Endometrioid Carcinoma of the Uterine Corpus With a Micropapillary Component: A Novel Prognostic Factor For Metastasis.

BACKGROUND/AIM: Micropapillary pattern is a morphologically distinctive form of carcinoma composed of small, hollow, or morula-like clusters of cancer cells surrounded by clear stromal spaces. The neoplastic cells characteristically display a reverse polarity, also known as an ''inside-out'' growth pattern, that is linked to higher frequencies of lymphovascular invasion and lymph nodal metastasis. To the best of our knowledge, it has not been previously recognized in uterine corpus. CASE REPORT: We report 2 cases of endometrioid carcinoma of the uterine corpus with a micropapillary component. In these cases, histological examination identified an endometrioid carcinoma that had invaded the myometrial layer. The carcinoma cells that constructed the micropapillary components were immunohistochemically positive for EMA. They lined the stromal facing surface of the cell membrane, confirming the inside-out growth pattern, and D2-40 immunohistochemistry confirmed lymphovascular invasion of carcinoma cells. CONCLUSION: We believe that the micropapillary pattern linked to higher frequencies of lymphovascular invasion and lymph nodal metastasis may be one of the most important invasive patterns in endometrioid carcinomas of the uterine corpus for predicting aggressive malignant potential, prognosis, and recurrence, although further, larger studies are required to evaluate its clinical significance.

Cytoplasmic streaming induced by intracytoplasmic spindle translocation contributes to developmental competence through mitochondrial distribution in mouse oocytes.

OBJECTIVE: To evaluate the developmental competency of mouse metaphase II oocytes and the pattern of mitochondrial positioning through cytoplasmic streaming in mouse metaphase II oocytes. DESIGN: We observed cytoplasmic streaming as movement indicated by fluorescently stained mitochondria using a newly developed method in which the spindle is translocated to the opposite site of the oocyte. This method is termed as intracytoplasmic spindle translocation (ICST). SETTING: University research laboratory. ANIMALS: Female B6D2F1 mice. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Fresh oocytes, postovulatory-aged oocytes, and oocytes treated with cytochalasin B were classified based on the presence of cytoplasmic streaming induced by ICST. The pattern of redistributed mitochondria and developmental competence caused by parthenogenetic activation were evaluated in oocytes with or without cytoplasmic streaming. RESULT(S): Induced cytoplasmic streaming occurred in 84% of the fresh oocytes but not in the postovulatory-aged oocytes and the oocytes treated with cytochalasin B. Abnormal mitochondrial aggregation was observed in oocytes in which cytoplasmic streaming was not induced. Furthermore, the developmental competence was significantly lower in oocytes without cytoplasmic streaming. CONCLUSION(S): Cytoplasmic streaming induced by ICST contributes to developmental competence through the redistribution of mitochondria and may be a valuable criterion for predicting early developmental competence in mouse oocytes.

Prognostication of Ovarian Function after Ovarian Torsion Using Intraoperative Indocyanine Green Angiography.

STUDY OBJECTIVE: To quantitatively evaluate the blood flow in ovaries (ischemic ovaries) that underwent torsion using indocyanine green angiography (ICGA) and assess the use of ICGA as an indicator for functional preservation of the ovaries. DESIGN: In vivo animal study. SETTING: The University of Yamanashi Animal Experimentation Center. SUBJECTS: Eighteen female Wistar albino rats. INTERVENTIONS: As an alternative to ovarian torsion, we occluded an ovary in each rat for 24 hours, after which we performed ICGA before and after releasing ischemia and extracted the following 8 parameters: Fmax (maximum F value before releasing ischemia); Tmax (time taken from the onset of an increase in F to reaching Fmax); T½max (time taken from the onset of an increase in F to reaching half of Fmax); slope (Fmax/Tmax); time ratio (T½max/Tmax); F'max (maximum F value after releasing ischemia); reperfusion rate (F'max/Fmax); and reperfusion gap (F'max - Fmax). Four weeks later, we counted the total number of primordial and primary follicles and classified the rats into functional and nonfunctional groups. MEASUREMENTS AND MAIN RESULTS: On the basis of the total number of primordial and primary follicles, 13 rats had "functional" ovaries on the clamped side, and 5 rats had "nonfunctional" ovaries. The area under the curve values for each parameter were as follows: Fmax, 0.908; Tmax, 0.569; T½max, 0.546; time ratio, 0.746; slope, 0.877; F'max, 0.723; reperfusion rate, 0.938; and reperfusion gap, 0.862. CONCLUSION: ICGA can be used to quantitatively evaluate ovaries that have been subjected to ischemia, and the magnitude of fluorescence intensity can be an excellent predictor of ovarian necrosis. Quantifying the degree of reperfusion immediately after the release of ischemia can be an equally excellent predictor of necrosis.

Leptomeningeal metastasis from cervical cancer: Report of two cases and a review of the literature.

Leptomeningeal metastases from cervical cancer are extremely rare, with only 24 cases reported in the English-language literature. Leptomeningeal metastasis (LM) is usually a late event, but it can develop at any stage. A 44-year-old woman presented with vertigo, tinnitus, diminution of hearing, and a cervical tumor at the initial visit. She underwent whole brain radiotherapy and systemic chemotherapy. Five months after the initial visit, her condition deteriorated rapidly and she died. A 49-year-old woman underwent surgery and pelvic radiotherapy for cervical cancer. She underwent resection of lung metastases 2 years later and received systemic chemotherapy for lymph node metastases 4 years later. Five years after the initial visit, the patient suddenly presented with diplopia, headache, and vomiting; her clinical course was fulminant and she died. Most patients with LM present with diverse clinical manifestations and deteriorate rapidly despite multiple treatment modalities. Gynecologic oncologists should be aware of this rare complication.

High-grade uterine sarcoma with osteosarcomatous differentiation arising from a MED12-mutated leiomyoma, a case report.

Uterine osteosarcoma has been reported, but it is an extremely rare tumor with highly aggressive behavior and poor prognosis. The pathogenesis of uterine osteosarcoma is not fully understood. Herein, we report on a high-grade uterine sarcoma with focal osteosarcomatous differentiation that developed from a long-standing MED12-mutated leiomyoma. A 47-year-old nulligravida woman, with known uterine leiomyoma presented with abdominal pain and distention. Imaging analyses revealed a tumor with a large cystic area in the uterine corpus and multiple metastases in intrapelvic and paraaortic lymph nodes, left ovary and left lung. With a clinical diagnosis of uterine sarcoma the patient underwent abdominal total hysterectomy, bilateral salpingo-oophorectomy, partial omentectomy and removal of the left obturator lymph node. Despite postoperative chemotherapy and radiation therapy, the tumor progressed rapidly. She died 18 weeks after the surgery. Histopathologic examination identified a high-grade pleomorphic sarcoma in which focal osteoid production was observed. This high-grade sarcoma with focal osteosarcomatous differentiation was located within the uterine leiomyoma, and Sanger sequencing showed the identical MED12 L36R mutation in both the osteosarcomatous and leiomyomatous components supporting the shared origin of these two components. We, therefore, concluded that the high-grade sarcoma with osteosarcomatous differentiation arose from the transformation of the precedent leiomyoma.

Improvement of early developmental competence of postovulatory-aged oocytes using metaphase II spindle injection in mice.

PURPOSE: Assisted reproductive technology (ART) is a widely applied fertility treatment. However, the developmental competence of aged oocytes from women of a late reproductive age is seriously reduced and the aged oocytes often fail in fertilization even when ART is used. To resolve this problem, we examined usefulness of a new method "the metaphase II spindle transfer (MESI)" as ART using mouse oocytes. METHODS: This work was composed of two experiments. First, 24 hours after collection, embryos from oocytes (1-day-old oocytes, called postovulatory-aged oocytes), were observed, after intracytoplasmic sperm injection (ICSI), and it was found that they were not able to reach the blastocyst stage. Next, the metaphase II chromosome-spindle complexes from 1-day-old oocytes were injected into cytoplasts from oocytes just collected, using piezo pulses to generate reconstructed oocytes. This procedure was named metaphase II spindle injection (MESI). RESULTS: After ICSI, embryos from the reconstructed oocytes (32/105), which contained the genes of 1-day-old oocytes, were able to develop into the blastocyst stage. The fragmentation rate after ICSI was 28.6%. Thus, the developmental competence of 1-day-old oocytes was improved by MESI. CONCLUSIONS: The MESI method has the potential to improve the success rate of infertility treatments for women of a late reproductive age.

Lesion-targeted cytology to improve cytological sampling for atypical polypoid adenomyomas of the uterus: A case series and review of the literature.

OBJECTIVE: Atypical polypoid adenomyomas (APAs) are uncommon tumours consisting of atypical endometrioid glands and fibromyomatous stroma. Identifying the biphasic nature of atypical glandular components and spindle mesenchymal components without atypia is crucial for the cytological diagnosis of APA. We investigated the utility of lesion-targeted cytology (LTC) to directly collect firm spindle components. METHODS: We recruited seven consecutive surgical patients who underwent cytological examinations before surgery and were diagnosed with APA on postoperative histological examinations. Cytological smears were obtained by routine sampling in five cases and by targeted sampling using transvaginal ultrasonography, that is, LTC, in two cases. We retrospectively analysed the cytological findings from our cases and compared them to those of APA cases previously reported in the English literature. RESULTS: Among 5/7 cases that involved routine cytological sampling, normal cytological findings were found in 2 and atypical glandular cells were found in 3, but spindle cells from mesenchymal components were not detected. In contrast, among 2/7 cases in which sampling involved LTC, spindle cells without atypia, in addition to atypical glandular cells were found. CONCLUSIONS: Lesion-targeted cytology is useful to assess mesenchymal components of APAs and may improve the cytological diagnosis of APA.

Utility of imaging modalities for predicting carcinogenesis in lobular endocervical glandular hyperplasia.

OBJECTIVES: To investigate the use of imaging methods for predicting carcinogenesis in lobular endocervical glandular hyperplasia (LEGH). METHODS: We retrospectively analyzed preoperative images on transvaginal sonography and magnetic resonance imaging (MRI) in 23 cases with histologically diagnosed LEGH. RESULTS: Shape of cervical multicystic lesions on MR images could be divided into two types the flower-type with many small cysts surrounded by larger cysts, and the raspberry-type with many tiny, closely aggregated cysts. Six (46%) of 13 cases had raspberry-type lesions that were not detected on transvaginal sonography but were seen on MRI. Adenocarcinoma in situ (AIS) was identified in 4 postmenopausal women with raspberry-type lesions during the follow-up periods. In these cases, cytologic examination by targeted endocervical sampling using sonography enabled early detection of AIS. CONCLUSIONS: MRI and cytologic examination by targeted endocervical sampling may be very useful for predicting carcinogenesis in LEGH.

Bone Marrow Invasion of Small Cell Neuroendocrine Carcinoma of the Endometrium: A Diagnostic Pitfall Mimicking a Haematological Malignancy.

Metastasis of cancer cells to the bone marrow is relatively rare, despite being one of the most important causes of myelosuppression in patients with solid tumours. A bone marrow examination via a biopsy is the standard method of diagnosing cancer cell invasion into the bone marrow. However, it is sometimes challenging to distinguish neuroendocrine carcinoma cells from haematopoietic cells due to their small, round shape and chromosomal abnormalities resembling haematological malignancies. We herein report a case of bone marrow invasion of small cell neuroendocrine carcinoma of the endometrium mimicking therapy-related myeloid malignancy.

Interpretation of Endocervical Cells With Gastric-Type Mucin on Pap Smears.

OBJECTIVES: Early detection of endocervical adenocarcinoma is especially important for cancers that are human papillomavirus (HPV) negative. We investigated the clinicopathologic significance of yellow gastric-type mucin observed on Papanicolaou smears. METHODS: We described "atypical endocervical cells with gastric-type mucin" (AEC-GAM) when yellow mucin was observed in endocervical cells. We retrieved AEC-GAM samples from 58,752 cervical smears performed at Yamanashi University Hospital during our study period and reviewed clinical, cytologic, and pathologic features. RESULTS: We detected AEC-GAM in 172 (0.29 %) smears from 65 patients, and 41 of these 65 patients were histologically diagnosed with lobular endocervical glandular hyperplasia (LEGH) (43%) or pyloric gland metaplasia (20%). The prevalence of adenocarcinoma was 25% (7/28) in LEGH cases and 11% (7/65) in AEC-GAM smears. CONCLUSIONS: Yellow mucin is a diagnostic clue for endocervical glandular lesions with gastric differentiation. We recommend describing AEC-GAM on cytologic reports to improve cytologic screening for HPV-negative cervical cancers.

A case of endocervical minimal deviation adenocarcinoma with varicolored cytopathologic features on Pap smear.

We report a case of minimal deviation adenocarcinoma (MDA) of the uterine cervix showing varicolored cytopathologic features on Papanicolaou (Pap) smear, which may indicate features suggestive of lobular endocervical glandular hyperplasia (LEGH)-adenocarcinoma sequence. A 57-year-old woman presented with a profuse amount of watery vaginal discharge. Gynecological examination revealed a cervical mass with involvement of the right parametrium. Conventional Pap smear showed hypercellularity consisting of approximately 4 types of clusters as follows: (1) clusters showing a monolayered honeycomb sheet of endocervical cells with golden-yellow mucin and bland nuclei, (2) three-dimensional clusters showing varicolored mucin and irregular nuclear overlapping, (3) irregularly shaped clusters showing distorted chicken-wire-mesh appearance with noticeable protrusions of the nuclei and clear or faint varicolored cytoplasm, and (4) crowded clusters showing scarce mucin and nuclear atypia. The surgically resected uterus revealed LEGH-mimicking lesion with fused papillae and a cribriform pattern in the endocervix and many glands exhibiting gastric differentiation that invaded deeper areas of the stroma with a subtle stromal reaction. Compared with histologic findings, two types of clusters, the crowded cluster with scarce mucin and the cluster with distorted chicken-wire-mesh-type appearance, were considered as adenocarcinoma, and the latter was interpreted as a gastric-type adenocarcinoma. Three-dimensional varicolored type clusters showed atypical features, but insufficient atypical features compared with those of adenocarcinoma. Detection of clusters with varicolored mucin on conventional Pap smear may provide a clue for the early recognition of the malignant potential of LEGH on cytology. The chicken-wire-mesh type clusters may be a characteristic cytologic finding of MDA.

Cytologic features of ovarian granulosa cell tumors in pleural and ascitic fluids.

Adult granulosa cell tumor (AGCT) is an uncommon neoplasm of the ovary with potential for aggressive behavior and late recurrence. The most important prognostic factor for AGCT is tumor stage. Thus, cytological assessment of pleural or ascitic fluids is crucial for initial staging and subsequent patient management. We report herein two cases of ovarian AGCT presenting with exfoliated tumor cells in pleural and ascitic fluid. The first case involved a 61-year-old woman who presented with stage Ic (a) AGCT. Seven years after initial diagnosis, pleural effusion and pleural dissemination were identified. The second case involved a 50-year-old woman who presented with stage IV AGCT with massive ascites and right pleural effusion. Fluid cytology from both cases showed cohesive or loose clusters of small uniform neoplastic cells with round-to-oval nuclei, coffee-bean-shaped nuclear grooves, small nucleoli, and scant cytoplasm. Call-Exner bodies were also observed in these cytologic specimens. In the differential diagnosis of small monomorphic tumor cells in pleural effusion or ascites, coffee-bean-shaped nuclear grooves and cell clusters forming Call-Exner bodies are diagnostic clues of AGCT.

Generation of healthy cloned mice using enucleated cryopreserved oocytes.

The successful generation of cloned animals and the establishment of embryonic stem (ES) cell lines from somatic cells suggest that these techniques may be used in human regenerative medicine. However, the fact that oocytes must be donated by women undergoing infertility treatment remains a fundamental ethical objection, as they might be concerned about the potential exploitation of their genome. Here, we investigated the reprogramming potential of enucleated and cryopreserved oocytes for the development of full-term cloned mice. BDF1 strain mouse oocytes were cryopreserved at metaphase II, before and after enucleation. After thawing, cumulus cell nuclei were microinjected to generate clones. Although the rate of development of cloned embryos to the blastocyst stage using the treated oocytes was lower than that obtained using fresh oocytes, three live pups were delivered after embryo transfer into pseudopregnant females (0.4% of the oocytes used). Thus, although cryopreservation reduces the potential of oocytes, these cells retain the ability to support the full-term development of cloned embryos. In addition, the removal of DNA from human oocytes may alleviate the ethical and psychological problems for women who are undergoing infertility treatment and are considering oocyte donation for research or therapeutic purposes.

Novel alpha-fetoprotein-V messenger RNA isoforms in humans.

It has been demonstrated that several messenger RNA (mRNA) isoforms have been transcribed from the alpha-fetoprotein (AFP) gene. In rats, it was reported that the novel exon, termed the exon V, exists between the exons 7 and 8, and the novel mRNA isoform (termed AFP-V mRNA) is synthesized using the exon V. In this study, a reverse transcription-polymerase chain reaction was performed and quantitative analysis was done on the AFP mRNA to identify the exon V and the AFP-V mRNA in humans. As a result, 2 novel exons, the exons VA and VB, were identified. Furthermore, 3 novel AFP mRNAs, the AFP-V1, -V2, and -V3 mRNA, were demonstrated to be expressed through alternative splicing. Expression of the AFP-V2 mRNA isoform and the wild-type mRNA was differentially regulated, implying that the AFP-V mRNA isoforms could be used in diagnosis and classification of hepatocellular carcinoma and ovarian carcinoma.

Novel human alpha-fetoprotein mRNA isoform lacking exon 1 identified in ovarian yolk sac tumor.

OBJECTIVE: Alpha-fetoprotein (AFP) is a major fetal serum protein, the biologic role of which has not been not fully elucidated. Recently, existence of a novel AFP mRNA isoform (del.1 AFP mRNA isoform), which is transcribed from the intron A (the intron between exons 1 and 2), has been reported in murine yolk sac and fetal liver. In the present study, we intended to identify the human homologue of the murine AFP mRNA isoform in the yolk sac tumor. METHODS: To investigate the existence of the mRNA isoform (which we termed the "AFP-C mRNA isoform"), reverse transcription-polymerase chain reaction (RT-PCR) was used. Moreover, the expression analysis of the AFP-C cDNA isoform using the AFP-negative human cell line was carried out. RESULTS: RT-PCR revealed the existence of the AFP-C mRNA isoform in the yolk sac tumor and human hepatocellular carcinoma cells. The expression analysis clarified that the molecular size of the AFP-C was approximately 65 kd, and that the protein was not secreted, in contrast to the traditional AFP. CONCLUSION: From these results, the existence of the AFP-C mRNA isoform has been demonstrated for the first time in humans. The AFP-C located in cytoplasm possibly plays physiologic/pathogenic roles distinct from those of the traditional AFP in the yolk sac tumor and hepatocellular carcinoma.