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Ovarian cancer has a high recurrence rate after platinum‐based chemotherapy. To improve the treatment of ovarian cancer and identify ovarian cancer‐specific antibodies, we immunized mice with the human ovarian carcinoma cell line, SKOV‐3, and generated hybridoma clones. Several rounds of screening yielded 30 monoclonal antibodies (mAbs) with no cross‐reactivity to normal cells. Among these mAbs, OV‐Ab 30‐7 was found to target integrin α3 and upregulate p53 and p21, while stimulating the apoptosis of cancer cells. We further found that binding of integrin α3 by OV‐Ab 30‐7 impaired laminin‐induced focal adhesion kinase phosphorylation. The mAb alone or in combination with carboplatin and paclitaxel inhibited tumor progression and prolonged survival of tumor‐bearing mice. Moreover, immunohistochemical staining of ovarian patient specimens revealed higher levels of integrin α3 in cancer cells compared with normal cells. By querying online clinical databases, we found that elevated ITGA3 expression in ovarian cancer is associated with poor prognosis. Taken together, our data suggest that the novel mAb, OV‐Ab 30‐7, may be considered as a potential therapeutic for ovarian cancer., The novel mAb, OV‐Ab 30‐7, can induce ovarian cancer cell apoptosis, and blockage integrin‐laminin signaling, and may be considered as a potential therapeutic for ovarian cancer.

Background DNA mismatch repair (MMR) proteins form 2 heterodimers-MutSα formed by MSH2 and MSH6, and MutLα by MLH1 and PMS2. In endometrial endometrioid adenocarcinomas, cases with MMR protein defect also usually harbor other recurrent genetic mutations of the neoplasm. However, it remains unknown whether defects of the 2 functionally different heterodimers are linked to mutations in different genes. We aimed to study the MMR protein expression, microsatellite instability (MSI), and other common genetic mutations of endometrial endometrioid adenocarcinoma. Materials and methods We investigated the MSI status of 107 endometrial endometrioid adenocarcinoma patients. MMR protein expression, and mutation of KRAS, CTNNB1, and PIK3CA were also evaluated by immunohistochemistry and sequencing. Results An overall 34.6% (37/107) of endometrial endometrioid adenocarcinomas were MSI-H. All MSI-H tumors exhibited loss of MMR protein expression (loss of MLH1, PMS2, MSH6, and MSH2 was noted in 22, 25, 12, and 7 cases, respectively). CTNNB1, PIK3CA, and KRAS mutation were present in 9, 7, and 7 MSI-H tumors. Compared with patients with loss of PMS2 and/or MLH1 expression, patients with loss of MSH6 and/or MSH2 expression were associated with higher frequencies of CTNNB1 mutation (P=0.036) and PIK3CA mutation (P=0.025). Conclusions In MSI-H endometrial endometrioid adenocarcinomas, different types of MMR protein deficiency indicate different molecular genetic alterations.

Nail gun injuries usually occur at the extremities due to working accidents. Intracranial or intrathoracic injuries are relatively rare, and cases combined with both injuries are even rarer. Such situations pose challenges for surgeons due to their uniqueness during operation. Radiologic imaging findings in our case were significant in indicating surgical findings. Herein, we report a patient who shot himself using a nail gun, damaging his brain and heart. Keywords: Nail gun injury, Computed tomography, Trauma

Objective To report a case and review published cases of large cell neuroendocrine carcinoma (LCNEC) of the endometrium. Case report A 51-year-old female presented with postmenopausal bleeding and a palpable pelvic mass. An endometrial biopsy showed a malignant mixed Mullerian tumor (MMMT). Suboptimal debulking surgery was performed. The final pathology revealed stage IVB endometrial LCNEC. Post-operative adjuvant chemotherapy with cisplatin and etoposide was administered. Two months after discontinuing adjuvant chemotherapy, salvage chemotherapy with cisplatin and ifosfamide was administered due to tumor progression; however, obstructive ileus was noted 2 months later. A segmental small bowel resection and palliative colostomy were performed. She died secondary to a post-operative infection 8 days after the operation. Conclusion Endometrial LCNEC is a rare but aggressive disease. If diagnosed, combined therapies, including staging surgery, following by adjuvant radiotherapy and chemotherapy, should be performed.

// Ruey-Jien Chen 1 , Chia-Tung Shun 2 , Men-Luh Yen 1 , Chia-Hung Chou 1 and Ming-Chieh Lin 2 1 Department of Obstetrics and Gynecology, National Taiwan University, Taipei 100, Taiwan 2 Department of Pathology, National Taiwan University, Taipei 100, Taiwan Correspondence to: Ruey-Jien Chen, email: rjchen@ntuh.gov.tw Keywords: G9a, angiogenesis, cancer cell proliferation, xenograft, patient survival Received: April 09, 2016 Accepted: May 12, 2017 Published: July 07, 2017 ABSTRACT Research suggests that the epigenetic regulator G9a, a H3K9 histone methyltransferase, is involved in cancer invasion and metastasis. Here we show that G9a is linked to cancer angiogenesis and poor patient survival. Invasive cervical cancer has a higher G9a expression than cancer precursors or normal epithelium. Pharmacological inhibition and genetic silencing of G9a suppresses H3K9 methylation, cancer cell proliferation, angiogenesis, and cancer cell invasion/migration, but not apoptosis. Microarray and quantitative reverse transcription polymerase chain reaction analyses reveal that G9a induces a cohort of angiogenic factors that include angiogenin, interleukin-8, and C-X-C motif chemokine ligand 16. Depressing G9a by either pharmacological inhibitor or gene knock down significantly reduces angiogenic factor expression. Moreover, promoting G9a gene expression augments transcription and angiogenic function. A luciferase reporter assay suggests that knockdown of G9a inhibits transcriptional activation of interleukin-8. G9a depletion suppresses xenograft tumor growth in mouse model, which is linked to a decrease in microvessel density and proliferating cell nuclear antigen expression. Clinically, higher G9a expression correlates with poorer survival for cancer patients. For patients’ primary tumors a positive correlation between G9a expression and microvessel density also exists. In addition to increasing tumor cell proliferation, G9a promotes tumor angiogenesis and reduces the patient survival rate. G9a may possess great value for targeted therapies.

Aims MED12 exon 2 mutations have been identified in most uterine leiomyomas and mammary fibroepithelial tumours. MED12 has not been genotyped in most other gynaecological mesenchymal tumours. The purpose of this study was to determine the prevalence of MED12 mutations in uncommon gynaecological mesenchymal tumours. Methods and results Sixty-eight uncommon gynaecological mesenchymal tumours were genotyped for MED12 exon 2, including 27 Mullerian adenosarcomas (including three tentatively diagnosed as ‘variant adenosarcomas’), six cellular angiofibromas, six aggressive angiomyxomas, five angiomyofibroblastomas, five superficial myofibroblastomas, five atypical polypoid adenomyomas, and 14 endometrial stromal sarcomas. Immunohistochemistry for CD10, myogenic markers, hormone receptors, MDM2, and CDK4, and fluorescence in-situ hybridization (FISH) for JAZF1, PHF1 and YWHAE rearrangement, were performed on selected cases. The three ‘variant adenosarcomas’ harboured MED12 exon 2 mutations (including p.L36R hotspot mutation, recurrent p.L39_A50del, and a novel splice site mutation). Three endometrial stromal sarcomas with JAZF1–SUZ12 or JAZF1–PHF1 fusion harboured unprecedented mutations (p.D54G in two, and p.Q48* in one). All remaining tumours were wild-type. The three MED12-mutated ‘variant adenosarcomas’ showed distinctive morphological features, including ‘fibromyomatous’ cytomorphology, a close association with adenomyosis, clustered thick-walled vessels, focal conspicuous hyalinization, and intralymphovascular tumour growth. Features of conventional adenosarcomas, including nuclear atypia, mitotic activity, periglandular condensation, and phyllodes-like architecture, were inconspicuous. All three cases showed immunoreactivity for desmin and hormone receptors, while being negative for MDM2 and CDK4; they showed no JAZF1, PHF1 or YWHAE rearrangement. Despite deep myoinvasion, these tumours followed an indolent clinical course. Conclusions These MED12-mutated adenosarcoma-like tumours might represent a distinct entity that requires more studies for its identification. MED12 exon 2 mutations seemed to have no significant role in other uncommon gynaecological mesenchymal tumours.

SummaryWe report a case of pseudolymphoma of the liver in a 49-year-old woman without an underlying disease except for liver hemangioma. A 20-mm nodule was incidentally found in segment 2 of the liver by abdominal ultrasonography during a regular follow-up of the hepatic hemangioma. After a series of radiological examinations, a left lateral sectionectomy was performed because malignant hepatic tumor could not be excluded. The patient was discharged uneventfully 7 days after the operation. The pathology examination revealed a pseudolymphoma. No recurrence of the tumor was found 5½ years after the operation. To the best of our knowledge, only 46 cases of pseudolymphoma of the liver have been reported to date. A review of the literature showed that pseudolymphomas occur predominantly in females (89.4%), usually occur as a single tumor (80.4%), are no more than 20 mm in size (90.6%), and are frequently associated with either autoimmune disease or chronic liver disease. Because an accurate diagnosis is difficult to establish, vigilant follow-up is indicated, and surgical intervention is the choice of treatment once the suspiciousness of malignancy has been raised.

Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth. Frequent gains of chromosomal 12q were noted, often involving cancer-associated genes CDK4 (six cases), MDM2, CPM, YEATS4, DDIT3, GLI1 (five each), HMGA2 and STAT6 (four), without association with sarcomatous overgrowth status. The most frequent losses involved chromosomes 13q (five cases), 9p, 16q and 17q (four cases each) and were almost limited to cases with sarcomatous overgrowth. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. By immunohistochemistry, all MDM2/CDK4-coamplified cases were confirmed to overexpress both encoded proteins, whereas all four cases with (plus an additional four without) gain of HMGA2 overexpressed the HMGA2 protein. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. With whole chromosome painting and deconvolution fluorescent microscopy, dividing tumor cells in all three cases were shown to have scattered extrachromosomal materials derived from chromosomes involved by chromothripsis, suggesting that this phenomenon may serve as visual evidence for chromothripsis in paraffin tissue. In conclusion, we identified frequent chromosome 12q amplifications, including loci containing potential pharmacological targets. Global chromosomal instability and chromothripsis were more frequent in cases with sarcomatous overgrowth. To our knowledge, this is the first time that evidence of chromothripsis has been demonstrated in paraffin-embedded clinical tissues and in adenosarcomas.

A 16-year-old male was brought to our hospital presenting with acute onset of a painful protruding left neck mass within a day, associated with left upper-arm tenderness. Chest computed tomography revealed high attenuation masses at the left supraclavicular and mediastinal regions, suspected of being venous vascular tumors. Surgery was arranged and then ruptured venous tumor was noted, with pathology results determining a venous malformation.

In this study, we aimed to investigate the antitumor effects of trichostatin A (TSA), an antifungal antibiotic that inhibits histone deacetylase (HDAC) family of enzymes, alone or in combination with anyone of the three chemotherapeutic agents (cisplatin, gemcitabine, and doxorubicin) for the treatment of human urothelial carcinoma (UC). Two high-grade human UC cell lines (T24 and NTUB1) were used. Cytotoxicity and apoptosis were assessed by MTT assay and flow cytometry, respectively. The expression of phospho-c-Raf, phospho-MEK1/2, and phospho-ERK1/2 was measured by western blotting. ERK siRNA knockdown and the specific MEK inhibitor U0126 were used to examine the role of Raf/MEK/ERK signaling pathway in combined cytotoxicity of TSA and chemotherapy. TSA co-treatment with any one of the three chemotherapeutic agents induced synergistic cytotoxicity (combination index

Recently, mutations of telomerase reverse transcriptase (TERT) promoter were found in several types of cancer. A few reports demonstrate TERT promoter mutations in ovarian clear cell carcinomas but endometrial clear cell carcinoma has not been studied. The aims of this study were to compare differences of molecular alterations and clinical factors, and identify their prognostic impact in endometrial and ovarian clear cell carcinomas. We evaluated mutations of the TERT promoter and PIK3CA, expression of ARID1A, and other clinicopathological factors in 56 ovarian and 14 endometrial clear cell carcinomas. We found that TERT promoter mutations were present in 21% (3/14) of endometrial clear cell carcinomas and 16% (9/56) of ovarian clear cell carcinomas. Compared with ovarian clear cell carcinomas, endometrial clear cell carcinomas showed older mean patient age (P0.001), preserved ARID1A immunoreactivity (P=0.017) and infrequent PIK3CA mutation (P=0.025). In ovarian clear cell carcinomas, TERT promoter mutations were correlated with patient age45 (P=0.045) and preserved ARID1A expression (P=0.003). In cases of endometrial clear cell carcinoma, TERT promoter mutations were not statistically associated with any other clinicopathological factors. In ovarian clear cell carcinoma patients with early FIGO stage (stages I and II), TERT promoter mutation was an independent prognostic factor and correlated with a shorter disease-free survival and overall survival (P=0.015 and 0.009, respectively). In recurrent ovarian clear cell carcinoma patients with early FIGO stage, TERT promoter mutations were associated with early relapse within 6 months (P=0.018). We concluded that TERT promoter mutations were present in endometrial and ovarian clear cell carcinomas. Distinct molecular alteration patterns in endometrial and ovarian clear cell carcinomas implied different processes of tumorigenesis in these morphologically similar tumors. In ovarian clear cell carcinoma of early FIGO stage, patients with TERT promoter mutation require close follow-up during the initial 6 months following chemotherapy.

Objective To report a case of isolated omental peritoneal carcinoma without peritoneal carcinomatosis. Case report A 60-year-old female with abdominal distention was found to have a pelvic mass. Under the impression of ovarian cancer, laparotomy was performed only to show one isolated mass over omentum. Serial examination and pathology study including immunochemical staining indicated primary peritoneal serous carcinoma. Conclusion Isolated omental peritoneal carcinoma without peritoneal carcinomatosis and ascites is rare, and whether this represented a unique entity with different chemotherapy response and treatment outcome from the disseminated form of primary peritoneal carcinoma needs to be reviewed in the future.

Objective: To investigate the changes of incidence and prognosis of epithelial ovarian cancer in thirty years in Taiwan. Methods: The databases of women with epithelial ovarian cancer during the period from 1979 to 2008 were retrieved from the National Cancer Registration System of Taiwan. The incidence and prognosis of these patients were analyzed. Results: Totally 9,491 patients were included in the study. The age-adjusted incidences of epithelial ovarian cancer were 1.01, 1.37, 2.37, 3.24, 4.18, and 6.33 per 100,000 person-years, respectively, in every 5-year period from 1979 to 2008. The age-specific incidence rates increased especially in serous, endometrioid and clear cell carcinoma, and the age of diagnosis decreased from sixty to fifty years old in the three decades. Patients with mucinous, endometrioid, or clear cell carcinoma had better long-term survival than patients with serous carcinoma (log rank test, p

Kao Y-C, Lin M-C, Lin W-C, Jeng Y-M & Mao T-L (2012) Histopathology 61, 760–768 Utility of hepatocyte nuclear factor-1β as a diagnostic marker in ovarian carcinomas with clear cells Aims: Overexpression of hepatocyte nuclear factor-1β (HNF-1β) has been found in ovarian clear cell carcinoma (OCCC) but not in other types of ovarian carcinoma. The aim of this study was to clarify whether the overexpression of HNF-1β is specific for OCCC, and does not occur in ovarian carcinoma with clear cell change. Methods and results: Immunohistochemistry was performed on 178 ovarian carcinomas with clear cells (80 OCCCs, 60 high-grade serous, 25 endometrioid, and 13 mixed endometrioid and clear cell), 22 ovarian high-grade serous carcinomas without clear cells, 41 renal cell carcinomas (RCCs) and 20 hepatocellular carcinomas (HCCs) with clear cytoplasm. Results were evaluated using an H-score (percentage × intensity). Most OCCCs were diffusely and strongly positive (mean H-score 15.1). High-grade serous carcinoma and endometrioid carcinoma with clear cells were usually negative or focally and weakly positive (mean H-scores 1.5 and 1.7, respectively). High-grade serous carcinoma without clear cells had a mean H-score of 0.77. The mean H-scores of the endometrioid and clear cell components in mixed endometrioid and clear cell carcinoma were 6.2 and 15.7, respectively. HNF-1β was expressed in 95.1% of RCCs and in 30% of HCCs. Conclusions: The diagnosis of ovarian carcinomas with clear cells can be made with greater accuracy by using the intensity and extent of immunoreactivity for HNF-1β.

► Malignant struma ovarii can result in cerebral ischemic stroke and Trousseau's syndrome. ► The combination of anti-neoplastic and anti-coagulant therapy should be undertaken to treat and correct the malignancy-associated coagulopathy.

The expression of lysophosphatidic acid (LPA)-specific receptors in cervical cancer has not been clearly defined. In this study, we identified LPA1, LPA2 and LPA3 receptors' mRNA in SiHa, HeLa and CaSki cell lines by RT-PCR. These receptors were not associated with tumor cell proliferation in vitro. We then used a xenograph animal model to evaluate the effects of these receptors on in vivo cervical cancer tumorigenicity. When SiHa cells with different receptor expression patterns were seeded on the backs of SCID mice, the resulting knockout of both LPA2 and LPA3 significantly attenuated tumor growth; this decrease in tumor growth was found to be linked with decreased angiogenesis (microvessel density), suggesting that LPA2 and LPA3 are crucial for in vivo tumor growth through an angiogenic mechanism. We further investigated this mechanism of LPA receptor 2/3-mediated angiogenic capability by analyzing angiogenic factors in protein lysates from receptor knockout tumors, by detecting interleukin (IL-8) mRNA expression after treating with siRNA, by evaluating the biological role of LPA-enhanced IL-8 via endothelial cell tube formation, monolayer permeability, migration and cell growth assays, and by IL-8 knockout xenograft mice modeling. We found that the angiogenesis is mediated through IL-8. Finally, we evaluated the regulation pathways involved in LPA-induced IL-8 expression. We found that LPA receptor 2/3-mediated IL-8 expression occurs through Gi/PI3K/AKT, Gi/PKC and IκB/NF-κB signaling. In conclusion, we propose that LPA2 and LPA3 might play an important role in cervical cancer tumor growth through IL-8-dependent angiogenesis.

Bronchogenic cysts are congenital malformations of the embryonic tracheobronchial tree and are the most common cause of mediastinal cysts, encountered mainly in pediatric patients and young adults. Conservative treatment has been proposed for asymptomatic patients. However, malignant transformation occurs occasionally and the clinicopathological features of secondary malignancy are not well characterized. In this report, we present a carcinoid tumor found in the thymic bronchogenic cyst of a 41-year-old female complaining of mild chest pain. The thymic tissue also shows follicular lymphoid hyperplasia. Atypical imaging features were found in her chest computed tomography. Additional 22 cases of bronchogenic cysts with malignant transformation were also reviewed from the literature. The clinicopathological data were summarized. The tumorigenesis of these tumors is unclear, but bronchogenic cysts of the lung may undergo malignant changes at a younger patient age and more frequently than mediastinal ones. Carcinoid tumors were also seemingly overrepresented in mediastinal cases. Some atypical imaging features may serve as clues for early detection and guide clinical management.

Eur J Clin Invest 2010; 40 (4): 310–318 Abstract Background Specific tumour suppressor genes with promoter methylation in ovarian clear cell adenocarcinoma (OCCA) can be one important epigenetic mark distinguishing OCCA from ovarian serous adenocarcinoma (OSA), benign endometriotic cysts and normal ovarian epitheliums. Materials and methods Five OCCA cell lines, 63 cancer tissues (48 OCCA and 15 OSA), 10 benign endometriotic cysts and five normal ovarian epitheliums were analysed by methylation-specific PCR using pooled DNAs to determine the methylation status of the promoter of the target genes, including genes for secreted frizzled-related proteins (sFRP1 to 5), adenomatous polyposis coli (APC), retinoblastoma protein 1 (Rb1), breast cancer 1 gene (BRCA1), p14ARF, p15INK4b, p16INK4a and survivin. Methylation frequencies of identified targets were further analysed with individual DNA samples. Results The sFRP5 promoter was significantly methylated in all OCCA cell lines, with 64·6% in OCCA tissues compared with 13·3% in OSA, and 0% in benign endometriotic cysts and normal ovarian epitheliums (P

Background This report analyzed a research project supported nationwide expert consultation of anatomic pathology in Taiwan. Methods The data were collected from the requisitions and consultation reports of 2,686 cases in this project from 2003 to 2006. The number of cases, tissue origin, additional special stains, turnaround time (TAT), concordance, discordance, referring pathologists, and consultants were analyzed. Results Skin, hematopoietic system, and bone and soft tissue were the most common (48.3%) specimens sent for consultation. The tentative diagnosis and consultation diagnosis were discordant in 1,074 (64.3%) cases. Major discrepancy was seen in 205 (12.3%) cases, of which 66.8% were changed from malignant to benign, 21.0% were changed from benign to malignant, whereas 12.2% were changed from one category of malignancy to another. Additional special stains were performed on 38.7% of cases and hematology specimen was the most frequent. The mean TAT was 3.4 days. Pathologists working in institutes having fewer pathologists sent more cases for consultation. The opinion of the estimated annual consultation rate from the pathologists in Taiwan was 0.7%. Conclusions This program was beneficial simply by helping the referring pathologists in the workup and diagnosis. This result made the entire program a reasonable quality improvement program. J. Surg. Oncol. 2010; 101:430–435. © 2010 Wiley-Liss, Inc.

Ovarian cancer with bone metastasis is relatively rare(about 1.2%) [1], compared with direct extension,transperitoneal seeding and lymphatic spread. Bonemetastasis of ovarian cancer is mostly found duringrecurrence, and is very rare at the initial diagnosis withonly a few cases reported [2]. We report a case withthe initial diagnosis of advanced ovarian cancer withthoracispinal metastasis, and discuss the differentialdiagnosis and clinical course.A 48-year-old women gravida 2, para 1, had sufferedfrom mid-back pain for 4 months. She had iron-deficiency anemia because of menorrhagia. She visiteda gynecologic clinic for regular Papanicolaou tests andpelvic examinations annually. The only abnormal findingwas adenomyosis using ultrasound in October 2005.She did not have changes in appetite, decreased bodyweight or bowel movement changes. However, her backpain had been present since October 2005. She visited aneurologic clinic in our hospital in February 2006, andan osteolytic lesion in the pedicle of T7 was noticed onan X-ray film of the spine. High signals in the pediclesof T7 and L3 and soft tissue around T7 on magneticresonance imaging were found (Figure 1). Her CA 125level was 102.22U/mL and CA 199 was 98.3U/mL.She underwent T2–T8 laminectomy and excision of atumor in February 2006. Pathologic findings revealedmetastatic poorly differentiated carcinoma with glan-dular differentiation. Postoperative follow-up revealednormal findings on chest X-ray, panendoscopy andcolonofiberscopy, and a large left ovarian multicystictumor measuring approximately 15×10cm adheredto her uterus and adenomyosis of the uterus on thecomputed tomography scan (Figure 2).In March 2006, she underwent exploratory laparo-tomy, and a left ovarian cystic tumor measuring approx-imately 14 ×11×8cm, which adhered to her uterus,bowel, retroperitoneum and left fallopian tube, andsome ascites, were found intraoperatively. The frozenpathology during the operation revealed ovarian malig-nancy. Abdominal total hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymph node dissectionand infracolic omentectomy were performed. There wasno residual tumor in the abdominal and pelvic cavityafter surgery. Grossly, the left ovary showed a hugeunilocular cystic tumor, which measured 6.5×5.0×2.0cm after cystic content evacuation, with a polypoidsolid nodule protruding from the cystic wall into thecystic cavity. The final microscopic finding showed: (1)left ovarian adenosarcoma with predominant rhab-domyosarcomatous differentiation over the solid part,and grade I endometrioid adenocarcinoma with squa-mous differentiation over the cystic part with deep,irregular invasion over the gland (Figure 3); (2) multiplelymph node metastasis; and (3) carcinoma

BACKGROUND: Inactivation of the PTEN suppressor gene has been shown to occur in the majority of endometrial cancer cases. Somatic PTEN inactivation by deletion and/or mutation, the first detectible change of endometrial carcinogenesis, has been reported to occur at a high frequency in the endometrium of normal premenopausal women, although few of these cases progress to cancer. It was hypothesized that the 50% to 60% reduced cancer risk attributed to oral contraceptives (OCPs) and intrauterine devices (IUDs) occurred in part through their activity as negative selection factors for these subclinical mutated glands. METHODS: A total of 71 women with a history of OCP use and 80 with a history of IUD use were age matched with 191 and 119 controls, respectively. Endometrial biopsy specimens were immunostained for PTEN, and each was scored for the presence or absence of PTEN-null glands (latent precancer). RESULTS: The frequency of latent precancers was found to be significantly reduced in OCP‒exposed (13%; odds ratio [OR], 0.19 [P < .001]) and IUD‒exposed (18%; OR, 0.42 [P = .015]) women compared with respective matched controls (43% and 34%). The presence or absence of endometritis did not appear to be significantly correlated with PTEN status within the IUD-exposed group (P = .24). CONCLUSIONS: Normal-appearing PTEN mutated endometrial glands, which are highly prevalent in the normal population, may be targets of endometrial cancer risk‒modulating exposures. Some exposures reported to diminish the incidence of endometrial cancer in epidemiologic outcome studies, including OCP and IUD use, are associated with a proportionate decline in the frequency of latent precancers. Involution of pre-existing endometrial latent precancers, as evaluated by PTEN analysis, may provide an accessible surrogate marker for long-term endometrial cancer risk. Cancer 2009. © 2009 American Cancer Society.

Squamous morules are a common component of premalignant glandular lesions that are followed by glandular, rather than squamous, carcinomas. We tested the hypothesis that the appearance of glands associated with morules predicts cancer risk, and undertook molecular testing to determine the clonal and hormonal response properties of admixed squamous and glandular elements. A total of 66 patients with squamous morules in an index endometrial biopsy had follow-up clinical data (average follow-up: interval 31 months, 2.5 biopsies) showing development of carcinoma in 11% (7/66) of cases. The histological appearance of morule-associated glands in the index biopsy was significantly associated with this clinical outcome, with the majority (71%, 5/7) of cancer occurrences following an overtly premalignant lesion (endometrial intraepithelial neoplasia) with squamous morules. Eight endometrial intraepithelial neoplasias with squamous morules were examined by immunohistochemistry for estrogen and progesterone receptors and mitotic activity (Ki-67 antigen percent stained). Glandular components had abundant estrogen and progesterone receptors, and high levels of mitotic activity in all cases. In sharp contrast, all squamous morules were devoid of sex hormone receptors and had undetectable or extremely low-proliferation rates. When mutated, the same specific PTEN mutation was detected in squamous and glandular elements, indicating that both are of common lineage. The clinical and laboratory data are consistent with a model of morule biology in which squamous morules are a hormonally incompetent subpopulation of endometrial glandular lesions. Isolated morules might result from artifactual displacement from their native glandular context, or selective hormonally induced regression of the glandular but not squamous components over time. Subsequent cancer risk, as promoted by estrogens, is greatest when the glandular component has the appearance of endometrial intraepithelial neoplasia. Even isolated morules should be carefully followed, however, to exclude a coexisting undersampled, or occult, glandular lesion.

Benign, premalignant, and malignant endocervical glandular lesions occasionally show a gastric phenotype. We report 2 cases of gastric-type adenocarcinoma in situ (AIS) of the endocervix, not associated with lobular endocervical glandular hyperplasia or gastric-type adenocarcinoma. Cytologically, both showed endocervical glands with slightly enlarged nuclei, distinctive nucleoli, pseudostratified strips, and intracytoplasmic golden yellow mucin. Histologically, both lesions were situated in preexisting endocervical glands and presented columnar cells with voluminous pale eosinophilic cytoplasm and evident nuclear atypia. In case 1, the lesion was located at the mid-zone of the endocervical canal and, in case 2, at the outer endocervical canal with extension to the transformation zone and prominent intestinal metaplasia. In both, the cells showed voluminous cytoplasm containing gastric-type mucin, stained red by combined alcian blue/periodic acid-Schiff stain. Immunohistochemically, both lesions were positive for HIK1083 and p53, while negative for p16 and ER. Human papilloma virus (HPV) DNA was not detected by polymerase chain reaction. Our cases illustrate that gastric-type AIS can occur without lobular endocervical glandular hyperplasia. The lesions can occur in the outer cervical canal and present extensive intestinal differentiation. Awareness of this rare type of endocervical glandular lesion is important since they are pathogenetically different from the more common HPV-associated lesions and may become more prevalent in the HPV-eradicating era.

Background/aim: It is generally assumed that similar pathways are involved in human papillomavirus (HPV) induced pathogenesis of cervical squamous intraepithelial lesions (SILs) and cancers and a subset of conjunctival intraepithelial neoplasm (CIN)—that the malignancies or pre-cancerous lesions arise through HPV oncoproteins E6 and E7, which disrupt the pathways of p53 and the product of the retinoblastoma (Rb) gene and, in turn, increase the protein product of gene p16 INK4 through the mechanism of positive feedback. Several cell cycle molecules are detected to test this hypothesis. Methods: Nine cases of CIN and eight non-CIN cases were analysed for the expression of Ki-67, pRb, p53, and p16 INK4 via immunohistochemistry. Nine cases of cervical high grade squamous intraepithelial lesion (HSIL), and 10 cases of cervical low grade squamous intraepithelial lesion (LSIL) were included for stain control of p16 INK4a , and comparison of p16 INK4a expression to CIN cases. A nested polymerase chain reaction and a genechip HPV typing were used to detect HPV infection and types in the CIN and non-CIN samples Results: HPV positivity was demonstrated in all of the CIN lesions but in none of the non-CIN lesions. The Ki-67 proliferative index (Ki-67 PI) was statistically higher in the CIN group than the non-CIN group; however, there were no differences of expression of pRb and p53 between the two groups and no expression of p16 INK4 in all cases. All nine cases of HSIL, and seven out of 10 cases of LSIL used for stain control were immunoreactive for p16 INK4a . There were statistically significant differences in overexpression of p16 INK4a between the CINs and SILs Conclusions: The Ki-67 proliferative index may be a sensitive marker for CIN lesions and these results, with significant differences in overexpression of p16 INK4a between CINs and SILs, may provide new evidence that HPV related mucosal dysplasia in different anatomical locations may lead to dissimilar molecular pathways.

Summary Objective Placenta accreta can be managed with preservation of the uterus, especially when further fertility is intended. We report a case of placenta accreta diagnosed intraoperatively and treated conservatively that was followed by an ectopic pregnancy. Case Report A 32-year-old woman was found to have placenta accreta during cesarean section. Some pieces of the placenta were left in situ after bleeding was controlled. The patient was followed up using levels of !-human chorionic gonadotropin. Hysteroscopy revealed fibrotic and scar tissue at the site of retained placenta 1 year later. The patient did not conceive until 2 years later, but it was an ectopic pregnancy. Conclusion There are few reports of successful pregnancy following conservative treatment for placenta accreta. Conservative treatment may increase the risk of secondary infertility, recurrent placenta accreta, and probably ectopic pregnancy.

To evaluate the etiologic role of human papillomavirus (HPV) in oral carcinogenesis, DNA samples were purified from 103 oral squamous cell carcinoma (OSCC) and 30 normal oral mucosal (NOM) specimens. A nested polymerase chain reaction, DNA sequencing, and gene-chip HPV typing were used to identify multiple HPV types in our samples. We found that the positive rates of all HPV types and of high-risk HPV types were significantly higher in OSCC samples (49.5% and 41.7%, respectively) than in NOM samples (6/30 [20%; P < .01] and 5/30 [17%; P < .05], respectively) and significantly higher in non-oral habits (OH)-associated OSCC samples (31/51 [61%] and 28/51 [55%], respectively) than in OH-associated OSCC samples (20/52 [38%; P < .05] and 15/52 [29%; P < .001], respectively). High-risk HPV types and all HPV types had odds ratios of 3.97 (P = .0097) and 3.92 (P = .006), respectively. Our results suggest that HPVs, particularly high-risk HPVs, might be associated with the development of OSCCs, especially the non-OH-associated OSCCs.

Aims: To investigate whether localization of β-catenin is helpful in differentiating primary ovarian mucinous carcinoma and colorectal adenocarcinoma metastatic to the ovary. Extra-ovarian cancers which metastasize to the ovaries, especially from colorectal adenocarcinoma, frequently mimic primary ovarian carcinomas, particularly endometrioid and mucinous types. Distinguishing primary ovarian carcinoma from metastatic colorectal carcinoma is important for both therapeutic and prognostic reasons. Even after thorough histological examination, metastatic colorectal adenocarcinomas are still often mistaken for primary ovarian adenocarcinomas. Although some tumour makers have been advocated and are helpful in most cases, sometimes the distinction between primary mucinous carcinoma and metastatic colorectal carcinoma remains a problem. Activation of Wnt signalling through mutations of APC or β-catenin is a key event in the development of colorectal cancer. These mutations lead to nuclear localization of β-catenin, which can be demonstrated immunohistochemically. Methods and results: Formalin-fixed paraffin-embedded specimens from 43 primary ovarian mucinous carcinomas and 23 metastatic colorectal adenocarcinomas were included in this study. Sections were immunostained with antibodies to β-catenin, cytokeratin (CK)7, CK20 and carcinoembryonic antigen (CEA). Nuclear localization of β-catenin was found in 83% (19/23) of metastatic colorectal cancers and 9% (4/43) of ovarian mucinous carcinomas. Ovarian mucinous carcinomas were usually positive for CK7 (34/43, 79%). For comparison, 40 non-mucinous carcinomas of the ovary and 42 metastatic adenocarcinomas from other organs were also immunostained with antibodies against β-catenin. Although nuclear localization of β-catenin was occasionally seen in non-mucinous carcinoma of the ovary and metastatic adenocarcinoma from other organs, such tumours were usually distinguishable by their clinicopathological picture and rarely raised diagnostic problems. Conclusions: Immunostaining of β-catenin is a useful marker for differentiating between ovarian mucinous carcinoma and metastatic colorectal adenocarcinoma.

Aims To compare the clinical and pathogenetic differences between high-grade (HG) endometrioid carcinomas with and without concurrent low-grade (LG) components. Methods and results The expression of ARID1A, PTEN, p53 and mismatch repair (MMR) proteins in HG endometrioid carcinomas without (n = 19) or with (n = 22) concurrent LG endometrioid carcinomas was studied by immunohistochemistry. Microsatellite instability (MSI) was also tested in 31 cases. The frequencies of ARID1A loss, PTEN loss, MMR deficiency or MSI and aberrant p53 expression were 58%, 37%, 37% and 47% in pure HG tumours, and 77%, 45%, 55% and 32% in HG tumours with concurrent LG components (P = 0.07 for ARID1A; P > 0.1 for other proteins). Pure HG tumours had a higher frequency of the type II phenotype (positive for ARID1A, PTEN and MMR proteins; aberrant p53 expression) than HG tumours with concurrent LG components (21% versus 5%) (P = 0.2). The 5-year overall survival rate was worse for pure HG tumours (61.7%) than for HG tumours with concurrent LG components (93.3%) (P = 0.07). Conclusions HG endometrioid carcinomas are heterogeneous in pathogenesis: some arise from LG endometrioid carcinomas via the type I pathway, whereas others may arise de novo through either the type I pathway or the type II pathway, and have a different prognosis. Thus, HG endometrioid carcinomas should be subclassified properly and treated accordingly.

Aims To understand the role of and differences in molecular alterations between endometrial and ovarian endometrioid adenocarcinomas. Methods and results We investigated the microsatellite status of 26 ovarian endometrioid adenocarcinomas (OVEMs), 42 endometrial endometrioid adenocarcinomas (EMCAs), and 19 concurrent (endometrial and ovarian) endometrioid adenocarcinomas. We evaluated the expression of the mismatch repair proteins, PTEN and ARID1A, and mutations of PTEN, KRAS, CTNNB1, and PIK3CA. High levels of microsatellite instability (MSI-H) were present in one of 26 OVEMs, 12 of 42 EMCAs, and four of 19 concurrent endometrioid adenocarcinomas. Only four of 19 concurrent endometrioid adenocarcinomas showed identical molecular alterations in their endometrial and ovarian components. Loss of ARID1A or loss of PTEN expression, and MSI-H, were more common in EMCAs than OVEMs (P = 0.044, P = 0.004, and P = 0.012, respectively). MSI-H in endometrial endometrioid adenocarcinomas was also related to loss of ARID1A expression (P

Background: PTEN tumor suppressor gene mutations are the most frequent genetic lesions in endometrial adenocarcinomas of the endometrioid subtype. Testing the hypothesis that altered PTEN function precedes the appearance of endometrial adenocarcinoma has been difficult, however, partly because of uncertainties in precancer diagnosis. Methods: Two series of endometrial cancer and precancer (endometrial intraepithelial neoplasia, as diagnosed by computerized morphometric analysis) tissue samples were studied, one for PTEN mutations by the use of denaturing gradient gel electrophoresis and another for PTEN protein expression by immunohistochemistry. Endometria altered by high estrogen levels that are unopposed by progestins-conditions known to increase cancer risk-were also studied by immunohistochemistry. Fisher's exact test was used for statistical analysis. Results: The PTEN mutation rate was 83% (25 of 30) in endometrioid endometrial adenocarcinomas and 55% (16 of 29) in precancers, and the difference in number of mutations was statistically significant (two-sided P = .025). No normal endometria showed PTEN mutations. Although most precancers and cancers had a mutation in only one PTEN allele, endometrioid endometrial adenocarcinomas showed complete loss of PTEN protein expression in 61% (20 of 33) of cases, and 97% (32 of 33) showed at least some diminution in expression. Cancers and most precancers exhibited contiguous groups of PTEN-negative glands, while endometria altered by unopposed estrogens showed isolated PTEN-negative glands. Conclusions: Loss of PTEN function by mutational or other mechanisms is an early event in endometrial tumorigenesis that may occur in response to known endocrine risk factors and offers an informative immunohistochemical biomarker for premalignant disease. Individual PTEN-negative glands in estrogen-exposed endometria are the earliest recognizable stage of endometrial carcinogenesis. Proliferation into dense clusters that form discrete premalignant lesions follows.

Frequent mutation of the PTEN tumor suppressor gene in endometrial adenocarcinoma has led to the prediction that its product, a phosphatase that regulates the cell cycle, apoptosis, and possibly cell adhesion, is functionally active within normal endometrial tissues. We examined PTEN expression in normal human endometrium during response to changing physiological levels of steroid hormones. PTEN ribonucleic acid levels, assessed by RT-PCR, increase severalfold in secretory compared to proliferative endometrium. This suggested that progesterone, a known antineoplastic factor for endometrial adenocarcinoma, increases PTEN levels. Immunohistochemistry with an anti-PTEN monoclonal antibody displayed a complex pattern of coordinate stromal and epithelial expression. Early in the menstrual cycle under the dominant influence of estrogens, the proliferative endometrium shows ubiquitous cytoplasmic and nuclear PTEN expression. After 3-4 days of progesterone exposure, glandular epithelium of early secretory endometrium maintains cytoplasmic PTEN protein in an apical distribution offset by expanding PTEN-free basal secretory vacuoles. By the midsecretory phase, epithelial PTEN is exhausted, but increases dramatically in the cytoplasm of stromal cells undergoing decidual change. We conclude that stromal and epithelial compartments contribute to the hormone-driven changes in endometrial PTEN expression and infer that abnormal hormonal conditions may, in turn, disrupt normal patterns of PTEN expression in this tissue.

Background. Few studies have addressed in detail the genetic alterations that occur in vulvar squamous carcinomas (VSCC) and their precursor lesions. In a previous study, we determined the most common chromosomal loci for allelic imbalance (AI) in HPV-positive and -negative VSCCs. The present study was designed to determine whether AI and the microsatellite instability phenotype (MIN) were present in epithelial lesions known to be associated with VSCC. Design. Fifty-seven epithelial loci were analyzed, including HPV-positive (classic) and -negative (differentiated) vulvar intraepithelial neoplasms (VINs), lichen sclerosus (LS), and nonatypical hyperplasias. Thirty-one epithelial loci (55%) were obtained from patients with associated invasive vulvar carcinoma. HPV status was determined by polymerase chain reaction analysis. AI and MIN were determined by comparisons of microdissected target tissues with stromal controls, targeting 11 chromosomal loci. Results. AI was identified in all epithelial categories, involving at least one chromosomal locus in 67, 53, 50, and 43% of classic VIN, differentiated VIN, hyperplasia, and LS. MIN was infrequent (10–13%), but confined to HPV-negative epithelial changes. HPV-positive lesions generally scored for AI more frequently, but certain loci scored nearly equally in both HPV-positive and -negative lesions, including 8p, 11q, and 17p. There were no differences in frequency of AI between epithelia with and without associated invasive carcinoma. Conclusions. The presence of allelic imbalance in vulvar hyperplasia and LS supports the hypothesis that these alterations are at greater risk for neoplasia despite the absence of conspicuous cellular atypia. A model is proposed in which these changes represent monoclonal expansion and are at empirically greater risk for subsequent "critical events" leading to morphologic atypia (VIN). The possibility that these early genetic changes influence both HPV-positive and -negative pathways merits further study.

Microsatellite instability is a frequent (13%-24%) finding in sporadic endometrial adenocarcinoma and its precursor lesions, but most studies are limited to patients who already have malignant or premalignant endometrial disease. We performed retrospective testing for microsatellite instability in women in whom cancers showing microsatellite instability developed later and prospective testing in randomly selected normal and anovular endometrial biopsy specimens. Microsatellite instability in cancer-bearing biopsy specimens accurately reflected that seen in matched malignant tissues obtained at hysterectomy. In 1 patient, microsatellite instability developed in a scanty sample of fragmented endometrial tissues 7 years before the onset of endometrial cancer. Prospective testing for microsatellite instability in the endometria of women unselected for subsequent appearance of endometrial cancer showed a very low rate of microsatellite instability. Only 1 endometrial specimen showing microsatellite instability was found among 75 anovulatory endometrial specimens, and none were found in 377 normal endometrial specimens and 46 polyps examined. Microsatellite instability may precede the onset of histologically diagnosed carcinoma but is rare in randomly sampled histologically normal endometrial tissues.

Vulvar squamous cell carcinoma (VSCC) is a biologically and morphologically diverse disease, consisting of human papillomavirus (HPV)-positive and -negative tumors that differ in their morphological phenotypes and associated vulvar mucosal disorders. This study analyzed the frequencies of allelic loss (loss of heterozygosity (LOH)) in HPV-positive and -negative VSCCs to identify potential targets for the study of preinvasive diseases, to determine whether HPV status influenced patterns of LOH, and to determine whether these patterns differed from HPV-positive tumors of another genital site, cervical squamous cell carcinomas (CSCC). DNA extracted from microdissected archival sections of two index tumors, one each HPV negative and positive, was analyzed for LOH at 65 chromosomal loci. Loci scoring positive with either sample were included in an analysis of 14 additional cases that were also typed for HPV. Frequencies of LOH at loci were computed in a panel of HPV-positive and -negative VSCCs. Twenty-nine loci demonstrated LOH on the initial screen and were used to screen the remaining 14 tumors. High frequencies of LOH were identified, some of which were similar to a prior karyotypic study (3p, 5q, 8p, 10q, 15q, 18q, and 22q) and others of which had not previously been described in VSCC (1q, 2q, 8q, 10p, 11p, 11q, 17p, and 21q). With the exception of 5q and 10p, there were no significant associations between frequency of LOH and HPV status in VSCC. LOH at 3p and 11q were frequent in both VSCC and CSCC; however, allelic losses at several sites, including 5q, 8q, 17p, 21q, and 22q, were much more common in VSCC. VSCCs exhibit a broad range of allelic losses irrespective of HPV status, with high frequencies of LOH on certain chromosomal arms. This suggests that despite their differences in pathogenesis, both HPV-positive and -negative VSCCs share similarities in type and range of genetic losses during their evolution. Whether the different frequencies of LOH observed between VSCC and CSCC are real or reflect differences in stage and/or tumor size remains to be determined by further comparisons. The role of these altered genetic loci in the genesis of preinvasive vulvar mucosal lesions merits additional study.

AT-rich interactive domain 1A (ARID1A) is a subunit of switch/sucrose non-fermentable (SWI/SNF) complex. Recently, alterations of ARID1A gene, phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathway and zinc-finger protein 217 (ZNF217) gene have been identified as frequent molecular genetic changes in ovarian clear cell carcinoma. The relationships between these events have not been studied and integrated in the same cohort. This study was aimed at determining the correlation between these molecular events and other clinicopathological factors, including the prognostic impacts of these clinicopathological factors. A total of 68 ovarian clear cell carcinoma cases were collected and subjected to immunohistochemistry testing for ARID1A, SMARCA2, SMARCA4, SMARCB1 and phosphatase and tensin homolog (PTEN), mutation analysis for phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene and fluorescence in situ hybridization for ZNF217 amplification. The correlations between ARID1A expression, PI3K-Akt pathway, ZNF217 amplification and other clinicopathological factors were analyzed. Loss of ARID1A expression was present in 35 cases (52%) and loss of SMARCA2 expression occurred in 1 case. SMARCA4 and SMARCB1 expressions were preserved in all cases. PIK3CA mutations were present in 23 cases (34%) and loss of PTEN expression occurred in 8 cases (12%). Alterations in the PI3K-Akt pathway (PIK3CA mutations or loss of PTEN expression) were found in 42 cases (62%). ZNF217 amplification was detected in 21 cases (31%). Loss of ARID1A expression was significantly related to younger patient age (P=0.048), PI3K-Akt pathway activation (P=0.046) and ZNF217 amplification (P=0.028). All of the clinicopathological factors were not prognostic factors for ovarian clear cell carcinoma after multivariate analysis, except International Federation of Gynecology and Obstetrics staging (P=0.001). Our results showed that loss of ARID1A expression usually coexisted with PI3K-Akt pathway activation and/or ZNF217 amplification. Synergic effects of loss of ARID1A and PI3K-Akt pathway activation as well as ZNF217 amplification may be related to the development of ovarian clear cell carcinoma.

Periocular sebaceous carcinoma is an aggressive neoplasm with significant morbidity and mortality. Its pathogenesis is poorly understood. It is only rarely associated with Muir-Torre syndrome. Previous studies from Asian countries, have suggested that human papillomavirus (HPV) infection plays a role in the pathogenesis and overexpression of p16(INK4a), a surrogate marker of HPV infection, have also been reported. However, data from western countries seem contradictory. In order to clarify and explore the molecular and epigenetic basis of HPV, CDKN2A status and role of microsatellite instability in the development of periocular sebaceous carcinoma, 24 cases of periocular sebaceous carcinoma were analyzed for the expression of p16(INK4a) and mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) via immunohistochemistry. Nested polymerase chain reaction (PCR) and genechip HPV typing were used to detect HPV infection and decide its genotype when present. PCR amplification using a consensus primer pair was also performed to detect β-HPV. The methylation status of CDKN2A promoter region was studied by methylation-specific polymerase chain reaction. HPV-positivity was demonstrated in only one of our cases (HPV 16), while another case showed p16(INK4a) overexpression. All cases showed preserved expression of mismatch repair proteins. CDKN2A promoter hypermethylation was noted in nearly half of our cases (11/24) and was associated with younger patient age (P = .013). Our results showed that periocular sebaceous carcinoma is rarely associated with HPV and microsatellite instability. Higher frequency of CDKN2A promoter hypermethylation in younger patients implies a significant epigenetic role in tumor development in this age group.

Objective Gastric type of adenocarcinoma (GAC) is a newly reported, morphologically distinct, mucinous subtype of cervical adenocarcinoma and is distinguished by aggressiveness and fatal outcomes. The association between human papillomavirus (HPV) and cervical carcinoma is well known; however, GAC is almost always HPV negative. Materials and methods We report an unusual case of cervical GAC in a 41-year-old woman with a metastatic ovarian mass. The histological morphology of both tumors consisted of irregular glands lined by mucous cells with mild to moderate nuclear atypia and containing abundant cytoplasmic mucin. Results Immunohistochemical studies of the tumor cells revealed positive reactivity for CK7 and carcinoembryonic antigen but negative reactivity for p16 and HPV DNA usually expressed in cervical adenocarcinoma. Further staining for mucin with monoclonal antibody HIK1083 showed positive reactivity in both cervical and ovarian tumors. A gastric type of cervical carcinoma is considered. The patient is free of detectable disease at a 12-month follow-up. Conclusions P16 staining and HPV DNA test result are usually positive in usual mucinous type of cervical adenocarcinoma, but they are negative in GAC. HIK1083 is becoming more commonly used for the diagnosis of GAC. Differentiation of GAC from usual mucinous type of cervical adenocarcinoma is important because GAC was related to a significant risk of recurrence and decreased 5-year disease-specific survival. We suggest applying HIK1083 in the diagnosis of cervical adenocarcinoma, especially in a small biopsy specimen.

Our study aims to make differential diagnosis by immunoelectrophoresis for some common conditions with elevated levels of serum alpha-fetoprotein (AFP). One hundred and nine cases with elevated AFP levels were included in this study: yolk sac tumor (n = 8), hepatocellular carcinoma (n = 26), gastric cancer (n = 12), chronic hepatitis (n = 27) and normal pregnancy (n = 36). Lectin agarose gel electrophoresis, antibody-affinity blotting, and immunoreaction were used to identify the specific patterns of AFP in the respective conditions. The results showed that there were three possible bands: L1, L2 and L3. Yolk sac tumor produced a prominent L2 band and a light L3 band. Hepatocellular carcinoma produced a prominent L1 band and a light L3 band. Gastric cancer produced only an L1 band. Chronic hepatitis had a light L1 band and a pronounced L3 band. In pregnancy, the AFP pattern is similar to that of hepatocellular carcinoma. Immunoelectrophoresis is a useful method facilitating the differentiation of AFP origins.

INTRODUCTION: Uterine cancer was the most rapidly increasing malignancy and the second most common gynecologic malignancy in Taiwan. METHODS: We analyzed the secular trend of uterine cancer incidence and compare the survival of women with uterine carcinomas and uterine sarcomas in Taiwan. Data on women diagnosed with uterine cancer between 1979 and 2008 were obtained from the Taiwan cancer registry. Survival data were analyzed by using Kaplan-Meier and Cox proportional hazards regression methods. RESULTS: Records of 11,558 women with uterine carcinomas and 1,226 women with uterine sarcomas were analyzed. The age-adjusted incidence rate of endometrioid adenocarcinoma increased from 0.83 per 100,000 women per year between 1979 and 1983 to 7.50 per 100,000 women per year between 2004 and 2008. The 5-year survival rate of women with endometrioid adenocarcinoma (83.2%) was higher than that for women with clear cell carcinoma (58.3%), serous carcinoma (54.4%), and carcinosarcoma (35.2%) (p

Small cell carcinoma of the uterine cervix (SCCUC) is an uncommon, aggressive disease accounting for less than 5% of all cervical cancers. Due to its rarity, definitive treatment strategies have not been developed. Our aim was to analyze the clinical factors, treatment modalities, sites of relapse, and overall survival of women with early stage SCCUC and thus determine prognostic factors. The clinical records of 18 women diagnosed with stage IB1 to IIA SCCUC were reviewed, and patient characteristics and treatment modalities were analyzed to determine the prognostic factors for disease-free survival (DFS) and overall survival (OS). DFS and OS were 39% and 44% at 2 years. Lymph node metastasis was a significant prognostic factor of DFS. International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis were significant prognostic factors of OS as determined by multivariate analysis (p < 0.05). Radical hysterectomy followed by adjuvant chemotherapy resulted in higher 2-year survival rates compared to radical hysterectomy followed by adjuvant radiotherapy (62.5% vs. 16.7%); however, the difference was not statistically significant due to the small sample size. FIGO stage and lymph node metastasis are significant indicators of OS in patients with early stage SCCUC. Further larger scale analysis is warranted to determine whether adjuvant chemotherapy may facilitate a better prognosis than adjuvant radiotherapy.

Most human papillomavirus-associated squamous intraepithelial lesions of the uterine cervix are flat; some have papillary architecture that shows a spectrum of differentiation from low-grade squamous intraepithelial lesions to high-grade squamous intraepithelial lesions. For this subset of lesions, there are few data relating human papillomavirus type to cytology and cell cycle activity. Here, we collected 24 cases of papillary squamous intraepithelial lesions with either low-risk (15 cases) or high-risk (9 cases) human papillomavirus infection. We described their morphology and performed immunohistochemical staining with cell cycle-related markers Ki-67, p53, pRb, and P16INK4a. The Ki-67 labeling index was significantly lower in the low-risk group than in the high-risk group (P < .001). A cut point of less than 50% labeling index detected all but one low-risk group case. Degradation of p53 and pRb was less evident in the low-risk group than in the high-risk group (p53, P < .001; pRb, P = .006). P16INK4a produced an unexpectedly high positive rate of staining in the low-risk group (60%). However, a specific top-heavy distribution pattern was noted, with evident nuclear but faint cytoplasmic staining, whereas the high-risk group showed strong full-thickness nuclear and cytoplasmic staining. The detection of these lesions by smear examination was not reliable, given the wide expression pattern. Papillary structure was evident in none. We conclude that cell cycle-related markers are helpful in distinguishing low- and high-risk lesions. The strong p16INK4a staining in the low-risk group may imply that more cell cycle-controlling pressure is elicited in papillary lesions than in flat lesions. The distribution pattern of p16INK4a staining is important when making a diagnosis; cytology is not effective. Human papillomavirus type, histology, and cell cycle markers could clearly separate these lesions into either a low-risk or a high-risk group, properly designated low-grade squamous intraepithelial lesions or high-grade squamous intraepithelial lesions in current management algorithms. Thus, the previously used terms papillary immature metaplasia and immature condyloma, although descriptive for low-risk group lesions, are confusing and should be discarded.

Objectives Loss of phosphatase and tensin homolog (PTEN) expression is common in ovarian clear cell adenocarcinomas (OCCA), but PTEN mutations are not frequently observed in OCCA. The mechanism of PTEN gene silencing in OCCA is still not clear. Materials and methods Immunohistochemical analysis of PTEN expression was performed in 40 OCCA paraffin-embedded tissues. PTEN promoter methylation in 24 OCCA tissues and 5 OCCA cell lines was examined by methylation-specific PCR. Eighteen OCCA patients and 13 serous adenocarcinomas were analyzed for loss of heterozygosity (LOH) at 10q23 with five polymorphic markers. Results Of the 40 OCCAs, 37.5% (15/40) had reduced PTEN immunoreactivity, LOH was found in 33% (6/18) of OCCAs, and 31% (4/13) of serous adenocarcinomas. In the 33% of OCCAs with LOH, only 33% (2/6) lost PTEN expression. PTEN promoter was unmethylated in 5 OCCA cell lines and 24 OCCA tissues detected by MSP-PCR. No significant correlation between PTEN expression and advanced stage disease or overall survival was found. Conclusion Our results indicate that reduced PTEN expression was detected in more than one third of OCCA cases. Neither PTEN promoter methylation nor LOH at 10q23 locus is significantly related to PTEN inactivation and is not an adverse prognostic factor in OCCA.

Presence of human papillomavirus (HPV) in variable proportions in tonsillar squamous cell carcinoma tissues has been demonstrated by several worldwide studies. Some reports emphasized the significance of HPV in predicting a better prognosis, as well as ethnic differences between Chinese and Caucasians. In order to understand the biological role of HPV and find out clinically accessible methods to determine its prognostic significance in primary tonsillar squamous cell carcinoma, we collected 92 patients with primary tonsillar squamous cell carcinoma diagnosed or treated in National Taiwan University Hospital, for whom archival tumor tissue were available. Immunohistochemical stains of p16(INK4A), high-risk HPV in situ hybridization, and nested polymerase chain reaction (PCR)-based genechips were performed to detect HPV infection and determine its genotype. Clinical data were compared with HPV infection detected by the different methods mentioned above. Real-time PCR was also performed on the HPV16-positive [HPV16(+)] lesions to understand viral integration status. The positive rates of nested PCR-based genechips, overexpression of p16(INK4A), and high-risk HPV in situ hybridization were 75% (69/92), 53% (49/92), and 44% (40/92), respectively. Both overexpression of P16(INK4A) and high-risk HPV in situ hybridization positivity were associated with favorable prognoses (P=0.004 and 0.001, respectively) and also independent prognostic factors in multivariate analyses (P=0.01 and 0.01, respectively). The positivity of nested PCR-based genechips was not statistically significant. From our data, primary tonsillar squamous cell carcinoma with positive immunohistochemical stains of p16(INK4A) and/or high-risk HPV in situ hybridization is associated with a better outcome, and both methods may serve as clinically accessible markers.

Choriocarcinoma is traditionally described as being composed of cytotrophoblast and syncytiotrophoblast. Microscopically, these 2 types of cells are intimately associated with each other, forming a characteristic biphasic plexiform pattern, however, the nature of these 2 types of trophoblastic cells is not well understood. In this study, we used immunohistochemistry for several trophoblastic markers to analyze the trophoblastic subpopulations in 36 gestational choriocarcinomas. Eighty-one specimens including placenta, complete mole, placental site nodule, epithelioid trophoblastic tumor, and placental site trophoblastic tumor were analyzed. The antibodies included Mel-CAM, HLA-G, MUC-4, and beta-catenin. A semiquantitative assessment of positive cells and the cellular localization of these markers were recorded. We found diffuse strong membranous and cytoplasmic staining for MUC-4 in mononucleate cells in all 36 cases (100%) and a similar pattern of localization in 28 cases (78%) for HLA-G. This distribution was similar to that in normal placentas, where MUC-4 and HLA-G are expressed in the trophoblastic cells of the trophoblastic columns and implantation site. In choriocarcinoma, mononucleate trophoblastic cells showed moderate immunoreactivity for Mel-CAM, a specific marker for implantation site intermediate trophoblast, in 78% of the cases. The MUC-4, HLA-G, and Mel-CAM-positive trophoblastic cells were larger than cytotrophoblastic cells, with more abundant cytoplasm, consistent with the morphology of intermediate trophoblast. In contrast, 31% of the choriocarcinomas contained a very small proportion (

Neuroendocrine carcinomas of the uterine cervix are rare tumors with early metastases, highly aggressive clinical behavior, and poor clinical outcome. Several adhesion molecules like cadherins have been tested in an attempt to explain their unique characteristics. Cluster differentiation 44 (CD44) is a widely expressed cell surface glycoprotein that serves as an adhesion molecule in cell-to-substrate and cell-to-cell interaction. We have examined the expression of the standard CD44 (CD44s) by immunohistochemical stains in the paraffin-embedded cervical neoplasm tissue of 17 cases of primary cervical neuroendocrine carcinoma, 28 cases of cervical adenocarcinoma, and 50 cases of cervical squamous cell carcinoma. Loss of CD44s expression was found in 16 of 17 neuroendocrine carcinomas, 14 of 28 adenocarcinomas, and three of 50 squamous cell carcinomas. The differences were statistically significant. We also examined immunohistochemically the expression of the BRG-1 subunit of the SWI-SNF complex, which has been reported to regulate the expression of CD44 in all cases. Loss of BRG-1 expression was observed in 12/16, 6/14, and 1/3 CD44s-negative neuroendocrine carcinomas, adenocarcinomas, and squamous cell carcinomas, respectively. This study suggests that loss of the CD44s molecule may imply special biological behaviors of cervical neuroendocrine carcinomas, and loss of expression of BRG-1 may contribute to this.

We report an epithelioid trophoblastic tumor, a recently delineated type of gestational trophoblastic tumor (GTT), discovered in the right broad ligament of a 41-year-old woman. The patient had gestational trophoblastic disease and was treated with methotrexate regimen 15 times 10 years earlier. The yellowish, spongy tumor with tiny hemorrhage spots was located in the right broad ligament, adherent to the right ovary. Microscopically, the tumor was circumscribed, with a pushing border, and the epithelial-differentiated tumor cells grew in cords, nests, and sheets within which were aggregates of hyaline material and necrotic debris. Most tumor cells were mononuclear with distinct cell borders, eosinophilic cytoplasm, and had nuclei with occasional indistinct nucleoli. Scattered multinucleated cells consistent with syncytiotrophoblastic cells were also present. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (AE1/AE3, CAM 5.2, CK18), and focal reactivity, mainly in syncytiotrophoblastic cells, for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha. The histologic and immunohistochemical features were characteristic of epithelioid trophoblastic tumor and helped to distinguish the tumor from other trophoblastic tumors and squamous cell carcinoma. Our unusual findings in this case included a high level of serum beta-human chorionic gonadotropin, an unusual tumor location, and a higher Ki-67 proliferative index of 47.2%.

Objective: To investigate the various genotypes of human papillomavirus (HPV) in Taiwanese women patients with abnormal cervical cytology and analyze the associations between HPV types, cervical preinvasive lesions, and the medical characteristics of these patients. Materials and Methods: We performed HPV genotyping GeneChip procedures and colposcopies for 784 women with abnormal Papanicolaou smears. The characteristics of the patients and the status of the HPV infection were correlated. Results: A total of 706 (90.1%) of the 784 women were positive for HPV infection, including 641 patients with high-risk HPV (HR-HPV). Among the patients with high-grade squamous intraepithelial lesions (HSILs), the average age of the 273 patients with other HR-HPV types (48.6 ± 13.8 years) was significantly older than the 222 patients infected with HPV 16/18 (39.8 ± 11.8 years) (p