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1/32. Rapid progression of squamous cell carcinoma of the cervix after hyperbaric oxygenation.

    The role of hyperbaric oxygenation in the treatment of radiation-induced sequelae and chronic ulcer is well established. On the contrary, a possible cancer-causing or growth-enhancing effect by hyperbaric oxygenation was highly controversial. Herein, we present a 55-year-old Chinese woman with recurrent squamous cell carcinoma of the cervix on her left inguinal area. She received concurrent chemoradiation therapy followed by radical inguinal lymphadenectomy due to persistent tumor mass. The patient was complicated with severe radiation fibrosis and unhealed wounds, so she was treated with hyperbaric oxygenation (HBO). However, the patient died of complications of the disease after completing HBO therapy I month later and autopsy of the patient showed carcinomatosis of the abdominal cavity and lower abdominal wall. Because previous studies have been inconclusive regarding the effect of HBO on tumor cells, we reviewed the possible relation between the HBO and tumor cells.
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2/32. Analysis of p53 and K-ras genes and their proteins in a sarcoma botryoides of the uterine cervix.

    Several data indicate that the activation of oncogenes and growth factors as well as inactivation of the tumor suppressor genes are implicated in the development of human neoplasms, including sarcomas. In the present study we described a case of the extremely rare, but highly malignant neoplasm of the female genital tract known as sarcoma botryoides of the uterine cervix and assessed, using molecular and an immunohistochemical analysis, p53 and K-ras alterations in the tumor. A point mutation in exon 6 of the p53 tumor suppressor gene was found but no K-ras gene point mutations at codons 12, 13 and 61 were detected using molecular analysis. p53 protein was overexpressed in more than half of the neoplastic cells, however, ras p21 protein expression was not immunohistochemically detected. Our data indicate that p53, but not K-ras gene alterations may play a role in the development and progression of sarcoma botryoides of the uterine cervix.
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3/32. Acute lower extremity paralysis following radiation therapy for cervical cancer.

    BACKGROUND: Acute lower extremity paralysis secondary to lumbosacral plexopathy is a rare but severe complication that may follow pelvic radiotherapy for cervical cancer. CASE: A 49-year-old female with newly diagnosed stage IIIB cervical cancer developed progressive bilateral lower extremity paralysis and pelvic pain only 10 weeks following completion of radiation therapy for cervical cancer with no evidence of metastasis or progression of disease. Her bladder and bowel function were not affected. Following extensive workup, the most likely etiology was presumed radiation-induced lumbosacral plexopathy. CONCLUSION: Although metastatic carcinoma is more commonly the reason for progressive lower extremity weakness with pelvic pain in women with advanced cervical cancer, radiation-induced lumbosacral plexopathy, a rare but devastating complication, may be the cause. Diagnosis is by exclusion.
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4/32. Granulocytic sarcoma: report of three cases.

    Granulocytic sarcoma (GS) is a rare extramedullary solid tumour composed of malignant immature cells of the granulocytic series. It may herald, accompany or signal acute myeloid leukaemia (AML) or chronic granulocytic leukaemia (CGL). GS may also occur in patients with myelodysplastic syndromes (MDS) where it is a sign of imminent disease progression. Three cases of GS are presented; the first one involving the pancreas and preceding AML, the second case affecting uterine cervix in stable phase CGL and the third case is GS of the breast accompanying AML. Any site of the body may be involved by the GS, and morbidity depends on the local organ/tissue affected in addition to the attending primary leukaemia or MDS. Treatment of GS involves surgery, radiotherapy and chemotherapy. The objective of this communication is to enhance awareness in personnel providing health care. Further, early diagnosis and treatment affects overall outcome.
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keywords = disease progression, progression
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5/32. Poor clinical outcome in early stage cervical cancer with human papillomavirus-18 positive lymph nodes.

    Epidemiologic and molecular studies have proven that human papillomavirus (HPV) plays an important role in the development of cervical cancer. However, the role of the virus in the progression of the disease, i.e. in the development of lymph node metastasis and in the adverse clinical outcome is poorly understood. We have been using the polymerase chain reaction (PCR) to study the presence and typing of human papillomavirus dna since 1980 in cervical cancers and pelvic lymph nodes from the same patients. Out of the series of 47 cervical cancer patients we focused on four women (age: 41, 33, 35 and 56 years) in this article. The follow-up of these patients revealed early recurrences of the disease (7, 7, 17, 22 months) with very short survival (9, 10, 21, 24 months). Although we detected HPV-18 positivity both in the cervical tumors and in the regional lymph nodes too in all four cases, lymph nodes were negative by routine hystology in case of the three young patients (21, 33, 35 years of age). Our observations suggest that HPV type 18 positive cervical cancer patients, despite negative histological findings in the lymph nodes should be consider as a subpopulation for poor outcome especially in the young age group (p=0,022, Fisher's exact test).
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6/32. Pseudoachalasia as a result of metastatic cervical cancer.

    BACKGROUND: Distinguishing achalasia from pseudoachalasia can be difficult, as the clinical, radiological, and manometric findings can be similar to those seen in achalasia. The features that may differentiate achalasia from pseudoachalasia are reviewed and the pathogenesis of pseudoachalasia is discussed. methods: A patient presented with a clinical scenario of achalasia that was documented by radiographic, endoscopic, and manometric studies. Her past medical history was significant for cervical cancer. Although brief improvement in symptoms was achieved with botulinum toxin injections and esophageal dilation, she had continued progression of symptoms. This direct involvement of the esophagus by a tumor was not demonstrated by any of the routine preoperative studies. RESULTS: At the time of surgery, extensive involvement of the diaphragm, esophagus, and pericardium by a tumor was noted. Pathologic analysis of the tumor was consistent with metastatic cervical cancer CONCLUSION: Pseudoachalasia has been known to occur in response to both benign and malignant causes. Differentiating between pseudoachalasia and achalasia is often difficult because of the similarities. As in this case, the diagnosis of pseudoachalasia may be made by surgical exploration.
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7/32. Simultaneous squamous cell carcinomas of the uterine cervix and upper genital tract: loss of heterozygosity analysis demonstrates clonal neoplasms of cervical origin.

    Five cases of cervical squamous cell carcinoma with synchronous superficial squamous cell carcinoma in the upper genital tract were genetically analyzed to demonstrate the possibility of a clonal neoplastic process. In these cases, the cervical lesions were squamous cell carcinoma in situ (cases 1, 2, and 3) and invasive squamous cell carcinoma (cases 4 and 5). loss of heterozygosity (LOH) analyses with a panel of microsatellite markers revealed a monoclonal process in four of the five cases. Homogeneous LOH throughout the microdissected lesions was most frequently detected on 6p and 6q (3 cases), followed by 11p and 11q (2 cases), loci known to be commonly lost in typical cervical squamous cell carcinoma. In two cases, genetic progression in terms of additional LOH was found in the upper genital tract but not in the cervix. Most of these squamous cell carcinomas were monoclonal neoplasms originating from the cervical mucosa with subsequent superficial migration of the tumor clone to the upper genital mucosa, and in some cases, genetic progression.
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8/32. Utilization of the human genome sequence localizes human papillomavirus type 16 dna integrated into the TNFAIP2 gene in a fatal cervical cancer from a 39-year-old woman.

    PURPOSE: The purpose of our study was to characterize a human papillomavirus (HPV) 16 dna integration in the genome of a rapidly progressive, lethal cervical cancer in a 39-year-old woman. EXPERIMENTAL DESIGN: An HPV 16 integration site from cervical cancer tissue was cloned and analyzed using Southern blot hybridization, nucleotide sequencing, fluorescence in situ hybridization analysis for chromosomal localization and comparison with the draft human genome sequence. RESULTS: HPV 16 dna (3826 bp) was integrated into the genome of the tumor sample and contained an intact upstream regulatory region and E6 and E7 open reading frames. Both 5' and 3' viral-cell junction regions contained direct repeat and palindrome sequences. The chromosomal location of the viral integration and cellular deletion was mapped to chromosome 14q32.3 using both a somatic cell hybrid panel and fluorescence in situ hybridization. Search of the draft human genome sequence confirmed the chromosomal location and revealed a disruption of the TNFAIP2 cytokine/retinoic acid-inducible gene. CONCLUSIONS: On the basis of the lack of sequence homology between the viral and cellular site of integration and the structure of the viral-cell junctions, it seems that HPV 16 dna integrates into the host genome by a mechanism of nonhomologous recombination. We suggest that, taken together, maintenance of E6 and E7 expression, loss of the E2 gene and disruption of the TNFAIP2 gene through viral integration contributed to the rapid progression of cervical cancer in this patient. Availability of the human genome sequence will facilitate identification of cellular genes involved in cervical cancer by high-throughput analysis of viral integration sites.
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9/32. Clonality analysis of synchronous lesions of cervical carcinoma based on x chromosome inactivation polymorphism, human papillomavirus type 16 genome mutations, and loss of heterozygosity.

    One of the most common forms of carcinoma in women, cervical invasive squamous cell carcinoma (CIC), often coexists with multiple lesions of cervical intraepithelial neoplasia (CIN). CIC and CIN show heterogeneity with respect to both histopathology and biology. To understand the causes, origin, and model of progression of cervical carcinoma, we assessed the clonality of a case with multiple synchronous lesions by analyzing x chromosome inactivation polymorphism, human papillomavirus type 16 (HPV16) sequence variation/mutations, and loss of heterozygosity (LOH). microdissection was performed on 24 samples from this case, representing the entire lesional situation. The combination of different x chromosome inactivation patterns, two HPV16 point mutations, and LOH at three genomic microsatellite loci, led to the identification of five different "monoclonal" lesions (CIN II, CIN III, and invasive carcinoma nests) and five different "polyclonal" areas (CIN II and normal squamous epithelium). This finding indicated that CIC can originate from multiple precursor cells, from which some clones might progress via multiple steps, namely via CIN II and CIN III, whereas others might develop independently and possibly directly from the carcinoma precursor cells. Our results also supported the view that HPV16 as a "field factor" causes cervical carcinoma, which is probably promoted by the loss of chromosomal material as indicated by the LOH.
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10/32. Uterine cervical metastasis of breast cancer: a rare complication that may be overlooked.

    BACKGROUND: Metastasis of distant malignancies to the cervix uteri is a rare occurrence and the frequency is approximately 4% for all tumours. However, the frequency of cervical metastasis of breast cancer is much lower and is estimated to range between 0.8 and 1.7%. With the exception of ovarian metastases, secondary tumours of the female genital tract are rather uncommon. Therefore, these conditions pose diagnostic problems for the clinician. PATIENT: A 40-year-old woman with the diagnosis of invasive ductal cell carcinoma of the right breast underwent mastectomy with dissection of axillary lymph nodes in 1998. Subsequently, the patient received 6 cycles of chemotherapy with cyclophosphamide, methotrexate and fluorouracil. The initial tumour stage was pT2, pN0 (0/13), M0, G2. The oestrogen and progesterone receptors were positive and expression of the C-erb-B2 coding oncogene was negative. Gynaecological and ultrasonographic examination revealed a normal cervix without evident lesions. Exfoliative cytology was negative. 14 months after treatment the patient presented with an axillary relapse and surgery, second-line chemotherapy with doxorubicine and radiation therapy of the chest wall and the axilla were performed. The patient developed liver metastases 14 months later and at this time ultrasonographic pelvic examination revealed a 2.2 cm tumour of the cervix with good vascularisation. The patient had no clinical symptoms, i.e. no vaginal bleeding or discharge. Sonomorphologically this tumour appeared as a leiomyoma of the cervix. Cervical biopsies and curettage, however, revealed metastatic carcinoma expressing oestrogen and progesterone receptors consistent with the primary breast cancer. Under palliative chemotherapy with docetaxel progression of liver metastases and cervical metastasis occurred and the patient died 9 months later. CONCLUSION: Metastatic involvement of the cervix should be considered in women with a history of breast cancer who present with vaginal bleeding or suspicious changes of the cervix on transvaginal ultrasound. Therefore, gynaecological and ultrasonographic examination of the pelvis represent an important part of the follow- up investigations in women with primary breast cancer.
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