Publications by authors named "Preetha Ramalingam"

69 Publications

TP53 variant allele frequency correlates with the chemotherapy response score in ovarian/fallopian tube/peritoneal high-grade serous carcinoma.

Hum Pathol 2021 Jun 19;115:76-83. Epub 2021 Jun 19.

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

Molecular findings in ovarian, fallopian tube, and peritoneal high-grade serous carcinoma (HGSCa) are emerging as potential prognostic indicators. The chemotherapy response score (CRS) has been proposed as a histologic-based prognostic factor in patients with HGSCa treated with neoadjuvant chemotherapy (NACT). No study details the relationship between the mutational landscape of HGSCa and the CRS. This study addresses this issue using next-generation sequencing (NGS). We retrospectively identified 25 HGSCas treated with NACT and pathology material available to calculate the CRS. All cases had NGS on the primary debulking specimen post-NACT. The three-tier Böhm CRS was applied to the omentum or adnexa and calculated as a combined score. Tumor mutation burden (TMB) and TP53 variant allele frequency (VAF) were calculated and used in correlative analysis. All cases had at least one mutation, most commonly TP53 (25 cases, 100%). Other mutations were BRCA2 (one case, 4%), ARID1A (two cases, 8%), and 1 (4%) of each of the following: ERBB2, NTRK3, STK11, NTRK2, TSC1, PIK3CA, NF1, NOTCH3, CDK2, SMAD4, and PMS2. TMB ranged from 2.58 to 7.75 (median 3.84). There was no statistically significant relationship between the TMB and omental CRS, R-squared = 0.011 (P = 0.62); adnexal CRS, R-squared = 0.005 (P = 0.74); or with the combined CRS, R-squared = 0.009 (P = 0.65). Statistically significant correlation was found between the TP53 VAF and the omental CRS (R-squared = 0.28, P = 0.007), adnexal CRS (R-squared = 0.26, P = 0.01), and the combined CRS (R-squared = 0.33, P = 0.0026). The TP53 VAF was adjusted for percent of tumor present on the slide resulting in an average per cell TP53 mutational load, resulting in similar results with a statistically significant correlation between the average per cell TP53 mutational load and the omental CRS (R-squared = 0.27, P = 0.02), adnexal CRS (R-squared = 0.16, P = 0.05), and the combined CRS (R-squared = 0.23, P = 0.02). In summary, NGS confirmed TP53 mutations in all cases of HGSCa. TMB showed no correlation with the CRS. TP53 VAF and average per cell TP53 mutational load showed significant correlation with the CRS, whether graded on the adnexa or omentum or as a combined score, indicating concordance between molecular and histological findings following NACT.
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http://dx.doi.org/10.1016/j.humpath.2021.06.003DOI Listing
June 2021

Uterine Inflammatory Myofibroblastic Neoplasms With Aggressive Behavior, Including an Epithelioid Inflammatory Myofibroblastic Sarcoma: A Clinicopathologic Study of 9 Cases.

Am J Surg Pathol 2021 Jun 17. Epub 2021 Jun 17.

Department of Pathology, The University of Texas MD Anderson Cancer, Houston, TX Vall d'Hebron University Hospital, Barcelona, Spain.

The experience with uterine inflammatory myofibroblastic neoplasms with an unfavorable outcome is limited. We present the clinicopathologic features of 9 such cases, including 8 inflammatory myofibroblastic tumors (IMTs) and 1 epithelioid inflammatory myofibroblastic sarcoma (EIMS). Median patient age for the IMT group was 50.5 years; the patient with EIMS was 43 years old. Patients presented with abnormal uterine bleeding, presumed fibroids, pelvic pain, arthralgia and low-grade fever, as well as an incidental finding. Median tumor size for the IMTs was 8.5 cm. The borders were either infiltrative or well-circumscribed. Histologically, IMTs were purely fascicular or myxoid or showed predominance of one or the other pattern. Seven tumors were spindled, and 1 was both spindled and epithelioid. Tumors had variable nuclear atypia, ranging from grade 1 to 3. All tumors had an inflammatory infiltrate-predominantly lymphocytic, majority had necrosis (62.5%) and none had lymphovascular invasion. 7/8 (87.5%) tumors were positive for ALK-1 by immunohistochemistry (IHC). One tumor was negative for ALK-1 by IHC but was positive for ALK fusion by fluorescence in situ hybridization and had TNS1-ALK fusion by next-generation sequencing (NGS). Three other tumors with NGS testing showed one of the following ALK-fusion partners: FN1, DCTN1, and IGFBP5. The EIMS had infiltrative borders, myxoid and hyalinized patterns, epithelioid cells, and no lymphovascular invasion. This tumor was ALK-1 positive by IHC, had ALK rearrangement by fluorescence in situ hybridization and RANBP2-ALK fusion by NGS. Extrauterine disease at time of diagnosis was noted in 2/8 (25%) of IMTs, and in the single case of EIMS. Seven patients had surgery as primary treatment, 1 patient had neoadjuvant chemotherapy and 1 patient declined treatment. Patients with recurrence were treated with a combination of chemotherapy, targeted therapy, radiotherapy or hormonal therapy. Most patients (71.4%) recurred within 24 months (mos). Two thirds of patients were alive with disease at last follow up (mean 43.6 mos). The patient with EIMS was alive with disease at 22 mos. IMT referral cases were initially diagnosed as smooth muscle tumors in 87.5% of cases; while the EIMS was diagnosed as high-grade endometrial stromal sarcoma. Lack of consideration of IMT in the differential diagnosis of smooth muscle tumors with myxoid features can result in misdiagnosis and under-utilization of targeted therapy in these patients.
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http://dx.doi.org/10.1097/PAS.0000000000001756DOI Listing
June 2021

Malignant Peritoneal Mesothelioma Associated With Endometriosis: A Clinicopathologic Study of 15 Cases.

Int J Gynecol Pathol 2021 Feb 11. Epub 2021 Feb 11.

Departments of Pathology (A.M., E.D.E., P.R.) Translational Molecular Pathology (M.L.M.-P.) Hematopathology (R.N.M.) Surgical Oncology (K.F.F.) Gastrointestinal Medical Oncology (K.P.R.), The University of Texas MD Anderson Cancer Center, Houston, Texas.

Only a few cases of malignant peritoneal mesothelioma (MPeM) associated with endometriosis have been published; with chronic inflammation of the peritoneum associated with the latter being postulated as an inducing factor in the pathogenesis of this tumor. We assessed the clinicopathologic characteristics of MPeM associated with endometriosis to determine if there were other factors besides inflammation that may contribute to the pathogenesis in this patient population. Fifteen MPeM associated with endometriosis were retrieved from our files. Most presented with abdominal/pelvic pain, mass or distention; median age was 45 yr. Only 16% of patients had a history of asbestos exposure. In contrast, a third of the patients had a personal history of other neoplasms, and >80% had a family history of malignancies. Although most tumors had gross and microscopic features typical of MPeM, some had confounding features including "adhesion-like" appearance or gelatinous cysts/nodules, and signet ring cells. Tumors were epithelioid (9) and biphasic (6). MPeM was misdiagnosed as Müllerian carcinoma in 40% of cases. All patients (n=15) had cytoreductive surgery in addition to other therapies. Only 2/12 patients died of disease (17%). The 3- and 5-yr overall survival was 90%. MPeM associated with endometriosis tends to occur in patients with personal/familial history of malignancies, which may be a predisposing factor. In light of this finding, the role of endometriosis in the pathogenesis of MPeM is likely less relevant. The favorable outcome seen in these patients may be related to germline mutations or the hormonal milieu and needs further investigation.
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http://dx.doi.org/10.1097/PGP.0000000000000762DOI Listing
February 2021

Role of radical hysterectomy in patients with early-stage high-grade neuroendocrine cervical carcinoma: a NeCTuR study.

Int J Gynecol Cancer 2021 Apr 9;31(4):495-501. Epub 2021 Feb 9.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Objective: Patients with early-stage, high-grade neuroendocrine cervical carcinoma typically undergo radical hysterectomy with pelvic lymphadenectomy followed by adjuvant radiotherapy and/or chemotherapy. To explore the role of radical surgery in patients with this disease, who have a high likelihood of undergoing postoperative adjuvant therapy, we aimed to determine the rate of parametrial involvement and the rate of parametrial involvement without other indications for adjuvant treatment in these patients.

Methods: We retrospectively studied patients in the Neuroendocrine Cervical Tumor Registry (NeCTuR) at our institution to identify those with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IA1-IB2, high-grade neuroendocrine cervical carcinoma who underwent up-front radical surgery with or without adjuvant therapy.

Results: One hundred patients met the inclusion criteria. The median age was 35 years (range 22-65), and 51% (51/100) had pure high-grade neuroendocrine carcinoma. No patient had a tumor >4 cm or suspected parametrial or nodal disease before surgery. Ten patients (10%) had microscopic parametrial compromise in the final surgical specimens. Ninety-four (94%) patients underwent nodal assessment, and 19 (19%) had positive nodes. Ten patients underwent both sentinel lymph node biopsy and pelvic lymphadenectomy, and none had false-negative findings. Patients with parametrial compromise were more likely to have positive pelvic nodes (80% vs 12%, p<0.0001), and a positive vaginal margin (20% vs 1%, p=0.03). All patients with parametrial compromise had lymphovascular space invasion (100% vs 73%, p=0.10). Of the 100 patients, 95 (95%) were recommended adjuvant therapy and 89 (89%) were known to have received it. Adjuvant pelvic radiotherapy reduced the likelihood of local recurrence by 62%.

Conclusions: In carefully selected patients with high-grade neuroendocrine cervical carcinoma, the rate of microscopic parametrial involvement is 10%. As most patients receive adjuvant treatment, we hypothesize that simple hysterectomy may be adequate when followed by adjuvant radiotherapy with concurrent cisplatin and etoposide followed by additional chemotherapy.
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http://dx.doi.org/10.1136/ijgc-2020-002213DOI Listing
April 2021

Immunohistochemical Loss of DPC4 in Tumors With Mucinous Differentiation Arising in or Involving the Gynecologic Tract.

Int J Gynecol Pathol 2021 Jan 5. Epub 2021 Jan 5.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

DPC4 immunohistochemistry (IHC) is usually part of the work-up of mucinous neoplasms in the ovary where the distinction between an ovarian primary and metastatic pancreaticobiliary adenocarcinoma (PanACa) must be made. Although DPC4 IHC is lost in about 55% (46%-61%) of PanACas and typically retained in most primary ovarian mucinous neoplasms, no study has evaluated the expression of this marker in a large cohort of neoplasms arising in or involving gynecologic (GYN) organs. In this study, we retrospectively analyzed the expression of DPC4 IHC in a total of 251 tumors and lesions related to the GYN tract in which DPC4 IHC stain was performed during the initial pathology evaluation. Of these, 138 were primary GYN tumors and lesions, 31 were metastatic GYN tumors involving non-GYN sites, and 83 were metastatic non-GYN tumors involving the GYN tract. We identified 27 cases with loss of DPC4 IHC expression of which 20 cases met the inclusion criteria (i.e. clinical information was available to determine the site of tumor origin). We observed that loss of DPC4 nuclear expression was most commonly seen in tumors of endocervical origin (n=7), of which 5 were gastric-type cervical adenocarcinomas (GCxACa) and 2 were usual-type cervical adenocarcinomas, either primary or metastatic. This was followed by tumors of the pancreaticobiliary tract (n=5), ovary (n=2), and appendix (n=1). In addition, 1 gastric-type vaginal adenocarcinoma (GVaACa) also showed loss of DPC4. Our findings indicate that in female patients with mucinous neoplasms involving the ovary or other sites, with loss of DPC4 by IHC, and negative pancreaticobiliary imaging, the possibility of an occult GCx/GVaACa, and rarely an ovarian primary must be considered.
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http://dx.doi.org/10.1097/PGP.0000000000000754DOI Listing
January 2021

Ovarian teratomas: clinical features, imaging findings and management.

Abdom Radiol (NY) 2021 06 4;46(6):2293-2307. Epub 2021 Jan 4.

Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Unit 1473, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.

Ovarian teratomas are the most common type of germ cell tumors. There are three major subtypes of ovarian teratomas including mature, immature, and monodermal teratomas. Ultrasound, computed tomography and magnetic resonance imaging can demonstrate specific imaging findings for mature teratoma. Imaging features of immature and monodermal teratomas are less specific, but a combination of clinical features and imaging findings can help in the diagnosis. Imaging is also very helpful in guiding management. In this article, we review the epidemiology, histopathology, clinical presentation, imaging features and management of ovarian teratomas.
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http://dx.doi.org/10.1007/s00261-020-02873-0DOI Listing
June 2021

Cervical cancer prevention in El Salvador: A prospective evaluation of screening and triage strategies incorporating high-resolution microendoscopy to detect cervical precancer.

Int J Cancer 2020 Dec 24. Epub 2020 Dec 24.

Department of Bioengineering, Rice University, Houston, Texas, USA.

Cervical cancer remains a leading cause of cancer death for women in low- and middle-income countries. The goal of our study was to evaluate screening and triage strategies, including high-resolution microendoscopy (HRME), to detect cervical abnormalities concerning for precancer at the point of care. Women (n = 1824) were enrolled at the Instituto de Cáncer de El Salvador. All underwent screening by both human papillomavirus (HPV) testing using careHPV and visual inspection with acetic acid (VIA). Screen-positives, along with 10% of screen-negatives, were invited to return for a follow-up examination that included triage with VIA, colposcopy and HRME imaging. Biopsies were taken of any abnormalities identified. If no abnormalities were identified, then the worst scoring site by HRME was biopsied. The sensitivities of HPV testing and VIA to screen for cervical intraepithelial neoplasia Grade 2 or more severe diagnoses (CIN2+) were 82.1% and 75% (P = .77), while the specificities were 90.4% and 80.9% (P < .001), respectively. The sensitivities of VIA, colposcopy and HRME as triage tests for CIN2+ were 82.1%, 82.1% and 71.4%, respectively (P ≥ .38). HRME had a significantly higher specificity (66.7%) than VIA (51.9%) (P < .001) and colposcopy (53.3%) (P < .001). When evaluating different theoretical screening and triage strategies, screening with HPV testing followed by triage with HRME would result in more women receiving appropriate care (97%) compared to screening with VIA (75%) or HPV alone (90%). Our findings demonstrate that screening with HPV is superior to VIA, and that triage with HRME imaging increases the specificity of detecting CIN2+ at the point of care in a low-resource setting.
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http://dx.doi.org/10.1002/ijc.33454DOI Listing
December 2020

Ovarian mucinous neoplasms, intestinal type, in premenopausal patients, develop in abnormal ovaries.

Hum Pathol 2021 02 21;108:32-41. Epub 2020 Nov 21.

Department of Pathology, Mexican Oncology Hospital, Mexico City, 06720, Mexico.

Although several studies have addressed different aspects of mucinous neoplasms arising in the ovary, such as their clinicopathologic features, immunohistochemical profile, and molecular characteristics, no study has presented an analysis of the ovarian tissue where these neoplasms arise. In this study, we included 196 cases of intestinal-type ovarian mucinous neoplasms in premenopausal patients. Our main goal was to perform a rigorous examination of the ovarian tissue surrounding these neoplasms. We also reviewed the clinicopathologic features of these cases. For comparison, the background ovarian tissue in 85 cases of ovarian serous neoplasm and in 29 cases of metastatic neoplasms to the ovary, as well as 57 normal ovaries, was examined. All the patients in this study, which included those with mucinous and with serous neoplasms primary in the ovary, those with metastatic tumors to the ovaries, and those with normal ovaries, were also premenopausal. Patients affected by ovarian mucinous neoplasms ranged in age from 13 to 52 years (median = 36 years). Nulligravidity was seen in 50%, 32%, and 22% of patients with mucinous carcinomas, mucinous borderline neoplasms, and mucinous cystadenomas, respectively. Ovarian mucinous intestinal neoplasms arise in abnormal ovaries characterized by two important features: (1) an abnormal ovarian cortex, seen in 95% of the cases, which is hypocellular or with no distinction between the cellular cortex and medulla, and (2) a remarkable paucity of primordial follicles. The abnormalities detected in the background ovarian tissue might provide insights into the tumorigenesis of these neoplasms and might facilitate their distinction from metastasis to the ovary, in premenopausal patients.
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http://dx.doi.org/10.1016/j.humpath.2020.11.003DOI Listing
February 2021

Transition From a Standard to a Hybrid On-Site and Remote Anatomic Pathology Training Model During the Coronavirus Disease 2019 (COVID-19) Pandemic.

Arch Pathol Lab Med 2021 01;145(1):22-31

Department of Pathology (Chin, Kwon, Gan, Ramalingam, Prieto, Aung), The University of Texas MD Anderson Cancer Center, Houston.

Context.—: As teaching hospitals institute social distancing and defer nonemergent procedures to cope with the coronavirus disease 2019 pandemic, the need for daily on-site presence, unless necessary, has been reduced for all medical staff, including trainees. Pathology training programs must adapt to these changes to ensure overall safety without significantly compromising training and the educational mission of the institution.

Objective.—: To describe the hybrid on-site and remote anatomic pathology training model in response to the coronavirus disease 2019 pandemic that was implemented in our pathology department and report the clinical fellows' responses to the survey about their experiences.

Design.—: The hybrid model was implemented March 25, 2020. Fellows alternate weekly between working on site and working remotely. On site, fellows wear personal protective equipment and maintain social distancing. Remotely, fellows use digital pathology to review cases and supplement with online educational activities. Virtual "coffee breaks," meditation, and exercise are part of the curriculum. Online platforms, including WebEx, Google Classroom, and Canvas, are used to continue educational activities. The survey was open May 19 through June 8, 2020.

Results.—: Twenty-eight of the 29 clinical fellows (96%) responded. Many of the respondents indicated substantial increase in their skill with using digital pathology and online platforms during the pandemic. The top most helpful resources were the United States and Canadian Academy of Pathology interactive microscopy courses (found very or somewhat helpful by 22 of 23 clinical fellows; 96%), ExpertPath (19 of 23; 82%), the College of American Pathologists virtual learning series (18 of 23; 78%), the World Health Organization Blue Books (16 of 23; 70%), the American Society of Cytopathology webinars (14 of 23; 61%), and our institutional digital slide collection (12 of 23; 52%).

Conclusions.—: Hybrid on-site and remote training can maximize anatomic pathology learning opportunities while maintaining the safety of trainees, hospital personnel, and the community.
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http://dx.doi.org/10.5858/arpa.2020-0467-SADOI Listing
January 2021

High-grade Neuroendocrine Carcinomas of the Vulva: A Clinicopathologic Study of 16 Cases.

Am J Surg Pathol 2021 03;45(3):304-316

Departments of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Vulvar high-grade neuroendocrine carcinomas (HGNECs) are rare and primarily thought to represent Merkel cell carcinoma (MCC). We present the clinicopathologic features of 16 such cases, the largest series to date. Patients were most often White, postmenopausal, and symptomatic from a palpable vulvar mass/nodule. Tumors ranged from 0.7 to 6 cm and most commonly involved the labium majus. Majority of the cases were pure HGNECs (15/16) with small cell (SC) morphology (14/16); 2 were large cell neuroendocrine carcinomas, of which 1 was combined with moderately differentiated adenocarcinoma. All tumors expressed synaptophysin. Of the 14 HGNECs with SC morphology, 6 were CK20-positive MCCs with characteristic CAM5.2 and neurofilament (NF) expression. Five of these MCCs were positive for Merkel cell polyoma virus large T-antigen (MCPyVLTAg). In contrast, 6 HGNECs with SC morphology were negative for CK20, NF, and MCPyVLTAg and classified as SCNECs. High-risk human papilloma virus was positive in all SCNECs and negative in all MCCs. One case of HGNEC with SC morphology could not be entirely characterized due to lack of tissue for ancillary testing. Five of 12 (42%) cases had a discrepant diagnosis initially rendered. Most patients (10/15) presented with International Federation of Gynecology and Obstetrics stage III or IV disease. Usual sites of metastasis included inguinal lymph node, liver, bone, and lung. Twelve patients underwent surgery with adjuvant chemotherapy and/or radiation therapy, 1 received adjuvant immunotherapy, and 1 patient received neoadjuvant chemotherapy followed by surgery and adjuvant radiation therapy. Median overall survival was 24 months (range: 7 to 103 mo), and overall 5-year survival was 12% (95% confidence interval: 1% to 39%). In summary, vulvar HGNECs are rare, aggressive neoplasms that can be further subclassified into MCC, SCNEC, and large cell neuroendocrine carcinoma. CK20, CAM5.2, NF, TTF-1, MCPyVLTAg, and high-risk human papilloma virus facilitate the distinction of MCC from SCNEC. Proper identification of vulvar HGNECs is critical for patient management.
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http://dx.doi.org/10.1097/PAS.0000000000001558DOI Listing
March 2021

Malignant Mesothelioma of the Peritoneum in Women: A Clinicopathologic Study of 164 Cases.

Am J Surg Pathol 2021 01;45(1):45-58

Departments of Pathology.

Malignant mesothelioma of the peritoneum in women is an uncommon tumor. In this study, we present the clinicopathologic features of 164 such cases seen in our institution over a period of 42 years (1974-2016). Clinical information, pathologic findings, immunohistochemical results, and follow-up were recorded. Hematoxylin and eosin-stained slides were reviewed in all cases. Patients ranged in age from 3 to 85 years, median: 49 years. Most patients presented with abdominal/pelvic pain, although some were asymptomatic, presented with paraneoplastic syndromes or cervical lymphadenopathy. Overall, 9% of patients had a history of direct or indirect exposure to asbestos. In total, 31% and 69% of patients had either a personal or family history of other tumors; most of these tumors are currently recognized as part of a syndrome. Genetic testing information was available in 5 patients: BAP-1 germline mutation (1), type 2 neurofibromatosis (1), Lynch syndrome (1), McCune-Albright syndrome (1), no BAP-1 or TP53 mutation (1). Most cases had gross and microscopic features typical of malignant mesothelioma of the peritoneum in women; however, some had confounding features such as gelatinous appearance, signet ring or clear cells, and well-differentiated papillary mesothelioma-like areas. Calretinin and WT-1 were the markers more frequently expressed, and up to 23% of the cases showed PAX-8 expression. Patients' treatments predominantly included: chemotherapy, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy. On multivariate analysis, the predominance of deciduoid cells, nuclear grade 3, and the absence of surgical treatment were associated with worse overall survival (OS). For all patients, the 3- and 5-year OS were 74.3% and 57.4%, respectively. The 3- and 5-year OS for patients treated with cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy were 88.9% and 77.8%, respectively.
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http://dx.doi.org/10.1097/PAS.0000000000001545DOI Listing
January 2021

Evaluation of PARP and PDL-1 as potential therapeutic targets for women with high-grade neuroendocrine carcinomas of the cervix.

Int J Gynecol Cancer 2020 09 29;30(9):1303-1307. Epub 2020 Jul 29.

Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Objectives: Women with recurrent high-grade neuroendocrine cervical cancer have few effective treatment options. The aim of this study was to identify potential therapeutic targets for women with this disease.

Methods: Specimens from patients with high-grade neuroendocrine carcinomas of the cervix were identified from pathology files at MD Anderson Cancer Center. Immunohistochemical stains for PD-L1 (DAKO, clone 22-C3), mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), somatostatin, and Poly (ADP-ribose) polymerase (PARP) were performed on sections from formalin-fixed paraffin-embedded tissue blocks. Nuclear PARP-1 staining was quantified using the H-score with a score of <40 considered low, 40-100 moderate, and ≥100 high.

Results: Forty pathologic specimens from patients with high-grade neuroendocrine carcinomas of the cervix were examined (23 small cell, 5 large cell, 3 high-grade neuroendocrine, not otherwise specified, and 9 mixed). The mean age of the cohort was 43 years and the majority of patients (70%) were identified as white non-Hispanic. All 28 (100%) samples tested stained for mismatch repair proteins demonstrated intact expression, suggesting they were microsatellite stable tumors. Of the 31 samples tested for PD-L1 expression, only two (8%) of the 25 pure high-grade neuroendocrine carcinomas were positive whereas three (50%) of the six mixed carcinoma tumors tested positive. Of the 11 small cell specimens tested for PARP-1, 10 (91%) showed PARP expression with six (55%) demonstrating high expression and four (36%) showing moderate expression. Somatostatin staining was negative in 18 of 19 small cell cases (95%).

Conclusions: Pure high-grade neuroendocrine cervical carcinomas were microsatellite stable and overwhelmingly negative for PD-L1 expression. As the majority of tumors tested expressed PARP-1, inclusion of PARP inhibitors in future clinical trials may be considered.
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http://dx.doi.org/10.1136/ijgc-2020-001649DOI Listing
September 2020

Comparative genomics of high grade neuroendocrine carcinoma of the cervix.

PLoS One 2020 16;15(6):e0234505. Epub 2020 Jun 16.

Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.

In order to improve treatment selection for high grade neuroendocrine carcinomas of the cervix (NECC), we performed a comparative genomic analysis between this rare tumor type and other cervical cancer types, as well as extra-cervical neuroendocrine small cell carcinomas of the lung and bladder. We performed whole exome sequencing on fresh-frozen tissue from 15 NECCs and matched normal tissue. We then identified mutations and copy number variants using standard analysis pipelines. Published mutation tables from cervical cancers and extra-cervical small cell carcinomas were used for comparative analysis. Descriptive statistical methods were used and a two-sided threshold of P < .05 was used for significance. In the NECC cohort, we detected a median of 1.7 somatic mutations per megabase (range 1.0-20.9). PIK3CA p.E545K mutations were the most frequency observed oncogenic mutation (4/15 tumors, 27%). Activating MAPK pathway mutations in KRAS (p.G12D) and GNAS (p.R201C) co-occurred in two tumors (13%). In total we identified PI3-kinase or MAPK pathway activating mutations in 67% of NECC. When compared to NECC, lung and bladder small cell carcinomas exhibited a statistically significant higher rate of coding mutations (P < .001 for lung; P = .001 for bladder). Mutation of TP53 was uncommon in NECC (13%) and was more frequent in both lung (103 of 110 tumors [94%], P < .001) and bladder (18 of 19 tumors [95%], P < .001) small cell carcinoma. These comparative genomics data suggest that NECC may be genetically more similar to common cervical cancer subtypes than to extra-cervical small cell neuroendocrine carcinomas of the lung and bladder. These results may have implications for the selection of cytotoxic and targeted therapy regimens for this rare disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234505PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297329PMC
August 2020

In vivo imaging of cervical precancer using a low-cost and easy-to-use confocal microendoscope.

Biomed Opt Express 2020 Jan 16;11(1):269-280. Epub 2019 Dec 16.

Department of Bioengineering, Rice University, 6100 Main Street, Houston, TX 77005, USA.

Cervical cancer incidence and mortality rates remain high in medically underserved areas. In this study, we present a low-cost (<$5,000), portable and user-friendly confocal microendoscope, and we report on its clinical use to image precancerous lesions in the cervix. The confocal microendoscope employs digital apertures on a digital light projector and a CMOS sensor to implement line-scanning confocal imaging. Leveraging its versatile programmability, we describe an automated aperture alignment algorithm to ensure clinical ease-of-use and to facilitate technology dissemination in low-resource settings. Imaging performance is then evaluated in and pilot studies; results demonstrate that the confocal microendoscope can enhance visualization of nuclear morphology, contributing to significantly improved recognition of clinically important features for detection of cervical precancer.
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http://dx.doi.org/10.1364/BOE.381064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968771PMC
January 2020

Toward development of a large field-of-view cancer screening patch (CASP) to detect cervical intraepithelial neoplasia.

Biomed Opt Express 2019 Dec 6;10(12):6145-6159. Epub 2019 Nov 6.

Department of Bioengineering, Rice University, 6100 Main Street, Houston, TX 77005, USA.

Cervical cancers are primarily diagnosed via colposcopy, in which the tissue is visually assessed by a clinician for abnormalities, followed by directed biopsies and histologic analysis of excised tissue. Optical biopsy technologies offer a less invasive method of imaging such that subcellular features can be resolved without removing tissue. These techniques, however, are limited in field-of-view by the distal end of the probe. We present a prototype that incorporates a rigid, machinable waveguide that is in direct contact with a fluorescently-labeled sample paired with a scanning fluorescent microscope. The system is capable of imaging large areas of tissue without the need to re-position the tissue-probe interface. A mosaicing algorithm was developed to quantify scanning shifts and stitch neighboring frames together to increase the field-of-view. Our prototype can yield a maximum axial resolution of <5 µm for individual frames and can produce mosaiced images with a field-of-view greater than 15 mm x 15 mm without sacrificing resolution. We validated the system with a 1951 USAF resolution target, fluorescent in vitro standards, and a patient study where conization samples of squamous cervical epithelium were imaged. The results of the patient study indicate that architectural features of subcellular components could be detected and differentiated between normal tissue and precancerous lesions.
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http://dx.doi.org/10.1364/BOE.10.006145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913391PMC
December 2019

Prophylactic Risk-reducing Hysterectomies and Bilateral Salpingo-oophorectomies in Patients With Lynch Syndrome: A Clinicopathologic Study of 29 Cases and Review of the Literature.

Int J Gynecol Pathol 2020 Jul;39(4):313-320

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Lynch syndrome (LS) is associated with an increased risk for colorectal, endometrial, and ovarian carcinomas in women. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy (RRHSO) has been shown to be a cost-effective form of management and prevention of gynecological malignancies in patients with LS. Studies of incidental gynecologic malignancies identified in RRHSO are limited. In addition, recommendations on optimal handling of this type of specimen have ranged from submitting for microscopic examination the entire endometrium, fallopian tubes and ovaries to submitting only routine representative sections of these organs. In this study, we present the clinicopathologic findings of 29 cases of LS patients that underwent risk-reducing gynecologic surgery at our institution over a period of 13 yr. Clinical-pathologic information was obtained from the patients' charts and pathology reports. Significant pathologic abnormalities were identified in 17% (5/29) of cases, all showing endometrial hyperplasia. Four of them with atypical and 1 without atypical. All of our cases with endometrial pathology had significant findings on preoperative endometrial sampling. To further study the recommendation of in toto submission of the endometrium, ovaries and fallopian tubes and the utility of preoperative endometrial sampling, we undertook a literature review of all the reported cases of incidental pathologic findings identified in RRHSO. The findings of our cohort and the literature reviewed support in toto submission of endometrium, and adnexal structures in the absence of gross lesions. In addition, our findings show a definite benefit for preoperative endometrial sampling as part of the workup for LS patients undergoing RRHSO.
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http://dx.doi.org/10.1097/PGP.0000000000000643DOI Listing
July 2020

Mesonephric-like Carcinoma of the Endometrium: A Subset of Endometrial Carcinoma With an Aggressive Behavior.

Am J Surg Pathol 2020 04;44(4):429-443

Departments of Pathology.

Endometrial mesonephric-like carcinomas (MLCa) are uncommon with <50 reported cases thus far. Previous studies have characterized the histologic, immunohistochemical, and molecular features of MLCa; however, there is limited information with respect to outcome. This single-institution study of 23 uterine MLCas characterizes the behavior of such a neoplasm. Uterine MLCas (2004-present) had review of histologic features, immunohistochemical results, molecular profile, and clinical information (stage, treatment, follow-up). The behavior of MLCa was compared with low-grade endometrioid carcinomas (ECas) and uterine serous carcinomas (USCs) treated at our institution from 2004 to present. All MLCas had a mixture of previously described architectural and cytologic features most notably ductal and/or tubular architecture (21/23), nuclei resembling those of papillary thyroid carcinoma (18/23), and at least focal intraluminal eosinophilic secretions (20/23). Immunoperoxidase studies facilitated diagnosis in 22 cases: CD10, 10/10; calretinin, 5/15; estrogen receptor (≥10% nuclei), 6/21; progesterone receptor, 1/15; GATA-3, 15/16; TTF-1, 11/16. Fourteen of 17 tested cases had a KRAS mutation (7 as the only alteration; 7 with additional mutations including PIK [n=5]; PTEN [n=2], CTNNB1 [n=1]).One case had mutations in PTEN, PIK, and CTNNB1 without KRAS; 2 cases had no detectable somatic mutation. Overall, 48% of patients presented with International Federation of Gynecology and Obstetrics (FIGO) stage 3 or 4 disease with the following uterine risk factors: >50% myometrial invasion, 20/23; lymphovascular space invasion, 16/23; cervical stromal invasion, 7/23. Twenty patients had adjuvant therapy (7 radiation only; 13 chemotherapy±radiation), whereas 3 patients had either unknown or declined therapy. Follow-up was known for 21 patients: 17 patients had recurrences or never achieved remission with the lung being the most common recurrence site (n=9); 7 patients died of disease. The median progression-free survival was 18.2 months for MLCa compared with 183 months for ECa and 67.1 months for USC. The median overall survival for MLCa was 70.6 months compared with 139.1 months for USC (median survival for ECa not reached). Uterine MLCa is uncommon with most tumors recognized by architectural heterogeneity, vesicular, overlapping nuclei with grooves, and eosinophilic luminal secretions. The typical immunoprofile includes low to absent expression of hormone receptors but at least focal expression of GATA-3 and/or TTF-1. Most tested cases had a KRAS mutation although genetic mutations typically associated with ECa are not uncommon. Compared with more commonly encountered types of ECa, MLCa is more aggressive with a tendency towards earlier and distant recurrence.
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http://dx.doi.org/10.1097/PAS.0000000000001401DOI Listing
April 2020

A 3-Tier Chemotherapy Response Score for Ovarian/Fallopian Tube/Peritoneal High-grade Serous Carcinoma: Is it Clinically Relevant?

Am J Surg Pathol 2020 02;44(2):206-213

Departments of Pathology.

The chemotherapy response score (CRS) is used to score histopathologic response to neoadjuvant chemotherapy (NACT) of patients with extrauterine high-grade serous carcinoma. This study was undertaken to determine if the CRS in the omentum, adnexa or when combined correlates with (1) progression-free survival (PFS) or overall survival (OS), (2) laparoscopic score of abdominal disease, (3) Cancer antigen 125 levels, (4) BRCA status, and (5) platinum-resistant disease. A total of 158 cases were retrospectively collected that received NACT between April 2013 and February 2018 at a single institution. The 3-tier Böhm CRS system was applied to the omentum and adnexa. Survival outcomes between scored subgroups were analyzed using Cox proportional hazards regression. Spearman rank correlation analyses were used to assess CRS and clinical data. A total of 119 cases were treated only with carboplatin/paclitaxel. Omental CRS was: 1 (23 cases, 19.3%), 2 (65 cases, 54.6%), and 3 (31 cases, 26.1%), whereas adnexal CRS was: 1 (50 cases, 42%), 2 (48 cases, 40.3%) and 3 (21 cases, 17.6%). The omental CRS was significantly associated with PFS as a 2-tier score (hazard ratio [HR]=0.612, 95% confidence interval [CI]: 0.378-0.989, P=0.045) but not associated with the PFS using the 3-tier score or with OS using either system. Adnexal CRS was not associated with OS but was significantly associated with PFS using the 3-tier (HR=0.49, 95% CI: 0.263-0.914, P=0.025) and 2-tier scores (HR=0.535, 95% CI: 0.297-0.963, P=0.037). The combined score was not associated with OS but was significantly associated with PFS using the 3-tier (HR=0.348, 95% CI: 0.137-0.88, P=0.026) and 2-tier scores (HR=0.364, 95% CI: 0.148-0.896, P=0.028). No CRS system used associated with laparoscopic assessment of disease. CRS in the omentum had no significant association with platinum resistance; however, the adnexal CRS 1/2 were 3 times as likely to develop platinum resistance compared with CRS 3 (relative risk=3.94, 95% CI: 1.03-15.09, P=0.046). The CRS, when used on the omentum, adnexa, and as a combined score, was significantly associated with PFS but not with OS. Adnexal CRS 1/2 are more likely to develop platinum-resistant disease. Therefore, the use of this pathology parameter may be useful for clinical management.
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http://dx.doi.org/10.1097/PAS.0000000000001391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954274PMC
February 2020

Perineural invasion (PNI) in vulvar carcinoma: A review of 421 cases.

Gynecol Oncol 2019 01 3;152(1):101-105. Epub 2018 Nov 3.

Department of Gynecologic Oncology & Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Objectives: To evaluate the prevalence and associated prognostic indicators in patients with vulvar carcinoma with and without evidence of perineural invasion (PNI).

Methods: A retrospective review identified 421 patients with invasive vulvar carcinoma evaluated at a single institution between 1993 and 2011. Medical records were reviewed for demographic data, pathologic information and presence or absence of PNI, treatment type, and recurrence/outcome information. Variables were compared between patients with PNI to those without PNI.

Results: Of the 421 patients included in the study, 32 (7.6%) had tumors with PNI. There were no significant differences in age, race/ethnicity, smoking history, histologic subtype, or grade between the group of patients with PNI and the group without PNI. The group with PNI was more likely to have lichen sclerosus (25.0% vs. 15.4%, p = 0.024), stage III/IV disease (59.4% vs. 36.0%, p = 0.007), lymph node involvement (50.0% vs. 21.6%, p = 0.002), and lymphovascular space invasion (LVSI) (53.1% vs. 15.9%, p < 0.001). A higher proportion of patients in the PNI group underwent primary or adjuvant radiation therapy (68.8% vs. 45.0%, p = 0.016). The median follow-up was 67.1 months (range < 1.0 to 284.3). Patients with PNI had significantly shorter overall survival (OS), median 25.5 vs. 94.3 months (p < 0.001), and progression-free survival (PFS), median 17.5 vs. 29.0 months (p = 0.004). After adjusting for stage, patients with PNI had a greater risk for death and progression (OS: hazard ratio, 2.71; p < 0.001; PFS: hazard ratio, 1.64; p-value = 0.020).

Conclusion: PNI should be considered an independent poor prognostic factor for patients with vulvar carcinoma, and should be included as part of the pathologic analysis.
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http://dx.doi.org/10.1016/j.ygyno.2018.10.035DOI Listing
January 2019

Imaging and staging of neuroendocrine cervical cancer.

Abdom Radiol (NY) 2018 12;43(12):3468-3478

Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.

Neuroendocrine cervical cancer (NECC) is a rare and aggressive subtype of cervical cancer, accounting for less than 2% of cervical tumors. They are divided into low-grade and high-grade tumors. High-grade NECC is associated with human papillomavirus (HPV) 18 and to a smaller extent type 16. The most common molecular alterations in NECC include PIK3CA, KRAS, and TP53 mutations. Immunohistochemical staining for CD56, synaptophysin, and chromogranin is a helpful tool in the diagnosis. NECCs pose a significant clinical and therapeutic challenge because of their aggressive nature which is explained by their tendency towards early nodal and hematogenous spread. They have a median survival of 21-22 months, compared to 10 years in cervical squamous cell carcinomas. NECCs have a homogeneous high T2 signal intensity, homogeneous contrast enhancement and lower ADC values in MRI, compared to non-neuroendocrine tumors of the cervix. It is recommended to treat NECC with a multimodality therapeutic approach combining radical hysterectomy, systemic chemotherapy, and radiotherapy. The objective of this manuscript is to address the pathogenesis of NECC, elaborate the role of radiological imaging in the diagnosis and staging of NECCs, evaluate their prognosis, and summarize the suggested management plans for this lethal disease.
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http://dx.doi.org/10.1007/s00261-018-1667-0DOI Listing
December 2018

Accuracy of Intraoperative Frozen Section Diagnosis of Borderline Ovarian Tumors by Hospital Type.

J Minim Invasive Gynecol 2019 01 19;26(1):87-93. Epub 2018 Apr 19.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Study Objective: To compare the accuracy of frozen section diagnosis of borderline ovarian tumors among 3 distinct types of hospital-academic hospital with gynecologic pathologists, academic hospital with nongynecologic pathologists, and community hospital with nongynecologic pathologists-and to determine if surgical staging alters patient care or outcomes for women with a frozen section diagnosis of borderline ovarian tumor.

Design: Retrospective study (Canadian Task Force classification II-1).

Setting: Tertiary care, academic, and community hospitals.

Patients: Women with an intraoperative frozen section diagnosis of borderline ovarian tumor at 1 of 3 types of hospital from April 1998 through June 2016.

Interventions: Comparison of final pathology with intraoperative frozen section diagnosis.

Measurements And Main Results: Two hundred twelve women met the inclusion criteria. The frozen section diagnosis of borderline ovarian tumor correlated with the final pathologic diagnosis in 192 of 212 cases (90.6%), and the rate of correlation did not differ among the 3 hospital types (p = .82). Seven tumors (3.3%) were downgraded to benign on final pathologic analysis and 13 (6.1%) upgraded to invasive carcinoma. The 3 hospital types did not differ with respect to the proportion of tumors upgraded to invasive carcinoma (p = .62). Mucinous (odds ratio, 7.1; 95% confidence interval, 2.1-23.7; p = .002) and endometrioid borderline ovarian tumors (odds ratio, 32.4; 95% confidence interval, 1.8-595.5; p = .02) were more likely than serous ovarian tumors to be upgraded to carcinoma. Only 88 patients (41.5%) underwent lymphadenectomy, and only 1 (1.1%) had invasive carcinoma in a lymph node.

Conclusions: A frozen section diagnosis of borderline ovarian tumor correlates with the final pathologic diagnosis in a variety of hospital types.
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http://dx.doi.org/10.1016/j.jmig.2018.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195486PMC
January 2019

Tumors in von Hippel-Lindau Syndrome: From Head to Toe-Comprehensive State-of-the-Art Review.

Radiographics 2018 May-Jun;38(3):849-866. Epub 2018 Mar 30.

From the Departments of Radiology (D.G.) and Pathology (P.R.), University of Texas MD Anderson Cancer Center, Pickens Academic Tower, 1400 Pressler St, Unit 1473, Houston, TX 77030-4009; Department of Radiology, Mayo Clinic Arizona, Phoenix/Scottsdale, Ariz (C.O.M.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Department of Radiology, Indiana University School of Medicine, Indianapolis, Ind (K.S.); and Section of Abdominal Imaging, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (S.B.).

Von Hippel-Lindau syndrome (VHL) is an autosomal-dominant hereditary tumor disease that arises owing to germline mutations in the VHL gene, located on the short arm of chromosome 3. Patients with VHL may develop multiple benign and malignant tumors involving various organ systems, including retinal hemangioblastomas (HBs), central nervous system (CNS) HBs, endolymphatic sac tumors, pancreatic neuroendocrine tumors, pancreatic cystadenomas, pancreatic cysts, clear cell renal cell carcinomas, renal cysts, pheochromocytomas, paragangliomas, and epididymal and broad ligament cystadenomas. The VHL/hypoxia-inducible factor pathway is believed to play a key role in the pathogenesis of VHL-related tumors. The diagnosis of VHL can be made clinically when the characteristic clinical history and findings have manifested, such as the presence of two or more CNS HBs. Genetic testing for heterozygous germline VHL mutation may also be used to confirm the diagnosis of VHL. Imaging plays an important role in the diagnosis and surveillance of patients with VHL. Familiarity with the clinical and imaging manifestations of the various VHL-related tumors is important for early detection and guiding appropriate management. The purpose of this article is to discuss the molecular cytogenetics and clinical manifestations of VHL, review the characteristic multimodality imaging features of the various VHL-related tumors affecting multiple organ systems, and discuss the latest advances in management of VHL, including current recommendations for surveillance and screening. RSNA, 2018 An earlier incorrect version of this article appeared online. This article was corrected on April 9, 2018.
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http://dx.doi.org/10.1148/rg.2018170156DOI Listing
October 2018

Ultrastaging of Sentinel Lymph Nodes in Endometrial Carcinoma According to Use of 2 Different Methods.

Int J Gynecol Pathol 2018 May;37(3):242-251

Departments of Pathology (E.E., P.R., A.M.) Biostatistics (D.S., R.B.) Gynecologic Oncology and Reproductive Medicine (P.S., S.W.), The University of Texas MD Anderson Cancer Center, Houston, Texas.

Sentinel lymph node (SLN) sampling may provide staging information without exposing patients to risks of lymph node dissection. There is no consensus protocol for optimal pathologic handling of these specimens. This study compares 2 ultrastaging protocols of SLN in endometrial carcinoma (EC). All SLN were serially sectioned perpendicular to the long axis in 2 mm intervals and entirely submitted for routine hematoxylin and eosin (H&E) processing. SLN negative by routine processing had ultrastaging (US) by one of the following: method 1 (M1), 5 H&E levels at 250 μm intervals with 2 unstained slides at each level; pankeratin immunohistochemistry (IHC) performed on level 1 in cases with negative H&E levels or method 2 (M2), 1 H&E level + 2 unstained slides cut 250 μm into the tissue block; pankeratin IHC performed in cases with negative H&E. Histologic subtype, numbers of SLN, positive SLN, non-SLN, positive non-SLN, and metastasis size were recorded. A total of 178 patients had 527 SLNs (1-16 per case; median, 2 SLN) sampled during hysterectomy for the following EC histotypes: endometrioid International Federation of Gynecology and Obstetrics grade 1/2, 117 (66%); endometrioid International Federation of Gynecology and Obstetrics grade 3, 18 (10%); serous, 20 (11%); carcinosarcoma, 11 (6%); clear cell, 9 (5%); and undifferentiated, 3 (2%). In all, 172 patients had ultrastaging: M1=65; M2=58. In total, 33 patients were SLN positive. Twenty-seven had SLN submitted for US: M1=11; M2=16. Eleven patients had additional SLN detected by US: M1=5; M2=6. Of these, 8 were patients whose SLN were only detected by US representing an increase of 32% in number of patients with positive SLN. Six patients (M1=2; M2=4) with negative SLN had a positive non-SLN. Mean size of ultrastage-detected metastasis was 0.24 mm for M1 and 0.38 mm for M2. Statistical analysis comparing M1 and M2 detected no statistically significant associations with respect to number of positive SLN detected, size of metastasis or false-negative rate and method. The methods performed similarly for both low-grade and high-grade EC. A more comprehensive US protocol had no significant advantages over a single wide interval and IHC in this study population. A pankeratin IHC stain enhances metastasis detection. Additional studies are required to further test this limited protocol as well as to evaluate the clinical significance of the low volume disease detected by ultrastaging.
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http://dx.doi.org/10.1097/PGP.0000000000000415DOI Listing
May 2018

Loss of expression of SMARCA4 (BRG1), SMARCA2 (BRM) and SMARCB1 (INI1) in undifferentiated carcinoma of the endometrium is not uncommon and is not always associated with rhabdoid morphology.

Histopathology 2017 Feb 16;70(3):359-366. Epub 2016 Nov 16.

Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK.

Aim: Abnormalities of SMARCB1 (INI1), which encodes a member of the SWI/SNF pathway, are found in neoplasms with rhabdoid morphology, such as malignant rhabdoid tumour of the kidney and atypical teratoid/rhabdoid tumour of the central nervous system. SMARCA4 (BRG1), which encodes another member of the SWI/SNF pathway, and which is mutated in almost all small-cell carcinomas of the ovary, hypercalcaemic type, has been investigated in endometrial carcinomas, and mutations with resultant loss of immunohistochemical staining have been demonstrated in some endometrial undifferentiated carcinomas/dedifferentiated carcinomas. The aim of this study was to evaluate immunohistochemical expression of SMARCA4, SMARCB1 and SMARCA2 in a cohort of undifferentiated endometrial carcinomas, and to correlate expression of these markers with rhabdoid morphology and clinical outcome.

Methods And Results: Forty undifferentiated endometrial carcinomas (18 pure and 22 dedifferentiated carcinomas) were stained with SMARCA4 (n = 40), SMARCB1 (n = 27), and SMARCA2 (n = 37). SMARCA4 expression was intact in 26 of 40 (65%) cases, lost in 13 of 40 (32.5%) cases, and unassessable in one case (2.5%). SMARCB1 expression was intact in 26 of 27 (96%) cases and lost in one of 27 (4%) cases. SMARCA2 expression was intact in 23 of 37 (62%) cases, lost in 10 of 37 (27%) cases, and unassessable in four cases. SMARCA2 expression showed corresponding loss in nine of the 13 (69%) SMARCA4-deficient cases. Rhabdoid morphology was present in three of 13 (23%) SMARCA4-deficient cases, in two of 10 (20%) SMARCA2-deficient cases, in four of 26 (15%) SMARCA4-intact cases, and in four of 23 (17%) SMARCA2-intact cases. There was no correlation between SMARCA4 or SMARCA2 expression and clinical outcome.

Conclusions: Our study demonstrated that almost one-third of endometrial undifferentiated carcinomas show loss of SMARCA4 and SMARCA2 expression, and that a subset show rhabdoid morphology. The majority of the SMARCA4-deficient cases show concomitant loss of SMARCA2 expression. There is no correlation between SMARCA4 or SMARCA2 expression and outcome. Our results confirm that the SWI/SNF chromatin-remodelling complex is involved in the pathogenesis of endometrial undifferentiated carcinomas.
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http://dx.doi.org/10.1111/his.13091DOI Listing
February 2017

Patterns of recurrence and survival in neuroendocrine cervical cancer.

Gynecol Oncol 2016 Dec 16;143(3):552-557. Epub 2016 Sep 16.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. Electronic address:

Objective: To analyze patterns of recurrence and survival and identify prognostic factors in women with neuroendocrine cervical cancer (NECC).

Methods: We reviewed patients with International Federation of Gynecology and Obstetrics stage I-IVA NECC who were enrolled in the Neuroendocrine Cervical Tumor Registry and treated with curative intent. Event-free survival (EFS) and overall survival (OS) according to disease and treatment characteristics were analyzed using the Kaplan-Meier method.

Results: Among 40 patients with NECC, 25 (62%) had small cell NECC, eight (20%) had large cell NECC, and seven (18%) had unspecified neuroendocrine histology. With a median follow-up of 21.5months, 32 patients (80%) experienced progression, and 28 (70%) died. For all patients, the 5-year EFS rate was 20%, and the 5-year OS rate was 27%. Patients with large cell NECC had significantly better median EFS (median not reached vs. 10.0months, p=0.02) and showed a trend toward better median OS (153months vs. 21months, p=0.08) than patients with other histologic types. In patients with early-stage clinically node-negative disease, chemoradiation was associated with significantly better median EFS than surgery (median not reached vs. 18.0months, p=0.04).

Conclusions: Patients with large cell NECC have better outcomes than patients with other subtypes of NECC. In early-stage node-negative NECC, chemoradiation yields better EFS than surgery. Most patients with NECC, even those with no evidence of nodal disease at diagnosis, rapidly develop widespread hematogenous metastases and die of their disease.
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http://dx.doi.org/10.1016/j.ygyno.2016.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053682PMC
December 2016

Yolk Sac Tumor in Extragonadal Pelvic Sites: Still a Diagnostic Challenge.

Am J Surg Pathol 2017 01;41(1):1-11

Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

We present the clinicopathologic features of 15 cases of extragonadal yolk sac tumor (EGYST) detected in female patients and reviewed at our institution from 1988 to 2016. We recorded: patient age, clinical presentation, tumor location, FIGO stage (where applicable), histologic patterns including presence/absence of Schiller-Duval bodies, other germ cell or somatic components, immunoperoxidase results, treatment, and outcome. Patients' ages ranged from 17 to 87 (median, 62) years and presentation included: abnormal uterine bleeding, 12; hematuria, 1; labial mass, 1; abdominal pain, 1. Primary sites were as follows: uterus (11), vagina (1), vulva (1), bladder (1), and peritoneum (1). Seven patients presented at FIGO stage III or IV. The following histologic patterns were observed: microcystic/reticular (7), glandular (8), solid (8), papillary (5), and hepatoid (1). An admixture of histologic patterns was present in 10 cases. Schiller-Duval bodies were seen in only 3 (23%) cases. Eight cases (46%), all uterine primaries, had associated somatic components, and 2 (15%) had a second germ cell component. In 13/14 (93%) cases, the yolk sac tumor component was either missed or misclassified as adenocarcinoma. Immunoperoxidase studies facilitated the diagnosis in all cases as follows: SALL4, 12/12; CDX2, 10/12; α fetoprotein, 7/14; glypican-3, 9/10; cytokeratin 20, 5/9 (rare cells); cytokeratin 7, 3/12 (nondiffuse); PAX8, 2/9 (variable expression). All patients received chemotherapy and all except 1 underwent surgical resection. Follow-up from 5 to 86 months was available for 13 patients: 5 died of disease, 6 are alive with disease, and 2 have no evidence of disease. EGYST arising in the female pelvis of peri/postmenopausal patients may be associated with a somatic component and represent either somatically derived YST or YST differentiation within a somatic carcinoma. EGYST in younger patients is likely a true germ cell neoplasm, and may respond to germ cell appropriate chemotherapy. The benefit of germ cell appropriate chemotherapy in somatically derived EGYST is less clear. Awareness that the presence of glandular or microcystic patterns may lead to under-recognition or misdiagnosis of EGYST in combination with immunomarkers for germ cell and yolk sac differentiation will facilitate the diagnosis.
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http://dx.doi.org/10.1097/PAS.0000000000000722DOI Listing
January 2017

Differential structured illumination microendoscopy for in vivo imaging of molecular contrast agents.

Proc Natl Acad Sci U S A 2016 09 12;113(39):10769-73. Epub 2016 Sep 12.

Department of Bioengineering, Rice University, Houston, TX 77030;

Fiber optic microendoscopy has shown promise for visualization of molecular contrast agents used to study disease in vivo. However, fiber optic microendoscopes have limited optical sectioning capability, and image contrast is limited by out-of-focus light generated in highly scattering tissue. Optical sectioning techniques have been used in microendoscopes to remove out-of-focus light but reduce imaging speed or rely on bulky optical elements that prevent in vivo imaging. Here, we present differential structured illumination microendoscopy (DSIMe), a fiber optic system that can perform structured illumination in real time for optical sectioning without any opto-mechanical components attached to the distal tip of the fiber bundle. We demonstrate the use of DSIMe during in vivo fluorescence imaging in patients undergoing surgery for cervical adenocarcinoma in situ. Images acquired using DSIMe show greater contrast than standard microendoscopy, improving the ability to detect cellular atypia associated with neoplasia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047189PMC
http://dx.doi.org/10.1073/pnas.1613497113DOI Listing
September 2016

Can reduced field-of-view diffusion sequence help assess microsatellite instability in FIGO stage 1 endometrial cancer?

J Magn Reson Imaging 2017 04 17;45(4):1216-1224. Epub 2016 Aug 17.

Department of Diagnostic Radiology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.

Purpose: To determine if a reduced-field-of-view (rFOV) diffusion intravoxel incoherent motion (IVIM) sequence can differentiate the imaging characteristics of tumors with microsatellite instability (MSI) from those that are microsatellite stable (MSS) in patients with clinical FIGO stage IA endometrial cancer and if MRI can be used to determine MSI status.

Materials And Methods: Sagittal rFOV diffusion-weighted images were obtained in 12 patients on a 3T scanner using six b-values (0, 50, 100, 150, 200, and 600). These images were used to derive apparent diffusion coefficient (ADC), true diffusion coefficient (D ), pseudodiffusion (D*), and perfusion fraction (f). Regions of interest (ROIs) were drawn on the dynamic contrast-enhanced magnetic resonance imaging (MRI) sequence on an Advantage Windows workstation and were copied to the same location on IVIM-derived images. The ROI mean of these images was recorded and compared with the microsatellite status. The depth of myometrial invasion and IVIM-derived parameters were tabulated by microsatellite status. The Wilcoxon rank sum test was used to compare T postcontrast images and IVIM-derived images and microsatellite status.

Results: Six patients had MSS tumors and six had MSI tumors. MSS tumors had a significantly higher ADC value (P = 0.03) and D (P = 0.045) than the MSI tumors. There was no association between < and ≥ 50% depth of myometrial invasion (measured on pathology and MRI analysis) and MSI stability P > 0.99.

Conclusion: IVIM, ADC and D may be able to determine microsatellite status noninvasively in patients with clinical FIGO stage I endometrial cancer.

Level Of Evidence: 1 J. Magn. Reson. Imaging 2017;45:1216-1224.
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http://dx.doi.org/10.1002/jmri.25427DOI Listing
April 2017