John W. McBroom

Hypoxia-Inducible Erythropoietin Signaling in Squamous Dysplasia and Squamous Cell Carcinoma of the Uterine Cervix and Its Potential Role in Cervical Carcinogenesis and Tumor Progression

Tissue hypoxia is a characteristic property of cervical cancers that makes tumors resistant to chemo- and radiation therapy. Erythropoietin (Epo) is a hypoxia-inducible stimulator of erythropoiesis. Acting via its receptor (EpoR), Epo up-regulates bcl-2 and inhibits apoptosis of erythroid cells and rescues neurons from hypoxic damage. In addition to human papillomavirus infection, increased bcl-2 expression and decreased apoptosis are thought to play a role in the progression of cervical neoplasia. Using reverse transcriptase-polymerase chain reaction and Western blotting we showed that HeLa and SiHa cervical carcinoma cells and human cervical carcinomas express EpoR, and that hypoxia enhances EpoR expression. Exogenous Epo stimulated tyrosine phosphorylation and inhibited the cytotoxic effect of cisplatin in HeLa cervical carcinoma cells. Using immunohistochemistry, we examined the expression of Epo, EpoR, p16, hypoxia-inducible factor (HIF)-1alpha, and bcl-2 in benign and dysplastic cervical squamous epithelia and invasive squamous cell carcinomas (ISCCs). EpoR expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse EpoR expression was found in all ISCCs. Expression of Epo and HIF-1alpha was increased in dysplasias compared to benign epithelia. Focal Epo and HIF-1alpha expression was seen near necrotic areas in ISCCs, and showed correlation in their spatial distribution. Significant correlation was found between expression of EpoR, and p16 and bcl-2 in benign and dysplastic squamous epithelia. Our results suggest that increased expression of Epo and EpoR may play a significant role in cervical carcinogenesis and tumor progression. Hypoxia-inducible Epo signaling may play a significant role in the aggressive behavior and treatment resistance of hypoxic cervical cancers.

Surgical staging in patients with ovarian tumors of low malignant potential

OBJECTIVE To compare the outcomes of patients with ovarian tumors of low malignant potential who had complete surgical staging with those who were unstaged to determine whether the rate of recurrence or survival was affected by surgical staging. METHODS A retrospective chart review was performed on 93 consecutive patients who had surgery for histologically confirmed tumors of low malignant potential between 1979 and 1997. Two cohorts of patients were identified: patients who had classic surgical staging (n = 48) versus those who were not staged (n = 45). Outcome data were recorded for patients and compared between the two groups. RESULTS Early stage (I or II) disease was diagnosed in 31 of 48 patients who had surgical staging and 42 of 45 patients who were not staged (P = .001). In 17% of patients their stage was upgraded on the basis of surgical staging, as a result of retroperitoneal involvement in only 6% of those cases (three of 48 staged patients). During the study interval, the frozen section diagnosis of low malignant potential tumor of the ovary was changed to a final diagnosis of invasive cancer in eight other patients. There were three recurrences and two deaths in both the staged and unstaged low malignant potential groups. The average duration of follow‐up was 6.5 ± 4.2 years and was similar in the two groups. Overall 5‐year survival was approximately 93% for all stages. CONCLUSION Survival and recurrence rates were not significantly different between staged and unstaged patients who had surgery for low malignant potential tumors of the ovary.

Associations between p53 overexpression and multiple measures of clinical outcome in high-risk, early stage or suboptimally-resected, advanced stage epithelial ovarian cancers: A Gynecologic Oncology Group study

OBJECTIVE The Gynecologic Oncology Group (GOG) performed a detailed analysis of p53 overexpression in previously-untreated women with invasive early or advanced stage epithelial ovarian cancer (EOC). METHODS Women were eligible for the study if they provided a tumor block for translational research and participated in either GOG-157, a randomized phase III trial of three versus (vs.) six cycles of paclitaxel+carboplatin in high-risk, early stage EOC, or GOG-111, a randomized phase III trial of cyclophosphamide+cisplatin vs. paclitaxel+cisplatin in suboptimally-resected, advanced stage EOC. The N-terminal DO-7 p53 antibody was used to examine the expression of the major normal and mutant p53-isoforms. p53 overexpression was defined as >or=10% tumor cells exhibiting nuclear staining. RESULTS p53 was overexpressed in 51% (73/143) and 66% (90/136) of cases in the GOG-157 and GOG-111 cohorts, respectively. In the GOG-157 cohort, p53 overexpression was not associated with any clinical characteristics or overall survival (OS) but was associated with worse progression-free survival (PFS) (logrank test: p=0.013; unadjusted Cox modeling: p=0.015). In the GOG-111 cohort, p53 overexpression was associated with GOG performance status (p=0.018) and grade (p=0.003), but not with age, stage, cell type or with tumor response and disease status after primary chemotherapy, PFS or OS. Adjusted Cox regression modeling demonstrated that p53 overexpression was not an independent prognostic factor for PFS or OS in either cohort. CONCLUSIONS p53 overexpression assessed by DO-7 immunostaining is common in early and advanced stage EOC, but has limited prognostic value in women treated with surgical staging and platinum-based combination chemotherapy.

Cervical adenocarcinoma in situ: a systematic review of therapeutic options and predictors of persistent or recurrent disease.

The incidence of cervical adenocarcinoma in situ is increasing in frequency, and our limited knowledge about this lesion presents the physician with a therapeutic dilemma. Treatment for this lesion has included conservative therapy, large loop excision or cold-knife cone biopsy, or definitive therapy consisting of hysterectomy. But, rates of residual adenocarcinoma in situ after cone biopsy with negative margins vary from 0% to 40%, and residual disease rates as high as 80% have been noted when the margins are positive. Despite these recent data on follow-up after conservative therapy such as cone biopsy, it seems that this method is safe and gaining acceptance by many physicians and patients. However, the short follow-up duration and small number of patients limit the conclusions of many studies. The relative infrequency of this diagnosis has precluded extensive clinical experience with the natural history of this lesion. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives After completion of this article, the reader will be able to summarize the current data on the treatment of adenocarcinoma in situ of the cervix, to outline potential treatment options for the patient with adenocarcinoma in situ of the cervix, and to list the factors associated with disease recurrence.

Current techniques for the evaluation of abnormal cervical cytology.

Background The Papanicolaou (Pap) smear has been one of the most successful strategies developed for the prevention of cancer. Since the introduction of the Papanicolaou test, deaths from cervical cancer in the United States has been reduced by nearly 70%. The false-negative rate of the Papanicolaou test for cervical screening is thought to be 15% to 25%; however, a recent review by the Agency for Health Care Policy and Research (AHCPR) determined the sensitivity of the conventional Pap testing to be only 50%. Although colposcopy was actually developed prior to widespread use of screening with Pap smears, colposcopy is now used as an adjunct to cervical cytology to enhance the diagnostic capabilities in women with an abnormal Papanicolaou test. The first account of colposcopy use was published by Hinselmann in 1925. Hinselmann’s initial premise was that early cervical cancers started as very small minute ulcers that could be recognized by means of suitable illumination and magnification. He developed an instrument using focused light with binocular magnification, which was called a ‘‘colposcope.’’ Hinselmann and his colleagues published their work almost entirely in German, and therefore, this new technology was not widely communicated initially. Hinselmann also developed terminology derived from his visual interpretations of the cervix; this terminology is still in use today. The colposcope itself is a stereoscopic binocular instrument, which provides a magnified 3-dimensional image. Colposcopic Correspondence: JohnFarley,MD,DivisionofGynecologic Oncology, Department of Obstetrics andGynecology, Tripler Army Medical Center, 1 Jarrett White Road, Honolulu, HI 96859-5000. E-mail: john.farley@us.army.mil The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense.

The utility of gastrojejunostomy in secondary cytoreduction and palliation of proximal intestinal obstruction in recurrent ovarian cancer

BACKGROUND Gastrointestinal obstruction is a common complication of recurrent ovarian cancer. Proximal intestinal obstruction, at the level of the duodenum or proximal jejunum, can result from bulky intraperitoneal or retroperitoneal disease. Classic management has been palliation of symptoms with a gastrostomy or jejunostomy tube. CASE We describe a series of four patients with recurrent ovarian carcinoma and proximal intestinal obstructions treated with a bypass stapled side-to-side gastrojejunostomy at the time of secondary cytoreduction or surgical palliation. The clinical history, preoperative evaluation, surgical technique, and outcomes of each patient are reviewed. CONCLUSIONS Gastrojejunostomy may offer patients with ovarian cancer and a proximal intestinal obstruction symptomatic relief and an opportunity for resumption of enteral feedings.