Charles A. Amezcua

The proto-oncogene c-kit is expressed in leiomyosarcomas of the uterus.

OBJECTIVE The proto-oncogene c-kit encodes for a 145-kDa transmembrane tyrosine kinase receptor. Interaction with its ligand, stem cell factor, is essential in the development of hematopoietic stem cells, mast cells, gametocytes, melanocytes, and interstitial cells of Cajal. C-kit expression has been identified in a number of different neoplasms that includes mastocytosis/mast cell leukemia, acute myeloblastic leukemia, seminoma/dysgerminoma, and gastrointestinal stromal tumors. This study examines c-kit expression in uterine endometrial stromal sarcomas, leiomyomas, and leiomyosarcomas using immunohistochemistry. METHODS Archival tissue from 38 patients with the uterine mesenchymal tumors (16 leiomyosarcomas, 8 leiomyomas, 11 low-grade endometrial stromal sarcomas, and 3 high-grade endometrial stromal sarcomas) was stained with polyclonal antibody for c-kit. Modified avidin biotin (ABC) immunoperoxidase method was employed for antibody detection. Individual tumors were considered positive if more than 10% of the cells comprising the neoplasm displayed immunoreactive staining. Staining intensity was graded 1+ to 3+ and distribution graded as focal (10-30% of the cells), intermediate (30-60% of the cells), or diffuse (>60% of the cells). RESULTS C-kit was positive in 12 (75%) of the 16 leiomyosarcomas. The staining was 3+ and diffuse in the majority of the positive tumors. C-kit expression was not detected in any of the 8 leiomyomas. Two of the 3 high-grade endometrial stromal sarcomas displayed c-kit positivity. Staining was diffuse and 3+ in both of these tumors. Expression of c-kit was observed in only 3 of the 11 low-grade endometrial stromal sarcomas. CONCLUSIONS C-kit is expressed in uterine leiomyosarcomas and endometrial stromal sarcomas. Adjunctive diagnostic studies using c-kit may be useful in distinguishing leiomyosarcomas from benign leiomyomas in uterine tumors that offer uncharacteristic features. Furthermore, studies should investigate the prospect of treating these malignant tumors with tyrosine kinase inhibitors.

Identification of micrometastases in histologically negative lymph nodes of early-stage cervical cancer patients.

OBJECTIVE: Despite histologically negative lymph nodes, approximately 15% of patients with early-stage cervical cancer will develop recurrence. Micrometastases have been shown to be important in staging and treatment of breast cancers and melanoma and have been identified by polymerase chain reaction analysis in cervical cancers. This study sought to estimate the frequency of micrometastases identified by immunohistochemistry in histologically negative lymph nodes and compare this to other known risk factors for recurrence of cervical cancer. METHODS: Early-stage (stages IA2, IB1, and IB2) cervical cancer patients of all histologic subtypes were identified from the surgical logs of the Los Angeles County–University of Southern California Medical Center for the period 1994–2000. One hundred thirty-two patients had histologically negative lymph nodes. Immunohistochemical assay was performed on 3,106 lymph nodes by using antibodies against cytokeratins AE-1 and CAM 5.2 in combination according to standard protocols. The stained nodes were then evaluated for the presence of micrometastases and compared against the respective clinicopathologic information in each case. RESULTS: Micrometastases were detected in 19 of 132 (15%, 95% confidence interval [CI] 9%, 22%) patients, found in 29 of the 3,106 (0.9%) lymph nodes evaluated. Vascular space invasion was seen in 50 of 132 cases (38%, 95% CI 30%, 47%) and in 8 of 19 (42%, 95% CI 21%, 66%) cases with micrometastases. Surgical margins of the resected specimen were negative in 120 of 132 cases (91%, 95% CI 84%, 95%) and in 16 of 19 (84%, 95%CI 60%, 96%) of those cases with micrometastases. Micrometastases were seen most frequently in pelvic lymph nodes (25 of 29, 86%). Patients with more than 20 lymph nodes removed were more likely to demonstrate metastasis (P < .001). There was no statistically significant association between micrometastasis and vascular space invasion or tumor volume. CONCLUSION: Micrometastases are identifiable in histologically negative lymph nodes in 15% (95% CI 9%, 22%) of early-stage cancer patients, a frequency which approximates the recurrence rate for patients with negative nodes. In this series, patients with greater numbers of lymph nodes analyzed were more likely to have lymph node micrometastasis identified. There appears to be no relationship between tumor volume and the identification of micrometastases. Although micrometastases can be identified in histologically negative lymph nodes, their presence is not strongly associated with other known factors of cervical cancer recurrence. Further research is needed to determine whether the presence of lymph node micrometastases is associated with an unfavorable prognosis. LEVEL OF EVIDENCE: II-3

Human chorionic gonadotropin suppresses ovarian epithelial neoplastic cell proliferation in vitro

OBJECTIVE To quantify the in vitro effects of gonadotropins on benign, borderline, and malignant ovarian cell lines. DESIGN In vitro cell culture. SETTING Research laboratory. PATIENT(S) None. INTERVENTION(S) Three hormonally sensitive ovarian neoplastic cell lines were exposed to control medium, FSH (40 mIU/mL), hCG (200 mIU/mL), and a combination of FSH and hCG. MAIN OUTCOME MEASURE(S) Cellular proliferation measured by a colorimetric (MTT) assay. RESULT(S) Growth of the cell lines was similar when exposed to control or FSH. In the presence of hCG alone, the cell lines demonstrated decreased proliferation when compared to control or FSH alone. When hCG was given in combination with FSH, there was decreased proliferation of the cell lines compared to control or FSH alone. CONCLUSION(S) Growth of benign, borderline, and malignant ovarian epithelial cell lines is inhibited by hCG at levels, which are commonly achieved with hCG administration during ovulation induction or as a result of trophoblastic production in early pregnancy.

Immunohistochemical Expression of Cell Cycle Proteins E2F-1, Cdk-2, Cyclin E, p27 kip1 , and Ki-67 in Normal Placenta and Gestational Trophoblastic Disease

The role of cell cycle protein expression in gestational trophoblastic disease is poorly understood. In this study we investigated the immunostaining patterns of G1 restriction point and G1-S regulatory proteins E2F-1, Cdk2, cyclin E, p27kip1, and the proliferation marker Ki-67 on routinely processed sections of 29 hydatidiform moles (10 partial moles and 19 complete moles, including 9 persistent moles), 7 choriocarcinomas, and 7 normal placentas. Ki-67 trophoblast staining decreased with increasing gestational age of the placenta, and showed maximal expression in gestational trophoblastic disease. Cyclin-dependent kinase activity, as reflected by Cdk2 expression patterns, also decreased with placental maturation. E2F-1 was uniquely expressed by trophoblasts of moles and choriocarcinoma. Cyclin E was maximally expressed by complete moles and choriocarcinomas, and showed an inverse relationship with the cyclin-dependent kinase inhibitor p27kip1. Abnormal trophoblastic proliferations may be mediated through interactions of Cdk-2, E2F-1, cyclin E, and p27kip1. Overexpression of cyclin E was associated with more aggressive forms of gestational trophoblastic disease. However, we did not find distinguishing features between complete moles that spontaneously resolved after evacuation and persistent moles that required chemotherapy. The different expression patterns of cyclin E and E2F-1 in partial and complete moles may be useful in distinguishing these two entities. Furthermore, loss of p27kip1 in malignant trophoblast may represent a necessary step in the development of choriocarcinoma.

Cervical biopsy and excision procedure specimens lack sufficient predictive value for lymph-vascular space invasion seen at hysterectomy for cervical cancer.

OBJECTIVE The purpose of this study was to determine whether lymph-vascular space invasion (LVSI) that is discovered in cervical biopsy and excision specimens is associated with LVSI in the hysterectomy specimen of patients with cervical cancer. STUDY DESIGN A retrospective pathologic review to determine the presence of LVSI in cervical biopsy specimens, cold-knife cone biopsy (CKC biopsy), and loop electrical excision procedure (LEEP) specimens that contained cervical cancer was performed if subsequent hysterectomy results were available for review. Data were analyzed with chi-square analysis testing. RESULTS One hundred six patients were identified. The negative predictive value of the biopsy is lower at 0.45 than either the CKC biopsy (0.83) or LEEP (0.57); however, the positive predictive value (0.83) is higher than either CKC biopsy (0.50) or LEEP (0.75). LVSI, when present in cervical biopsy (odds ratio, 4.13; 95% CI, 0.414-98.446), CKC biopsy (odds ratio, 4.8; 95% CI, 0.542-46.280), and LEEP (odds ratio, 4.0; 95% CI, 0.439-43.793) specimens, is associated with a statistically insignificant increased risk of LVSI in the hysterectomy specimen. CONCLUSION Cervical biopsy and excision specimens lack sufficient negative predictive value for the detection of LVSI in the hysterectomy specimen.

In vitro adjuncts to the Pap smear

The Pap smear has been recognized widely as the most effective cancer screening test in the history of medicine. It is widely believed that the use of this test has been responsible for the drastic reduction in the incidence and mortality of cervical cancer in the United States, Canada, and much of Western Europe in the last 50 years. Several adjuncts to the Pap smear including liquid based cytology, computer-assisted screening, human papilloma virus and molecular testing are discussed.

Lymph Node Micrometastases in Early-Stage Cervical Cancer are Not Predictive of Survival

Although patients with early-stage cervical cancer have in general a favorable prognosis, 10% to 40% patients still recur depending on pathologic risk factors. The objective of this study was to evaluate if the presence of lymph node micrometastasis (LNmM) had an impact on patient’s survival. We performed a multi-institutional retrospective review on patients with early-stage cervical cancer, with histologically negative lymph nodes, treated with radical hysterectomy and pelvic lymphadenectomy for the study period 1994 to 2004. Tissue blocks of lymph nodes from the patient’s original surgery were recut and then evaluated for the presence of micrometastases. One hundred twenty-nine patients were identified who met inclusion criteria. LNmM were found in 26 patients (20%). In an average follow-up time of 70 mo, there were 11 recurrences (8.5%). Of the 11 recurrences, 2 (18%) patients had LNmM. Patients with LNmM were more likely to have received adjuvant radiation and chemotherapy. In stratified log-rank analysis, LNmM were not associated with any other high-risk clinical or pathologic variables. Survival data analysis did not demonstrate an association between the presence of LNmM and recurrence or overall survival. The presence of LNmM was not associated with an unfavorable prognosis nor was it associated with other high-risk clinical or pathologic variables predicting recurrence. Further study is warranted to understand the role of micrometastases in cervical cancer.