Safety and efficacy of neoadjuvant chemotherapy containing bevacizumab and interval debulking surgery for advanced epithelial ovarian cancer: A feasibility study.

BACKGROUND AND OBJECTIVES: The optimum treatment strategy for patients with unresectable advanced epithelial ovarian cancer is controversial. This study examined bevacizumab combined with neoadjuvant chemotherapy (NAC; paclitaxel plus carboplatin), followed by interval debulking surgery (IDS), for these patients. METHODS: In a prospective nonrandomized study, newly diagnosed patients received four cycles of NAC (three cycles combined with bevacizumab), followed by IDS. The primary endpoint was the complete resection rate at IDS. Secondary endpoints were the NAC response rate, adverse events during NAC, and perioperative complications. RESULTS: Twenty-three patients were enrolled. The complete resection rate at IDS was 60.9% (95% confidence intervals [CI]: 38.5% to 80.3%). The NAC response rate was 86.9% (95% CI: 66.4% to 97.2%). Adverse events ≥ grade 3 during NAC were neutropenia (78.3%), anemia (52.2%), hypertension (17.4%), and proteinuria (8.7%). There was no thromboembolism or gastrointestinal perforation. Grade 2 complications of IDS included lymphatic complications (13.6%), infections (9.1%), ileus (4.5%), and wound dehiscence (4.5%). There were no thromboembolic complications, fistula/abscess, or perforation/anastomotic leak, and no complications ≥ grade 3. CONCLUSIONS: In Japanese patients with advanced ovarian cancer, bevacizumab + NAC followed by IDS is an acceptable strategy. Further investigation of its prognostic effect is warranted.

Multicenter Clinicopathological Study of High-Grade Serous Carcinoma Presenting as Primary Peritoneal Carcinoma.

OBJECTIVE: We conducted a multicenter clinicopathological study to characterize patients with high-grade serous carcinoma presenting as primary peritoneal carcinoma (clinical PPC). METHODS: At 9 sites in Japan, patients with clinical PPC diagnosed according to Gynecologic Oncology Group criteria were enrolled retrospectively. The Gynecologic Oncology Group criteria allow for minor ovarian involvement by high-grade serous carcinoma. There was no systematic detailed histopathological review of the fallopian tubes to determine whether they were involved by serous carcinoma. RESULTS: There were 139 patients and 64% were aged 60 years or older. Median pretreatment serum CA-125 was 1653.5 IU/mL. Pretreatment performance status was poor in more than 50%, endometrial cytology was positive in 40.3%, and the preoperative clinical diagnosis was correct in 72.7%. Primary debulking surgery was performed in 36% of patients, whereas 64% underwent neoadjuvant chemotherapy (NAC) with interval debulking surgery (IDS). The main tumor sites were the upper abdomen (greater omentum), extrapelvic peritoneum, mesentery, and diaphragm. Lymph node metastasis was found in 46.8% of patients undergoing systematic retroperitoneal node dissection. The optimal surgery rate was 32.0% with primary debulking surgery versus 53.9% with NAC and IDS (P = 0.0139). The response rate was 82.0% with NAC and 80.6% with postoperative chemotherapy. Median progression-free survival was 19.0 months and median overall survival was 41.0 months. Multivariate analysis showed that prognostic factors for progression-free survival were NAC and residual tumor diameter after debulking surgery, whereas the only prognostic factor for overall survival was the residual tumor diameter. CONCLUSIONS: This study identified various characteristics of clinical PPC. Neoadjuvant chemotherapy with IDS is a reasonable treatment strategy, and complete debulking surgery is optimum.

Platinum-resistant recurrent ovarian cancer with long survival on bevacizumab and gemcitabine.

Platinum-resistant recurrent ovarian cancer has a poor prognosis, but combined therapy with bevacizumab and anticancer agents may be useful. We report a patient with long-term disease control by the combination of bevacizumab and gemcitabine (BEV + GEM). The patient was a 77-year-old woman with high-grade Stage IIIC serous ovarian carcinoma. In 2012, a complete response (CR) was obtained by neoadjuvant and adjuvant chemotherapy using paclitaxel plus carboplatin and tumor debulking surgery. After recurrence in 2013, CR was achieved again with gemcitabine plus carboplatin. In 2014, recurrence was detected again, but CR was achieved by third-line combination therapy with gemcitabine, carboplatin and bevacizumab. In 2015, the third recurrence was found during bevacizumab maintenance therapy. Fourth-line treatment was initiated with BEV + GEM, which has maintained stable disease for 29 months. This is the first report about marked prolongation of survival by BEV + GEM in a patient with platinum-resistant recurrent ovarian cancer.

Effective Selection of a Well-Differentiated Type of Human Uterine Endometrial Carcinoma Cells by Transfection of the Sulfotransferase Gene and Possible Association of Sulfoglycolipids With Well-Differentiated Phenotypes.

OBJECTIVES: Sulfatide has been shown to be characteristically increased on the apical surface of the normal endometrium at the secretory phase, and to be related with the formation of the glandular structure and the secretion of mucin from glands for the implantation of a fertilized egg. Additionally, sulfatides are expressed in the well-differentiated type, but not in the poorly differentiated type, of endometrial carcinomas. This suggests that sulfatides are a molecular marker of differentiated phenotypes. To further elucidate the biological significance of sulfoglycolipids, we transfected the sulfotransferase gene into endometrial carcinoma-derived cells without sulfoglycolipids and compared their glycolipid compositions and phenotypes with those of the original cells. MATERIALS AND METHODS: The glycolipid sulfotransferase gene was transfected into endometrial carcinoma-derived SNG-II cells, the resultant transfected cells being found to frequently form a domelike structure, and some of them were selected as SNG-II-GST cells. We compared the glycolipid compositions and phenotypes of SNG-II and SNG-II-GST cells. RESULTS: Although the original SNG-II cells grew in a paving stone pattern, SNG-II-GST cells formed a domelike structure. SNG-II-GST cells exhibited high GST activity and contained sulfoglycolipids, IISO3-LacCer and IISO3-Gg3Cer, which were not found in SNG-II cells. The amounts of sulfoglycolipids in SNG-II-GST cells were 1.5 times higher than those of gangliosides, and the proportions of LacCer and GM3 in SNG-II-GST cells were greatly different from those in SNG-II cells. SNG-II and SNG-II GST cells exhibited poorly differentiated and well-differentiated phenotypes on histochemical examination of cancerous nodules in nude mice. However, by means of an oxygen electrode, SNG-II-GST cells were found to be more resistant to anticancer drugs than SNG-II cells. CONCLUSION: Enhanced expression of sulfoglycolipids in poorly differentiated cells is a feasible means of selecting well-differentiated ones, and sulfoglycolipids are involved in the well-differentiated phenotype like those in the normal endometrium at the secretory phase.

Japan Society of Gynecologic Oncology guidelines 2013 for the treatment of uterine body neoplasms.

The third version of the Japan Society of Gynecologic Oncology guidelines for the treatment of uterine body neoplasms was published in 2013. The guidelines comprise nine chapters and nine algorithms. Each chapter includes a clinical question, recommendations, background, objectives, explanations, and references. This revision was intended to collect up-to-date international evidence. The highlights of this revision are to (1) newly specify costs and conflicts of interest; (2) describe the clinical significance of pelvic lymph node dissection and para-aortic lymphadenectomy, including variant histologic types; (3) describe more clearly the indications for laparoscopic surgery as the standard treatment; (4) provide guidelines for post-treatment hormone replacement therapy; (5) clearly differentiate treatment of advanced or recurrent cancer between the initial treatment and the treatment carried out after the primary operation; (6) collectively describe fertility-sparing therapy for both atypical endometrial hyperplasia and endometrioid adenocarcinoma (corresponding to G1) and newly describe relapse therapy after fertility-preserving treatment; and (7) newly describe the treatment of trophoblastic disease. Overall, the objective of these guidelines is to clearly delineate the standard of care for uterine body neoplasms in Japan with the goal of ensuring a high standard of care for all Japanese women diagnosed with uterine body neoplasms.

Performance of p16INK4a/Ki-67 immunocytochemistry for identifying CIN2+ in atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion specimens: a Japanese Gynecologic Oncology Group study.

BACKGROUND: p16(INK4a) immunohistochemistry has revealed a high rate of positivity in cervical intraepithelial neoplasia grade 2 (CIN2) and more severe conditions (CIN2+). The Lower Anogenital Squamous Terminology Standardization project proposed p16(INK4a) immunohistochemistry as an ancillary test for CIN. Immunocytochemistry involving dual staining for p16(INK4a) and Ki-67 in the triage of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) is reported to be useful in the identification of CIN2+. However, it is unclear whether p16(INK4a)/Ki-67 immunocytochemistry is of practical relevance for the triage of ASCUS and LSIL in the Japanese screening system. METHODS: From 427 women fulfilling the eligibility criteria, 188 ASCUS and 239 LSIL specimens were analyzed. The accuracy of p16(INK4a)/Ki-67 immunocytochemistry and genotyping of high-risk human papillomaviruses (HPVs) in detecting CIN2+ were compared. RESULTS: p16(INK4a)/Ki-67 immunocytochemistry was positive in 33.5 % (63/188) of ASCUS, and 36.8 % (88/239) of LSIL specimens. The sensitivity and specificity of p16(INK4a)/Ki-67 immunocytochemistry was 87.3 % (95 % confidence interval 78.0-93.8 %) and 76.4 % (71.6-80.8 %), respectively. The positive and negative predictive values were 45.7 % (37.6-54.0 %) and 96.4 % (93.4-98.3 %), respectively; positive and negative likelihood ratios were 3.71 and 0.17, respectively. Using the McNemar test, p16(INK4a)/Ki-67 immunocytochemistry showed equivalent sensitivity but higher specificity than the HPV genotyping test CONCLUSIONS: Compared with high-risk HPV genotyping, p16(INK4a)/Ki-67 immunocytochemistry was a more accurate triage test for identifying CIN2+ in ASCUS and LSIL specimens.

Feasibility study on the effectiveness of Goreisan-based Kampo therapy for lower abdominal lymphedema after retroperitoneal lymphadenectomy via extraperitoneal approach.

AIM: To evaluate the efficacy and safety of Kampo therapy based on Goreisan for lower abdominal lymphedema after surgical treatment of endometrial cancer or cervical cancer. METHODS: Radical surgery, including retroperitoneal lymphadenectomy, was performed for endometrial cancer and cervical cancer. After surgery, Kampo therapy based on Goreisan and integrated physical therapy were provided for patients with lower abdominal lymphedema, especially lymphedema affecting the pubic-inguinal-vulval region. Goreisan (7.5 g/day) was given orally three times a day (tds). If a significant response was not observed, Saireito (9 g/day; 3 g tds) or Gosyajinkigan (7.5 g/day; 2.5 g tds) was administered concomitantly. RESULTS: A total of 21 patients received treatment. The response rate to Goreisan monotherapy was 78%, with 22% being non-responders. Median reduction of abdominal circumference was 2.1cm (95% CI 1.3-2.85). When Goreisan was combined with another Kampo agent, the response rate was 92% and the non-response rate was 8%. The median reduction of the abdominal circumference was 2.85 cm (95% CI: 2.25-3.3). In particular, concomitant Goreisan and Saireito therapy achieved satisfactory results. No severe adverse reactions occurred. CONCLUSIONS: Goreisan-based Kampo therapy might be effective and safe for lower abdominal lymphedema after retroperitoneal lymphadenectomy. We will perform a prospective control study in the near future.

Ovarian pulmonary-type small cell carcinoma: case report and review of the literature.

Ovarian pulmonary-type small cell carcinoma is a rare and extremely aggressive neoplasm. We report the occurrence of an ovarian small cell carcinoma of pulmonary type in a 54-year-old woman. She underwent a total abdominal hysterectomy with a bilateral salpingo-oophorectomy and infracolic omentectomy. A diagnosis of stage IIIA pulmonary-type small cell carcinoma was rendered. The tumor appeared to be composed of a solid growth of small cells arranged in sheets and closely packed nests with insular arrangements separated by a fibrous stroma. The tumor cells had hyperchromatic nuclei with inconspicuous nucleoli and scanty cytoplasm. Rosette and rosette-like structures were scattered. Immunohistochemical staining showed positivity for synaptophysin, neural cell adhesion molecule (NCAM), and focally for chromogranin. Cytokeratin and neuron-specific enolase (NSE) were also positive. Over 80% of the tumor cells showed strong reactivity for MIB-1. Electron microscopy showed neuroendocrine granules. She was effectively treated with paclitaxel plus carboplatin after the surgery.

Laparoscopically resected uterine adenomatoid tumor with coexisting endometriosis: case report.

Adenomatoid tumors are rare benign mesothelial tumors of the genital tract, and only a few cases of uterine adenomatoid tumors treated at laparoscopic surgery have been reported. Herein is reported the case of a laparoscopically resected uterine adenomatoid tumor with coexisting endometriosis. A 34-year-old nulliparous woman with suspected uterine fibroma and endometrial cysts underwent laparoscopic surgery in which both the uterine tumor and the endometrial cysts were enucleated. Enucleation of the uterine tumor was difficult, and, therefore, the border between the tumor and normal myometrium was divided using a harmonic scalpel for tumor resection. Microscopic examination of the tumor showed irregularly proliferating smooth muscle cells and many round hiatuses lined by epithelial-like cells. These epithelial-like cells were immunohistochemically positive for mesothelin and podoplanin, and negative for CD34, which suggests that the tumor was an adenomatoid tumor. This may be the fourth reported case of an adenomatoid tumor resected using the laparoscopic approach.

Case of atypical polypoid adenomyoma that possibly underwent a serial progression from endometrial hyperplasia to carcinoma.

Atypical polypoid adenomyoma is a rare uterine tumor composed of atypical endometrial glands, which often exhibit squamous metaplasia, and a cellular smooth muscle stroma. Although atypical polypoid adenomyoma is categorized as a benign lesion, it is reportedly associated with endometrial cancer, and it shows persistence and recurrence even after conservative medical treatment. We present a rare case of atypical polypoid adenomyoma that possibly underwent a serial pathological change from endometrial hyperplasia to carcinoma in a 40-year-old woman with no history of pregnancy. She was diagnosed with atypical polypoid adenomyoma during polypectomy surgery. After resecting the atypical polypoid adenomyoma, endometrial hyperplasia complex was detected. This condition eventually progressed from atypical hyperplasia complex to endometrial adenocarcinoma, and total abdominal hysterectomy was performed. A patient with atypical polypoid adenomyoma who wishes to preserve her fertility should be carefully monitored for endometrial carcinoma. If endometrial hyperplasia is detected in such a patient, a meticulous follow-up examination by performing endometrial biopsy is mandatory.

Supraclavicular lymph node metastasis as the initial presentation of primary fallopian tube carcinoma.

Supraclavicular lymph node metastasis is a rare presentation of primary fallopian tube carcinoma. A 76-year-old woman presented with an enlarged supraclavicular lymph node. A biopsy was performed, and its findings confirmed metastatic adenocarcinoma. Subsequent exploratory laparotomy revealed right fallopian tube carcinoma as the primary lesion; consequently, right salpingo-oophorectomy was performed. After adjuvant chemotherapy, she underwent a laparotomy with total abdominal hysterectomy, left salpingo-oophorectomy, pelvic and para-aortic lymph node sampling, and omentectomy. Supraclavicular lymph node metastasis was thought to be, although rarely, the first manifestation of primary fallopian tube carcinoma (PFTC). When supraclavicular lymph node metastasis of an unknown origin is encountered, the possibility of PFTC should be considered.

Characteristic expression of Lewis-antigenic glycolipids in human ovarian carcinoma-derived cells with anticancer drug-resistance.

By comparing ovarian carcinoma-derived KF28 cells with the corresponding anticancer drug-resistant cells, the taxol- and cisplatin-resistant properties were found to be closely related with MDR1 and BSEP, and MRP2 transporters, respectively. In addition to the transporters expression, the amounts of glycolipids, particularly their longer carbohydrate structures, in the resistant cells increased to 3-4-fold of those in the sensitive cells due to enhanced transcription of the respective glycosyltransferases. The major glycolipids in the sensitive and resistant cells were GlcCer and Gb(3)Cer, respectively, and extension of the carbohydrate structure into Lewis antigen characteristically occurred in the resistant cells. Le(b), which was not detected in the cisplatin-resistant cells, was present in the taxol-resistant cells, while Le(x) was present in the cisplatin-resistant cells at a higher concentration than in the taxol-resistant cells. 2-Hydroxy fatty acids were significantly abundant in glycolipids of the resistant cells, but they were not detected in free ceramides or sphingomyelin, indicating that the enhanced synthesis of glycolipids in the resistant cells was not linked with the removal pathway for virulent ceramides derived from sphingomyelin. The resistant cells with abundant glycolipids exhibited lower membrane fluidity than the KF28 cells, and this property might be involved in the anticancer drug-resistance.

Spontaneously Ruptured Paraovarian Tumor of Borderline Malignancy with Extremely Elevated Serum Carbohydrate Antigen 125 (CA125) Levels: A Comparison of the Imaging and Pathological Features.

BACKGROUND Paraovarian cysts are common and are generally benign; however, they are frequently misdiagnosed as being of ovarian origin. Conversely, paraovarian tumors of borderline malignancy are extremely rare. Especially, no cases of spontaneous rupture have been reported, and all previous reports had normal serum carbohydrate antigen (CA) 125 level. As for imaging findings, the presence of papillary projections in the lumen of paraovarian tumors does not always indicate malignancy or benignancy, which makes the preoperative distinction difficult. CASE REPORT We report a case involving a 22-year-old Asian woman with a spontaneously ruptured paraovarian tumor of borderline malignancy. The serum CA125 concentration was extremely elevated, at 28,831 U/mL. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a collapsed unilocular cystic lesion with multiple papillary projections. On MRI, the papillary projections showed two different patterns, which corresponded to the pathological findings. CONCLUSIONS Ruptured paraovarian tumors of borderline malignancy may show extremely high serum CA125 values. Furthermore, specific MRI findings may be useful in evaluating the malignancy of paraovarian tumors.

Intratumor injection of small interfering RNA-targeting human papillomavirus 18 E6 and E7 successfully inhibits the growth of cervical cancer.

Human papillomavirus (HPV) 18 is related not only to squamous cell carcinoma of the cervix, but also to adenocarcinoma and small cell carcinoma of the cervix, in which prognosis is known to be poor. Small interfering RNA (siRNA) that targets HPV18 E6 and E7 was tested in HPV18-positive cell lines to investigate its effect and investigate its mechanism of action. Nude mice were also tested in a combination of siRNA and atelocollagen to determine whether it might be useful as a new molecule-targeting therapy for cervical cancer. siRNAs targeting HPV18 E6 and E7 were transfected into cervical cancer cells in vitro and they were investigated for cell growth inhibition, expression of E6 and E7 mRNA, expression of retinoblastoma protein, and senescence-associated beta-galactosidase staining. Sequence-specific siRNA inhibited cell growth. Decreased expression of E6 and E7 mRNA followed with E7 protein was observed in the transfected cells, but the expression of retinoblastoma protein and the beta-galactosidase staining increased, suggesting cell growth inhibitory effect through senescence. Treatment of xenografts established from SKG-II cells with siRNA specific for E6 and E7 obviously suppressed tumor growth in vivo. These results indicate that atelocollagen-mediated delivery of siRNA HPV18 E6 and E7 can be used as a novel therapeutic approach for cervical cancer.

Less Invasive Endometrial Cancer Surgery with Extraperitoneal Pelvic and Para-aortic Lymphadenectomy via a Small Midline Abdominal Incision and the Retroperitoneal Approach.

[Objective] To achieve less invasive lymphadenectomy in endometrial cancer patients, we performed extraperitoneal pelvic and para-aortic lymphadenectomy via a small midline abdominal incision with retroperitoneal approach. The feasibility and safety of this method were investigated. [Methods] Inclusion criteria were 1) endometrioid adenocarcinoma diagnosed by preoperative biopsy, 2) myometrial invasion by magnetic resonance imaging, and 3) no peritoneal dissemination or distant metastasis by computed tomography. Systematic extraperitoneal dissection of pelvic and para-aortic lymph nodes was performed via an approximately 12-cm midline lower abdominal incision, after which hysterectomy and bilateral salpingo-oophorectomy were done (extraperitoneal group). The historical control group was patients who underwent standard transperitoneal lymphadenectomy followed by hysterectomy and bilateral salpingo-oophorectomy. The two groups were compared for demographic characteristics, perioperative factors, and complications. [Results] A total of 62 patients were enrolled. Demographic and clinicopathological factors showed no differences between the extraperitoneal group (n = 34) and the historical control group (n = 28). The median number of pelvic (30 vs. 28) and para-aortic (14 vs. 17) nodes dissected was also similar. However, median intraoperative blood loss was significantly smaller in the extraperitoneal group than the control group (220 vs. 573 g). Median operating time (265 vs. 323.5 min), median laparotomy time (60 vs. 295 min), and median initial flatus time (8 vs. 32 hours) were all significantly shorter in the extraperitoneal group, while complications and severe postoperative pain were significantly less frequent. [Conclusions] Our new technique was feasible, safe, and less invasive than standard laparotomy. It is an alternative to laparoscope-assisted or robotic procedures.

Comparison between in situ hybridization and real-time PCR technique as a means of detecting the integrated form of human papillomavirus 16 in cervical neoplasia.

Integration of the human papillomavirus (HPV) genome is thought to be one of the causes of cancer progression. However, there is controversy concerning the physical status of HPV 16 in premalignant cervical lesions, and there have been no reports on the concordance between detection of the integrated form of HPV16 by real-time PCR and by in situ hybridization. We investigated specimens of cervical intraepithelial neoplasia (CIN) and invasive carcinomas for the physical status of HPV 16 by real-time PCR and in situ hybridization. The presence of the integrated form was detected by both real-time PCR and in situ hybridization in zero of four cases of CIN1, three of six cases of CIN2, nine of 27 cases of CIN3, and two of six cases of invasive carcinomas. Integrated HPV 16 was present in some premalignant lesions but was not always present in carcinomas. The concordance rate between the two methods for the detection of the presence of the integrated form was 37 of 43 (86%) cases. Real-time PCR and in situ hybridization were found to be complementary and convenient techniques for determining the physical status of the HPV genome. We conclude that a combination of both methods is a more reliable means of assessing the physical status of the HPV genome in cervical neoplasia.

Peptides inhibitory for the transcriptional regulatory function of human papillomavirus E2.

PURPOSE: Human papillomavirus (HPV) infections are associated with cervical neoplasia. Cellular and viral proteins are known to interact with the papillomavirus E2 protein to initiate transcription and DNA replication in the HPV life cycle. Our aim was to identify peptides that bind to the HPV16 E2 protein and thereby inhibit its ability to alter the transcriptional activity of other genes. EXPERIMENTAL DESIGN: The HPV16 E2 protein was expressed and purified to near homogeneity in bacteria. We screened a phage display library of random peptides for ones that bound to HPV16 E2 protein. Among the isolated phage clones, we found that tryptophan-rich peptide sequences appeared repetitively in successive cycles of phage library panning. Replacement of the tryptophan amino acids in these dodecapeptides reduced the degree to which these peptides bound to the E2 protein. These E2-binding peptides were tested for their ability to inhibit the transcriptional regulatory function of E2 in a test cell line, which contained an E2 gene and a luciferase reporter gene driven by an E2-dependent transcriptional promoter. RESULTS: Delivery of four of the E2 binding peptides into the intracellular compartment of the test cell line resulted in suppression of the E2-dependent luciferase expression. Deletion of the tryptophan residues from these peptides reduced their E2 binding and their ability to suppress E2-dependent luciferase expression in the test cell line. CONCLUSIONS: These results suggest a strategy for the development of chemical inhibitors of E2-dependent transcription of viral genes in HPV-infected cells as an approach to the therapy of chronic HPV infections.

Human Papillomavirus Test for Triage of Japanese Women With Low-Grade Squamous Intraepithelial Lesions.

We evaluated high-risk human papillomavirus (HR-HPV) DNA testing for high-grade cervical intraepithelial neoplasia (CIN) lesions by cobas HPV test and diagnostic HPV16/18 genotyping in Japanese women with low-grade squamous intraepithelial lesions. Of 357 patients, HR-HPV positivity prevalence was 75.6%, and 21.3% had grade 2 or higher CIN lesions (CIN2+), with the highest prevalence at 30 to 34 years. Negative predictive values of HR-HPV for CIN2+ in our patients were 93.1% (any age) and 94.9% (40-50 years). Absolute risk for CIN2+ in HR-HPV positive and HPV16/18 positive individuals was 25.9 and 35.1, respectively. Relative risk for CIN2+ lesions was 5.1 for HPV16/18 positive versus HR-HPV negative, and 3.8 for HR-HPV positive versus HR-HPV negative women. Predictive values of CIN2+ positive were higher for HPV16/18 positive women (any age) than 12 other HPV positive-genotypes, and highest (50%) at 40-50 years. The HPV16/18 genotyping might prevent women (>40 years) at risk of high-grade CIN lesions from undergoing unnecessary colposcopy/overtreatment of nonprogressive lesions.

P16 overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix.

Carcinogenesis of cervical cancer has been investigated, and p16(INK4a) overexpression in squamous cell carcinoma of the cervix has been reported as a result of infection by human papillomavirus (HPV) (eg, HPV 16), and the consequence of the retinoblastoma (Rb) protein inactivation by HPV E7 protein. However, to our knowledge, there have been no studies on the relation between p16(INK4a) overexpression associated with HPV and small cell carcinoma of the cervix, which behaves more aggressively clinically than squamous cell carcinoma. The purpose of this study was to determine whether p16(INK4a) is overexpressed in small cell carcinoma, and if p16(INK4a) is overexpressed, the types of HPV that are related to this cancer. We reviewed 10 cases of small cell carcinoma and examined them for p16(INK4a) overexpression by immunohistochemistry. We also performed HPV typing with polymerase chain reaction (PCR)-sequencing analysis and in situ hybridization and found that p16(INK4a) was overexpressed in every case. PCR-sequencing analyses revealed that all cases were HPV-positive and that 9 cases were positive for HPV 18. Five of the 9 cases positive for HPV 18 were also positive by in situ hybridization and yielded a punctate signal, considered to represent the integrated form. In conclusion, p16(INK4a) was overexpressed and HPV 18 was frequently detected in an integrated form in small cell carcinoma. Therefore, inactivation of Rb protein by HPV 18 E7 protein may be associated with carcinogenesis of small cell carcinoma the same as inactivation of Rb protein by HPV 16 E7 protein is associated with carcinogenesis of squamous cell carcinoma.