Yao S. Fu

Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva☆

One hundred and thirty-five patients with squamous carcinoma of the vulva were treated at UCLA and City of Hope Medical Centers between 1957 and 1985. Sixty-two cases were stage I, 48 stage II, 18 stage III, and 7 stage IV. Twenty-one patients developed a local vulvar recurrence after primary radical resection. Ninety-one patients had a surgical tumor-free margin greater than or equal to 8 mm on tissue section and none had a local vulvar recurrence. Forty-four patients had a margin less than 8 mm; 21 had a local recurrence and 23 did not (P less than 0.0001). Of the 23 patients with a margin less than 8 mm who did not recur locally, 14 remained free of disease, and 9 had either advanced disease, declining health, or short follow-up. Depth of invasion is associated with local recurrence, with a 9.1-mm reference value correctly predicting outcome in 81.5% of cases. Increasing tumor thickness is associated with local recurrence, with a 10-mm reference value predictive of 90% non-recurrence and 33% recurrences. A pushing border pattern is less likely to recur than an infiltrative growth pattern. Lymph-vascular space invasion has a combined predictive accuracy of 81.5%. Increasing keratin and greater than 10 mitoses per 10 high-power fields correlate with local recurrence. Neither clinical tumor size nor coexisting benign vulvar pathology correlates with local recurrence. Fourteen of twenty-one patients with vulvar recurrence died of metastatic disease, four died of intercurrent disease, and three were alive at 32, 68, and 157 months, with 16 recurring in less than 1 year. Surgical margin is the most powerful predictor of local vulvar recurrence. Combining factors in a stepwise logistical regression does not significantly improve this predictive value. Accounting for specimen preparation and fixation, a 1-cm tumor-free surgical margin on the vulva results in a high rate of local control, whereas a margin less than 8 mm is associated with a 50% chance of recurrence.

Definition of precursors

Abstract In this retrospective study of 100 cases of cervical intraepithelial abnormalities, the nuclear DNA content was correlated with the histologic findings and follow-up data. All cases had initial biopsies and were followed for more than a year with cytologie and/or histologic examinations. Of the 34 cases having a subsequent normal follow-up, 29 (85%) had a euploid or polyploid pattern and 5 (15%) had an aneuploid distribution. Of the 58 cases persisting as cervical intraepithelial neoplasia (CIN), 3 (5%) had a polyploid pattern and 55 (95%) had an aneuploid distribution. Of the 8 cases which progressed to invasive carcinomas, all had an aneuploid pattern. These findings suggest that euploid or polyploid lesions are more likely to have normal follow-up studies (91%) and rarely persist (9%). Of the aneuploid lesions, 81% persisted as CIN, 12% progressed to invasive carcinoma, and 7% had a normal follow-up. The presence of abnormal mitoses was the most reliable histologic criterion for aneuploidy. By using nuclear DNA analysis and histologic features, as defined in this study, it is possible to distinguish aneuploid precursors from less significant euploid or polyploid lesions.

Squamous papillary neoplasia of the adult upper aerodigestive tract

Selected papillary squamous tumors of the upper aerodigestive tract (UADT) mucosa in adult patients do not have well-defined histologic criteria and the clinical behavior is poorly understood. To better characterize this spectrum of neoplasms, UADT papillary neoplasms were evaluated by routine histology, determination of cellular DNA content using Feulgen-stained tissue sections, and the typing of human papillomavirus (HPV) by in situ hybridization. Solitary papillomas were studied in two patients; there was no recurrence in either case, both had normal DNA content, and one was typed as HPV-6 while the other was typed as HPV-11. Seven adult patients with recurrent papillomatosis and at least one biopsy with dysplasia/atypia were identified (mean age at diagnosis, 13.3 years; mean age at last contact, 42.7 years). Six of seven patients had abnormal DNA cellular content in foci of epithelial atypia. In all biopsies evaluated, the papillomas of the seven patients were consistently typed as either HPV-6 or HPV-11. Six patients with malignant papillary neoplasms also had abnormal DNA cellular content, but none revealed evidence of HPV type 6, 11, 16, or 18 by in situ hybridization of tissue sections. In many of the recurrent papillomas, the degree of epithelial atypia encountered was pronounced and was commonly misdiagnosed as carcinoma in situ or papillary carcinoma. The aneuploid DNA content of these foci of atypia reflected the abnormal cellular appearance and partially explained the overdiagnosis of malignancy. However, none of the seven patients were treated for malignant disease and none progressed to invasive carcinoma, with an average follow-up period of almost 30 years. We conclude that histologic and cytologic atypia in HPV-containing papillomatosis may be appreciable. The aneuploid DNA content may represent premalignant conditions and the patient may be at an increased risk for the subsequent development of squamous cancer. However, none of the seven patients with recurrent papillomatosis developed any evidence of malignancy. In addition, none of the patients with papillary carcinomas had previous recurrent papillomatosis.

Chondrosarcoma of the head and neck. The UCLA experience, 1955-1988.

Chondrosarcoma of the head and neck is a rare tumor. In an attempt to clarify optimal treatment of these lesions, we reviewed the records and pathologic material of 18 consecutive cases of head and neck chondrosarcoma seen at our institution between 1955 and 1988. Follow-up ranged from 3 to 168 months with a median of 72. Absolute 5-year survival was 68% (11/16), with 9/16 (56%) patients surviving disease-free. Grade was the most important prognostic factor. Only one of 7 (14%) patients known to have high grade histology was rendered disease-free, as opposed to 9/10 (90%) with low-grade lesions. Tumor size and completeness of surgical resection were also important prognostic factors. Four of 10 patients managed initially with surgery alone achieved local control with greater than 5-year survival. All four had low-grade lesions. Five patients received surgery and radiation as primary treatment, and three are disease-free with greater than 5-year follow-up. Two of these were irradiated because of positive margins. One patient received radiation alone and has persistent disease. Two patients received combined chemotherapy and surgery because of high-grade lesions, and one is free of disease with greater than 5-year follow-up. Patients with incomplete resections should receive further surgery or postoperative radiation therapy. High-grade lesions should be treated aggressively.

Intraepithelial squamous lesions of the vulva: Biologic and histologic criteria for the distinction of condylomas from vulvar intraepithelial neoplasia

We reviewed 65 intraepithelial lesions of the vulva and distal vagina and compared the presence of koilocytosis, abnormal mitoses, and parabasal or basal nuclear enlargement with DNA microspectrophotometric distribution patterns and the presence of human papillomavirus antigen as determined by immunoperoxidase. Abnormal mitoses and cytologically atypical nuclear enlargement were specific predictors of aneuploidy and were reliable for distinguishing vulvar intraepithelial neoplasia (VIN) from condylomas. Koilocytosis was present in 100% of condylomas and 71% of aneuploid (VIN) lesions, but there were qualitative and quantitative differences in the distribution of koilocytic cells in the two classes of lesions. On the basis of these findings, criteria for distinguishing between VIN and condyloma are proposed.

Adenocarcinoma and mixed carcinoma of the uterine cervix: I. A clinicopathologic study

Ninety-two primary glandular neoplasms of the uterine cervix, including 51 endocervical adenocarcinomas, four endometrioid carcinomas, and 37 mixed carcinomas, were reviewed to define the biologic significance of pathologic features. Pure adenocarcinomas were found to have a better prognosis from mixed carcinomas of comparable stage (overall five-year survival rate, 49 vs. 36%). Endocervical adenocarcinomas with glandular and papillary patterns had a better prognosis than mucinous adenocarcinomas. When mixed carcinomas were separated into mature, signet-ring, and glassy-cell types, patients with the glassy-cell type had a better five-year survival rate than patients with the other types. However, the long-term prognosis was equally poor. The degree of differentiation as determined by the nuclear features was useful in predicting the outcome in patients with adenocarcinomas. Although the number of cases was small, combined surgery and radiotherapy achieved the best long-term survival for patients with pure adenocarcinomas. This was less apparent for mixed carcinomas.

Postirradiation sarcoma of the gynecologic tract : a report of 13 cases and a discussion of the risk of radiation-induced gynecologic malignancies

With improvement in survival after cancer treatment, it is becoming increasingly important to examine treatment-related morbidity and mortality. Sarcomas can develop within the irradiated field after radiation therapy (RT) for gynecologic malignancies. We undertook a study to assess the outcome after treatment of postirradiation sarcoma (PIS) of the gynecologic tract. In reviewing our data and the literature, we compare the absolute risk of PIS and other radiation-associated second malignant neoplasms (SMNs) with the mortality risk of surgery and general anesthesia. Between 1955 and 1987, 114 patients with uterine sarcomas were seen at the University of California, Los Angeles (UCLA), Medical Center. Thirteen had a prior history of RT. Conditions for which these patients received RT included choriocarcinoma (one), menorraghia (four), cervical cancer (six), and ovarian cancer (two). RT doses were known in six cases and ranged from 4,000 to 8,000 cGy. Latency time from RT to the development of PIS ranged from 3 to 30 years, with a median of 17 years. Twelve patients were treated with surgery or additional RT. Two patients remain alive 5 months and 57 months, respectively, following salvage therapy. Five-year disease-specific survival for all patients is 17%. From our data and a review of the literature, we estimate that the absolute risk of PIS with long-term follow-up ranges from 0.03 to 0.8%. Postirradiation sarcoma of the gynecologic tract is a relatively rate event associated with a poor prognosis. Mortality risks of radiation-associated SMN are similar to mortality risks of surgery and general anesthesia. Given the large number of patients with gynecologic malignancies who can be cured or palliated with RT, concern regarding radiation sarcomagenesis should not be a major factor influencing treatment decisions.

Histologic, nuclear DNA, and human papillomavirus studies of cervical condylomas

Fifty‐four cervical condylomatous lesions, with and without nuclear atypia, from 42 women, were studied with the Feulgen microspectrophotometric technique for nuclear DNA quantitation and an immunoperoxidase technique for human papillomavirus (HPV) antigen. All ordinary cervical condylomas (without atypia/dysplasia) had a diploid or polyploid nuclear DNA distribution; 61% had detectable HPV antigen. Among the cervical condylomas with atypia/dysplasia, 55% (17/31) had diploid or polyploid nuclear DNA pattern, and, of these, 59% (10/17) had demonstrable papillomavirus antigen. Fourteen (45%) were aneuploid lesions, 2 of which had a small number of cells with papillomavirus antigen (14%). These findings suggest that the majority of cervical condylomas are related to papillomavirus infection. That lesions with dysplasia, including high degrees of dysplasia, may also exhibit coexistence of papillomavirus infection suggests the possibility of an infectious etiology in the genesis of cervical squamous neoplasia.

Risk factors for the development of lymph node metastasis in vulvar squamous cell carcinoma

One hundred and ten women who underwent vulvectomy and inguinal-femoral lymphadenectomy for stages I-IV vulvar squamous cell carcinoma were studied. The most important factors that affected the inguinal lymph node status in the order of importance were vascular invasion, clinical stage, tumor thickness, depth of stromal invasion, and amount of keratin. Fourteen (88%) of 16 tumors with vascular invasion in the primary tumor metastasized. In the absence of vascular invasion, 18 (19%) of 94 tumors metastasized. Overall, 82% of tumors were correctly classified into lymph node negative and positive groups on the basis of vascular invasion. Tumor thickness and depth of stromal invasion had a similar accuracy in predicting lymph node status. The risk of lymph node metastasis increased from 0% when tumor thickness or depth of stromal invasion was less than 2 mm, to over 20% when depth of stromal invasion was greater than 2 mm, and to over 40% when tumor thickness exceeded 4 mm. A combination of vascular invasion, tumor thickness (or depth of stromal invasion), and the amount of keratin correctly classified 97% (76/78) of the lymph node negative group and 63% (20/32) of the positive group with an overall accuracy of 87%. The probability of having lymph node metastasis was computed for individual patients on the basis of one or more pathologic parameters using a logistic regression model. This feasibility is an important step toward individualized therapy for vulvar carcinoma.

Vulvovaginal melanoma: report of seven cases and literature review.

Five cases of primary vaginal melanoma were treated at UCLA Medical Center between 1976 and 1986. Two additional cases of melanoma arising at the junction of the vulva and vagina are presented. One of seven (13%) patients is alive, with a median time to recurrence of 7 months, and median survival of 31 months. Four of five vaginal melanomas were located in the distal vagina, and all were advanced at diagnosis (greater than 3 mm depth). Mean size was 3 cm. Initial therapy was local excision in four patients and radical surgery in three. All patients had suboptimal surgical margins: two vaginal primaries had positive margins after local excision, both recurred vaginally within 5 months. Two patients had margins less than 1 mm, one died of distant metastases, the other is alive with disease 30 months after radical distal vaginectomy and hemivulvectomy with post-op pelvic radiotherapy. Three patients had melanoma in situ at the surgical margins, and each had pelvic recurrences between 6 and 26 months. Five of seven cases developed local recurrence as the initial site of treatment failure. All five vaginal cases ultimately developed distant disease, but only two patients had distant disease without local-regional recurrence. Chemotherapy and immunotherapy enabled disease stabilization in three patients. The vulvovaginal junction at the introitus is a high risk site for vaginal and vulvar melanoma. Intraoperative management requires assessment of lateral and deep spread of invasive and in situ melanoma.