Mari Kasai

Potential role of LMP2 as tumor-suppressor defines new targets for uterine leiomyosarcoma therapy

Although the majority of smooth muscle neoplasms found in the uterus are benign, uterine leiomyosarcoma (LMS) is extremely malignant, with high rates of recurrence and metastasis. We earlier reported that mice with a homozygous deficiency for LMP2, an interferon (IFN)-γ-inducible factor, spontaneously develop uterine LMS. The IFN-γ pathway is important for control of tumor growth and invasion and has been implicated in several cancers. In this study, experiments with human and mouse uterine tissues revealed a defective LMP2 expression in human uterine LMS that was traced to the IFN-γ pathway and the specific effect of JAK-1 somatic mutations on the LMP2 transcriptional activation. Furthermore, analysis of a human uterine LMS cell line clarified the biological significance of LMP2 in malignant myometrium transformation and cell cycle, thus implicating LMP2 as an anti-tumorigenic candidate. This role of LMP2 as a tumor suppressor may lead to new therapeutic targets in human uterine LMS.

Potential role of LMP2 as an anti-oncogenic factor in human uterine leiomyosarcoma: Morphological significance of calponin h1

Uterine leiomyosarcoma (LMS) is a highly metastatic smooth muscle neoplasm for which calponin h1 is suspected to have a biological role as a tumor‐suppressor. We earlier reported that LMP2‐null mice spontaneously develop uterine LMS through malignant transformation of the myometrium, thus implicating this protein as an anti‐tumorigenic candidate as well. In the present study, we show that LMP2 may negatively regulate LMS independently of its role in the proteasome. Moreover, several lines of evidence indicate that although calponin h1 does not directly influence tumorigenesis, it clearly affects LMP2‐induced cellular morphological changes. Modulation of LMP2 may lead to new therapeutic approaches in human uterine LMS.

Preoperative Diagnosis of Usual Leiomyoma, Atypical Leiomyoma, and Leiomyosarcoma

Uterine smooth muscle tumors (SMTs) are common pelvic tumors in women, and most of them are diagnosed as usual leiomyoma (UL). Exclusion of malignant disease is important in the management of SMTs. However, differentiation of SMTs remains difficult. In this study, we aimed to improve the preoperative diagnosis of SMTs. We examined 21 ULs, 7 atypical leiomyomas (ALs), and 6 leiomyosarcomas (LMSs), all of which were diagnosed by uterine tumor biopsy. Immunohistochemical findings (low-molecular-mass polypeptide 2 (LMP2) and Ki-67) and clinical features (serum lactate dehydrogenase level and menopause) were evaluated. Statistically significant differences in the expression of LMP2 and Ki-67 were observed between UL and AL and between UL and LMS. The combined LMP2 and Ki-67 score was significantly different between UL and AL, between UL and LMS, and between AL and LMS. The combined immunohistochemistry and clinical findings score (total score) was also significantly different between pathological types. The findings of this study suggest that the accuracy of the preoperative diagnosis of SMTs may be improved by using a combination of immunohistochemical and clinical findings.

Chemotherapy-induced neutropenia and febrile neutropenia in patients with gynecologic malignancy

Chemotherapy-induced neutropenia is a common complication in cancer treatment. In this study, we investigated chemotherapy-induced neutropenia that was recently detected in all patients with gynecologic malignancy. Between January 2009 and December 2011, we examined cases of chemotherapy-induced neutropenia reported in our hospital. We analyzed the incidence and clinical features of chemotherapy-induced neutropenia and febrile neutropenia in patients with gynecologic malignancy. During the study period, we administered over 1614 infusions (29 regimens) to 291 patients. The median age of the patients was 60 years (range 24–84 years). Chemotherapy-induced neutropenia occurred in 147 (50.5%) patients over 378 (23.4%) chemotherapy cycles. Febrile neutropenia occurred in 20 (6.9%) patients over 25 (1.5%) cycles. The mean duration of neutropenia and fever was 3.6 days (range 1–12 days) and 3.4 days (range 1–9 days), respectively. The source of fever was unexplained by examination or cultures in 14 (56.0%) cycles. There were two cases of neutropenia-related death. Chemotherapy-induced neutropenia was associated with older age (over 70 years) (P<0.0001), less than five previous chemotherapy cycles (P=0.02), disseminated disease (P=0.03), platinum-based regimens (P<0.0001), taxane-containing regimens (P<0.0001), and combined therapy (P<0.0001). Febrile neutropenia was associated with poor performance status (P<0.0001), no previous chemotherapy (P<0.05), disseminated disease (P<0.0001), and distant metastatic disease (P=0.03). Neither chemotherapy-induced neutropenia nor febrile neutropenia was associated with bone marrow metastases or previous radiotherapy. By identifying risk factors for febrile neutropenia, such as performance status, no previous chemotherapy, disseminated disease, and distant metastatic disease, the safe management of chemotherapy-induced neutropenia may be possible in patients with gynecologic malignancy.

Prediction of the shrinking rate of uterine leiomyoma nodules using needle biopsy specimens

OBJECTIVE To determine correlations between shrinkage of uterine leiomyomas after treatment with GnRH agonists (GnRH-a) or menopause and expression levels of estrogen receptors (ER), progesterone receptors (PR), and vascular endothelial growth factor (VEGF). DESIGN Cohort study. SETTING University teaching hospital. PATIENT(S) A total of 26 women with uterine leiomyoma. INTERVENTION(S) Ten women were treated with buserelin acetate injection (1.8 mg), four courses every 4 weeks, and 16 women went into menopause naturally. MAIN OUTCOME MEASURE(S) Tumor shrinkage rates determined from magnetic resonance images taken before and after GnRH-a therapy and before and after natural menopause; immunohistochemical analysis of ER, PR, and VEGF in uterine leiomyoma biopsy specimens taken before intervention or within 6 months before menopause. RESULT(S) Shrinkage rates of uterine leiomyomas were positively correlated with expression levels of ER in women treated with GnRH-a and in postmenopausal women managed conservatively, and with VEGF expression in women treated with GnRH-a. There were no significant correlations with PR expression levels in either group. CONCLUSION(S) Estrogen plays the predominant role in myoma shrinkage for women with GnRH-a therapy and naturally menopausal women.

Involvement of proteasome β1i subunit, LMP2, on development of uterin leiomyosarcma

Background: Although the majority of smooth muscle neoplasms found in the uterus are benign, uterine leiomyosarcoma is extremely malignant, with high rates of recurrence and metastasis. The development of gynecologic tumors is often correlated with secretion of female hormone; however, the development of human uterine leiomyosarcoma is not substantially correlated with hormonal conditions, and the risk factors are unclearly understood. Importantly, a diagnostic-biomarker, which distinguishes malignant human uterine leiomyosarcoma from benign tumor leiomyoma is yet to be established. Aims: It is necessary to analyze risk factors associated with human uterine leiomyosarcoma, in order to establish a diagnostic-biomarker and a clinical treatment method. Patients and Methods: Histology and Immunofluorescence Staining: Uteri obtained from LMP2–/– mice or its parental mice (C57BL/6 mice) were fixed in 10% buffered formalin, incubated in 4% paraformaldehyde for 8 hours, and embedded in paraffin. Tissue sections (5 μm) were prepared and stained with H&E for routine histological examination or were processed further for immunofluorescence staining with appropriate antidodies. Furthermore, a total of 101 patients between 32 and 83 years of age and diagnosed as having smooth muscle tumors of the uterus were selected from pathological files. Immunohistochemistry staining for LMP2 was performed on serial human uterine leiomyosarcoma, leiomyoma and myometrium sections. Results: Homozygous deficient mice for a proteasome β1i subunit, LMP2 spontaneously develop uterine leiomyosarcoma, with a disease prevalence of ~40% by 14 months of age. Defective LMP2 expression in human uterine leiomyosarcoma was demonstrated, but present in human leiomyoma and myometrium. Conclusions: Loss in LMP2 expression may be one of the risk factors for human uterine leiomyosarcoma. LMP2 may be a potential diagnostic-biomarker and targeted-molecule for a new therapeutic approach.

Two cases of uterine malignant lymphoma diagnosed by needle biopsy

The incidence of primary malignant lymphoma arising in the female genital tract is extremely rare and constitutes approximately 0.05% of malignant tumors. Uterine malignant lymphoma develops in the endometrial stroma, causing minimal necrosis. It is therefore difficult to diagnose malignant lymphoma, as it does not involve genital bleeding or epithelial defects. We have performed transcervical needle biopsies from deep in the myometrium, with the purpose of diagnosing uterine muscle layer lesions, such as leiomyosarcoma, but this is an unusual method. In this report, we suggest that transcervical needle biopsy is useful in the diagnosis of uterine malignant lymphoma.

A retrospective clinical analysis of 5 cases of vaginal melanoma

Vaginal melanoma is a rare tumor, accounting for <1% of all melanomas and ~1-5% of all vaginal malignant tumors. The prognosis of vaginal melanoma is extremely poor, as it is often resistant to chemotherapy and radiotherapy, and metastases may develop in the early stages of the disease. The present study investigated 5 patients with vaginal melanoma treated at the Department of Gynecology of Osaka City University Hospital (Osaka, Japan) between October, 2000 and April, 2014. All the cases presented with abnormal genital bleeding as the main complaint. Notably, in 3 of the 5 cases the tumors appeared as non-pigmented polyps. Local resection was performed as the primary treatment in all 5 cases. After surgery, dermal injection of interferon β (feron maintenance therapy) was performed in 3 cases, and dacarbazine, nimustine, vincristine and interferon β (DAVFeron therapy) was administered in 1 case as adjuvant therapy. All 5 cases recurred within 1 year. The site of recurrence varied, and included the vaginal wall, liver, brain and lung. The median overall survival was 419 days and the median progression-free survival 177 days. In this cohort, all the cases presented with abnormal genital bleeding as the main complaint. Therefore, malignant melanoma of the vagina must be considered along with other gynecological malignancies in patients with abnormal genital bleeding. In this study, over half of the cases had a non-pigmented polypoid lesion of the vagina. Therefore, malignant melanoma of the vagina must be considered when a polypoid lesion is identified on the vaginal wall.

Primitive neuroectodermal tumor originating in the vulva: A case report

Primitive neuroectodermal tumors (PNETs) exhibit chromosomal translocations in common with those of Ewing’s sarcoma. They usually originate in bone or soft tissue but rarely arise in the vulva. The current case report presents a case of PNET originating in the vulva in a 60-year-old female, who previously underwent enucleation of a vulvar tumor in another hospital. The pathologist suspected a histopathological diagnosis of PNET, and simple vulvectomy and resection of the inguinal lymph nodes were performed. An ~3 cm mass recurred in the right side of the vulva four years following the initial surgery and the tumor was excised. The tumor comprised small, round-to-oval nuclei and stained positively for MIC-2, synaptophysin, neuron-specific enolase and neurofilament antibodies. To date, the patient remains alive and with no evidence of disease four years following multidisciplinary treatment, despite PNETs usually exhibiting a poor prognosis. This is due to the small tumor size and the absence of distant metastasis.

Examination of the use of needle biopsy to perform laparoscopic surgery safely on uterine smooth muscle tumors

The warning statement issued by the United States Food and Drug Administration against the use of laparoscopic power morcellators prompted a discussion about the methods of preoperative diagnosis of uterine myometrial lesions. Since 1994, transcervical needle biopsies have been performed to differentiate between uterine leiomyomas and leiomyosarcomas. Needle biopsies are also useful for performing laparoscopic surgery on uterine smooth muscle tumors with histopathological safety. In the present study, data from hematoxylin and eosin (HE)-stained specimens obtained by transcervical needle biopsies from 331 patients with smooth muscle tumors and high intensity regions on T1 weighted images (WI) and/or T2WI from magnetic resonance imaging (MRI) scans were retrospectively examined. From a total of 10 patients with moderate or severe cytological atypia, 4 exhibited smooth muscle tumors of uncertain malignant potential and 6 exhibited leiomyosarcomas. The final diagnosis in 3 patients with ≥10 mitotic figures/high-power field was leiomyosarcoma. A total of 5 patients with coagulative tumor cell necrosis exhibited final diagnoses of leiomyosarcoma. Patients without cytological atypia, mitotic figures or coagulative tumor cell necrosis were not diagnosed with either leiomyosarcomas or smooth muscle tumors of uncertain malignant potential. The present study revealed that laparoscopic surgery is safe when HE-stained specimens obtained by transcervical needle biopsy from areas of high intensity on an MRI scan are negative for all three criteria assessed-cytological atypia, mitotic figures and coagulative tumor cell necrosis.