Fu-Shing Liu

Molecular Carcinogenesis of Endometrial Cancer

In 1983, Bokhman proposed a dualistic model of endometrial tumorigenesis based on the clinical observations and clinicopathologic correlations. The majority of endometrial cancers (approximately 70-80%), designated as type I carcinomas, follow the estrogen-related pathway. Histologically, most of the type I tumors seem to arise in the background of hyperplastic endometrium, show an endometrioid differentiation, and are of low grade. Clinically, they are overall characterized by a favorable behavior. Another 10-20% of endometrial cancers, designated as type II carcinomas, follow the estrogen-unrelated pathway and arise in the background of atrophic endometrium. Type II tumors usually occur at an older age, approximately 5-10 years later than type I tumors. They are typically high-grade carcinomas of nonendometrioid differentiation, most frequently serous, less frequently clear cell. Type II carcinomas behave as an aggressive clinical course and poor prognosis. This dualistic model was subsequently supported by the molecular studies, approximately a decade later. At present, endometrioid and serous carcinoma, which represent the major phenotypes of types I and II endometrial carcinomas, respectively, are characterized by distinctive types of genetic instability and molecular alterations. In endometrioid (type I) carcinoma, four major genetic changes are responsible for the tumorigenesis, i.e. silencing of PTEN tumor suppressor gene, presence of microsatellite instability due to alterations of the mismatch repair genes, mutation of K-ras protooncogene, and alteration of beta-catenin gene. On the other hand, p53 mutation and overexpression of Her2/neu oncogene are two major genetic alterations in serous and clear cell (type II) carcinomas. However, like in any model, there is evidence for exceptions. Many endometrial carcinomas are in the gray zone with overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II endometrial cancers. Finally, a small group of endometrial carcinoma is noted to be hereditary. It is known as the most common extracolonic malignancy in hereditary nonpolyposis colorectal cancer (Lynch syndrome), an autosomal dominantly inherited disorder of cancer susceptibility. Inactivation of the mismatch repair genes MSH2 and MSH6 seems to play a central role in the tumorigenesis.

KAI1 Metastasis Suppressor Gene Is Frequently Down-Regulated in Cervical Carcinoma

KAI1 is a metastasis suppressor gene located on human chromosome 11p11.2. It belongs to a structurally distinct family of cell surface glycoproteins. Decreased KAI1 expression has been observed in several common solid epithelial tumors, including prostatic, pancreatic, lung, hepatic, colorectal, ovarian, and esophageal cancers. A recent study also observed frequent loss of KAI1 expression in a number of squamous cell carcinomas of the cervix by immunohistochemical technique. To further confirm whether this gene is altered in this malignancy, we analyzed KAI1 expression in various stages of cervical carcinoma by a molecular method. Total cellular RNA was extracted from 84 primary invasive cervical carcinomas and 6 metastatic or recurrent lesions. cDNA was synthesized and was used for real-time quantitative polymerase chain reaction analysis. The level of KAI1 expression was obtained as the value of threshold cycle (Ct) and was quantitated with a comparative Ct method. In addition, paraffin blocks of the tumors were selected and prepared for immunohistochemical study with an anti-KAI1 polyclonal antibody, C-16. Both the real-time quantitative polymerase chain reaction method and immunohistochemical study revealed a frequent decrease in KAI1 expression in invasive cervical cancers and metastatic or recurrent lesions. However, the reduction in KAI1 was not related to progression of the disease. When tumor cell differentiation was analyzed, poorly differentiated tumors showed a greater decrease in KAI1 expression than well or moderately differentiated tumors (P < 0.001). Histologically, KAI1 loss was observed equally in both squamous cell carcinoma and adeno-/adenosquamous carcinoma. Since down-regulation of KAI1 occurs in both early and late stages of cervical cancer, we suggest that its involvement in the progression of this malignancy is an early event.

Prediction of persistence or recurrence after conization for cervical intraepithelial neoplasia III.

OBJECTIVE: To estimate the predictive factors for persistent/recurrent disease before and after conization for cervical intraepithelial neoplasia III. METHODS: Patients who received conization due to histologic diagnosis of cervical intraepithelial neoplasia III from 1998 to 2000 and who had at least one cytologic/histologic follow-up within one year of conization (n = 449) were enrolled in our study. All available demographic and pathologic parameters were analyzed. RESULTS: We performed multivariable logistic regression analysis to identify predictive factors for cervical intraepithelial neoplasia III persistence/recurrence. Age (greater than 50 years) was the only preoperative predictor and had an odds ratio equaling 3.070 (95% confidence interval [CI] 1.421–6.630, P = .004). Post–cone endocervical curettage was found to be the most statistically significant factor for predicting persistent disease (odds ratio 7.940, 95% CI 3.428–18.390, P < .001). Positive endocervical curettage was associated with 65.5% (36/55) of persistent disease, whereas negative endocervical curettage was associated with only 7.6% (26/342). Positive endocervical resection margins and multiple-quadrant disease also had predictive values with odds ratios equaling 2.972 (95% CI 1.401–6.281, P = .004) and 2.180 (95% CI 1.014–4.689, P = .046), respectively. The positive predictive values for age (> 50 years), positive endocervical curettage, positive endocervical resection margin, and multiple quadrant disease were 31.7%, 65.5%, 40.0%, and 21.9%, respectively. CONCLUSION: We found that age is the only preoperative predictive factor. Pathologic parameters, including endocervical curettage, endocervical resection margins, and multiple-quadrant disease are the only postoperative predictive factors for cervical intraepithelial neoplasia persistence or recurrence found in our study. These factors should be considered in patient management before and after therapeutic conization for cervical intraepithelial neoplasia III. LEVEL OF EVIDENCE: II-3

Transitional cell carcinoma of the ovary.

OBJECTIVE Transitional cell carcinoma (TCC) of the ovary is a rare, recently recognized, subtype of ovarian surface epithelial cancer. We present a case of TCC of the ovary, managed by staging operation and followed by postoperative chemotherapy with carboplatin and cyclophosphamide. CASE REPORT A 67-year-old postmenopausal woman presented with a 2-year history of progressive enlargement of an abdominal mass. Pelvic sonography and abdominal computed tomography showed a pelvic mass measuring 210 x 165 x 203 mm. The serum CA-125 titer was also elevated (65.01 U/mL). A staging operation with total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy and pelvic lymph node dissection was performed. After surgery, the pathologic report of the left ovarian tumor was TCC, grade 2-3, stage IA. The patient then underwent four cycles of postoperative chemotherapy with carboplatin and cyclophosphamide. CA-125 levels declined to within the normal range after the first cycle of chemotherapy. CONCLUSION TCC of the ovary is a rare subtype of epithelial ovarian cancer. It differs from malignant Brenner tumor by the absence of a benign or borderline Brenner component. Surgical resection is the primary therapeutic approach, and patient outcomes after chemotherapy are better than for other types of common epithelial ovarian cancers.

Expression Analysis of Apoptosis-related Markers TP53, BCL-2, BAX and c-MYC in Female Genital Tract Sarcomas

Background: Most female genital tract sarcomas are highly malignant and fatal. Their aggressive growth pattern and poor response to chemotherapy are the major causes of death. Deregulation of the apoptosis pathway is related to tumorigenesis and chemodrug resistance. The purpose of this study was to investigate the expression status and relationship of the apoptosis‐related markers TP53, BCL‐2, BAX and c‐MYC in this group of tumors. In addition, correlations of these markers with clinicopathologic findings and their prognostic significance were also examined. Methods: Paraffin blocks of female genital tract sarcoma tissue from 54 patients were obtained after pathology review. Protein expression of TP53, BCL‐2, BAX and c‐MYC was examined using immunohistochemical staining with standard procedures. A semiquantitative method was used to assess the staining result where scoring 1–3 was negative and 4–9 was positive for expression. The mutual relationships between TP53, BCL‐2, BAX and c‐MYC were examined. Associations between expression of the apoptotic markers and tumor stage as well as outcome were also analyzed. Results: We found that all 4 of the apoptosis‐related markers were frequently expressed in female genital tract sarcomas. Of the 54 cases, 24 (44%) were positive for TP53, 23 (43%) for BCL‐2, 25 (46%) for BAX, and 30 (56%) for c‐MYC. A significant positive association was observed between BAX and c‐MYC (p < 0.001). There was no significant difference for the expression status of the 4 markers in early and late stage tumors. In prognostic analysis, overexpression of TP53, late stage, and age were significant prognostic factors in both univariate and multivariate analyses. Conclusion: Since changes in TP53, BCL‐2, BAX and c‐MYC frequently occur in female genital tract sarcomas, deregulation of apoptosis appears to be involved in the pathogenesis of this group of tumors. This mechanism may occur early in tumorigenesis and include the c‐MYC/BAX apoptotic pathway or BCL‐2. However, TP53 mutation may play a crucial role in this process, and clinically, it could be used as a prognostic indicator.

Loss of Smad4 protein expression occurs infrequently in endometrial carcinomas

Smad4 is a member of the Smad proteins, which are needed for mediating signals of transforming growth factor &bgr; from the cell surface to the nucleus. Smad4 is also a tumor suppressor gene for cancers of the pancreas, colon, and lung. The aim of this study was to investigate the expression and prognostic significance of this gene product in endometrial cancer. Immunohistochemical staining for Smad4 was performed on formalin-fixed, paraffin-embedded specimens of endometrial tumors with an anti-Smad4 monoclonal antibody (clone B8): 97 primary endometrial carcinomas, 20 cases of endometrial hyperplasia, and 26 cases of metastases from endometrial carcinoma. The immunoreactivity of each tumor was correlated with the clinical and histopathologic parameters of the patients. Diffusely positive expression of Smad4 protein was detected in all 20 cases of endometrial hyperplasia and in most of the primary and metastatic endometrial cancers. The frequency of positive expression decreased progressively with tumor grade. Clinically, however, it was not associated with tumor progression, nor did it predict patient outcome. Although loss of heterozygosity at chromosome 18q21 (the location of the Smad4 gene) is frequent in endometrial carcinomas, the authors show in this immunohistochemical study that inactivation of this gene occurs infrequently in this tumor.

Management of Pelvic Lymphocysts by Ultrasound-Guided Aspiration and Minocycline Sclerotherapy

Objective: The purpose of this study was to describe our experience with ultrasound-guided aspiration of postoperative pelvic lymphocysts followed by intracavitary minocycline injection as sclerotherapy. Patients and Methods: From 1997 to 2003, patients who developed either symptomatic or persistent lymphocyst after pelvic lymphadenectomy for gynecological malignancy were recruited in this study. All of the lymphocysts were palpable and were further examined by ultrasonography. Percutaneous ultrasound-guided needle aspiration of the lymphocyst was performed and then immediately followed by a single-dose injection of minocycline into the collapsed cavity. Follow-up was conducted every 4 weeks with pelvic examination and ultrasonography. Results: Nineteen patients with a total of 21 pelvic lymphocysts underwent this procedure. The median size of the lymphocysts was 6 cm in diameter (range, 4–9 cm). Fifteen patients received 1 treatment, 3 received 2, and 1 patient with bilateral lymphocysts received 3 treatments. Complete resolution occurred in 14 patients (74%), and the other 5 patients (26%) had partial resolution with the volume of the lymphocyst decreasing at least 50%. For the 14 patients with complete resolution, the median time from treatment to disappearance of the lymphocyst was 3 months (range, 1–10 months), and none of them developed recurrence during the average follow-up period of 40 months (range, 2–62 months). No significant complication occurred with this procedure except for transient mild to moderate pelvic pain. Discussion: Minocycline sclerotherapy seems to be a simple and safe method with a satisfactory success rate in treating lymphocysts which develop after pelvic lymphadenectomy. It can be performed in an outpatient setting and can be repeated if necessary. This procedure may be considered as the initial treatment modality for patients suffering from symptomatic or persistent lymphocysts after radical gynecological surgery.

Extrauterine Low-Grade Endometrial Stromal Sarcoma

Summary Objective Endometrial stromal sarcoma is a rare cancer that accounts for 0.2% or less of all female genital tract malignancies. We present a case of extrauterine low-grade endometrial stromal sarcoma arising from endometriosis, which was managed by unilateral salpingo-oophorectomy with postoperative high-dose progesterone adjuvant therapy. Case Report A 28-year-old nulligravid woman had suffered from progressive abdominal distension accompanied by a palpable firm mass for about 3 months. An abdominal pelvic mass, measuring 13 × 12 × 8 cm, was seen on pelvic sonography and abdominal computed tomography. The CA125 titer was also elevated. Left salpingo-oophorectomy was performed when frozen section examination of the tumor indicated a benign tumor. However, the pathology of the tumor was extrauterine low-grade endometrial stromal sarcoma with extensive endometrioid glandular differentiation arising from endometriosis. The resection margin was also involved. The patient has been receiving high-dose progesterone therapy for 2 months without any adverse effects, except for an increase in body weight of 2 kg. Conclusions Low-grade endometrial stromal sarcoma typically has an indolent clinical course and favorable prognosis. Surgical resection is the primary therapeutic approach, and adjuvant therapy with radiotherapy, chemotherapy, or progesterone therapy should be considered for the management of residual or recurrent low-grade endometrial stromal sarcomas.