Angiogenesis in the uterine cervix

Abstract. Abulafia O, Sherer DM. Angiogenesis in the uterine cervix.
Our objective was to present current data pertaining to angiogenesis of the uterine cervix. We conducted a computerized search to identify relevant studies published in the English language literature. MEDLINE, Current Contents and Index Medicus were searched utilizing the terms: angiogenesis, uterine cervix, intraepithelial neoplasia, squamous cell carcinoma, and adenocarcinoma, from 1966 through June 1999. In contrast to the cyclic phases of the menstrual cycle of the ovary and endometrium in which angiogenesis plays a significant physiologic role, angiogenesis in the uterine cervix is involved primarily in neoplastic processes. These include intraepithelial disease, human papilloma-related disease, and microinvasive and invasive squamous cell and adenocarcinoma of the cervix. In invasive squamous cell and adenocarcinoma of the uterine cervix, angiogenesis appears to be a prognostic indicator for overall survival and disease-free survival. Initial trial studies with anti-angiogenic (angio-inhibitor) therapy such as TNP-470 have been reported and concurrent antitumor activity observed in a limited number of patients with advanced (inoperable or metastatic) disease.     

Prognostic factors of the uterine cervix adenocarcinoma

Background: Prognosis factors for adenocarcinoma of the uterine cervix after primary treatment are poorly established. Methods: A retrospective study of 45 cases of adenocarcinoma of the cervix with a follow-up of 96 months on average was performed. The primary treatment consisted in combined radical surgery and radiotherapy for stage I-II patients while patients with advanced disease were treated by radiotherapy. In case of poor prognosis factors, they were given chemotherapy. Survival rates were established and prognosis factors influencing survival and recurrences were studied. Results: Fifteen women remained alive without evolutive disease. FIGO stage and pelvic node involvement were the most important parameters influencing overall survival. Local failures (27%, average period of 30 months) were unpredictable and led to a dramatic outcome. Histological grade and pelvic node status were significant predictive factors for metastatic recurrence (40%, average period of 29 months). Conclusions: Local recurrence and metastatic dissemination of cervical adenocarcinoma after primary treatment prove to be rapidly fatal although life expectancy can be prolonged with adjuvant treatment of the recurrence. In the event of aggressive tumors with high histological grade and pelvic node involvement, an attempt to assess adjuvant systemic chemotherapy could be useful.     

Primary malignant lymphoma of uterine cervix

Primary malignant lymphoma of the uterine cervix is a rare disease. Malignant lymphoma can be clinically and histopathologically misdiagnosed for the infrequent presentation in this are. A case of 56-year-old woman with uterine cervical tumor with infiltration to both parametria is presented. A biopsy was performed and histopathological studies reported a large cell B lymphoma. After the diagnosis CT abdominal, pelvic and thoracic scan was performed and shows infiltration to posterior bladder without evidence of disease in lymph nodes or another organ. The patient was treated with chemotherapy and radiotherapy. Six month after finish the treatment is well and free of disease.     

Primary hepatoid adenocarcinoma of the uterine cervix

Hepatoid adenocarcinoma is characterized histologically by neoplastic epithelial cells that resemble hepatocellular carcinoma (HCC) and produce alpha-fetoprotein (AFP). We describe a case of hepatoid adenocarcinoma of the uterus that, unlike any other previously reported case, was strictly confined to the cervix. A cervical biopsy demonstrated poorly differentiated adenocarcinoma, and hysterectomy and bilateral salpingo-oophorectomy were subsequently performed. Histologically, the lesion consisted of solid sheets of hepatoid cells accompanied with areas of endometroid adenocarcinoma. The tumor cells showed strong and diffuse cytoplasmic immunoreactivity with AFP in both medullary and adenocarcinoma components. Metastases to bilateral pelvic lymph nodes were detected 12 months after surgery. Since undergoing total pelvic irradiation, the patient has been alive and in full remission for 22 months. To our knowledge, this is the first report of primary hepatoid adenocarcinoma of the uterine cervix.     

Granulocytic sarcoma of the uterine cervix

Granulocytic sarcoma (GS) is a rare manifestation of leukemia and has been reported in 3-5% of acute myelogenous leukemia (AML) patients. GS in the uterine cervix is very rare and is also called chloroma because of its greenish appearance. We present the case of a patient whose disease relapsed as chloroma of the uterine cervix after bone marrow transplantation (BMT). She remained in continuous complete remission for 2 years after allogeneic BMT. However, she visited the hospital because of painless vaginal bleeding. She was diagnosed as having chloroma by cervical smear and colposcopically directed biopsy of the cervix. Systemic chemotherapy was administered on the presumption that myelogenous leukemia had recurred as chloroma, and a good clinical response was achieved. We describe the first case of AML that relapsed as chloroma of the uterine cervix after complete remission of the AML, which had complete response to only systemic chemotherapy.     

Minimal deviation adenocarcinoma of the uterine cervix

Background

Precise preoperative diagnosis of minimal deviation adenocarcinoma (MDA) of the uterine cervix is often difficult because the histological features of MDA closely resemble those of normal cervical glands.

Objective

To review the developments in the diagnosis and treatment of MDA over the past 35 years.

Search strategy

We performed a meta-analysis of all case reports published in the English and Chinese languages between 1975 and 2009 that included a histopathologic diagnosis of MDA. Pooled odds ratios and 95% CIs were calculated for comparisons and analyzed.

Results

The histopathologic diagnosis of MDA remains difficult and is currently based on antigen detection by immunohistochemistry. Cytologic assessment and routine biopsy have low detection rates for MDA. Cross-sectional imaging techniques are helpful but a deep cervical biopsy or cervical conization is necessary for a definitive diagnosis. The mean survival is about 5 years for patients with stage I, 38.1 months for patients with stage II, 22.8 months for patients with stage III, and 5.4 months for patients with stage IV MDA.

Conclusion

Early diagnosis and treatment are key to improving prognosis and survival in patients with MDA.     

Pelvic insufficiency fracture after pelvic irradiation in uterine cervix cancer

OBJECTIVES: Pelvic insufficiency fractures (IF) are well known but uncommon and are frequently misinterpreted sequelae. The clinical features were investigated. METHODS: Four hundred sixty-three patients, who were treated between 1994 and 2000 for uterine cervix cancer, were clinically examined. All patients had been treated with 10 or 15 MV photons, with 50.4-55.8 Gy in 28 fractions with adjuvant intent (n = 235) in addition to high-dose-rate brachytherapy 24 Gy in 6 fractions for curative treatment (n = 228). The median follow-up was 38 months. RESULTS: Eight patients (8/463, 1.7%) developed pelvic IF 7-19 months (median, 12 months) after the treatment. Among these, seven patients (7/228, 3.1%) were treated with curative intent and one (1/235, 0.4%) was treated with adjuvant intent. All patients were postmenopausal and complained of moderate to severe pelvic pain, which resolved after 1-11 months with conservative therapy in all patients. Two of these patients also had radiation proctitis. CONCLUSION: In women who present with pelvic pain after radiotherapy for cervical cancer, bony destruction and fractures may be indicative of a late radiation effect rather than osseous metastasis. IF are more common in the curative treatment group than in the postoperative adjuvant group.     

The expression of glycosaminoglycans and proteoglycans in the uterine cervix of albino rats after local hyaluronidase infusion

Abstract

Objective: To assess the local effect of hyaluronidase injection on the expression of glycosaminoglycans (GAGs) and proteoglycans (PGs) in the extracellular matrix of the uterine cervix from pregnant albino rats.

Methods: Ten pregnant rats were divided into two groups on day 18 of pregnancy. The experimental group (Gexp) of rats received an intracervical infusion of 0.02?mL of hyaluronidase diluted to 1?mL with distilled water, whereas the control group (Gc) received 1?mL of distilled water. On day 20 of pregnancy, the pregnant rats were sacrificed and the uterine cervixes from all rats were then dissected. The qualitative expression of hyaluronic acid (HA) was assessed by immunohistochemistry and quantified by sandwich ELISA. To compare the quantitative GAG values between groups, a Student’s t-test for independent samples was performed. PGs were also assessed by immunohistochemical analysis.

Results: The electrophoretic profile of newly synthesized radioactively labeled GAGs degraded by specific enzymes showed that there were two predominant GAGs in both Gc and Gexp, i.e. heparan sulfate (HS) and a mixture of hondroitin sulfate (CS) and dermatan sulfate (DS). The concentrations of GAGs showed a significant reduction of CS/DS (p?<?0.004) and HS (p?<?0.005) relative to Gc. HA staining was less intense in the lamina propria and area surrounding the blood vessels in Gexp compared to Gc. The HA contents were also significantly reduced (p?<?0.012).

Conclusions: Intracervical hyaluronidase infusion promoted a significant reduction in the concentration of sulfated GAGs as assessed by both qualitative (histochemical) and quantitative (fluorometric) measurements of HA.     

Density and distribution of Langerhans cells in the human uterine cervix

Summary Using a combination of immunohistochemistry and planimetric observation we report the density and distribution of Langerhans cells (LCs) in epithelium from the normal ectocervix and from the normal transformation zone (TZ). The density of LCs increased towards the basement membrane. Dendritic LCs aspect was more prominent in the superficial layers.     

A short and intensive single-agent cisplatin regimen for recurrent carcinoma of the uterine cervix

Between May 1991 and September 1993, 36 patients with recurrent carcinoma of the uterine cervix were treated with single-agent cisplatin using an intensive regimen of four weekly cycles of 50 mg m⁻² followed in responders by a further four cycles given every fortnight. The response rate was 47% (95% CI: 27–66%), 56% in those with pelvic recurrence, and 38% in those with metastatic disease. All responses but one were seen within 4 weeks of commencing treatment. Three patients (9%) had a complete response, although in two cases this was of short duration. The treatment was moderately well tolerated and the principle toxicities were myelotoxicity and emesis. The median survival was 32 weeks, and the 18-month survival was 13%.
This regimen gives a response rate similar to that seen with more toxic combination chemotherapy regimens such as BIP (bleomycin, ifosfamide and cisplatin). It has the particular advantages of a short duration of treatment and early response, allowing treatment to be stopped after 4 weeks in non-responders. The response rate in pelvic recurrence was better than that seen in most previous chemotherapy trials, particularly as 78% of the evaluable patients with pelvic recurrence had previously received radical radiotherapy to the pelvis.
Weekly, followed by fortnightly cisplatin, is an appropriate palliative treatment for patients with recurrent carcinoma of the uterine cervix for whom chemotherapy is indicated.     

Erythropoietin receptor expression in biopsy specimens from patients with uterine cervix squamous cell carcinoma

Hypoxia, an important mechanism of radioresistance, is a strong stimulus for erythropoietin (EPO) production. The stimulatory effects of EPO are mediated through the activation of its receptors, EPO receptors (EPORs). The objective of this study is to determine whether EPORs are expressed in biopsy specimens of patients with squamous cell carcinoma of the cervix. Eighteen biopsy specimens were studied after obtaining Institutional Review Board-approved consent. Standard immunohistochemistry techniques were utilized. Expression of EPORs was present in 16 out of 18 (88.9%) specimens. The intensity (qualitative) and the frequency (semiquantitative) of EPORs expression showed a statistically significant correlation (P= 0.00379). Statistical analysis was performed to determine whether EPORs expression is related to other parameters such as age, FIGO stage, histologic grade, and hemoglobin levels. Only age showed a statistically significant correlation with EPORs frequency of expression (P= 0.00878). Currently, work is in progress in our laboratory to study the radiobiologic effects of EPO on the radiation response of cultured cancer cell lines in vitro.     

High intraepithelial expression of estrogen and progesterone receptors in the transformation zone of the uterine cervix

OBJECTIVE: Because sex hormones may be involved in tumor initiation and progression, we analyzed the presence of hormone receptors in the transformation zone of the uterine cervix where the majority of human papillomavirus infections and associated (pre)neoplastic lesions develop. STUDY DESIGN: By using 23 total hysterectomy samples from young women who underwent surgery for noncervical benign uterine disease, we analyzed, by immunohistologic techniques, the in situ expression of estrogen (E(2)-R) and progesterone (P(4)-R) receptors in the transformation zone and ectocervix of the same women. RESULTS: The expression of estrogen receptors and progesterone receptors is significantly higher in the transformation zone compared with the ectocervix. Immunohistochemical localization indicated that hormone receptor-positive cells are mainly observed in (para)basal and intermediate cell layers in both the transformation zone and ectocervical epithelium. When transformation zone samples were segregated into epithelial tissues with a predominantly mature (7/23 samples) or immature (16/23 samples) squamous metaplasia, only biopsy specimens with immature squamous metaplasia showed a significantly higher density of hormone receptor-positive cells compared with ectocervical epithelium (P<.01). CONCLUSION: Our results suggest that the cervical transformation zone may be at increased risk of the development of cancer because of a high sensitivity to sex hormone regulation.     

An unusual endometrioid adenofibroma of the uterine cervix: a histologic and immunohistochemical study

An unusual adenofibroma of the uterine cervix is reported. The cervix was bulkily enlarged but did not have a polypoid appearance. The neoplastic epithelium was in continuity with the covering epithelium of the cervix and consisted predominantly of endometrioid cells which proliferated to form numerous glandular structures of irregular size and shape. The glandular component resembled an endometrial hyperplasia, and was set in an abundant fibrous stroma which was moderately cellular and hyalinized. Both the epithelial and mesenchymal cells lacked cytologic atypia. Despite its benign appearance, the tumor occupied almost all the uterine cervix and extended into the upper vaginal wall. The epithelial cells showed diffuse positive staining for CA19-9 and were focally positive for carcinoembryonic antigen. The presence of dense periglandular fibrosis distinguished the present case from a minimal deviation adenocarcinoma of endometrioid type.     

Small-cell carcinoma of the uterine cervix: a clinicopathologic study of 11 cases

We report the clinical profiles and immunohistochemical features of small-cell carcinoma of the uterine cervix. Eleven cases that we have encountered at the Department of Gynecology, Kitasato University Hospital, between 1971 and 2003 are presented. Of 1370 invasive carcinomas of the uterine cervix, the incidence of small-cell carcinoma was 0.8%. Patient ages ranged between 32 and 65 years, with a mean age of 46.3 years. The clinical stages at diagnosis were Ib in four patients, IIb in three, IIIb in three, and IVb in one. All patients presented with abnormal vaginal bleeding. Two patients who are alive with no evidence of disease for 12 years and 3 years 6 months, while eight patients died of primary carcinoma between 4 and 25 months after treatment. Histopathologic findings showed solid nests with marked peripheral palisading pattern and rosette formation. Small tumor cells with scant cytoplasm demonstrated a very high nuclear/cytoplasm ratio and indistinct cell borders. The nuclei were round to oval and demonstrated increased but fine granular chromatin. Nucleoli were indistinct in all cases. Immunohistochemical findings were positive in 81.8% each for neuron-specific enolase and protein gene product 9.5, 72.7% for synaptophysin, 63.6% for chromogranin A, and 54.5% for neural cell adhesion molecule. All specimens were positive for at least one of the above. In conclusion, small-cell carcinoma of the uterine cervix revealed poor prognosis. Making an accurate diagnosis of small-cell carcinoma before performing treatment is of great significance but often difficult. Immunohistochemical analysis using several kinds of neuroendocrine markers is helpful in establishing the correct diagnosis in addition to focusing on characteristic histo- and cytopathologic features.     

Clear cell variant of malignant melanoma of the uterine cervix: a case report and review of the literature

BACKGROUND: A rare variant of malignant melanoma of the uterine cervix mimicking clear cell carcinoma or clear cell sarcoma is described. CASE: A 33-year-old Japanese woman was admitted to the hospital complaining of genital discharge and lower back pain. The stage was FIGO IIB and radical hysterectomy and pelvic lymphadenectomy were done. Pathological examination, immunohistochemical studies of melanin granules, and molecular analysis of the EWS/ATF-1 fusion gene were also done. A diffuse proliferation of amelanotic clear cells was detected in the uterine cervix. Tumor cells were positive for HMB 45, Melan-A (MART-1), and S-100 protein and negative for epithelial markers. The EWS/ATF-1 fusion gene was not detected. CONCLUSION: This is apparently the first report of a case of clear cell melanoma of the uterine cervix. Despite its rarity, this variant of malignant melanoma should be considered when diagnosing clear cell neoplasms of the uterine cervix.     

Prospective comparison of clinical and computed tomography assessment in detecting uterine perforation with intracavitary brachytherapy for carcinoma of the cervix

Brachytherapy (BT) is an essential component of radical treatment for cervix cancer. Uterine perforation is a potential complication of intrauterine applicator (tandem) insertion. Postprocedure pelvic computed tomography (CT) scans are routinely performed at this center. The objective of this study was to prospectively compare radiation oncologists' (RO) clinical impression of satisfactory tandem placement with actual tandem placement as determined from pelvic CT. Patients with cervix cancer undergoing low-dose rate BT from April 2003 to December 2005 were prospectively identified. After tandem placement, patients were brought to the radiotherapy department for pelvic imaging (plain films and CT). Prior to viewing imaging, the RO specified whether they were concerned vs not concerned about uterine perforation. The CT was then reviewed to determine actual tandem placement (perforation vs no perforation). One hundred twenty-four sequential tandem insertions were performed in 114 patients and eligible for analysis. The incidence of CT detected uterine perforation was 13.7% (17/124). Physician concern, age greater than or equal to 60, and tumor size were significant predictors of uterine perforation (P < 0.0001, P= 0.0019, and P= 0.0016, respectively). The overall sensitivity and specificity for physician concern was 52.9% and 84.1%, respectively. CT detected perforation in 8.2% (8/98) of insertions where the RO was clinically confident of correct tandem placement. Pelvic CT was a useful modality to accompany clinical assessment in identifying uterine perforation in cervix BT. As a low but potentially clinical significant number of perforations identified on CT were not suspected clinically, we recommend acquiring pelvic imaging in all patients following tandem insertion to ensure intrauterine tandem positioning.     

Gross omental metastasis of mucoepidermoid carcinoma of the uterine cervix: A case report

Reich O, Tamussino K. Gross omental metastasis of mucoepidermoid carcinoma of the uterine cervix: A case report. Int J Gynecol Cancer 1998; 8 : 349–351.
A 54-year-old female with invasive mucoepidermoid carcinoma (MEC) of the uterine cervix had an uncommon type of spread. On clinical examination the patient had FIGO stage IIB disease; MRI showed a tumor volume of 15 ml and extension to right parametrium. Radical hysterectomy was planned but laparotomy revealed gross extrapelvic metastases in the greater omentum. The unexpected spread of this tumor may suggest that MECs of the cervix are more aggressive than their squamous cell counterparts.     

Placental site trophoblastic tumor of the uterine cervix occurring from undetermined antecedent pregnancy

A cervical polyp complicated by severe hemorrhage was removed from a 43-year-old Japanese woman (gravida 0), who had undergone tubectomy on the right side 10 years previously. The polyp was diagnosed by immunohistochemical studies as placental site trophoblastic tumor of the cervix, but no metastatic foci were found in any other uterine site. The tumor was further demonstrated by PCR polymorphisms to possess two genomic DNA of the patient and her husband. Serum beta-hCG and urinary hCG titers were both low, which rapidly fell to 0.8 mIU/mL after a total hysterectomy and remained 0.2 mIU/mL after dismission. She has been uneventful for 3 years.