Journal of Pathology and Translational Medicine

Original Article

MAD2 Expression in Ovarian Carcinoma: Different Expression Patterns and Levels among Various Types of Ovarian Carcinoma and Its Prognostic Significance in High-Grade Serous Carcinoma: Po Eun Park, Ji Yun Jeong, Sun Zoo Kim, Ji Young Park; Korean J Pathol. 2013;47(5):418-425. Published online October 25, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.5.418

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Background

Mitotic arrest deficiency protein 2 (MAD2) is a key component of spindle assembly checkpoint function, which mediates cell apoptosis through microtubule kinetics. Aberrant expression of MAD2 is believed to be associated with the development of chromosome instability. MAD2 also has a signihicant role in cellular drug resistance to taxane chemotherapeutic agents.

Methods

Expression of MAD2 and p53 was investigated using immunohistochemistry in 85 cases of ovarian carcinomas. Clinicopathological data including progression-free survival were analyzed.

Results

A significant (p=.035) association was observed between the grade of serous carcinoma and the expression level of MAD2. While low-grade serous carcinoma showed a low-level expression of MAD2, high-grade serous carcinoma showed a high-level expression of MAD2. We also determined that low-level expression of MAD2 was associated with reduced progression-free survival (PFS) (p=.016) in high-grade serous carcinoma.

Conclusions

MAD2 expression in ovarian carcinoma is related to the grade of serous carcinoma and PFS of high-grade serous carcinoma. Expression level of MAD2 detected by immunohistochemistry may serve as an indicator in predicting the response of microtubule-interfering chemotherapeutic agents.

Citations

Citations to this article as recorded by

The role of the MAD2-TLR4-MyD88 axis in paclitaxel resistance in ovarian cancer
Mark Bates, Cathy D. Spillane, Michael F. Gallagher, Amanda McCann, Cara Martin, Gordon Blackshields, Helen Keegan, Luke Gubbins, Robert Brooks, Doug Brooks, Stavros Selemidis, Sharon O’Toole, John J. O’Leary, David Wai Chan
PLOS ONE.2020; 15(12): e0243715. CrossRef
Aneuploidy: Cancer strength or vulnerability?
Giorgia Simonetti, Samantha Bruno, Antonella Padella, Elena Tenti, Giovanni Martinelli
International Journal of Cancer.2019; 144(1): 8. CrossRef
The association between MAD2 and prognosis in cancer: a systematic review and meta-analyses
Tara Byrne, Helen G. Coleman, Janine A. Cooper, W. Glenn McCluggage, Amanda McCann, Fiona Furlong
Oncotarget.2017; 8(60): 102223. CrossRef
Identification of transcription factors (TFs) and targets involved in the cholangiocarcinoma (CCA) by integrated analysis
L Yang, S Feng, Y Yang
Cancer Gene Therapy.2016; 23(12): 439. CrossRef
Proteins of the mitotic checkpoint and spindle are related to chromosomal instability and unfavourable prognosis in patients with myelodysplastic syndrome
Kelly Roveran Genga, Francisco Dário Rocha Filho, Francisco Valdeci de Almeida Ferreira, Juliana Cordeiro de Sousa, Fernando Sergio Studart, Silvia Maria Meira Magalhães, Fabíola Fernandes Heredia, Ronald Feitosa Pinheiro
Journal of Clinical Pathology.2015; 68(5): 381. CrossRef

Case Reports

Urothelial (Transitional Cell) Carcinoma Arising in Mature Cystic Teratoma: A Case Report.: Ok Jun Lee, Ho chang Lee; Korean J Pathol. 2010;44(6):666-669.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.6.666

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Abstract PDF

Mature cystic teratoma (MCT) is one of the most common benign ovarian tumors, but 1-2% of MCTs are transformed to a malignant neoplasm. Urothelial carcinoma (UC) or transitional cell carcinoma is the most common cancer in the urinary tract. However, UC is a very rare component of transformed malignancy of MCT. Here we report a case of UC arising in an MCT in a 52-year-old woman. Grossly, the ovary was partly cystic and partly solid. Microscopically, the cyst revealed the classic features of MCT and the solid area was papillary UC. By immunohistochemistry using cytokeratins and thrombomodulin, the UC showed a similar expression to that of UC arising in the urinary tract, rather than resembling a primary transitional cell carcinoma of the ovary. When UC is found in a component of MCT, the origin of the carcinoma should be evaluated and urinary tract examinations are required to rule out metastasis.

Citations

Citations to this article as recorded by

A Rare Urothelial Malignant Transformation in a Mature Cystic Teratoma of the Ovary
Moito Iijima, Iori Kisu, Tetsuro Shiraishi, Rie Irie, Nobumaru Hirao
Cureus.2021;[Epub] CrossRef
Transitional Cell Carcinoma arising in Ovarian Cystic Teratoma: A Rare Case Report
Abhay V. Deshmukh, Vitaladevuni B. Shivkumar, Neha V. Fulzele, Nitin M. Gangane
Indian Journal of Gynecologic Oncology.2020;[Epub] CrossRef
A Rare Malignant Transformation of an Ovarian Cystic Teratoma: A Case Report
Manju Rachel Mathew, Anita Ramdas, Susy S. Kurian, Linu Kuruvilla, Neelima Singh
Case Reports in Pathology.2018; 2018: 1. CrossRef
Urothelial carcinoma arising from an ovarian mature cystic teratoma
Hui-Yu Chuang, Yi-Ting Chen, Tak-Loi Mac, Yu-Chieh Chen, Hung-Sheng Chen, Wan-Shan Wang, Eing-Mei Tsai
Taiwanese Journal of Obstetrics and Gynecology.2015; 54(4): 442. CrossRef

Sex Cord Tumor with Annular Tubules and Serous Surface Papillary Carcinoma of the Ovary: A case report.: Dae su Kim, Sang Yong Song, Geung hwan Ahn; Korean J Pathol. 1999;33(8):627-630.

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Abstract PDF: Sex cord tumor with annular tubules (SCTAT) is a rare ovarian neoplasm which usually occurs in two forms. In patients associated with Peutz-Jeghers syndrome, the tumors are usually small, bilateral or multifocal, and show benign clinical course. However, tumors from patients without the syndrome are often large, usually unilateral, and rarely show malignant behavior. Serous surface papillary carcinoma (SSPC) is an aggressive neoplasm which involves peritoneal linings, including ovarian surface. Recently, we encountered a case of an unusual combination of SCTAT and SSPC in the ovary of a 55-year-old Korean woman presented with abdominal distention for one year. Systemic review and physical examination were within normal limit, except for abdominal discomfort and distention. There was no stigmata of Peutz-Jeghers syndrome in all diagnostic examinations, including gastroscopy and colonoscopy. Pelvic computed tomography showed adnexal mass with multiple peritoneal nodules. Exploration revealed uterine and ovarian surfaces covered with multiple, yellow-white papillary nodules. However, the sizes of both ovaries were within normal limit. Typical serous papillary carcinomas were identified in nodules from peritoneum and ovarian surfaces. Well-circumscribed columnar epithelial cell nests composed of ring-shaped tubules encircling hyalinized basement membrane-like materials were found in the ovary away from serous surface papillary carcinoma.

Original Article

Expression of p27kip1 and Cyclin D1 in Serous Epithelial Ovarian Tumors.: Sun Young Kwon, Eun Sook Chang, Kun Young Kwon, Kwan Kyu Park, Soo Kyung Kim; Korean J Pathol. 2001;35(3):220-225.

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Abstract PDF: BACKGROUND
p27kip1 is a member of the Cip/Kip family of the cyclin-dependent kinase inhibitors and is a potential tumor suppressor gene. Decreased expression of p27kip1 is associated with high histologic grade and poor prognosis in a variety of human tumors.
METHODS
Sixty-six cases of serous epithelial ovarian tumors were investigated by immunohistochemical staining for p27kip1, cyclin D1, and Ki-67. Clinicopathologic parameters (WHO classification, histologic grade and FIGO stage) were compared with the incidence of p27kip1, cyclin D1 and Ki-67 protein expression in ovarian serous tumors.
RESULTS
Reduced expression of p27kip1 was found more freguently in serous cystadenocarcinoma than in serous cystadenoma and borderline malignancy (p<0.05). The decreased expression of p27kip1 was correlated with a high histologic grade and an advanced FIGO stage. Overexpression of cyclin D1 is associated with borderline malignancy and grade I serous cystadenocarcinoma. An inverse relationship was observed between the p27kip1 protein and the Ki-67 labeling index within serous cystadenocarcinoma, but it was not significant.
CONCLUSIONS
Reduced expression of p27kip1 protein plays an important role in the biologically aggressive behavior of serous epithelial ovarian tumors and might represent a useful prognostic marker for predicting the recurrence in primary ovarian tumors.

Case Reports

Mixed Germ Cell-Sex Cord-Stromal Tumor of Non-Gonadoblastoma Type of Ovary: A Case Report.: Kwangseon Min, Byungha Choi, Kyu Rae Kim; Korean J Pathol. 2002;36(1):62-65.

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Abstract PDF: We described a case of mixed germ cell-sex cord-stromal tumor of non-gonadoblastoma type (GCSCT-NG) of the ovary in a 2-year-old girl and compared its histological, immunohistochemical and ultrastructural findings with those of gonadoblastoma. The germ cell component showed an immunopositivity for cytokeratin and epithelial membrane antigen (EMA), and a negative reaction for -inhibin, alpha-fetoprotein (AFP), placental alkaline phosphatase (PLAP), vimentin and CD99. The sex cord elements showed an immunopositivity for cytokeratin, EMA, vimentin and inhibin, but negativity for AFP, PLAP, and CD99. The ultrastructural features showed desmosome-like cell junctions, suggesting spermatocytic differentiation from the primordial germ cells or gonocytes. Immunohistochemical and ultrastructural findings suggested that GCSCT-NG is probably a more differentiated form of mixed germ cell- sex cord-stromal tumor than gonadoblastoma.

Alpha-Fetoprotein Producing Sertoli-Leydig Cell Tumor of the Ovary: A Case Report.: Kee Taek Jang, Hye Rim Park, Duck Hwan Kim, Chang Mo Kim, Woo Seok Sohn, Hyung Sik Shin; Korean J Pathol. 2002;36(2):128-131.

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Abstract PDF: A 26-year-old woman had an ovarian Sertoli-Leydig cell tumor (SLCT) associated with an elevated level of serum alpha-fetoprotein (AFP). The tumor had a heterologous element of intestinal-type mucinous epithelium, retiform and intermediately differentiated tubules of the Sertoli cells, and AFP-producing Leydig cells. AFP was demonstrated within the Leydig cells by an immunohistochemical technique. After surgery, the serum AFP level of the patient fell to the normal range. The present case is the first documented case of AFP producing a SLCT of the ovary reported in Korea.

Original Articles

Analysis of Microsatellite Instability in Ovarian Epithelial Cancer.: Mee Young Sol, Kyung Un Choi, Jee Yeon Kim, Hyun Jeong Kang, Dong Hoon Shin, Ik Doo Kim, Hyo Seon Choi, Soon Jung Seo; Korean J Pathol. 2007;41(6):380-386.

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Abstract PDF: BACKGROUND
The aim of this study was to clarify the incidence and role of microsatellite instability (MSI) in sporadic ovarian epithelial cancers (OEC). We investigated the MSI status and mismatch repair (MMR) protein expression in OEC.
METHODS
MSI was examined by fluorescence- based polymerase chain reaction using five NCI panel markers (BAT25, BAT26, D2S123, D5S346 and D17S250) in 46 cases of OEC. Immunohistochemistry (IHC) for hMLH1 and hMSH2 was performed.
RESULTS
Seven cases (15.2%) exhibited high-frequency MSI (MSIH), one exhibited low-frequency MSI (MSI-L), and the remaining 38 demonstrated microsatellite stability (MSS). MSI-H in OEC was not associated with histologic grade, FIGO stage, tumor size, mitoses or histologic type. Loss of expression of either hMLH1 or hMSH2 was observed in 4 of the 7 (59.3%) MSI-H cases, whereas 4 of the 39 (10.3%) MSI-L or MSS tumors revealed loss of expression of MMR proteins. The sensitivity and specificity of immunohistochemistry for hMLH1 and hMSH2 were 57.1% and 89.7%.
CONCLUSIONS
Our data suggest that a genetic defect in the MMR system might play a role in the carcinogenesis of a minor subset of sporadic OEC however, immunohistochemical testing for hMLH1 and hMSH2 cannot accurately determine microsatellite instability status in OEC.

The Expression of c-erbB-2, EGFR, p53 and Ki-67 in Ovarian Borderline Tumors and Carcinomas of the Ovary.: Kyueng Whan Min, Moon Hyang Park; Korean J Pathol. 2007;41(5):296-306.

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Abstract PDF: BACKGROUND
An ovarian surface epithelial tumor is a heterogenous disease, and various biological and molecular factors are important for its development and progression. Several findings support EGFR or c-erbB-2 as adverse prognostic indicators for an ovarian carcinoma.
METHODS
We reviewed the histological and clinical findings of 52 carcinomas (17 endometrioid, 16 serous, 13 mucinous and 6 clear cell tumors), and 26 borderline (10 serous and 16 mucinous) tumors. Expression of c-erbB-2, EGFR, p53, and Ki-67 was evaluated on paraffinembedded tissue from a primary ovarian tumor by immunohistochemical methods.
RESULTS
Expression of c-erbB-2 was found in 7.6% of tumors and expression of EGFR was found in 9.6% of tumors by immunohistochemical analysis. No significance was found between cerbB- 2 and EGFR expression as indicators of a poor prognosis. The expression of p53 and Ki-67 (>50%) correlated with the grade and type of tumor in the ovarian cancers. p53 and Ki- 67 overexpression (>50%) was absent in the borderline ovarian tumors, whereas ovarian carcinomas showed expression of both p53 and Ki-67.
CONCLUSION
Expression of c-erbB- 2, EGFR, p53, and Ki-67 as determined by immunohistochemical analysis did not correlate with prognostic significance. However, p53 and Ki-67 expression may be used as markers to predict aggressive behavior, and to differentiate between malignant and borderline epithelial ovarian tumors. Further large-scale studies are required to clarify the significance of c-erbB-2 and EGFR expression in ovarian tumors.

Correlations between the Expression of c-Abl, c-Kit, Platelet-derived Growth Factor Receptor (PDGFR)-alpha and PDGFR-beta and Survival in Patients with Ovarian Cancer.: Heejeong Lee, Keun Ho Lee, Kyo young Lee, Chang Suk Kang; Korean J Pathol. 2006;40(3):210-216.

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Abstract PDF: BACKGROUND
:Protein tyrosine kinases (PTKs) such as c-Abl, c-KIT, PDGFR-alpha and PDGFR-bata are key proteins in the regulation of cell growth. In this study, we evaluated the correlations between the expression of c-Abl, c-KIT, PDGFR-alpha and PDGFR-beta and the survival of patients with ovarian cancer.
METHODS
We performed the immunohistochemistry for 102 patients with ovarian cancer and we retrospectively reviewed the overall and disease free survival and also the response to platinum-based chemotherapy in those patients.
RESULTS
The short disease free survival rate was significantly associated with the increased expression of PDGFR-alpha (p=0.0459). The short overall survival time in patients with advanced (stage III and IV) ovarian cancer was associated with the overexpression of c-Abl (p=0.0268) and the reduced expression of c-KIT (p=0.0307). On multivariate analysis, the tumor stage and c-Abl maintained their prognostic influence. Meanwhile, none of the four PTK expression patterns predicted the response to the platinum-based chemotherapy.
CONCLUSIONS
Our data suggest that for patients with advanced ovarian cancer, the overexpression of c-Abl and the reduced expression of c-KIT might be used as poor prognostic factors for overall survival. It is further noteworthy that the tumor stage and c-Abl may be useful in predicting the patients' survival. Although any of the four PTKs could not predict the response to platinum chemotherapy, the expression of the kinases targeted by tyrosine kinase inhibitor suggests the potential usefulness of imatinib mesylate for the treatment of ovarian cancer.

Case Reports

Synchronous Invasive Ductal Carcinoma and Metastatic Ovarian Serous Papillary Adenocarcinoma in the Same Breast: A Case Report.: Hyun Jung Kim, Sung jig Lim, Sehwan Han, Ji Young Kim, Kyeongmee Park; Korean J Pathol. 2006;40(1):66-69.

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Abstract PDF: A 59-year-old woman displayed multiple palpable right breast masses along with ipsilateral cervical and axillary lymphadenopathy. She had a previous history of bilateral salpingo-oopho- rectomy for serous papillary adenocarcinoma two and half years ago. She underwent mastectomy for the lesions located in the upper inner breast quadrant. A 1 cm-sized primary ductal carcinoma was present; however, the other breast lesions and the metastatic axillary lymph nodes were confirmed as showing papillary serous adenocarcinoma, which were similar to the previous ovarian tumor. After the patient underwent postoperative adjuvant chemotherapy, of 8 cycles of doxorubicin and docetaxel, she has been stable during the clinical follow-up for 10 months with decreases in size of the metastatic nodules.

Myxoma of the Ovary with Uncertain Malignant Potential: A Case Report.: Min A Kim, Ji Hoon Kim, Jae Y Ro, Geunghwan Ahn, In Ae Park; Korean J Pathol. 2004;38(6):434-437.

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Abstract PDF: Primary ovarian myxoid tumor such as myxoma, myxoid liposarcoma and myxoid leiomyosarcoma is extremely rare neoplasm. We experienced a case of unusual myxoid tumor of the ovary in a 25 year-old woman. She was admitted for an incidentally found ovarian mass during antenatal check. Radiologic studies revealed a 5.5x5 cm-sized solid mass in left ovary and she was undertaken left oophorectomy. Grossly, the round ovarian mass was measuring 8x6x5 cm, and the cut surface was predominantly solid with myxoid appearance. Microscopically, the tumor was surrounded by thick collagenous capsule and had moderate cellularity and rich vascularity. The tumor cells were stellate-shaped with abundant extracellular myxoid material without atypia. We initially thought this lesion as myxoma, but the cellularity was too high as an ordinary myxoma. Myxoid liposarcoma could also be considered as the differential diagnosis, however there was no convincing lipoblast. So, we diagnosed that tumor as myxoma with uncertain malignant potential.

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