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MiR-130b modulates the invasive, migratory, and metastatic behavior of leiomyosarcoma

Danielson, Laura S; Guijarro, Maria V; Menendez, Silvia; Higgins, Brett; Sun, Qiang; Mittal, Khushbakhat; Popiolek, Dorota A; Overholtzer, Michael; Palmer, Glyn D; Hernando, Eva
Leiomyosarcoma (LMS) is an aggressive, often poorly differentiated cancer of the smooth muscle (SM) lineage for which the molecular drivers of transformation and progression are poorly understood. In microRNA (miRNA) profiling studies, miR-130b was previously found to be upregulated in LMS vs. normal SM, and down-regulated during the differentiation of mesenchymal stem cells (MSCs) into SM, suggesting a role in LMS tumor progression. In the present study, the effects of miR-130b on human LMS tumorigenesis were investigated. Stable miR-130b overexpression enhanced invasion of LMS cells in vitro, and led to the formation of undifferentiated, pleomorphic tumors in vivo, with increased growth and metastatic potential compared to control LMS cells. TSC1 was identified as a direct miR-130b target in luciferase-3'UTR assays, and shRNA-mediated knockdown of TSC1 replicated miR-130b effects. Loss-of-function and gain-of-function studies showed that miR-130b levels regulate cell morphology and motility. Following miR-130b suppression, LMS cells adopted a rounded morphology, amoeboid mode of cell movement and enhanced invasive capacity that was Rho/ROCK dependent. Conversely, miR-130b-overexpressing LMS cells exhibited Rho-independent invasion, accompanied by down-regulation of Rho-pathway effectors. In mesenchymal stem cells, both miR-130b overexpression and TSC1 silencing independently impaired SM differentiation in vitro. Together, the data reveal miR-130b as a pro-oncogenic miRNA in LMS and support a miR-130b-TSC1 regulatory network that enhances tumor progression via inhibition of SM differentiation.
PMCID:9879492
PMID: 36701370
ISSN: 1932-6203
CID: 5426622

Origin of a Post-Cesarean Delivery Niche: Diagnosis, Pathophysiologic Characteristics, and Video Documentation [Letter]

Antoine, Clarel; Pimentel, Ricardo N; Timor-Tritsch, Ilan E; Mittal, Khush; Bennett, Terri-Ann; Bourroul, Filipe M
PMID: 32557736
ISSN: 1550-9613
CID: 4505092

Inflammatory Myofibrobalstic Tumor in Female Genital Tract

Shukla, Pratibha Sharma; Mittal, Khushbakhat
CONTEXT/BACKGROUND:- Inflammatory myofibroblastic tumor is a mesenchymal neoplasm of low malignant potential. It was first described in lung, but is known to occur in many extrapulmonary sites including female genital organs, most commonly the uterus. It has a high recurrence rate and a low risk for metastasis. A more recently described aggressive variant, epithelioid myofibroblastic sarcoma with a predilection for the abdominal cavity of males, has also been recently reported to occur in ovary. This tumor is composed of spindled and epithelioid myofibroblasts in a variably myxoid stroma and commonly shows a fascicular growth pattern with positive staining for desmin, smooth muscle actin, and CD10, which may mimic a smooth muscle or endometrial stromal neoplasm. In the female genital tract it has the potential for being misdiagnosed as a leiomyoma, endometrial stromal tumor, or as a myxoid leiomyosarcoma, resulting in undertreatment or overtreatment. It harbors rearrangements in the ALK gene, resulting in abnormal expression of ALK protein. Immunostaining for ALK is a helpful diagnostic tool. OBJECTIVE:- To provide a brief review of clinical, histologic, immunohistochemical, and molecular features of inflammatory myofibroblastic tumor with emphasis on possible diagnostic pitfalls in the female genital tract. DATA SOURCES/METHODS:- Review of pertinent literature on inflammatory myofibroblastic tumor occurring in the female genital tract and personal experience of the authors. CONCLUSIONS:- Inflammatory myofibroblastic tumor in the female genital tract can mimic other more common benign and malignant tumors like leiomyoma, leiomyosarcoma, and endometrial stromal sarcoma. Familiarity with clinical and histologic features and use of ALK immunostaining can be critical for correct diagnosis.
PMID: 29965784
ISSN: 1543-2165
CID: 3186042

Issues in the Differential Diagnosis of Uterine Low-grade Endometrioid Carcinoma, Including Mixed Endometrial Carcinomas: Recommendations from the International Society of Gynecological Pathologists

Rabban, Joseph T; Gilks, C Blake; Malpica, Anais; Matias-Guiu, Xavier; Mittal, Khush; Mutter, George L; Oliva, Esther; Parkash, Vinita; Ronnett, Brigitte M; Staats, Paul; Stewart, Colin J R; McCluggage, W Glenn
This article provides practical recommendations developed from the International Society of Gynecological Pathologists Endometrial Carcinoma Project to address 4 issues that may arise in the diagnosis of uterine corpus low-grade endometrioid carcinoma: (1) The distinction between atypical hyperplasia and low-grade endometrioid carcinoma. (2) The distinction between low-grade endometrioid carcinoma and serous carcinoma. (3) The distinction between corded and hyalinized or spindle cell variants of low-grade endometrioid carcinoma and carcinosarcoma. (4) The diagnostic criteria for mixed endometrial carcinomas, a rare entity that should be diagnosed only after exclusion of a spectrum of tumors including morphologic variants of endometrioid carcinoma, dedifferentiated endometrial carcinoma, carcinosarcoma, and endometrial carcinomas with ambiguous morphology.
PMCID:6296831
PMID: 30550482
ISSN: 1538-7151
CID: 3556402

High-grade Endometrial Carcinomas: Morphologic and Immunohistochemical Features, Diagnostic Challenges and Recommendations

Murali, Rajmohan; Davidson, Ben; Fadare, Oluwole; Carlson, Joseph A; Crum, Christopher P; Gilks, C Blake; Irving, Julie A; Malpica, Anais; Matias-Guiu, Xavier; McCluggage, W Glenn; Mittal, Khush; Oliva, Esther; Parkash, Vinita; Rutgers, Joanne K L; Staats, Paul N; Stewart, Colin J R; Tornos, Carmen; Soslow, Robert A
This review of challenging diagnostic issues concerning high-grade endometrial carcinomas is derived from the authors' review of the literature followed by discussions at the Endometrial Cancer Workshop sponsored by the International Society of Gynecological Pathologists in 2016. Recommendations presented are evidence-based, insofar as this is possible, given that the levels of evidence are weak or moderate due to small sample sizes and nonuniform diagnostic criteria used in many studies. High-grade endometrioid carcinomas include FIGO grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas, undifferentiated carcinomas, and carcinosarcomas. FIGO grade 3 endometrioid carcinoma is diagnosed when an endometrioid carcinoma exhibits >50% solid architecture (excluding squamous areas), or when an architecturally FIGO grade 2 endometrioid carcinoma exhibits marked cytologic atypia, provided that a glandular variant of serous carcinoma has been excluded. The most useful immunohistochemical studies to make the distinction between these 2 histotypes are p53, p16, DNA mismatch repair proteins, PTEN, and ARID1A. Endometrial clear cell carcinomas must display prototypical architectural and cytologic features for diagnosis. Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas. Of note, clear cells are found in all types of high-grade endometrial carcinomas, leading to a tendency to overdiagnose clear cell carcinoma. Undifferentiated carcinoma (which when associated with a component of low-grade endometrioid carcinoma is termed "dedifferentiated carcinoma") is composed of sheets of monotonous, typically dyscohesive cells, which can have a rhabdoid appearance; they often exhibit limited expression of cytokeratins and epithelial membrane antigen, are usually negative for PAX8 and hormone receptors, lack membranous e-cadherin and commonly demonstrate loss of expression of DNA mismatch repair proteins and SWI-SNF chromatin remodeling proteins. Carcinosarcomas must show unequivocal morphologic evidence of malignant epithelial and mesenchymal differentiation.
PMCID:6296248
PMID: 30550483
ISSN: 1538-7151
CID: 3556412

Arias-Stella Reaction With Signet Ring-Like Cell Histomorphology

Hernandez, Andrea; Chiaffarano, Jeanine; Mittal, Khushbakhat; Marcus, Alan
Cells with their nucleus pushed to the periphery in a crescent-like fashion by intracytoplasmic vacuole(s) are referred to as signet ring cells when the vacuole(s) contain mucin and signet ring-like cells when they are empty or contain a material other than mucin. Signet ring cells are commonly associated with adenocarcinomas. These cells are uncommon in the endometrium and have been found to be associated with both malignant and benign processes. We report the first case of signet ring-like cells within endometrial glands with Arias-Stella reaction.
PMID: 29172819
ISSN: 1940-2465
CID: 3055392

Giant Cell Tumor of the Uterus: Report of a Rare Entity [Meeting Abstract]

Hernandez, Andrea; Chiaffarano, Jeanine; Mittal, Khushbakhat
ISI:000422938200252
ISSN: 0002-9173
CID: 3219782

Expression of Ezrin and Estrogen Receptors During Cervical Carcinogenesis

Fadiel, Ahmed; Choi, Seung Do; Park, Bora; Kim, Tae-Hee; Buldo-Licciardi, Julia; Ahmadi, Mitra; Arslan, Alan; Mittal, Khushbakhat; Naftolin, Frederick
RATIONALE: Development of cervical squamous carcinoma (CXCA) is accompanied by changes in estrogen receptors (ERs, ERalpha and ERbeta) and ezrin expression; however, reports have been conflicting. Using histologically documented staging of cervical biopsies, we determined ezrin and ER relationships during CXCA development. METHODS: Immunoreactive (ir) ezrin, ir-ERalpha, and ir-ERbeta were studied in normal epithelium, carcinoma in situ/cervical intraepithelial neoplasia (CIN) 1 to 3, and local invasion or metastatic CXCA. Results were compared using H scoring. Cultures of Caski metastatic CXCA cells were treated with estradiol and/or tamoxifen and studied for ER-driven ir-ezrin and the morphologic response. RESULTS: Koilocytosis was present and indicated viral presence. The ezrin H score increased from CIN1 to CIN3, reaching significant differences from normal by CIN3 (P = .004) and 2x normal in metastatic CXCA. Estrogen receptor alpha and ERbeta H scores fell, reaching significance by CIN3 (ERalpha, P = .0001; ERbeta, P = .024). During estradiol treatment, ezrin in Caski cells increased and localized to the periphery, in ruffles and processes. The selective ER modulator tamoxifen blocked the estradiol-induced changes. CONCLUSIONS: During cervical carcinogenesis, the usual relationship between estrogen and ezrin induction is abridged. This is consistent with the effects of human papilloma virus viral proteins such as E6 and E7 that upregulate SIX1, a protein that induces ezrin. Cervical carcinogenesis is progressive but arrests at the preinvasive stage for varying lengths of time. These studies suggest that changes in ezrin may be associated with the development of the invasive phenotype and penetration of the basement membrane. They also raise the possibility that inhibiting ezrin expression could be a target for the prevention of invasive CXCA.
PMID: 27688241
ISSN: 1933-7205
CID: 2262782

Excessive Placental Macrocalcifications: Role in Pregnancy Outcome [Meeting Abstract]

Buhtoiarova, Tatiana N; Zeng, Jennifer; Mittal, Khush
ISI:000393724401392
ISSN: 1530-0307
CID: 2506772

Excessive Placental Macrocalcifications: Role in Pregnancy Outcome [Meeting Abstract]

Buhtoiarova, Tatiana N; Zeng, Jennifer; Mittal, Khush
ISI:000394467301392
ISSN: 1530-0285
CID: 2517592