Poor Treatment Outcomes of Locally Advanced Cervical Adenocarcinoma of Human Papilloma Virus Independent Type, Represented by Gastric Type Adenocarcinoma: A Multi-Center Retrospective Study (Sankai Gynecology Study Group).

The revised World Health Organization classification of cervical cancer divides adenocarcinomas into human papillomavirus-associated (HPVa) and -independent (HPVi) types; the HPVi type is represented by the gastric type. The treatment outcomes of locally advanced adenocarcinoma (LaAC), based on this classification, are understudied. We investigated the outcomes of patients with HPVa and HPVi LaACs. Data for all consecutive patients with stage IB3 to IIIC1 adenocarcinoma who received treatment at 12 institutions throughout Japan between 2004 and 2009 were retrieved to analyze progression-free and overall survival. Central pathological review classified 103 and 48 patients as having HPVa and HPVi tumors, respectively. Usual- (84%) and gastric- (90%) type adenocarcinomas were the most frequent subtypes. Surgery was the primary treatment strategy for most patients. Progression-free and overall survival of patients with HPVi were worse than those of patients with HPVa (p = 0.009 and 0.032, respectively). Subgroup analysis by stage showed that progression-free survival was significantly different for stage IIB. The current surgical treatment strategy for LaACs is less effective for HPVi tumors than for HPVa tumors, especially those in stage IIB.

Analysis of gastric-type mucinous carcinoma of the uterine cervix - An aggressive tumor with a poor prognosis: A multi-institutional study.

OBJECTIVE: Gastric-type mucinous carcinoma (GAS) is a novel variant of mucinous carcinoma of the uterine cervix. As shown in the original Japanese group description, in recent studies, GAS represents a more aggressive disease than the usual-type endocervical adenocarcinoma (UEA). Detailed clinicopathological features of this variant remain to be elucidated in a larger series of patients. METHODS: Patients were enrolled by the Gynecologic Cancer Study Group of the Japan Clinical Oncology Group after receiving the approval of each Institutional Review Board. The study population comprised of women with stage I to II endocervical adenocarcinomas who underwent surgery between 2000 and 2009. Representative slides were evaluated by central pathological review (CPR), categorized into either GAS or UEA, and correlated with clinicopathological features and outcome. RESULTS: Among the 393 enrolled patients with endocervical adenocarcinoma, 328 patients met the criteria for CPR and the study eligibility criteria and were included in further analysis. A total of 95 of the 328 tumors were classified as GAS. Compared with UEA, GAS was more significantly associated with bulky mass, deep stromal invasion, lymphovascular space invasion, parametrial invasion, ovarian metastasis, positive ascitic fluid cytology, pelvic lymph node metastasis, and pathological (p) T stage but was not related to the degree of histological differentiation. Disease-free survival (P < 0.0001) and overall survival (P < 0.0001) were poorer in patients with GAS than in those with UEA. CONCLUSIONS: GAS showed aggressive behavior with ominous histopathological predictors as well as decreased survival. GAS is therefore considered a distinct entity that should be distinguished from UEA. CLINICAL TRIAL INFORMATION: UMIN Clinical Trials Registry: UMIN000007987.

Chemoresistance of Gastric-Type Mucinous Carcinoma of the Uterine Cervix: A Study of the Sankai Gynecology Study Group.

OBJECTIVE: Gastric-type mucinous carcinoma (GAS) is a novel variant of mucinous carcinoma of the uterine cervix, characterized by aggressive clinical behavior and absence of high-risk human papillomavirus. We conducted this study to evaluate the chemosensitivity of GAS compared with that of usual-type endocervical adenocarcinoma (UEA) in patients who had been enrolled in our previous study. METHODS: Of 52 patients from our previous phase 2 study (SGSG005) of neoadjuvant chemotherapy with docetaxel and carboplatin for stage IB2 to IIB nonsquamous cervical cancer, 47 (stage IB2, 12; stage IIA2, 7; stage IIB, 28) were enrolled in this study with written informed consent. The biopsy specimens before neoadjuvant chemotherapy and surgical specimens after chemotherapy were centrally reviewed based on the updated World Health Organization classification (2014). RESULTS: Of 47 patients with nonsquamous cell carcinoma, 20 (42.6%) were diagnosed with UEA, 13 (27.7%) with GAS, 12 (25.5%) with adenosquamous carcinoma, and 1 patient each (2%) with small cell carcinoma and serous carcinoma. Consequently, 33 patients, consisting of 20 patients with UEA and 13 patients with GAS, were eligible for the current study. The response rate of GAS was significantly lower than that of UEA (46.2% vs 85.0%, P = 0.048). Of 16 cases of stage II UEA, 11 (68.8%) were downstaged on microscopic examination of postsurgical specimens, but none of the 8 patients with stage II GAS showed any response (P < 0.01). Two inoperative tumors were GAS. With a median follow-up duration of 56 months, the 5-year progression-free and overall survival rates of GAS were significantly worse than those of UEA (38.5% vs 75.0% [P = 0.011] and 36.9% vs 90.0% [P < 0.001], respectively). CONCLUSIONS: These findings suggest that GAS should be distinguished from UEA by its chemoresistance, necessitating an alternative treatment strategy established for this distinct subtype of endocervical adenocarcinoma.

Type C2 radical hysterectomy may improve outcomes of locally advanced mucinous adenocarcinoma of the uterine cervix.

BACKGROUND: It is not known whether radiotherapy or surgery is better as initial treatment for locally advanced mucinous adenocarcinoma of the uterine cervix. METHODS: We reviewed the medical records and pathological materials of 32 patients with International Federation of Gynecology and Obstetrics stage IB2-IIB mucinous adenocarcinoma, who had undergone radiotherapy or radical hysterectomy as primary treatment between 2001 and 2010. p16(INK4a) immunohistochemistry was performed as a marker for human papillomavirus-related adenocarcinoma. RESULTS: Thirteen patients received radiotherapy and 19 patients underwent radical hysterectomy. The cumulative 3-year locoregional control rates in the radical hysterectomy and radiotherapy groups were 79.0 and 46.2 % (P = 0.03), and 5-year overall survival rates were 70.7 and 38.5 % (P = 0.09), respectively. Of patients with p16(INK4a)-positive tumors (n = 19), the cumulative 3-year locoregional control rates in the radical hysterectomy and radiotherapy groups were 100 and 60.0 % (P = 0.01), and 5-year overall survival rates were 88.9 and 40.0 % (P = 0.04), respectively. Conversely, the cumulative 3-year locoregional control rates in the human papillomavirus-negative radical hysterectomy group and radiotherapy group were 20.0 and 37.5 % (P = 0.66), and 5-year overall survival rates were 20.0 and 37.5 % (P = 0.60), respectively. CONCLUSIONS: Radical hysterectomy may significantly improve locoregional control and overall survival compared with radiotherapy for stage IB2-IIB mucinous adenocarcinoma patients, especially those with p16(INK4a)-positive mucinous adenocarcinoma.

[A case of platinum-resistant, recurrent ovarian clear cell adenocarcinoma successfully treated with irinotecan (CPT-11) and paclitaxel (PTX) chemotherapy].

A 40-year-old woman presented to a local clinic with abdominal distension. She was referred to our hospital for suspected ovarian cancer. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed an ovarian tumor with mural nodules, ascites, pleural effusion, and peritoneal dissemination. Laparotomy revealed a 20-cm right ovarian tumor with strong adhesion to the uterus and rectum. Bilateral salpingo-oophorectomy was performed as a primary surgery. The histopathological diagnosis was stage IVovarian clear cell adenocarcinoma, and 6 cycles of postoperative chemotherapy with a combination of TC (paclitaxel [PTX] and carboplatin) and the mTOR inhibitor temsirolimus was administered. During maintenance treatment with temsirolimus, the lesion recurred, and progressive disease was confirmed. Because relapse occurred after 5 months from the last TC treatment, the disease was considered platinum-resistant ovarian cancer, and second-line chemotherapy with 6 cycles of irinotecan (CPT-11 ) and PTX was administered. Partial response was observed after 2 cycles, and the response period was 7 months. We suggest that chemotherapy with CPT-11/PTX could be a treatment option for platinum resistant recurrent ovarian clear cell adenocarcinoma.

Maximum standardized uptake value of fluorodeoxyglucose positron emission tomography/computed tomography is a prognostic factor in ovarian clear cell adenocarcinoma.

BACKGROUND: Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is useful for diagnosing malignant tumors. Intracellular FDG uptake is measured as the standardized uptake value (SUV), which differs depending on tumor characteristics. This study investigated differences in maximum SUV (SUVmax) according to histologic type in ovarian epithelial cancer and the relationship of SUVmax with prognosis. METHODS: This study included 80 patients with ovarian epithelial cancer based on histopathologic findings at surgery and who had undergone PET/CT before treatment. Maximum SUV on PET/CT of primary lesions and histopathology were compared based on histologic type, and the prognosis associated with different SUVmax was evaluated. RESULTS: Clinical tumor stage was I in 35 patients, II in 8, III in 25, and IV in 12. Histologic type was serous adenocarcinoma (AC) in 33 patients, clear cell AC in 27, endometrioid AC in 15, and mucinous AC in 5. Median SUVmax was lower in mucinous AC (2.76) and clear cell AC (4.9) than in serous AC (11.4) or endometrioid AC (11.4). Overall, median SUVmax was lower in clinical stage I (5.37) than in clinical stage ≥II (10.3). However, in both clear cell AC and endometrioid AC, when histologic evaluation was possible, no difference was seen between stage I and stage ≥II. Moreover, in clear cell AC, the 5-year survival rate was significantly higher in the low-SUVmax group (100%) than in the high-SUVmax group (43.0%, P = 0.009). CONCLUSIONS: Maximum SUV on preoperative FDG-PET/CT in ovarian epithelial cancer differs according to histologic type. In clear cell AC, SUVmax may represent a prognostic factor.

Absence of high-risk human papillomavirus (HPV) detection in endocervical adenocarcinoma with gastric morphology and phenotype.

A subset of endocervical-type mucinous adenocarcinomas (ACs) of the uterine cervix exhibit a gastric phenotype and morphology, as reported in cases of minimal deviation AC in which the presence of human papillomavirus (HPV) has been rarely detected. To investigate the HPV-independent pathway of carcinogenesis in cases of gastric-type AC, we investigated the common high-risk HPV (hr-HPV) status in 52 nonsquamous cell carcinomas, using a PCR-based typing method and immunohistochemistry of p16INK4a (a cyclin-dependent kinase inhibitor that is overexpressed in both cancerous and precancerous cervical tissue, making it an ideal biomarker for cervical cancer cases). Using novel morphological criteria, seven of 52 (13.5%) carcinomas were designated as gastric-type ACs, all of which were negative for both hr-HPV DNA and p16INK4a. Nongastric-type ACs were frequently positive for both hr-HPV DNA (90%, 28/31) and p16INK4a (94%, 29/31) with adenosquamous and neuroendocrine carcinomas demonstrating the presence of hr-HPV DNA in 86% (6/7) and 83% (5/6) of cases, respectively. In these two types of carcinoma, 86% (6/7) and 100% (6/6) were positive for p16INK4a, respectively. Our data suggests that gastric-type AC appears to represent an oncogenic hr-HPV-independent neoplasm and therefore is a potential pitfall of HPV DNA testing and vaccination.

Establishment and characterization of a human cell line derived from a uterine papillary serous carcinoma with wild-type p53 function.

Uterine papillary serous carcinoma is an uncommon histologic subtype of endometrial cancer that behaves aggressively and has a poor prognosis. We successfully established a uterine papillary serous carcinoma cell line. The population-doubling time was approximately 16 h. Although loss of p53 function is considered critical for the molecular pathogenesis of uterine papillary serous carcinoma, p53 was not only mutated but functionally active in this cell line. This newly established cell line should be useful for investigating the characteristics of uterine papillary serous carcinoma.

Gastric morphology and immunophenotype predict poor outcome in mucinous adenocarcinoma of the uterine cervix.

Endocervical-type mucinous adenocarcinoma (ECA) of the uterine cervix is defined as a tumor composed of cells resembling those of the endocervical glands, but recent studies have demonstrated that a minority of ECAs displays a gastric immunophenotype. The aim of this study was to assess the significance of the gastric phenotype. Fifty-three cases of mucinous adenocarcinoma of the uterine cervix (37 FIGO stage IB, 4 stage IIA, and 12 stage IIB) were reviewed and reevaluated using a newly established morphologic criteria for distinguishing gastric type adenocarcinoma, which was defined as a tumor showing clear and/or pale eosinophilic and voluminous cytoplasm, with distinct cell borders. The results were correlated with gastric immunophenotype, determined by HIK1083 and MUC6 immunostaining, and patient outcome. Following the current World Health Organization scheme (2003), 47 tumors (89%) were classified as ECA, 1 (2%) as intestinal type, 1 (2%) as mixed endocervical and intestinal type, and 4 (8%) as minimal deviation adenocarcinoma. Twelve of 47 (26%) ECAs and all 4 minimal deviation adenocarcinomas, reclassified as gastric type using the novel criteria, were frequently positive for HIK1083 with a rate of 75% (12/16), whereas only 11% (4/37) of nongastric tumors were positive. There was no significant difference in MUC6 reactivity between gastric and nongastric type tumors (31%, 5/16 vs. 16%, 6/37; P=0.4). Patients with gastric-type adenocarcinomas had a significantly decreased 5-year disease-specific survival rate (30 vs. 77%; P<0.0001), and the gastric type morphology was related to a significant risk for disease recurrence compared with the nongastric type (P=0.001; HR, 4.5; 95% confidence interval, 1.42-14.2). HIK1083-positivity was also related to decreased 5-year disease-specific survival rate (38% vs. 74%; P<0.005). Mucinous adenocarcinoma of the uterine cervix with gastric immunophenotype can be a distinct morphologic variant showing an aggressive clinical course.

Correlative expression of cyclooxygenase-1 (Cox-1) and human epidermal growth factor receptor type-2 (Her-2) in endometrial cancer.

OBJECTIVES: Cyclooxygenase-2 (Cox-2) is known to be associated with tumorigenesis in many cancers including endometrial cancer, while there is substantial evidence for the tumorigenicity of cyclooxygenase-1 (Cox-1). However, little is known about the involvement of Cox-1 in the development of endometrial cancer. The aim of this study was to determine whether cyclooxygenase-1 or -2 (Cox-1, Cox-2) is tumorigenetic, as well as whether these two cyclooxygenase isoforms correlate with the clinicopathological characteristics or with another two biomarkers, human epidermal growth factor receptor type-2 (Her-2) and vascular endothelial growth factor (VEGF), of endometrial cancer. METHODS: At first, Cox-1 and Cox-2 levels in eight endometrial cancer cell lines were determined by means of real-time PCR. At second, the levels of four biomarkers (Cox-1, Cox-2, Her-2, and VEGF) in 70 endometrial cancer samples were determined by means of real-time PCR. Pairs of these biomarkers were subjected to correlation as each biomarker and clinical status or survival. RESULTS: In the eight cell lines, the expression of Cox-1 and Cox-2 showed major variations in their mRNA levels. Analysis of the patient samples showed that the mRNA expression of Cox-1 was elevated significantly in the G1 (P=0.021) and G2 (P=0.036) groups, as was the mRNA expression of Her-2 in the two groups (P=0.036 and P=0.0029, respectively). The mRNA expression of Cox-1 and Her-2 were correlated (CI=0.671). None of the three biomarkers, Cox-1, Cox-2, and Her-2, was correlated with clinical status such as FIGO classification, myometrial invasion, or clinical outcome. CONCLUSION: Cox-1, together with Her-2, may be involved in the early stage of endometrial cancer development.

Poor prognosis of patients with stage Ib1 adenosquamous cell carcinoma of the uterine cervix with pelvic lymphnode metastasis.

From January 1990 to December 2004, the prognosis of 28 patients with stage Ib1 adenosquamous cell carcinoma (ASC) were assessed in comparison with those of matched counterparts of pure adenocarcinoma (ADC) and squamous cell carcinoma (SCC). The mean ages were 46.6, 48.3, and 48.5 years for patients with ASC, ADC, and SCC, respectively. All the patients underwent radical hysterectomy with pelvic lymphadenectomy and postoperative adjuvant therapy was given to the patients with positive pathological risk. The incidence of lymph node metastasis for ASC at 21.4% was not significantly different from those for ADC (13.6%) and SCC (15.8%). There was also no significant difference in the incidence of lymphatic or vascular space involvement (LVSI) and depth of stromal invasion between three cell types. Since the tumor sizes of all ASC cases examined in this study were less than 4 cm, the prognoses were compared among stage Ib1 disease according to the classification system of the International Federation of Gynecology and Obstetrics (FIGO). The overall 5-year survival rates of stage Ib1 ASC, ADC, and SCC were 82.4%, 92.4%, and 94.0%, respectively, suggesting poor prognosis of ASC, but there was no significant difference. Patients with stage Ib1 ASC were retrospectively assigned to a low- or high-risk group based on the surgical-pathologic factors including positive lymph node metastasis, 2-4 cm of tumor size, positive LVSI, and/or deep stromal invasion. While all 9 patients in the low-risk group are alive without disease, 7 of the 19 patients in the high-risk group developed recurrence. The overall 5-year survival rates were 100% for a low risk group and 74.8% for a high-risk group, respectively, but this difference did not reach statistical significance. However, the prognosis of high-risk patients with lymph node metastasis was significantly (p=0.01) worse than low-risk group. The present study suggests that ASC histology appears to carry a poor prognosis than SCC, but low-risk group of stage Ib1 ASC has a good prognosis without postoperative adjuvant therapy.

Eradication and reinfection of human papillomavirus after photodynamic therapy for cervical intraepithelial neoplasia.

BACKGROUND: Photodynamic therapy (PDT) has been proven to be a promising therapeutic modality for selected dysplasias and malignancies in a variety of organs. We assessed the effectiveness of PDT for treating cervical intraepithelial neoplasia (CIN) by cytological and histological examinations and investigated its impact on human papillomavirus (HPV) infection. METHODS: A series of 31 patients with CIN (2 with CIN2, 29 with CIN3) were given polyhematoporphyrin ether/ester (PHE) 2 mg/kg IV. After 60 h their cervices were exposed to a 630-nm YAG-OPO laser. HPV-DNA extracted from cervical smears was amplified by the polymerase chain reaction and typed for HPV using restriction fragment length polymorphism. RESULTS: At 3 months after PDT, cytology and directed biopsy of the cervix revealed regression of the disease in 28 [complete remission (CR) rate 90%] of 31 patients, and HPV-DNA could be no longer detected in the cervical smears of 22 (76%) of 29 HPV-positive patients. After 12 months, all 31 patients had achieved a CR on biopsy, although HPV-DNA was still present in the cervical smears of 6 patients. The types of HPV-DNA detected 12 months after PDT were different from those seen before PDT in each of the 6 patients, suggesting that they might be reinfected with other HPV types after PDT. CONCLUSION: PDT is effective not only in improving the cytological and histological measures when treating CIN but also for eradicating cervical HPV.