 high-grade lesions associated with the presence of papillomavirus antigens, a morphologic transition from areas of moderate dysplasia containing papillomavirus antigens to the areas of severe dysplasia and CIS was present in five instances. The results of this study, therefore, provide direct evidence demonstrating the relationship of papillomavirus to intraepithelial cervical neoplasia ranging from mild dysplasia to severe dysplasia and CIS.

Correlation of the Histologic Appearance of Intraepithelial Neoplasia of the Cervix with Human Papillomavirus Types. Emphasis on Low Grade Lesions Including So-called Flat Condyloma

Cervical condylomas and intraepithelial neoplasia (CIN) were correlated with human papillomavirus (HPV) types and analyzed for the presence of abnormal mitotic figures. Colposcopically directed cervical biopsies were divided in half and processed for routine microscopy and Southern blot hybridization. Of 83 specimens from 71 patients, 70 (84%) contained HPV-DNA sequences. The HPV distribution was as follows: HPV 16 in 6/25 flat condylomas (FC), 2/8 CIN I, 8/18 CIN II, 12/14 CIN III; HPV 18 in 1/25 FC; HPV 31 in 3/25 FC, 3/18 CIN II, and 1/14 CIN III; HPV 6/11 in 12/18 exophytic condylomas (EC), 5/25 FC, 2/8 CIN I, and 3/18 CIN II. Uncharacterized HPVs were identified in 4/18 EC, 5/25 FC, 2/8 CIN I, and 1/18 CIN II. A similar heterogeneous distribution of HPV types was found in flat condylomas and CIN I. A more homogeneous distribution was noted in the exophytic condylomas and high grade CIN lesions, with HPV 6/11 found in the former and predominantly HPV 16 in the latter. Abnormal mitotic figures were predominantly seen in the high grade CIN lesions. Based on our findings, we would recommend that the term flat condyloma be abandoned and that low grade flat lesions of the cervix be graded according to CIN criteria.

Predicting the outcome of endometrial hyperplasia by quantitative analysis of nuclear features using a linear discriminant function

Nuclear parameters from 24 cases of atypical endometrial hyperplasia were determined by means of graphic tablet and microcomputer. Eight of the 24 hyperplasias progressed to carcinoma, but the remaining 16 did not progress during a mean follow-up period of 11.8 years. A linear discriminant function selected the mean and standard deviation of maximal nuclear diameter as useful predictors of clinical outcome. The linear discriminant function predicted the correct outcome in 83% of the cases. This study suggests that measurement of nuclear parameters in atypical endometrial hyperplasia may provide a more objective means of predicting the behavior of the various forms of hyperplasia.

Papillomavirus infection of the cervix i. Correlation of histology with viral structural antigens and DNA sequences

Eight cervical biopsies showing mild dysplasia and one showing squamous metaplasia were studied for the presence of papillomavirus (PV) antigens using an immunoperoxidase method having immunospecificity against the genus-specific (common) structural antigen(s) and for PV-specific DNA sequences by molecular hybridization under nonstringent conditions. Of the eight cases showing mild dysplasia, both PV antigens and PV DNA sequences were detected in five, PV antigens only in one, and PV DNA sequences only in one; viral antigens and DNA sequences were not detected in the remaining lesion. A characteristic cellular atypia (PV-induced atypia) was present in the superficial and intermediate layers of the epithelium in the six cases positive for viral antigens, and a proliferation of basal and parabasal cells (PV-induced hyperplasia) occurred in five of these. PV structural antigens were localized within nuclei of some of the cells displaying atypia but not in the proliferating cells. The PV-specific DNA sequences in all six cases had the properties of unintegrated PV-DNA. In view of the demonstration of both PV antigens and DNA sequences in this distinctive lesion (PV-induced atypia and/or hyperplasia), traditionally regarded as a form of dysplasia, it is proposed that this lesion be referred to as “papillomavirus infection of the cervix.

Human Papillomavirus: Detection of Viral DNA Sequences and Evidence for Molecular Heterogeneity in Metaplasias and Dysplasias of the Uterine Cervix

Colposcopic-directed biopsies of the uterine cervix from 22 patients were analyzed for the presence of human papillomavirus (HPV) DNA and structural antigens. 11 of the biopsies were classified microscopically as mild dysplasia, 3 as moderate dysplasia, 1 as severe dysplasia, and 7 as squamous metaplasia. Nonstringent hybridization with a bovine papillomavirus type 1 DNA probe and immunocytochemical analysis with an antiserum against papillomavirus genus-specific structural antigens were performed on all specimens. Of the 11 mild dysplasias, both HPV DNA and structural antigens were detected in 5, only HPV antigens in 3, only HPV DNA in 1, and neither DNA nor structural antigens in 2. Both HPV DNA and structural antigens were present in the 3 cases of moderate dysplasia. Only HPV DNA sequences were detected in the single case of severe dysplasia. HPV DNA was detected in 2 cases of squamous metaplasia. The 5 remaining cervical biopsies showing squamous metaplasia, tissue from 3 placentas, and 6 cervical carcinomas were negative for HPV DNA and structural antigens. Restriction enzyme cleavage patterns of HPV DNA in the dysplasias suggested that there are multiple virus types or subtypes associated with cervical dysplasia. Stringent hybridization with a HPV type 11 (HPV-11) probe revealed that only 1 of 10 dysplasias contained sequences with homology to the probe. Of the remaining 9 dysplasias, 5 contained HPV sequences detected under nonstringent hybridization. 2 of 4 squamous metaplasias contained viral sequences which hybridized to the HPV-11 probe as well as 1 of 6 cervical carcinomas.

Papillomavirus infection of the cervix. III: Relationship of the presence of viral structural proteins to the expression of involucrin

Forty-two cervical biopsies with cervical intraepithelial neoplasia were compared with respect to the expression of human papillomavirus (HPV) structural proteins and the expression of the cellular structural protein involucrin, a marker of suprabasal squamous differentiation. HPV structural protein and involucrin expression displayed an inverse correlation with the severity of dysplasia. Both of these proteins were detected in 11 of 28 cases (39%) of mild and moderate dysplasia, but in only two of 14 (14%) cases of severe dysplasia. This difference was statistically significant (p less than 0.001). The presence of HPV was also associated with expression of involucrin in the full thickness of the epithelium, including the basal layer, and an altered staining pattern in the more superficial cells, particularly the koilocytotic cells. These findings support the hypothesis that squamous differentiation is required for the expression of viral structural proteins and that HPV infection begins in the basal epithelium. The study also demonstrates the utility of involucrin staining in differentiating virus-induced cytologic atypia from true neoplasia.