Publications by authors named "Margaret Steinhoff"

62 Publications

Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer.

N Engl J Med 2019 06;380(24):2317-2326

From Northwestern University (D. Matei) and Loyola University (W.S.) - both in Chicago; NRG Oncology Statistical and Data Center, Roswell Park Comprehensive Cancer Center, Buffalo, NY (V.F., H.Q.H.); University of Kentucky, Lexington (M.E.R.); Washington University School of Medicine, Siteman Cancer Center, St. Louis (D. Mutch, M.A.P.); Women and Infants Hospital in Rhode Island-The Warren Alpert Medical School of Brown University, Providence (M.M.S., P.A.D.); Stephenson Cancer Center Gynecologic Cancers Clinic, University of Oklahoma Health Sciences Center, Oklahoma City (K.M.M.); Asan Medical Center, University of Ulsan, Songpa-gu, Seoul, South Korea (Y.M.K.); Ohio State University, Columbus (D.M.O.); Women's Cancer Center of Nevada, Las Vegas (N.M.S.); University of California Irvine Medical Center, Irvine (K.S.T.); Lewis Cancer and Research Pavilion at St. Joseph's-Candler, Savannah, GA (W.E.R.); Case Western Reserve University Hospital, Cleveland (J.N.); Dana-Farber Cancer Institute, Boston (U.A.M.); and the University of Texas Southwestern Medical Center, Dallas (D.S.M.).

Background: Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence.

Methods: In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life.

Results: Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group.

Conclusions: Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.).
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http://dx.doi.org/10.1056/NEJMoa1813181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948006PMC
June 2019

Evaluating agreement, histological features, and relevance of separating pleomorphic and florid lobular carcinoma in situ subtypes.

Hum Pathol 2018 08 9;78:163-170. Epub 2018 May 9.

Women and Infants Hospital of Rhode Island, Department of Pathology, Providence, RI, United States.

Morphological variants of lobular carcinoma in situ (LCIS) include classical (CLCIS), pleomorphic (PLCIS) and florid type (FLCIS). Treatment guidelines suggest managing PLCIS and FLCIS like ductal carcinoma in situ (DCIS); therefore accurate identification of LCIS subtypes is critical. However, the significance of separating PLCIS from FLCIS is not clear. Also, interobserver agreement in identifying LCIS subtypes, using contemporary criteria, is not known. We aimed to evaluate interobserver agreement amongst breast pathologists in diagnosing LCIS subtypes and use the agreement data to justify LCIS classification for management purposes. Six breast pathologists independently reviewed 50 hematoxylin and eosin-stained slides comprised of a mix of LCIS subtypes. After reviewing published criteria, participants diagnosed PLCIS, CLCIS and apocrine change in a marked region of interest and FLCIS based on entire section. PLCIS was identified in 8 to 37 slides with overall moderate agreement (Fleiss' κ = 0.565) and pairwise κ (Cohen's) ranging from -.008 to 0.492. FLCIS was diagnosed in 15-26 slides with overall substantial agreement (Fleiss' κ = 0.687) and pairwise κ ranging from -.068 to 0.706. Both FLCIS and PLCIS coexisted in 45% of slides with consensus on non-classical LCIS. Comedo-type necrosis (odds ratio = 5.5) and apoptosis (odds ratio = 1.8) predicted FLCIS. We found moderate and substantial agreement in diagnosing PLCIS and FLCIS respectively. Objective histological features linked with aggressive behavior were more frequent with FLCIS. PLCIS and FLCIS patterns frequently coexist, contain similar molecular aberrations, and are managed similarly (like DCIS); therefore, combining FLCIS and PLCIS into one category (non-classical LCIS) should be considered.
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http://dx.doi.org/10.1016/j.humpath.2018.04.026DOI Listing
August 2018

Evaluating the Age Cutoff Criterion for Reporting Benign-Appearing Endometrial Cells in Routine Pap Tests: An 8-Year Retrospective Review.

Acta Cytol 2017 10;61(3):194-198. Epub 2017 May 10.

Department of Pathology, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.

Objective: The 2014 Bethesda System recommends that benign-appearing endometrial cells (BECs) in routine Pap tests should be reported in patients aged ≥45 years. This is a change from previous guidelines to report BECs in women ≥40 years of age. BECs are reported to have 1% chance of endometrial lesion on follow-up. This study tests whether the new threshold may increase the specificity of the test for the detection of clinically significant endometrial lesions.

Study Design: After institutional review board approval, 1,177 BECs, reported during an 8-year study period in patients aged ≥40 years, were retrieved from 672,000 routine ThinPrep Pap tests. The results of subsequent workup were collected by chart review, and the Fisher exact test was used to compare results in patients aged <50 and ≥50 years.

Results: No endometrial carcinoma and only 2 cases of endometrial hyperplasia were detected in women aged <50 years, whereas 5.5% of women aged ≥50 years with BECs had carcinoma and/or endometrial hyperplasia (p = 0.000169).

Conclusion: Investigation of BECs on routine Pap test are useful in patients aged ≥50 years as 5.5% of cases were confirmed to have significant endometrial disease. Our data as well as other studies support raising the BEC-reporting age threshold from ≥45 to ≥50 years, as the new threshold may improve the specificity of the test.
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http://dx.doi.org/10.1159/000473694DOI Listing
July 2017

Comparison of estrogen receptor, progesterone receptor and HER2 results in concurrent ipsilateral samples with invasive breast carcinoma: a retrospective study of 246 biopsies from 119 patients.

Hum Pathol 2017 07 27;65:123-132. Epub 2017 Apr 27.

Women and Infants Hospital of Rhode Island, Department of Pathology, Providence, RI 02905, USA.

There is no consensus regarding biomarker testing on the ipsilateral breast carcinomas present in separate biopsies, irrespective of whether the biopsies are performed concurrently or consecutively. We aimed to investigate estrogen receptor (ER), progesterone receptor (PR) and HER2 concordance in ipsilateral concurrent biopsies with invasive breast tumors. Consecutive ipsilateral concurrent biopsies with invasive breast tumors were identified retrospectively. Biomarker results, histologic grade and histologic subtype among the tumors in concurrent samples were compared. ER, PR, and HER2 expression was different in 3 (2.5%), 11 (9.2%) and 7 (5.9%) cases, respectively. All ER-discordant cases were sets of ER-negative (ER-) and weak-low ER-positive (ER+), ductal subtype and histologic grade 2 or 3 tumors. All PR-discordant cases were ER+, and comprised of histologic grades 1 to 3 ductal as well as lobular tumors. All HER2 discordant cases were histologic grade 2 to 3 ductal tumors. Biomarker discordance was independent of grade and subtype discordance. We found very low biomarker discordance among tumors in concurrent samples from ipsilateral breast. Our results suggest that ER and HER2 discordance in concurrent samples is predictable. ER discordance is present only in a setting of low ER+ tumors. Low-grade ductal and/or lobular tumors are ER and HER2 concordant. HER2 discordance is noted in grade 2 to 3 ductal tumors only. Histologic subtype and grade may guide extent of biomarker testing in concurrent ipsilateral breast biopsies.
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http://dx.doi.org/10.1016/j.humpath.2017.04.016DOI Listing
July 2017

Fibroadenoma With Pleomorphic Stromal Giant Cells: It's Not as Bad as It Looks!

Int J Surg Pathol 2017 Aug 16;25(5):425-427. Epub 2017 Apr 16.

2 Brown University, Providence, RI, USA.

Clinically relevant histological categorization of fibroepithelial lesions can be a daunting task, especially in a core needle biopsy. Assessment of stromal nuclear atypia, including nuclear pleomorphism and mitotic activity, is a key morphological feature employed to classify fibroepithelial lesions. We describe a case of fibroadenoma with markedly atypical nuclear features in the stromal cells that led to misclassification as phyllodes tumor in the core needle biopsy. Excision showed a fibroadenoma containing pleomorphic stromal giant cells, with occasional mitotic figures, including atypical forms. Aforementioned nuclear findings in a fibroepithelial lesion raise a legitimate question of phyllodes tumor. Knowledge of this pitfall may help avoid overtreatment of an otherwise benign fibroepithelial lesion.
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http://dx.doi.org/10.1177/1066896917704901DOI Listing
August 2017

Updated 2013 College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) guideline recommendations for human epidermal growth factor receptor 2 (HER2) fluorescent in situ hybridization (FISH) testing increase HER2 positive and HER2 equivocal breast cancer cases; retrospective study of HER2 FISH results of 836 invasive breast cancers.

Breast Cancer Res Treat 2016 06 14;157(3):405-11. Epub 2016 May 14.

Department of Pathology and Laboratory Medicine, Women & Infants Hospital, Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02903, USA.

For dual probe HER2 FISH assay, the 2013 CAP/ASCO guideline recommendations lowered the HER2/CEP17 ratio cut off for HER2 amplification to ≥2.0 and introduced an average HER2 copy number criterion for HER2 amplification (≥6.0/cell) and HER2 equivocal categories (≥4 and <6/cell). The HER2/CEP17 equivocal category is eliminated. The aim of this study is to assess the impact of 2013 HER2 FISH testing guideline recommendations update on the assignment of HER2 status with dual probe HER2 FISH assay. Dual probe HER2 FISH assay results on breast cancers from 09/2009 to 07/2015 that underwent reflex HER2 FISH testing after equivocal HER2 (2+) immunohistochemistry (IHC) were reviewed. HER2 copy number, CEP17 signals, and HER2/CEP ratios were noted. HER2 status was assigned as HER2 negative (HER2-), HER2 equivocal (HER2e), and HER2 amplified (HER2+) by applying both 2007 and 2013 CAP/ASCO HER2 FISH guideline recommendations and results were compared. New guidelines reclassified HER2 FISH status in a significant proportion of cases (8.3 %, 69/836; p = .021). There were 22 (2.6 %) more HER2+, 17 (2.1 %) more HER2e, and 39 (4.1 %) fewer HER2- tumors. Change of HER2 status correlated significantly with ≥3 CEP17 signals (38 vs. 2 %; p < .001). The 2013 CAP/ASCO guideline recommendations for HER2 FISH testing by dual probe assay increased the HER2 amplified and HER2 equivocal tumors. Increase in HER2 equivocal tumors would potentially increase the frequency of repeat HER2 testing. Tumors with ≥3 CEP17 signals, so-called chromosome 17 polysomy, are more likely to be impacted and classified as HER2 equivocal.
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http://dx.doi.org/10.1007/s10549-016-3824-xDOI Listing
June 2016

Comparison of Inhibin Alpha Subunit and Antimüllerian Hormone Immunoreactivity in Granulosa Cell and Mucinous Ovarian Tumors.

Appl Immunohistochem Mol Morphol 2017 01;25(1):71-77

*Department of Pathology and Laboratory Medicine and the †Program in Women's Oncology and Center for Biomarkers and Emerging Technology §Department of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School at Brown University, Providence, RI ‡Ansh Labs, Webster, TX.

The inhibin alpha subunit protein is used in the histopathologic diagnosis of granulosa cell tumors (GCTs), and as a serum marker for disease progression. Yet, the availability of antibodies for inhibin has been limited. Serum antimüllerian hormone (AMH) levels have also been described as a GCT marker. The goal of this study was to compare inhibin and AMH immunoreactivity in tissues and serum from GCT (n=6) using existing and new antibodies. Expression was also explored in cases of mucinous tumors (n=15), where inhibin is also a serum marker in some cases. Immunocytochemistry was performed using a commercial and newly developed inhibin alpha subunit and AMH antibodies. Serum levels were examined with total inhibin and AMH immunoassays. Inhibin alpha subunit and AMH were equivalent markers of GCT in both tissue and serum. In mucinous samples, inhibin alpha subunit was detected in tumor and stromal cells, and levels in serum were also frequently elevated. In contrast, AMH protein was detected in mucinous tissues, but there was no evidence of secretion in serum. The new inhibin alpha subunit and AMH antibodies provide needed resources for examination of granulosa cell and mucinous tumors.
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http://dx.doi.org/10.1097/PAI.0000000000000251DOI Listing
January 2017

Application of HER2 CISH pharmDX for DNA Ploidy Determination.

Appl Immunohistochem Mol Morphol 2016 08;24(7):465-9

*Department of Pathology and Laboratory Medicine, Women and Infants Hospital of Rhode Island †Warren Alpert Medical School, Brown University, Providence, RI.

Products of conception (POC) are encountered daily in general pathology practice. The molar workup is an important part of POC examination. Ploidy analysis, expressed as DNA index (DI), is part of the pathologic workup of molar pregnancy. For the past decade, chromogenic in situ hybridization (CISH) has become a popular way to detect HER2 gene amplification. Current study aims to determine whether HER2 CISH dual-color assay can be used to determine DI in POCs. Twenty-two POC cases were chosen from the departmental archives, including 6 complete hydatidiform mole (CM), 10 partial mole (PM), and 6 hydropic POC (HP). CISH assay was performed using the HER2 CISH PharmDx Kit (SK109; Dako). This kit generates red (HER2) and blue (CEN-17) chromogenic signals on the same tissue section. In the 10 triploid PM cases, CISH generated HER2 signal value of 2.925±0.19. Nine cases (90%) had values within this range, except 1 case (2.5). In diploid cases, CISH generated HER2 signal value of 2.063±0.19. Results from 11 (91.7%) cases fell within this range, except 1 HP case (2.35). Sensitivity is 90%, specificity 91.6%, and overall accuracy 90.9%. The current study is the first one that demonstrates HER2/CEN-17 dual-color CISH can be used for microscopic analysis of cell ploidy. This technique provides a relatively easy and straight way to access DI using regular bright-field microscope. Concurrent CEN-17 signal and ploidy in both placental and maternal tissue can be used as internal control. This assay can be performed in any laboratory that can perform immunohistochemistry.
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http://dx.doi.org/10.1097/PAI.0000000000000220DOI Listing
August 2016

KRAS Mutations in Mucinous Lesions of the Uterus.

Am J Clin Pathol 2015 Jun;143(6):778-84

From the Department of Pathology and Laboratory Medicine, Women and Infants Hospital of Rhode Island, Providence; Warren Alpert Medical School of Brown University, Providence, RI; and.

Objectives: The current study examined the KRAS mutation status in a spectrum of mucinous lesions of the uterus, including mucinous metaplasia (MM), atypical mucinous proliferation (AMP), endocervical mucosa, and microglandular hyperplasia (MGH).

Methods: Thirty-nine cases, including 15 AMPs, nine MMs, nine MGHs, and six normal endocervical mucosas, were selected from the departmental archive. All AMP cases with follow-up biopsies or hysterectomies were reviewed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue and KRAS codons 12 and 13 sequence analyzed.

Results: KRAS codon 12 and 13 mutations were detected in 10 (67%) of the 15 AMP cases. No KRAS mutations were identified in MMs, MGHs, and endocervical mucosas (P = .002, AMP vs MM or MGH, Fisher exact test). Most women with AMP were postmenopausal (13/15 [86.7%]) and presented with dysfunctional uterine bleeding. Among the 10 cases of AMP harboring KRAS mutations, six (60%) cases were subsequently diagnosed with carcinoma, one with atypical complex hyperplasia, and two with AMP within endometrial polyps.

Conclusions: The results suggest a possible association between KRAS mutations and mucinous differentiation in endometrial carcinogenesis. KRAS status can help in assessing benign from precursor or malignant mucinous lesions as well as differentiate endometrial lesions from those of cervical origin.
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http://dx.doi.org/10.1309/AJCP69RBNUHHOJRIDOI Listing
June 2015

Predictive factors for the presence of malignant transformation of pelvic endometriosis.

Eur J Obstet Gynecol Reprod Biol 2015 Feb 2;185:23-7. Epub 2014 Dec 2.

Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School at Brown University, Providence, RI, United States.

Objectives: To determine predictive factors for the presence of malignant transformation in ovarian endometriotic cysts.

Study Design: This was an IRB approved, case control study analyzing patient data from 2004 to 2013. Pathology database records were searched to identify patients with benign endometrioma and ovarian carcinoma arising in the background of endometriosis. Inclusion criteria required each patient to have a preoperative diagnosis of adnexal mass and no other findings concerning for malignancy. Patient clinical records were queried for preoperative symptoms, serum CA125 levels and radiologic findings. Pathologic data were collected including histology, tumor grade and stage.

Results: A total of 138 patients met inclusion criteria; 42 women with ovarian cancer arising in the background of endometriosis and 96 women with benign endometrioma. Women diagnosed with ovarian cancer were significantly older than women with endometriosis (53.6 vs. 39.2 years). There was no difference in presence of symptoms between the two groups. Women with malignant tumors were found to have significantly larger cysts (14 cm vs. 7.5 cm; p<0.0001) that were more often multilocular (45.7% vs. 12.2%; p<0.0001), and contained solid components (77.1% vs. 14.5%; p<0.0001). Among patients that were observed prior to surgery there was a significant difference in the change in size of the mass over time with 4.2 cm increase for cases vs. 1.0 cm increase for controls (p=0.02). Multiple logistic regression analysis indicated that for every 5 years increase in age there was an adjusted OR of 2.17 (p=0.003). An age of 49 years or greater had an 80.6% sensitivity (95% CI: 62.5-92.5%) and an 82.9% specificity (95% CI: 67.9-92.8%) for malignancy, and solid component on imaging had an adjusted OR of 23.7 (p<0.0001). Serum CA125 levels tended to be higher in patients with malignant tumors but did not reach statistical significance with a mean of 204.9 vs. 66.9 (p=0.1).

Conclusions: Significant predictors for malignant transformation of endometriosis include cyst characteristics and age. Women above the age of 49 with multilocular cysts and solid components are at high risk for malignant transformation of endometriosis. Serum CA125 level is not a significant predictor of malignant transformation.
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http://dx.doi.org/10.1016/j.ejogrb.2014.11.029DOI Listing
February 2015

Incidental gynecologic neoplasms in morcellated uterine specimens: a case series with follow-up.

Hum Pathol 2014 Nov 16;45(11):2311-7. Epub 2014 Aug 16.

Department of Pathology of Alpert Medical School of Brown University/Women & Infants Hospital, Providence, RI 02905.

Laparoscopic hysterectomy with morcellation (LHM) is considered a safe and less invasive alternative to other hysterectomy techniques by shortening postoperative hospital stay and patient recovery. Sparse incidental gynecologic neoplasms after LHM have been reported; however, the frequency and subsequent follow-up have not been systematically investigated in a large case series. We aimed to determine the frequency and types of incidental findings after LHM with clinical outcomes. An electronic chart review was conducted searching all cases of LHM performed within 5 years to determine the incidence of unexpected gynecologic neoplasms and subsequent peritoneal disease. Patient demographics, prior preoperative investigation, and subsequent follow-up were investigated. For comparison, the overall frequency of pertinent uterine neoplasms was noted during the study period. Of the 352 cases of LHM identified, 3 harbored unsuspected malignancies, an incidence of 0.9%. Four variant smooth muscle tumors (1.1%) and 5 benign non-smooth muscle neoplasms (1.4%) were identified at the time of initial morcellation. Two cases of subsequent peritoneal "implanted" leiomyoma were identified (0.6%). Of malignant or atypical mesenchymal neoplasms diagnosed at our institution during the study period, 8.6% were diagnosed in a morcellated specimen. There is a clinically important risk of occult malignant or atypical neoplasms in morcellated uterine specimens. Proper pathologic evaluation of malignant or atypical uterine neoplasms is limited when a uterus is morcellated. Patients undergoing morcellation procedures are also potentially at risk for dissemination of disease. Clinicians and patients should be aware of these risks when discussing surgical options for hysterectomy.
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http://dx.doi.org/10.1016/j.humpath.2014.07.018DOI Listing
November 2014

Expression profiling of primary and metastatic ovarian tumors reveals differences indicative of aggressive disease.

PLoS One 2014 14;9(4):e94476. Epub 2014 Apr 14.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America.

The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094476PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986100PMC
January 2015

Long-term follow-up of vulvar cancer patients evaluated with sentinel lymph node biopsy alone.

Gynecol Oncol 2014 Jun 11;133(3):416-20. Epub 2014 Mar 11.

Department of Obstetrics and Gynecology, Program in Women's Oncology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, 101 Dudley Street, Providence, RI, USA.

Objective: The objective of this study was to examine SLN evaluation alone in women with squamous cell carcinoma (SCC) of the vulva and evaluate the inguinal recurrence and complication rates.

Methods: An IRB approved prospective study enrolled patients with SCC of the vulva. Peritumoral injection of Tc-99 sulfur colloid and blue dye was used to identify SLNs intraoperatively. Patients with negative SLN for metastasis were followed clinically without further treatment. Patients with metastasis to a SLN underwent full groin node dissection followed by standard treatment protocols.

Results: A total of 73 women were enrolled onto protocol with 69 patients undergoing SLN dissection. Mean age was 66.9years (range: 29-91) with 47 stage I, 12 stage II, 9 stage III, 2 stage IV and 3 unstaged patients. SLN dissections were successful in 63 patients. Of the 111 groins evaluated with a SLN dissection 93% had a SLN identified with an average of 2 SLN per groin. There were 92 groins with negative SLN and 11 groins with positive SLN. 57 patients had negative SLN and underwent conservative management with the median follow-up of 58.3months. Three patients experienced groin recurrences (2 unilateral, 1 bilateral) for a recurrence rate of 5.2% (3/57). The complication rate for the inguinal incisions was 17.5% (1 cellulitis, 1 abscess, 2 lymphoceles, 5 lymphedema and leg pain).

Conclusions: Isolated SLN dissection alone has a low inguinal recurrence rate with decreased complications and should be considered as an option for women with SCC of the vulva.
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http://dx.doi.org/10.1016/j.ygyno.2014.03.010DOI Listing
June 2014

Phase III randomized trial of weekly cisplatin and irradiation versus cisplatin and tirapazamine and irradiation in stages IB2, IIA, IIB, IIIB, and IVA cervical carcinoma limited to the pelvis: a Gynecologic Oncology Group study.

J Clin Oncol 2014 Feb 6;32(5):458-64. Epub 2014 Jan 6.

Paul A. DiSilvestro and Margaret M. Steinhoff, Women and Infants Hospital, Providence, RI; Shamshad Ali, Roswell Park Cancer Institute, Buffalo; Yi-Chun Lee, State University of New York Health Science Center, Brooklyn, NY; Peter S. Craighead, Tom Baker Cancer Center, Calgary, Alberta, Canada; Joseph A. Lucci, University of Miami School of Medicine, Miami, FL; David E. Cohn, Ohio State University, Columbus, OH; Nicola M. Spirtos, Women's Cancer Center of Nevada, Las Vegas, NV; Krishnasu S. Tewari, University of California Medical Center, Irvine, Orange, CA; Carolyn Muller, University of New Mexico Memorial Medical Center, Albuquerque, NM; Walter H. Gajewski, Zimmer Cancer Center, Wilmington, NC; and Bradley J. Monk, Creighton University School of Medicine, Phoenix, AZ.

Purpose: This prospective, randomized phase III intergroup trial of the Gynecologic Oncology Group and National Cancer Institute of Canada Clinical Trials Group was designed to test the effectiveness and safety of adding the hypoxic cell sensitizer tirapazamine (TPZ) to standard cisplatin (CIS) chemoradiotherapy in locally advanced cervix cancer.

Patients And Methods: Patients with locally advanced cervix cancer were randomly assigned to CIS chemoradiotherapy versus CIS/TPZ chemoradiotherapy. Primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and tolerability.

Results: PFS was evaluable in 387 of 402 patients randomly assigned over 36 months, with enrollment ending in September 2009. Because of the lack of TPZ supply, the study did not reach its original target accrual goal. At median follow-up of 28.3 months, PFS and OS were similar in both arms. Three-year PFS for the TPZ/CIS/RT and CIS/RT arms were 63.0% and 64.4%, respectively (log-rank P = .7869). Three-year OS for the TPZ/CIS/RT and CIS/RT arms were 70.5% and 70.6%, respectively (log-rank P = .8333). A scheduled interim safety analysis led to a reduction in the starting dose for the TPZ/CIS arm, with resulting tolerance in both treatment arms.

Conclusion: TPZ/CIS chemoradiotherapy was not superior to CIS chemoradiotherapy in either PFS or OS, although definitive commentary was limited by an inadequate number of events (progression or death). TPZ/CIS chemoradiotherapy was tolerable at a modified starting dose.
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http://dx.doi.org/10.1200/JCO.2013.51.4265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912330PMC
February 2014

Prevalence, distribution, and viral burden of all 15 high-risk human papillomavirus types in adenosquamous carcinoma of the uterine cervix: a multiplex real-time polymerase chain reaction-based study.

Hum Pathol 2014 Feb 1;45(2):303-9. Epub 2013 Oct 1.

Department of Pathology, Women & Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02905.

Human papillomavirus (HPV) 16 and 18 are the types most commonly found in cervical adenosquamous carcinoma. Multiple HPV types have been found in cervical adenocarcinoma but not in the adenosquamous variant. Type-specific detection of high-risk (HR) HPV allows the detection of co-infection by multiple HPV types and assessment of viral load per cell. Our aim was to identify and quantify all HR HPV types in cervical adenosquamous carcinoma and to correlate viral loads with prognosis-related histologic features. All 15 HR HPV types were tested for by multiplex real-time polymerase chain reaction, and standard curves were created for each type. Viral loads were determined retrospectively. Prognosis-related histologic features were correlated with specific HPV types and the viral loads. A total of 80% of the tumors examined expressed HPV. Types 16/18 were detected in 86% of these cases, whereas the remaining 14% of the positive cases were infected by other types. A single type of virus was detected in 67% of cases, 2 in 29%, and 3 in 4%. Poor prognostic features were seen in 84.6% of the tumors infected with HPV 16, 46% of those infected with HPV 18, and 100% of those infected with other types. As expected, HPV 16, HPV 18, or both were the most frequent viral types; HPV 73 was the next most frequent type. Multiple HPV types were detected in 33% of the tumors. Non-HPV 16/18 cases had low viral loads, but all of these had poor prognosis-related histologic features. Two of the three recurrent cases had multiple viral types.
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http://dx.doi.org/10.1016/j.humpath.2013.07.048DOI Listing
February 2014

Endometrial carcinomas with significant mucinous differentiation associated with higher frequency of k-ras mutations: a morphologic and molecular correlation study.

Int J Gynecol Cancer 2013 Sep;23(7):1231-6

Department of Pathology, Women & Infants Hospital of Rhode Island, Brown University, Providence, RI 02905, USA.

Objectives: K-ras gene product in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway is critical in the development of certain types of malignancies. K-ras mutation-associated pancreatic and ovarian carcinomas often display mucinous differentiation. Previous studies have shown that k-ras mutation is found in 10% to 30% of endometrial carcinomas. We investigated k-ras mutations in several morphologic subtypes of endometrial carcinomas with particular emphasis on various degrees of mucinous differentiation.

Methods: Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue sections. Polymerase chain reaction amplification for k-ras codons 12 and 13 were performed, followed by sequencing using capillary electrophoresis. The Fisher exact test is used to compare the prevalent difference of k-ras mutation among the groups. P < 0.05 was considered significant.

Results: K-ras mutations were detected in 8 (80%) of 10 mucinous carcinomas, 12 (67%) of 18 endometrioid carcinomas (ECs) with significant mucinous differentiation (ECMD), 4 (25%) of 16 ECs, and 1 (9%) of 11 serous carcinomas. The differences were statistically significant between mucinous carcinomas versus EC (P < 0.01) and ECMD versus EC (P < 0.05).

Conclusion: The findings suggest that mucinous carcinoma and endometrioid carcinoma with significant mucinous component are more likely to be associated with k-ras mutation. Potential clinical implications of k-ras mutation lies in the management of recurrent or higher-stage endometrial mucinous tumors, which would not be responsive to treatment protocols containing epidermal growth factor receptor inhibitors.
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http://dx.doi.org/10.1097/IGC.0b013e31829ea82fDOI Listing
September 2013

Identification of ovarian cancer metastatic miRNAs.

PLoS One 2013 12;8(3):e58226. Epub 2013 Mar 12.

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA.

Serous epithelial ovarian cancer (EOC) patients often succumb to aggressive metastatic disease, yet little is known about the behavior and genetics of ovarian cancer metastasis. Here, we aim to understand how omental metastases differ from primary tumors and how these differences may influence chemotherapy. We analyzed the miRNA expression profiles of primary EOC tumors and their respective omental metastases from 9 patients using miRNA Taqman qPCR arrays. We find 17 miRNAs with differential expression in omental lesions compared to primary tumors. miR-21, miR-150, and miR-146a have low expression in most primary tumors with significantly increased expression in omental lesions, with concomitant decreased expression of predicted mRNA targets based on mRNA expression. We find that miR-150 and miR-146a mediate spheroid size. Both miR-146a and miR-150 increase the number of residual surviving cells by 2-4 fold when challenged with lethal cisplatin concentrations. These observations suggest that at least two of the miRNAs, miR-146a and miR-150, up-regulated in omental lesions, stimulate survival and increase drug tolerance. Our observations suggest that cancer cells in omental tumors express key miRNAs differently than primary tumors, and that at least some of these microRNAs may be critical regulators of the emergence of drug resistant disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058226PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595263PMC
September 2013

Iniparib plus paclitaxel and carboplatin as initial treatment of advanced or recurrent uterine carcinosarcoma: a Gynecologic Oncology Group Study.

Gynecol Oncol 2012 Sep 24;126(3):424-7. Epub 2012 May 24.

Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA.

Objective: To estimate the activity and tolerability of iniparib plus paclitaxel and carboplatin as initial therapy of uterine carcinosarcoma.

Methods: Eligible patients had advanced, persistent or recurrent carcinosarcoma of the uterus, measurable disease and no prior chemotherapy. Patients received paclitaxel 175 mg/m(2) IV over 3h followed by carboplatin area under the curve (AUC)=six over 30 min on day one of 21 day cycles plus iniparib 4 mg/kg IV over 1h twice weekly beginning on day one. Treatment continued until disease progression or adverse effects prohibited further therapy. Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was used to grade adverse events. The primary endpoint was tumor response. The study was conducted with a 2-stage group sequential design, targeting 20 and 25 patients in each stage. The study was designed to distinguish between 45% versus 65% responding with alpha=10% and 90% power.

Results: Twenty-two patients were entered onto the study with five excluded from analysis, leaving 17 evaluable for analysis. Treatment resulted in the expected hematologic and non-hematologic toxicities of the paclitaxel-carboplatin backbone. The observed proportion responding was 23.5% (4/17 patients). The two-sided, 90% confidence interval for the true probability of response was 8.5-46.1%. The required minimal number of responses to proceed to second stage was eight.

Conclusions: Iniparib plus paclitaxel and carboplatin did not show significant activity to warrant further study. The rate of exclusion upon central pathology review (23%) suggests that review of pathology slides for confirmation of eligibility is important in this tumor type.
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http://dx.doi.org/10.1016/j.ygyno.2012.05.024DOI Listing
September 2012

Patterns of cellular distribution with the sentinel node positive for breast cancer.

Int J Breast Cancer 2011 8;2011:873987. Epub 2011 Sep 8.

Program in Women's Oncology, Women and Infants Hospital, 101 Dudley Street, Providence, RI 02905, USA.

Background. Sentinel node biopsy (SNB) represents the standard of care in breast cancer axillary evaluation. Our study aims to characterize the patterns of malignant cell distribution within the sentinel nodes (SN). Methods. In a retrospective IRB-approved study, we examined the anatomic location of the nodal area with the highest radioactive signal or most intense blue staining (hot spot) and its distance from the metastatic foci. Results. 58 patients underwent SNB between January 2006 and February 2007. 12 patients with 19 positive SN were suitable for analysis. 4 (21%) metastases were located in the nodal hilum and 15 (79%) in the cortex. 6 (31%) metastases were found adjacent to the hotspot, and 9 (47%) within 4 mm of the hotspot. Conclusions. In our pilot series, SN metastases were within 4 mm of the hotspot in 78% of the cases. Pathologic analysis focused in that area may contribute to the more accurate identification of nodal metastases.
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http://dx.doi.org/10.4061/2011/873987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262578PMC
August 2012

Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders.

Am J Obstet Gynecol 2012 Apr 30;206(4):351.e1-8. Epub 2011 Dec 30.

Center for Biomarkers and Emerging Technologies, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI 02905, USA.

Objective: The human epididymis protein 4 (HE4) is a novel biomarker for ovarian cancer. This study measured the HE4 and CA125 levels in women with benign gynecological disorders.

Study Design: Sera were obtained from women prior to surgery for a pelvic mass and HE4 and CA125 levels were determined. The proportions of patients with elevated biomarker levels were compared.

Results: There were 1042 women with benign disease. HE4 levels were less often elevated than CA125 (8% vs 29%, P < .001). A marked difference was observed in patients with endometriosis in which HE4 was elevated in 3% of patients and CA125 in 67% (P < .0001). Serous ovarian tumors were associated with elevated levels of HE4 in 8% of patients and CA125 in 20% (P = .0002); uterine fibroids in 8% vs 26% (P = .0083); dermoids in 1% vs 21% (P = .0004); and inflammatory disease in 10% vs 37% (P = .014).

Conclusion: HE4 is elevated less frequently than CA125 in benign disease, particularly in premenopausal patients.
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http://dx.doi.org/10.1016/j.ajog.2011.12.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985608PMC
April 2012

Utility of the Thin Prep Imaging System® in the detection of squamous intraepithelial abnormalities on retrospective evaluation: can we trust the imager?

Diagn Cytopathol 2012 Feb 2;40(2):124-7. Epub 2010 Nov 2.

Department of Pathology, Pennsylvania Hospital, University of Pennsylvania, Philadelphia, Pennsylvania 19107, USA.

Prospective studies analyzing the ThinPrep Imaging System (TIS) have demonstrated a significant decrease in screening time and detection rates comparable or better than manual screening. We retrospectively analyzed the accuracy of the TIS in detecting cervical abnormalities. Our study included all new HSIL diagnoses in 2007 with previous negative (NIL) pap tests screened with TIS. The original 22 fields of view (FOV) were reviewed by 2 blinded screeners followed by manual screening of all slides. Any ASC-US or above was considered "abnormal." Of a total of 111,080 pap tests performed in 2007, 180 were reported as HSIL. Of these, 45 cases had a previous NIL pap diagnosed within the last year, screened with TIS. Following re-examination of the NIL pap, 31 diagnoses remained unchanged and 9 were reclassified as abnormal on the basis of cells present within the original FOV. When manually reviewed, all nine cases were confirmed as abnormal. Four cases were reclassified as abnormal on the basis of the manual screen (abnormal cells absent in the FOV). The sensitivity of TIS for the detection of abnormality was 99.95% (false-negative rate FNR: 0.05%) and the sensitivity for detection of HSIL was 99.07% (FNR: 0.92%). When analyzing the cytotechnologist interpretation of the FOV, the sensitivity for detection of abnormality and HSIL was 99.89% (FNR: 0.1%), and 99.53% (FNR: 0.4%), respectively. On retrospective analysis based on newly diagnosed HSIL cases, the sensitivity of TIS was comparable to that of manual screening with a slightly decreased rate of false negatives.
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http://dx.doi.org/10.1002/dc.21516DOI Listing
February 2012

Reclassification of serous ovarian carcinoma by a 2-tier system: a Gynecologic Oncology Group Study.

Cancer 2012 Jun 9;118(12):3087-94. Epub 2011 Nov 9.

The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Background: A study was undertaken to use the 2-tier system to reclassify the grade of serous ovarian tumors previously classified using the International Federation of Gynecology and Obstetrics (FIGO) 3-tier system and determine the progression-free survival (PFS) and overall survival (OS) of patients treated on Gynecologic Oncology Group (GOG) Protocol 158.

Methods: The authors retrospectively reviewed demographic, pathologic, and survival data of 290 patients with stage III serous ovarian carcinoma treated with surgery and chemotherapy on GOG Protocol 158, a cooperative multicenter group trial. A blinded pathology review was performed by a panel of 6 gynecologic pathologists to verify histology and regrade tumors using the 2-tier system. The association of tumor grade with PFS and OS was assessed.

Results: Of 241 cases, both systems demonstrated substantial agreement when combining FIGO grades 2 and 3 (overall agreement, 95%; kappa statistic, 0.68). By using the 2-tier system, patients with low-grade versus high-grade tumors had significantly longer PFS (45.0 vs 19.8 months, respectively; P = .01). By using FIGO criteria, median PFS for patients with grade 1, 2, and 3 tumors was 37.5, 19.8, and 20.1 months, respectively (P = .07). There was no difference in clinical outcome in patients with grade 2 or 3 tumors in multivariate analysis. Woman with high-grade versus low-grade tumors demonstrated significantly higher risk of death (hazard ratio, 2.43; 95% confidence interval, 1.17-5.04; P = .02).

Conclusions: Women with high-grade versus low-grade serous carcinoma of the ovary are 2 distinct patient populations. Adoption of the 2-tier grading system provides a simple yet precise framework for predicting clinical outcomes.
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http://dx.doi.org/10.1002/cncr.26618DOI Listing
June 2012

The presence and location of epithelial implants and implants with epithelial proliferation may predict a higher risk of recurrence in serous borderline ovarian tumors: a clinicopathologic study of 188 cases.

Hum Pathol 2012 May 1;43(5):747-52. Epub 2011 Nov 1.

Department of Pathology, Women and Infants Hospital, The Alpert Medical School of Brown University, Providence, RI 02905, USA.

Serous borderline ovarian tumors have a favorable prognosis, and recurrences are uncommon. The factors influencing recurrence are not fully understood. Epithelial inclusions are identified in serous borderline ovarian tumors and are traditionally referred to as epithelial implants, which often show epithelial proliferation. We investigated whether the presence of epithelial implant and epithelial proliferation portends a higher risk for recurrence of serous borderline ovarian tumors in patients who underwent surgical removal of these tumors. Also examined was whether the anatomical site of epithelial implant and epithelial proliferation was associated with a higher risk of recurrence. One hundred eighty-eight cases of pure serous or predominantly serous borderline ovarian tumors were studied for the presence of epithelial implant and epithelial proliferation, and subsequent recurrences were recorded. The anatomical sites of epithelial implant and epithelial proliferation were compared between serous borderline ovarian tumors with or without recurrence. Statistical analysis was performed using the χ(2) test. Epithelial implant was noted in 106 cases (56%), and epithelial proliferation, in 26 cases (14%). Recurrence was identified in 10.4% cases with epithelial implant and 23% cases with epithelial proliferation. Statistical analyses of patients with recurrence showed significant differences in the following groups: epithelial implant versus no epithelial implant (P < .025) and epithelial proliferation versus no epithelial implant (P < .001). Recurrence rates were higher in the epithelial implant and epithelial proliferation groups as compared with no epithelial implant or epithelial proliferation groups. Epithelial implant and epithelial proliferation appear to pose a statistically significantly higher risk of recurrence in serous borderline ovarian tumors as compared with the absence of epithelial implant. Although the anatomical location of such implants was not significantly associated with a higher risk, the presence of epithelial proliferation at multiple sites was more frequently seen in recurrent serous borderline ovarian tumors.
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http://dx.doi.org/10.1016/j.humpath.2011.06.023DOI Listing
May 2012

Utility of tumor marker HE4 to predict depth of myometrial invasion in endometrioid adenocarcinoma of the uterus.

Int J Gynecol Cancer 2011 Oct;21(7):1185-90

Department of Obstetrics and Gynecology, Women and Infants Hospital, Brown University, Providence, RI, USA.

Objective: The purpose of this pilot study was to determine whether the biomarker human epididymis protein 4 (HE4) correlates with depth of myometrial invasion, histologic grade, lymph vascular space invasion, positive cytologic washings, and nodal metastases in patients with endometrioid adenocarcinoma of the uterus.

Methods: This was a prospective, observational study in women with biopsy-proven endometrioid adenocarcinoma. Concentrations of HE4 were assessed before surgery, and all surgical specimens were reviewed by dedicated gynecologic pathologists.

Results: Included were a total of 96 women with endometrioid adenocarcinomas of the uterus, most (77%) with stage I disease. Levels of serum HE4 greater than 70 pM displayed a sensitivity of 94% and a negative predictive value of 97% in identifying stage IA (<50% myometrial invasion) versus stage IB (≥ 50% myometrial invasion) tumors and a sensitivity of 82% and negative predictive value of 82% versus all more advanced tumors.

Conclusions: Human epididymis protein 4 may be a useful marker preoperatively in the clinical decision process for determining the need for lymph node dissection in women with endometrioid endometrial cancer.
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http://dx.doi.org/10.1097/IGC.0b013e3182229ad8DOI Listing
October 2011

Tubal metaplasia of the endometrium with cytologic atypia: analysis of p53, Ki-67, TERT, and long-term follow-up.

Mod Pathol 2011 Sep 13;24(9):1254-61. Epub 2011 May 13.

Department of Pathology, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.

Tubal metaplasia of the endometrium may occasionally display cytologic atypia (atypical tubal metaplasia) resembling serous carcinoma or endometrial intraepithelial carcinoma. Although atypical tubal metaplasia is presumed to be reactive or degenerative in etiology, its clinical significance is unknown. In this study, we investigated atypical tubal metaplasia in regard to its immunoexpression of p53, Ki-67, and human telomerase reverse transcriptase (TERT), and its long-term clinical outcome. A total of 63 cases of atypical tubal metaplasia and 200 cases of endometrial samples with typical tubal metaplasia were followed for a mean of 64 and 61 months, respectively. Of the 63 atypical tubal metaplasia cases, formalin-fixed, paraffin-embedded tissue sections from 16 cases were immunostained with antibodies to p53, Ki-67, and TERT. Sections from 13 cases of uterine serous carcinoma were also stained for TERT as control. After long-term follow-up, 5% of patients in the atypical tubal metaplasia group developed hyperplasia without atypia compared with 4% of patients in the control group (P=0.44), whereas 3% in the atypical tubal metaplasia group developed atypical hyperplasia or carcinoma compared with 2% in the control group (P=0.44). p53 immunoreactivity was either focal and weak or negative in all cases of both atypical and typical tubal metaplasia (P>0.05). Ki-67 immunoreactivity was present in 0-5% of cells in 94% of both atypical and typical tubal metaplasia (P>0.05). TERT immunoexpression was absent in all 16 cases of atypical tubal metaplasia, but present in all 13 cases of uterine serous carcinoma (P<0.0001). Our study indicates that atypical tubal metaplasia displays an immunostaining pattern similar to otherwise typical tubal metaplasia of the endometrium, and distinct from uterine serous neoplasms. The presence of atypical tubal metaplasia in endometrial samplings does not increase the risk of developing endometrial hyperplasia or malignancy.
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http://dx.doi.org/10.1038/modpathol.2011.78DOI Listing
September 2011

In vitro maturation of oocytes via the pre-fabricated self-assembled artificial human ovary.

J Assist Reprod Genet 2010 Dec 25;27(12):743-50. Epub 2010 Aug 25.

Division of Reproductive Endocrinology & Infertility, Department of Obstetrics & Gynecology, Women & Infants' Hospital, Alpert Medical School, Brown University, Providence, RI 02905, USA.

Purpose: create a 3-Dimensional artificial human ovary to mature human oocytes.

Methods: theca and granulosa cells were isolated from antral follicles of reproductive-aged women, seeded into micro-molded gels and self-assembled into complex 3D microtissues. Immunohistochemistry and live-dead staining confirmed theca cell identity and cellular viability at one week respectively. Placement of granulosa cell spheroids or cumulus-oocyte complexes into theca cell honeycomb openings resulted in creation of an artificial human ovary. Oocytes from this construct were assessed for polar body extrusion.

Results: theca and granulosa cells self-assembled into complex microtissues, remaining viable for one week. At 72 h after artificial human ovary construction, theca cells completely surrounded the granulosa spheroids or COCs without stromal invasion or disruption. Polar body extrusion occurred in one of three COCs assessed.

Conclusions: an artifical human ovary can be created with self-assembled human theca and granulosa cell microtissues, and used for IVM and future oocyte toxicology studies.
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http://dx.doi.org/10.1007/s10815-010-9468-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997950PMC
December 2010

A case of Peutz-Jeghers syndrome with breast cancer, bilateral sex cord tumor with annular tubules, and adenoma malignum caused by STK11 gene mutation.

Int J Gynecol Cancer 2009 Dec;19(9):1591-4

Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Brown University, Providence, RI, USA.

Background: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder, and women with this syndrome are at an increased risk of developing intestinal and extraintestinal malignancies including breast and gynecologic malignancies. This case report presents a patient with PJS with a concomitant breast cancer, bilateral stromal tumors with annular tubules of the ovaries, and adenoma malignum of the cervix.

Case: A 43-year-old woman presented with an advanced-stage breast cancer and a pelvic mass. The patient was treated with neoadjuvant chemotherapy followed by laparotomy with a hysterectomy and oophorectomy. Final pathologic examination revealed a concomitant breast cancer with metastasis to the ovaries, bilateral stromal tumors with annular tubules of the ovaries, and adenoma malignum of the cervix.

Conclusions: Patients with PJS are at a high risk for intestinal and extraintestinal malignancies and can present with multiple concomitant malignancies.
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http://dx.doi.org/10.1111/IGC.0b013e3181ae3f71DOI Listing
December 2009

Progressive loss of selenium-binding protein 1 expression correlates with increasing epithelial proliferation and papillary complexity in ovarian serous borderline tumor and low-grade serous carcinoma.

Hum Pathol 2010 Feb 6;41(2):255-61. Epub 2009 Nov 6.

Department of Pathology, Women and Infants Hospital of Rhode Island, Providence, RI 02905, USA.

Ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma often show a spectrum of histologic components with increasing epithelial proliferation and papillary complexity from flat cyst wall, hierarchical structures (with primary papillae branching into secondary papillae), micropapillae, and invasive carcinoma. Although tremendous research has been carried out to elucidate the causes of these tumors, the pathogenesis remains unclear. Literature has described a relationship between insufficient selenium intake and increased risk of cancer. The anticancer action of selenium has been suggested to be mediated by selenium-binding protein 1 as selenium-binding protein 1 is decreased in several cancers. The aim of the study was to examine by immunohistochemistry the expression of selenium-binding protein 1 in the various histologic components within ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma. Our study consisted of 62 cases of ovarian serous borderline tumor, 11 of micropapillary serous borderline tumor, and 7 of low-grade serous carcinoma. Review of archival slides showed flat cyst wall in 69 cases, primary and secondary papillae of hierarchical structures in 75 cases, micropapillae in 26 cases, microinvasion in 1 case, and frankly invasive carcinoma in 7 cases. The strongest immunoreactivity of selenium-binding protein 1 was seen in epithelial cells of flat cyst wall and primary papillae, followed by secondary papillae of the hierarchical structures. Micropapillae and invasive carcinoma (including microinvasion) exhibited a near complete loss of selenium-binding protein 1 expression. Selenium-binding protein 1 immunoreactivity remained the same regardless of the size of the micropapillae. Similar selenium-binding protein 1 expression was seen in the same histologic components from either ovarian serous borderline tumor or micropapillary serous borderline tumor. The gradual loss of selenium-binding protein 1 associated with increasing epithelial proliferation and papillary complexity indicates that selenium-binding protein 1 is involved in tumorigenesis of ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma. Our findings may provide a basis for future studies concerning the molecular mechanisms of selenium-binding protein 1 in tumorigenesis as well as a possible role of selenium in chemoprevention and treatment of ovarian serous borderline tumor, micropapillary serous borderline tumor, and low-grade serous carcinoma.
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http://dx.doi.org/10.1016/j.humpath.2009.07.019DOI Listing
February 2010

Does the ThinPrep Imaging System increase the detection of high-risk HPV-positive ASC-US and AGUS? The Women and Infants Hospital experience with over 200,000 cervical cytology cases.

Cytojournal 2009 Aug 6;6:15. Epub 2009 Aug 6.

Department of Pathology, Women and Infants Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.

Background: Published reports have demonstrated that introduction of the ThinPrep Imaging System (Imager) to the cytology screening services has increased the detection rate of high-grade squamous intraepithelial lesions (HSILs). In accordance with recent clinical treatment guidelines, patients with atypical squamous or glandular cells of undetermined significance (ASC-US or AGUS) are often tested for high-risk HPV infection using the Hybrid Capture HPV DNA test. We took the opportunity to investigate whether the Imager had resulted in any significant differences in our diagnostic categories, as well as whether the Imager increased the detection of high-risk HPV-DNA-positive (HRHPV+) ASC-US or AGUS.

Materials And Methods: Cytology cases with the diagnosis of ASC-US and AGUS were retrieved from the archival files of our institution during periods of 11 months prior to and 11 months after the introduction of the Imager. The total number of cases in each category was correlated with results of reflex high-risk HPV DNA testing when the latter were available. All AGUS diagnoses were correlated with subsequent biopsy follow-up. Statistical analyses were performed using the chi-Square test with Yate's Correction and Fisher's Exact test.

Results: A total of 108,371 and 104,555 of ThinPrep Pap Test (TPPT) cases were reviewed during 11 months pre- and post-imager introduction. The ASC-US rate was 5.4% in the pre-Imager and 5.3% in the post-Imager period. The HPV reflex test was 38% and 34% positive respectively in the pre- and post-Imager period (P>0.124). Similarly, 0.14% and 0.12% AGUS were found in the pre- and post-Imager period. The positive HPV reflex test was 14% versus 23% (P = 0.1690). The abnormal biopsy follow-up rate in the AGUS category was increased from 20.9% in the pre-Imager period to 31% in the post-Imager period (P = 0.1471). The ASCUS/SIL ratios were 1.9 and 1.6 respectively.

Conclusions: The ASC-US and AGUS rates did not change statistically before and after the introduction of the Imager in our cytology laboratory. Although use of the Imager did not increase detection of HPV+ ASC-US, it did appear to increase the detection rate of HPV+ AGUS and subsequent abnormal biopsy follow-up rates in all categories. However, the increase in the detection rate did not reach the point of statistical significance.
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http://dx.doi.org/10.4103/1742-6413.54917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758304PMC
August 2009

Utility of PTEN expression of endometrial "surface epithelial changes" and underlying atypical endometrial hyperplasia.

Int J Gynecol Pathol 2009 Sep;28(5):471-6

Department of Pathology, Women & Infants Hospital, Providence, RI, USA.

Surface epithelial changes (SECs) have been reported to be associated with endometrial carcinoma in about 49% of cases. They have also been seen to be associated with endometrial hyperplasia. Although morphologically benign, these lesions are considered a marker for underlying malignancy. Their true biologic nature, however, is not known. PTEN has been reported to be altered in endometrial carcinomas and endometrial precancers where no morphologic changes are appreciated. The current study aims to investigate PTEN status in the endometrial SECs. Thirty-two cases of endometrial biopsy are divided into 2 groups: group 1 had 18 cases of SEC and underlying endometrial atypical hyperplasia and group 2 had 14 cases of SEC alone. Four-micron sections were cut from each block and stained with antibodies to PTEN. One section was stained with hematoxylin and eosin to confirm the presence of the area of interest. Positive and negative control slides were run with each batch of staining. All 32 cases were followed for a median period of 54 (range, 21 to 84) months. Overall, PTEN alteration (NULL) was found in 12 of the 32 cases of endometrial samples (37.5%) examined. In group 1, 10 of the 18 cases (56%) of atypical endometrial hyperplasia with "SECs" showed PTEN NULL. Of these 10 cases, 6 (60%) cases showed FIGO grade 1 endometrioid carcinoma in subsequent hysterectomy specimens. Two other cases (20%) had atypical endometrial hyperplasia only. In group 2, two of the 14 (14%) cases of SECs alone showed PTEN NULL phenotype. These 2 patients were followed for 26 and 63 months, respectively, and subsequent endometrial biopsies and pap smears were negative. Of the remaining 12 cases that retained PTEN, 9 cases (75%) were negative when followed for a median of 54 months (range, 21 to 84 mo). SECs seem to be a heterogeneous entity. Presence of PTEN NULL phenotype in SECs and associated endometrial hyperplasia does not necessarily predict an increased incidence of endometrioid carcinoma in subsequent follow-up. However, absence of PTEN NULL phenotype in SECs alone may predict a benign follow-up.
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http://dx.doi.org/10.1097/PGP.0b013e3181a06f96DOI Listing
September 2009