Interstitial thermoradiotherapy in recurrent gynecologic malignancies

In patients with ovarian carcinoma, the presence of metastatic disease in a retroperitoneal lymph node is indicative of a poor prognosis. Although a “staging laparotomy” is required for proper treatment, definitive information concerning para-aortic and pelvic lymph node metastasis often is not available. To determine the incidence of retroperitoneal lymph node metastases in untreated cases of ovarian carcinoma, a prospective study by selective nodal biopsy was undertaken in 61 unselected patients with the following distribution: Stage I, 11; Stage II, 10; Stage III, 31; and Stage IV, 9. The incidence of para-aortic node metastasis overall was 37.7% and of pelvic node metastasis, 14.8%. Of 23 patients with positive para-aortic nodes, 30.4% had no concomitant pelvic node involvement. Direct relationships between nodal metastasis and clinical stage, tumor grade, and histologic type of tumor were demonstrated. The incidence of positive para-aortic nodes in Stage I disease was 18.2%; in Stage II, 20.0%; in Stage III, 41.9%; and in Stage IV, 66.7%. The corresponding incidence of pelvic node metastasis was 9.1% in Stage I, 10.0% in Stage II, 12.9% in Stage III, and 33.3% in Stage IV. Grade 3 tumors were associated most frequently with nodal involvement, with an incidence of positive para-aortic nodes of 52.5% and of positive pelvic nodes of 15.5%. In patients with a serous type of malignancy, the frequencies of positive para-aortic/pelvic nodes were 44.4%/16.7%, respectively; in the undifferentiated type, 50.0%/10.0%; in the clear cell type, 25.0%/25.0%; and in the mucinous type, 14.3%/ 14.3%. In this small series, 32 patients (52.5%) had positive retroperitoneal nodal involvement. It is concluded that selective biopsies of the para-aortic and pelvic lymph nodes should be part of any “staging laparotomy” for ovarian carcinoma, and that the true incidence of nodal involvement in these patients awaits further investigation.     

Lymph node involvement in primary carcinoma of the fallopian tube

Although the bad prognosis of primary fallopian tube carcinoma has been mostly ascribed to early lymphogenous dissemination, precise information regarding the characteristics of retroperitoneal spread are still missing. Our study was designed to evaluate the incidence and clinical significance of lymph node metastases in 33 patients with primary carcinoma of the fallopian tube. During primary surgery nine patients (27%) were submitted to systematic pelvic and para-aortic lymphadenectomy, whereas 24 received lymph node sampling. The clinicopathologic characteristics of the patients (intraperitoneal spread, grading, peritoneal cytology, depth of tubal infiltration and residual disease after primary surgery) were compared with lymphnodal status.
Overall 15 patients (45%) had positive nodes, that is, invaded by tumor; whereas 18 (55%) showed no lymphatic spread. Six patients (40%) had exclusively positive para-aortic lymph nodes; five (33%) had only tumor metastases in pelvic lymph nodes, three (20%) manifested simultaneously pelvic and para-aortic spread, and one patient with pure primary squamous cell carcinoma had a massive groin node metastasis as presenting sign of the tumor. The rate of lymphogenous metastases was not significantly related to progressive intra-abdominal dissemination, histologic grade or depth of tubal infiltration. On the other hand, the presence of residual disease after primary surgery and positive peritoneal cytology significantly increased the risk of nodal metastases. Patients with lymph node metastasis had a significantly ( P = 0.02) worse prognosis compared with patients without nodal involvement (median survival 39 vs 58 months).
Considering the high incidence of lymph node metastasis, correct staging of tubal carcinoma should include a thorough surgical evaluation of both pelvic and para-aortic lymph nodes. The role of systematic lymph node dissection in the treatment of tubal carcinoma remains controversial.     

Retroperitoneal metastatic spread of ovarian cancer

Four patients with ovarian cancer, after chemotherapy or combined immunochemotherapy, were found to have retroperitoneal disease at the time of second-look exploratory laparotomy, even though there was no evidence of intra-abdominal residual cancer. Ovarian cancer can metastasize to both the pelvic and para-aortic lymph nodes, and therefore these areas must be evaluated in order to assess appropriately the true extent of disease in patients with ovarian cancer.     

Use of second-look laparotomy in the management of patients with ovarian epithelial malignancies

Between June 1976 and January 1986, 94 evaluable patients with stage I-IV disease underwent second-look laparotomy as part of their treatment for ovarian epithelial carcinomas. Stage and residual tumor size after initial debulking surgery demonstrated a significant association with absence of disease at reexploration. Forty-nine patients (52%) had no evidence of disease at second-look laparotomy. Thirty patients (32%) had macroscopic residual tumor, and 15 patients (16%) had microscopic disease at reexploration. Patients with a negative second-look laparotomy had an excellent prognosis; uncorrected 2- and 5-year survival rates exceed 90%. None of the patients with stage I or II disease developed recurrent tumor after a negative second-look laparotomy. However, 7 of the 25 (28%) patients with stage III disease and a negative second-look have demonstrated recurrent carcinomas. Recurrences were documented from 15.4 to 51.7 months after second-look laparotomy and were located within the abdominal cavity. Life table methods demonstrated improved survival for patients with microscopic disease as compared to those with gross tumor at second-look survey. Both groups had similar mean patient ages and tumor stage distributions. Patients with microscopic residual disease had uncorrected 2- and 5-year survival rates of 76 and 64%. The 2-year uncorrected survival rate for patients with gross tumor at second-look laparotomy was 25%. Thirty patients with macroscopic disease at second-look laparotomy underwent a repeat attempt at tumor debulking. Seventeen patients completed second-look surgery with residual disease less than 1 cm in maximum dimensions. Life table methods demonstrated improved survival when residual disease was less than 1 cm. Regardless of residual tumor size after reexploration, patients with gross tumor had a worse survival than those with microscopic disease.     

Uterine sarcoma: an analysis of 74 cases

In order to determine whether recent methods of diagnosis and treatment have resulted in an improved survival for patients with uterine sarcoma, we reviewed 99 cases treated in our center from 1970-1985. Morphologic characteristics of 74 tumors were specifically reassessed for this study. All tumors were graded. Of 42 Stage I cases that were morphologically assessed, tumor-positive pelvic lymph nodes were found in two of the 15 patients in whom sampling was done. No cases of tumor-positive para-aortic nodes were found in 14 patients with Stage I disease. In Stage I and Stage II, no cases of positive para-aortic nodes were found in association with negative pelvic nodes. The 2- and 5-year survival rates in Stage I were 47.4% and 29.4%, respectively. Local recurrence decreased (p less than 0.01) in Stage I from nine of 22 cases in which operation alone was performed to none of 15 cases in which pelvic radiotherapy was added, but no improvement in the 5-year survival rate was observed. As with lymphadenectomy and radiotherapy, the recent use of chemotherapy for uterine sarcoma had no impact on survival.     

Influence of secondary cytoreduction at the time of second-look laparotomy on the survival of patients with epithelial ovarian carcinoma

The value of secondary cytoreductive surgery at the time of second-look laparotomy in patients with epithelial ovarian carcinoma is not established. Sixty-seven patients with residual carcinoma found at the time of second-look laparotomy performed at Memorial Sloan-Kettering Cancer Center between December 1, 1978, and May 30, 1986, were evaluated for survival relative to the success of secondary cytoreductive surgery. At second-look laparotomy, 17 patients had microscopic disease, 28 patients had disease less than 2 cm and 22 patients had disease greater than 2 cm. After secondary cytoreductive surgery 33 patients had microscopic disease, 26 patients had disease less than 2 cm, and 7 patients had disease greater than 2 cm (1 unknown). Five-year survival by Kaplan-Meier calculation was 62% for patients found to have microscopic disease at second-look laparotomy and 51% for patients whose disease was rendered microscopic by secondary cytoreductive surgery (P = 0.55). Patients left with gross disease (either less than or greater than 2 cm) had 5-year survivals of less than 10% (P = 0.013 compared with microscopic residual). Secondary cytoreductive surgery at the time of second-look laparotomy in patients with epithelial ovarian carcinoma may result in improved survival of patients who are reduced to microscopic residual disease.     

Platinum-Based Chemotherapy for Advanced-Stage Serous Ovarian Carcinoma of Low Malignant Potential

Purpose: To evaluate the effect of platinum-based chemotherapy on tumor response in patients with advanced-stage serous ovarian carcinoma of low malignant potential. Patients and methods: We conducted a retrospective review of hospital records, pathology slides, and office charts of patients identified as having Stage III or IV serous ovarian cancer of low malignant potential. Results: Between November 1979 and April 1993, 21 patients with advanced-stage serous ovarian carcinoma of low malignant potential received platinum-based chemotherapy following initial cytoreductive surgery. The amount of residual disease was recorded in 20 patients; 8 (40%) had macroscopic residual tumor <2 cm in largest diameter, and 12 (60%) had only microscopic disease. Sixteen patients underwent a second-look laparotomy following chemotherapy; 10 (62.5%) had no evidence of disease, 1 (6%) had a partial response, 2 (12.5%) had stable disease, and 3 (19%) had progressive disease. During a mean follow-up of 64 months, only 1 patient had died of disease. She had progressive disease noted at second-look laparotomy. Five of 6 patients who did not have a complete response to initial chemotherapy underwent further therapy with oral etoposide (1), intraperitoneal platinum (2), intraperitoneal mitoxantrone (1), or both (1). The sixth patient received no further therapy. Three of the patients subsequently receiving salvage intraperitoneal therapy underwent a third-look laparotomy. Two had partial responses noted, while the third patient had stable disease. Conclusions: Platinum-based chemotherapy is effective in achieving surgically documented responses in patients with advanced-stage serous ovarian tumors of low malignant potential. The benefit of this therapy in improving survival is unproven.     

The prognostic implications of low serum CA 125 levels prior to the second-look operation for stage III and IV epithelial ovarian cancer.

Second-look laparotomy is performed to evaluate response to chemotherapy and to determine the need for additional treatment. The relationship between absolute levels of serum CA 125 less than 35 u/ml and disease status at second-look operation was evaluated in 95 patients with advanced-stage epithelial ovarian cancer. Eighty-six patients had Stage III disease and nine patients had Stage IV cancer. Residual tumor was documented at second-look laparotomy in 52 (55%) of the patients studied. Forty-nine percent of the 82 patients with serum CA 125 values less than 20 u/ml had residual disease. In contrast, 12 of 13 (92%) patients with serum CA 125 values of 20-35 u/ml had residual tumor at second-look laparotomy. All patients with serous cystadenocarcinomas and serum CA 125 values of 20-35 u/ml had residual tumor, and two-thirds of these cases had grossly visible disease. The positive predictive value of a serum CA 125 level of 20-35 u/ml was 0.92. These data suggest that second-look laparotomy should be deferred in patients with advanced-stage ovarian cancer until serum CA 125 values are less than 20 u/ml.     

Prognostic significance of morphology of tumor and retroperitoneal lymph nodes in epithelial carcinoma of the ovary: I. Correlation with lymph node metastasis

The prognostic indices based on a morphologic study of tumor and retroperitoneal lymph nodes in 63 patients with epithelial carcinoma of the ovary are reported. The purpose of the study was to identify those variables most frequently related to nodal involvement. The cases in the series consisted of 11 Stage I, 10 Stage II, 34 Stage III, and 8 Stage IV. Histologic distribution was 60.4% serous type, 11.1% mucinous, 6.3% endometrioid, 6.3% clear cell and 15.9% unclassified. All patients had maximal surgery and selective biopsy of para-aortic and pelvic lymph nodes. The results showed statistically significant variables associated with nodal metastasis in both primary tumor and regional lymph nodes. The indices in primary tumor were grade of tumor, vascular invasion, lymphocytic infiltration, and stromal fibrosis; those in lymph node were type of lymph node reaction, sinus histiocytosis, and fibroblastic proliferation. The nodes with lymphocyte depletion were associated with nodal spread in 81.3% of cases. It is concluded that morphologic study of tumor and lymph node could identify prognostic factors predicting regional nodal metastasis in ovarian carcinoma.     

Survival of patients with ovarian epithelial carcinomas after second-look laparotomy

Survival of ovarian carcinoma patients undergoing second-look laparotomy after primary surgery and adjunctive chemotherapy was evaluated by retrospective chart review. From August 1976 to August 1987, 102 patients with stage I-IV disease underwent second-look laparotomy. Optimal tumor debulking and early (stage I or II) disease were positively correlated with a negative second-look laparotomy. Of the 49 patients with a "negative" second look, 15 demonstrated recurrent tumor from 12.5 to 52.5 months after laparotomy. Of the 15 recurrences, 6 were documented more than 3 years following second look. Half of the 28 patients with stage III disease and a "negative" second look have demonstrated recurrent tumor. Fifty-three patients (52%) were found to have residual disease at second-look laparotomy. Initial chemotherapy (melphalan or multiple agent) and the adequacy of primary debulking surgery (optimal vs suboptimal) were not significant factors contributing to patient survival after a positive second look. However, the size of residual disease at second-look laparotomy was a significant factor in subsequent patient survival (P less than or equal to 0.01). Fifteen patients were free of gross disease at laparotomy, but had residual tumor on microscopic examination of the specimens submitted. These patients had a 2-year actuarial survival of 78%. Forty-seven percent have survived 5 or more years after second look. Nineteen patients with tumor implants 2 cm or smaller had 2- and 5-year actuarial survivals of 61 and 31%, respectively. Nineteen patients with tumor nodules larger than 2 cm in diameter had a 2-year actuarial survival of 6%. Only 1 of 19 patients with nodules greater than 2 cm could be effectively redebulked.     

Prognostic significance of morphology of tumor and retroperitoneal lymph nodes in epithelial carcinoma of the ovary: II. Correlation with survival

Correlation between prognostic indices derived from morphologic studies of retroperitoneal lymph nodes as well as primary tumor and survival in 39 patients with epithelial carcinoma of the ovary is reported. All had maximal surgery, adjuvant chemotherapy, and were followed for more than 2 years. A selective biopsy of pelvic and para-aortic lymph nodes was performed during the staging laparotomy in all instances. The chemotherapeutic regimen was a combination of Adriamycin, cis-platinum, and Cytoxan in a majority of cases.Prognostic indices, which showed positive correlation with survival, were cancer involvement, type of lymph node reaction, sinus histiocytosis, and fibroblastic proliferation in the regional lymph nodes; tumor grade, lymphocytic infiltration, stromal fibrosis, and histologic type in primary tumor; and stage of disease. Unfavorable factors for survival were nodal metastasis, lymphocytic depletion in abdominal nodes, and Grade 3 tumor. Clinical implications of our findings are discussed.     

Lymph node metastasis in stage I epithelial ovarian cancer

OBJECTIVES: A relatively high incidence of para-aortic and pelvic lymph node metastasis is found in epithelial ovarian cancer. This paper investigates the clinicomorphological features of intra-abdominal stage I epithelial ovarian cancer that may predict the occurrence of lymph node metastasis and the prognosis of patients in whom lymph node metastases are identified. METHODS: From November 1988 to December 1997 we performed systematic para-aortic and pelvic lymphadenectomy as primary surgery in 47 patients with intra-abdominal stage I epithelial ovarian cancer. The incidence of lymph node metastasis in these patients and the clinicomorphological features of the patients with lymph node involvement were examined. RESULTS: Five patients (10.6%) were metastasis positive (IC: four; IA: one), of whom four had serous adenocarcinoma. Serous adenocarcinoma was associated with a significantly higher incidence of metastases than other histological types (P < 0.05). The number of positive lymph nodes was one in four patients and two in one patient, and the metastatic sites ranged from the para-aortic to the suprainguinal lymph nodes. All five metastasis-positive patients were alive and disease free at the time of this report (survival 28-85 months: median 59 months). CONCLUSION: This clinical study suggests that serous adenocarcinoma carries a high risk of lymph node metastasis, requiring systematic lymphadenectomy for accurate staging in intra-abdominal stage I epithelial ovarian cancer.     

Prognostic factors for outcome of and survival after second-look laparotomy in patients with advanced ovarian carcinoma

In ovarian cancer stages IIB-IV, pre-treatment variables and variables obtained intraoperatively at second-look laparotomy were investigated for their prognostic influence on the outcome of 109 patients and survival after second-look laparotomy in 131 patients. The subjects came from a randomized trial of sequential versus alternating combination chemotherapy. The overall median survival after second-look laparotomy was 62 months. Logistic regression analysis identified stage and hysterectomy plus bilateral salpingo-oophorectomy and omentectomy as significant prognostic covariates for second-look laparotomy outcome. Based on a Cox multivariate stepwise analysis, independent prognostic factors for survival after second-look laparotomy were secondary residual tumor size, pre-treatment histologic differentiation grade, and performance status. A high differentiation grade and a good performance status at the start of therapy thus still had a prolonging effect on survival after second-look laparotomy. The prognostic power of these pre-treatment variables was increased substantially by the addition of the secondary residual tumor size variable. The 3-year survival rate after second-look laparotomy for high- and low-risk patients was 15 and 87%, respectively. Second-look laparotomy thus provides prognostic information in patients with advanced ovarian carcinoma, but the benefit in terms of survival is still unclear.     

化疗对晚期卵巢、输卵管及腹膜浆液性癌淋巴结转移的临床疗效(附70例临床分析)

目的:探讨化疗对晚期卵巢、输卵管及腹膜浆液性癌腹膜后淋巴结转移的临床疗效。方法:将晚期卵巢、输卵管及腹膜浆液性癌70例患者,根据淋巴结切除术与化疗的先后顺序分为2组:A组21例,化疗后行淋巴结切除术。B组49例,淋巴结切除术后化疗。比较2组患者的一般情况、治疗方案及淋巴结转移情况。结果:2组患者的年龄,肿瘤分期分级,治疗前的肿瘤标记物,切除淋巴结的数量等均无显著性差异(P>0.05)。初治时A组患者盆腹腔黏连及转移重于B组;初次手术A组进行满意的肿瘤细胞减灭术的几率明显低于B组(0%vs73.47%,P<0.05)。化疗后A组患者淋巴结转移率低于B组(38.10%vs49.00%,P>0.05),腹主动脉旁淋巴结为肿瘤最常侵犯的淋巴结。A组行TC(泰素/紫杉醇+伯尔定/卡铂)或TP(泰素/紫杉醇+顺铂)方案化疗的患者淋巴转移率低于行CAP(顺铂+阿霉素+环磷酰胺)方案的患者(33.33%vs50%,P=0.045)。结论:化疗对卵巢、输卵管及腹膜浆液性癌淋巴结转移有一定的疗效。初治时不能进行淋巴结切除的患者可考虑先行化疗后再次手术切除淋巴结。     

The value of second-look operation in patients with advanced epithelial ovarian carcinoma

Summary A second-look operation was performed on 151 patients with stage III and IV epithelial ovarian carcinoma who had responded to primary surgery and chemotherapy. 19% of the 79 patients who appeared clinically to be free of disease had microscopic recurrences and 23% had macroscopic residual disease at a second-look operation. The 5-year survival rate for patients with no histological and for those with microscopic secondaries at second-look operation were 55% and 35% respectively (P=0.45). Only patients with well or moderately well differentiated tumors and a small residual tumor mass at first operation had a good prognosis after a second-look operation even without further chemotherapy. Median survival after secondary debulking was 15 to 17 months and was independent in the radicality of the second-look procedure. Outside of clinical trials second-look laparotomy should therefore only be performed as a diagnostic procedured as a diagnostic procedure in patients with well or moderately well differentiated tumors who are left with a small residual tumor mass at the time of the first operation. Because this is a group of patients in whom chemotherapy can be discontinued after a negative second-look operation.     

Role of "third-look" laparotomy in the guidance of ovarian cancer treatment

Twenty-seven patients with Stage III epithelial ovarian carcinoma received a "third-look" celiotomy. Each patient received a minimum of an additional 12 courses of chemotherapy after persistent tumor had been documented at a "second-look" procedure. Twelve of the twenty-seven patients have died. No tumor-associated deaths occurred in patients with grade 1 neoplasms. Of the patients with microscopic disease at the second-look procedure who came to third-look laparotomy, none had died secondary to tumor growth. The survival time of patients with microscopic disease at third-look is greater than that of patients with macroscopic disease (P = 0.0009). In patients who had effective tumor reductive surgery performed at second-look, the third-look findings were highly predictive as to survival. Long-term chemotherapy had a significant incidence of related mortality. Four of the twenty-seven patients died as a direct result of the chemotherapeutic toxicity. The patients receiving melphalan for at least 24 courses appeared to be at greatest risk, with 23% dying from either aplastic bone marrow changes or leukemia. The morbidity associated with third-look laparotomy was not excessive. Many factors need careful review prior to planning a third-look laparotomy. This retrospective study demonstrates that patients with either a grade 1 neoplasm or only microscopic disease at the second-look procedure do well regardless of the third-look findings.     

Use of CA 125 to monitor patients with ovarian epithelial carcinomas

The CA 125 radioimmunoassay has been increasingly used to monitor the course of patients with ovarian epithelial carcinomas. The purpose of this report is to describe our experience in the use of this assay and to better define its clinical utility. Fifty-one patients had serum CA 125 follow-up during primary chemotherapy. All 51 patients demonstrated either a normal CA 125 level at the completion of chemotherapy or a substantial fall in CA 125 values with treatment. In 48 of 51 patients, the drop in CA 125 levels was temporally related to the clinical regression or remission of tumor. Forty of these patients underwent second-look laparotomy; 23 patients (58%) had residual disease. A total of 45 patients had serum CA 125 determinations at the time of second-look laparotomy. Eight patients with microscopic disease and 11 of 18 patients with gross residual disease had a "negative" (less than 35 U/ml) CA 125 level. The predictive value of an elevated CA 125 level was 1.00. However, the predictive value of a negative value was only 0.50. Hence, a negative CA 125 level cannot be a substitute for a second-look laparotomy. Only 7 of 18 patients (39%) with gross residual disease at second-look surgery had an elevated CA 125 level. Patients with an elevated CA 125 and gross residual tumor at the second-look laparotomy uniformly demonstrated large, bulky disease. Furthermore, the survival of patients with gross residual disease at second-look laparotomy correlated with the preoperative CA 125 value. Serum CA 125 determinations also show promise in the follow-up of patients with a negative second-look laparotomy. The serum CA 125 level from patients with a "negative" second-look laparotomy can become elevated months before recurrent disease is appreciated.     

Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer

One hundred eighty patients with ovarian cancer underwent complete pelvic lymphadenectomy (n = 75) or pelvic and paraaortic lymphadenectomy (n = 105). Twenty-one patients underwent a preoperative biopsy of the scalene lymph nodes. The incidence of positive lymph nodes was 24% in stage I (n = 37), 50% in stage II (n = 14), 74% in stage III (n = 114), and 73% in stage IV (n = 15). Of the 105 patients who underwent pelvic and paraaortic lymphadenectomy, 13 (12%) had positive pelvic and negative paraaortic nodes and 10 (9%) had positive paraaortic and negative pelvic nodes. Positive scalene nodes were found in four patients (19%) later shown to have stage IV disease. One hundred forty patients were studied for number of involved nodes and node groups, size of nodal metastases, residual tumor, and survival. Of the 81 patients with positive nodes, most had only one or two positive node groups or one to three positive individual nodes. A few patients had seven to eight involved node groups with up to 44 positive nodes. Greater numbers of positive nodes were found in stage III than stage IV. The size of the largest nodal metastasis was not related to the clinical stage or survival, but did correlate with the number of positive nodes. Stage III patients with no residual tumor had a significantly lower rate of lymph node involvement than those with tumor residual (P less than 0.01). Actuarial 5-year survival rates of patients with stage III disease and no, one, or more than one positive nodes were 69, 58, and 28%, respectively.     

Whole abdominal and pelvic irradiation in patients with minimal disease at second-look surgical reassessment for ovarian carcinoma

Aggressive cytoreductive surgery followed by combination chemotherapy for stage III ovarian carcinoma has resulted in a significant percentage of complete clinical responses. However, 30-50% of patients with no clinical evidence of disease are found to have residual carcinoma at second-look surgical reassessment. Because recent reports have indicated a high degree of effectiveness utilizing abdominal and pelvic irradiation as primary therapy for ovarian carcinoma with small residual disease, the authors treated eight patients found to have residual disease of less than 1 cm at second-look reassessment with either open field or split field abdominal and pelvic irradiation. All eight patients had initially undergone aggressive cytoreductive surgery and seven of the eight patients had received multidrug chemotherapy. Patients were treated either at the National Cancer Institute or the Naval Hospital Bethesda both with and without intraperitoneal radiation sensitizers. Fifty percent of the patients required early termination of therapy due to myelosuppression. All eight patients have recurred and three have died. Six of the eight patients have required major surgical procedures for gastrointestinal complications. Based on this experience, we cannot advocate this form of therapy in patients with minimal residual ovarian carcinoma following second-look surgical reassessment.