Mitsuya Ishikawa

p16INK4a 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.

Correlation of p16INK4A overexpression with human papillomavirus infection in cervical adenocarcinomas.

As human papillomavirus (HPV) infection is the main risk factor for squamous cell carcinoma of the cervix and overexpression of p16INK4a occurs when retinoblastoma protein is inactivated by high-risk HPV, the authors studied the association of HPV infection and expression of p16INK4a in cervical adenocarcinomas. Specimens of cervical glandular neoplasias were immunostained with a p16INK4a-specific monoclonal antibody (clone E6H4). Approximately 80% of glandular neoplasms showed overexpression of p16INK4a. Exfoliated cells from 14 adenocarcinomas were further examined by p16INK4a-specific immunocytochemistry, and 12 cases showed overexpression of p16INK4a, suggesting that immunostaining for p16INK4a may be a useful diagnostic tool for cervical adenocarcinomas. The authors further examined HPV DNA in cervical adenocarcinomas with the polymerase chain reaction method. Overexpression of p16INK4a was positive in 94% of cases in which HPV16 or 18DNA was positive, a finding suggesting that HPV16 or 18 may play an important role in cervical adenocarcinomas. Overexpression of p16INK4a may be an indicator of pathogenic activity of high-risk HPVs.

Clinicopathological and prognostic impact of human epidermal growth factor receptor type 2 (HER2) and hormone receptor expression in uterine papillary serous carcinoma

Uterine papillary serous carcinoma (UPSC) is a rare and aggressive variant of endometrial carcinoma. Little is known about the pathological and biological features of this tumor. Human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) expression have an important role in tumor behavior and clinical outcome, but their relevance in UPSC is not clear. In the present study, the immunohistochemical expression of HER2 and HR was assessed in 27 patients with Stage I disease, 13 with Stage II disease, 25 with Stage III disease, and 6 with Stage IV disease. Correlations between HER2 and HR expression and the clinicopathological parameters of UPSC were evaluated using Coxs univariate and multivariate analyses. For all patients, the 5‐year recurrence‐free survival (RFS) and overall survival (OS) rates were 51% and 66%, respectively; in patients with Stage I, II, III and IV disease, the RFS and OS were 67%/81%, 59%/77%, 43%/54% and 0%/0%, respectively. Of all 71 patients, 14% (10/71) were positive for HER2 and 52% (37/71) were positive for HR. Overexpression of HER2 was correlated with lower OS (P = 0.01), whereas HR overexpression was correlated with higher OS (P = 0.008). In multivariate models, HER2, HR, and histologic subtype were identified as independent prognostic indicators for RFS (P = 0.022, P = 0.018, and P = 0.01, respectively), but HR was the only independent factor associated with OS (P = 0.044). Thus, HER2 and HR are prognostic variables in UPSC, with HR an independent prognostic factor for OS. (Cancer Sci 2012; 103: 926–932)

Prognostic significance of positive peritoneal cytology in adenocarcinoma of the uterine cervix

OBJECTIVE A retrospective analysis was carried out to evaluate the prognostic significance of peritoneal cytology in cervical adenocarcinoma. METHODS The records of 107 patients with FIGO stage IB to IIB cervical adenocarcinoma who underwent hysterectomy were reviewed. RESULTS Sixteen patients (15%) had positive peritoneal cytology. The 5-year survival rate among patients with positive or negative cytology was 50% or 87%, respectively, showing a significant difference (log-rank, P<0.001). The recurrence-free survival (RFS) rate at 36 months in the cytology-positive or -negative group was 53% or 87%, respectively, the difference being significant (log-rank, P=<0.001). Cox model analysis revealed positive cytology [hazards ratio (HR) 6.27, 95% confidence interval (CI) 2.13-18.41], positive lymph node (HR 6.20, 95% CI 1.87-20.57), ovarian metastasis (HR 5.20, 95% CI 1.18-22.82), and histological grade (HR 5.97, 95% CI 2.00-17.78) to be independent adverse risk factors for survival among the factors analyzed (lymph node status, lymph-vascular space invasion, tumor size, depth in cervical wall, pathological parametrial involvement, infiltration to vagina, ovarian metastasis, and histological grade). Cox model analysis showed that positive cytology (HR 4.58, 95% CI 1.48-14.16), positive lymph node (HR 7.61, 95% CI 2.69-21.54), and histological grade (HR6.13, 95% CI 2.14-17.77) were independent adverse risk factors for RFS. The incidence of peritoneal spread at the first recurrence among the cytology-positive group (62.5%) was significantly higher than that among the cytology-negative group (12.5%) (Fishers exact test, P=0.021). CONCLUSION The presence of positive peritoneal cytology appears to be an independent prognostic risk factor in patients with cervical adenocarcinoma.

Expression of TGFß1 and its receptors is associated with biological features of ovarian cancer and sensitivity to paclitaxel/carboplatin

It has been suggested that expression of TGFß1 and its receptors [TGFß receptor type I (TßRI) and TGFß receptor type II (TßRII)] may play a key role in the proliferation and progression of epithelial ovarian cancer. We investigated the biological significance of TGFß1 and its receptors, as well as their association with the tumor response to paclitaxel (PTX) and carboplatin (CBDCA). We studied 24 patients with ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who had undergone surgery and chemotherapy with PTX and CBDCA. Tissues from the primary tumor were examined and the expression of TGFß1, TßRI, and TßRII mRNA was assessed by the RNase protection assay. It was found that TGFß1 mRNA expression was significantly lower in the tumors of patients who had optimal surgery than in the tumors of patients with suboptimal surgery. TGFß1 mRNA expression was also significantly lower in tumors with high sensitivity to PTX and CBDCA than in those with low sensitivity. TßRI mRNA expression was not associated with any clinicopathological factors. Expression of TßRII mRNA was significantly higher in clear cell adenocarcinoma and mucinous adenocarcinoma, while it was lower in serous adenocarcinoma and endometrioid adenocarcinoma. Moreover, it tended to be higher in early-stage tumors compared with advanced tumors. Among TGFß1, TßRI, and TßRII, expression of TGFß1 mRNA was most strongly associated with progression-free survival. When the prognosis of the patients with advanced cancer was compared on the basis of TGFß1 mRNA expression, those whose tumors showed low expression tended to have a better prognosis than those whose tumors showed high expression. It is suggested that TGFß1 mRNA expression is an indicator of tumor sensitivity to standard therapy with PTX and CBDCA, that it can identify biologically aggressive and highly malignant tumors and that it can predict the prognosis of patients with ovarian cancer.

A case of ovarian cancer with remote metastases, with emphasis on changes in tumor marker values

BACKGROUND The prognosis of cancer patients with distant metastases is extremely poor. CASE A 51-year-old Japanese woman with Stage IIIc serous cystoadenocarcinoma of the ovary achieved complete remission. At 30 and 39 months after the initiation of therapy, solitary brain and then spleen metastases without intraperitoneal lesions were found, respectively. A simultaneous elevation in tumor markers (CA125 and CA72-4) was noted at the spleen metastasis; however, only a marked elevation in CA 72-4 levels at the brain metastasis was noted. Immunohistochemical studies revealed that although CA125-positive cells could be observed in both the original tumor and the spleen metastasis, CA125-positive cells could not be observed in the brain metastasis and that CA72-4-positive cells could be observed in both the original ovarian tumor and the metastatic tumor. CONCLUSION It is important to monitor with tumor markers with different characteristics, such as CA125 and CA72-4.

Serous Adenocarcinoma of the Uterine Cervix: A Clinicopathological Study of 12 Cases and a Review of the Literature

Background/Aims: To determine the clinicopathological characteristics and potentially associated outcomes in patients diagnosed with serous adenocarcinoma of the uterine cervix. Methods: The records of surgically-treated patients with pathological stage pT1b–2b serous adenocarcinoma were reviewed. Results: Of 12 patients with serous adenocarcinoma who underwent radical hysterectomy, five had pT1b1N0 disease, two pT1b1N1, two pT1b2N0, and three pT2bN1. The 5-year overall survival rate for patients with or without parametrial involvement (pT2b vs. pT1b) was 0 and 89%, respectively. The 3-year recurrence-free survival rate for those with or without parametrial involvement was 33 and 89%, respectively. Four patients suffered recurrence, namely one of those who had pT1b (1/9, 11%) and 3 of those who had pT2b disease (100%). The sites of recurrence of pT2b disease were outside the pelvis in all 3 patients. Of these, 2 (67%) had peritoneal spread and 1 distant node metastasis. Conclusion: While patients with pathological stage pT1b disease may have a relatively favorable outcome after radical surgery, those with more advanced disease have a poor prognosis because of extra-pelvic recurrence.

Successfully treated case of epithelioid sarcoma of the vulva.

Epithelioid sarcoma of the vulva is an extremely rare and aggressive tumor. This tumor most commonly occurs on the labia majora in women of reproductive age. The molecular pathogenesis remains largely unknown. Only 20 cases of vulvar epithelioid sarcoma have been reported to date and more than half have had poor outcomes. We report a successfully treated case of vulvar epithelioid sarcoma in a 33‐year‐old woman. We performed a radical vulvectomy with flap reconstruction. Three years after surgery, the patient remains well, showing no evidence of recurrence. Early tissue diagnosis of vulvar epithelioid sarcoma is essential because this tumor can be clinically misdiagnosed as a benign lesion. Gynecologists should be aware of this rare tumor variant and carefully plan the treatment.

Combination of squamous cell carcinoma‐antigen, carcinoembryonic antigen, and carbohydrate antigen 19‐9 predicts positive pelvic lymph nodes and parametrial involvement in early stage squamous cell carcinoma of the uterine cervix

Aim:  We examined the correlations between the pretreatment values of four tumor markers (squamous cell carcinoma [SCC]‐antigen, carcinoembryonic antigen [CEA], carbohydrate antigen [CA]19‐9, and CA125) and postsurgical high‐risk factors (parametrial involvement and positive pelvic lymph nodes) in women with SCC of the uterine cervix who had International Federation of Gynecology and Obstetrics clinical stage IB and IIA disease and underwent radical hysterectomy.

A rare case of recurrent ovarian cancer presenting as a round ligament metastasis

We report a rare case of recurrent ovarian cancer presenting as a round ligament metastasis. A 44-year-old woman presented with a lower abdominal mass. Computed tomography showed a pelvic mass. Primary surgery was performed. A histopathological examination showed an ovarian serous adenocarcinoma of Stage IIIb. The patient received 6 cycles of paclitaxel and carboplatin. Almost 2 years after the initial operation, the patient noticed a left inguinal mass. Computed tomography showed a left inguinal mass, 18 mm in size. An excisional biopsy was performed and the tumor was found to originate in the left round ligament. A histopathological examination showed serous adenocarcinoma and there was no evidence of lymph node tissue. Recurrence of ovarian cancer in the round ligament is extremely rare. This unique case suggests, however, that the round ligament in rare cases may be a recurrence site for ovarian cancer, and that accurate differentiation including confirmation by diagnostic imaging and excisional biopsy, is necessary for a definitive pathological diagnosis.