- Pediatric Pathology
- Anatomic and Clinical Pathology
Director, Pediatric Surgical Pathology (2008 - Present)
Board Certification: Anatomic and Clinical Pathology, American Board of Pathology (2007)
Medical Education:Georgetown University (2002) DC
Fellowship:Stanford Hospital and Clinics (2007) CA
Residency:Stanford Hospital and Clinics (2006) CA
Internship:Stanford Hospital and Clinics (2003) CA
Board Certification: Pediatric Pathology, American Board of Pathology (2011)
Board Certification, Pediatric Pathology, American Board of Pathology (2011)
Fellowship:The Children's Hospital of Philadelphia (2008) PA
--, Children's Hosp of Philadelphia, Pediatric Pathology Fellowship (2008)
--, Stanford University, Surgical Pathology Fellowship (2007)
--, Stanford University, Anatomic and Clinical Pathology Residency (2006)
--, Stanford University, Anatomic and Clinical Pathology Internship (2003)
M.D., Georgetown University, Medicine (2002)
B.A., Princeton University, Ecology and Evolutionary Biology (1997)
Current Research and Scholarly Interests
My scholarly pursuits are primarily focused on the study of death and disease in the pediatric population. Most notably to characterize pediatric tumor pathology, evaluate abnormalities of the juvenile reproductive system, demonstrate the histologic and ultrastructural changes of metabolic disorders on specific organs, and elucidate new scientific techniques to aid in the study of childhood disease.
1. Ovarian Surface Epithelial Neoplasms:
Ovarian cancer is the fifth most common cause of malignancy in adult women; with those involving the surface epithelium of the ovary being the most common. In stark contrast, ovarian neoplasms account for approximately 1% of all childhood malignancies with those affecting the epithelium being extraordinarily rare. It is partially due to their low frequency that little is known about the overall incidence, histologic subtypes, optimal treatment strategies, and natural history of ovarian surface epithelial neoplasms in children.
2. Liver Pathology in Mitochondrial DNA Depletion Syndrome:
Mitochondrial disorders are rare causes of childhood disease and dysfunction. Syndromes caused by depletion of mitochondrial DNA (mtDNA) are exceptionally rare, but can often cause devastating outcomes. These depletion syndromes are caused by anomalous mtDNA or nuclear DNA encoding for mitochondrial proteins resulting in a quantitative reduction in mtDNA and abnormal oxidative phosphorylation. To date, three genes have been implicated in this process MPV17, polymerase gamma, and deoxyguanosine kinase. In neonates, these abnormalities most often manifest with hepatic and neurologic dysfunction; the hepatocerebral phenotype. Recognition of the clinical signs and symptoms of mitochondrial DNA depletion coupled with the histologic and ultrastructural features can result in early diagnosis and optimal treatment.
3. Liver Explant Pathology In Argininosuccinate Lyase Deficiency:
Argininosuccinate (ASA) lyase deficiency is the second most common urea cycle disorder in the pediatric population. It manifests in either a neonatal or late onset form with seizures, lethargy, and often hyperammonemia. Due to the risk of cognitive impairment, children are closely followed by monitoring serum ammonia levels and treated with arginine supplementation, dietary restriction, and recently liver transplantation. Characterization of the histologic features of livers in children with ASA lyase deficiency will aid pathologists in providing prompt diagnoses and allow clinicians to impart early therapy before the onset of life threatening complications and cognitive impairment.
4. Tissue Microarray Analysis of Small Volume Cellular Suspensions:
The use of small volume tissue samples in tissue microarray analysis has been plagued by inefficiency and poor reproducibility. Therefore, tissue samples such as cerebrospinal fluid, pleural fluid, bone marrow aspirates, and fine needle aspirates are often excluded from scientific research. A new technique developed by a team of researchers at Stanford University School of Medicine has made utilization of these low volume tissue samples possible. In fact, this technique can be used to establish diagnoses and confirm other ancillary testing results, such as gene expression arrays.
Pilot Development of Radiation Free Whole Body Magnetic Resonance (MR) Imaging Technique for Staging Children With Cancer
A research study on the diagnosis of spread of disease for children who have been diagnosed with solid tumors using a new whole body imaging technique and a new MR contrast agent (ferumoxytol). Standard tests that are used to determine the extent and possible spread of a child's disease include magnetic resonance (MR) imaging, computed tomography (CT), Positron Emission Tomography (PET) as well as bone scanning, and metaiodobenzylguanidine (MIBG) scanning. The purpose of this study is to determine if newer imaging tests referred to as whole body diffusion-weighted MR and whole body PET/MR can detect the extent and spread of the disease as accurately or even better as the standard tests (CT, MR and/or PET/CT). The advantage of the new imaging test is that it is associated with no or significantly reduced radiation exposure compared to standard CT and PET/CT imaging tests. The results of whole body MR and PET/MR will be compared with that of the conventional, standard imaging studies for tumor detecting.
Efficacy Study of Preconception Treatment of an Asymptomatic Bacterial Infection in an Infertility Population
Bacterial vaginosis (BV) is a common vaginal infection characterized by a pathologic shift in the normal vaginal flora. BV has been associated with a number of poor reproductive outcomes, including infertility, preterm labor and premature rupture of membranes. If BV does disrupt normal embryologic development, then the treatment of BV prior to conception may improve implantation rates and other pregnancy outcomes in the infertile population. This is a prospective, randomized, double-blind, placebo-controlled trial in which infertile women undergoing intrauterine insemination or embryo transfer are screened for BV prior to treatment. Those patients who screen positive for BV will then be randomized into the treatment arm(metronidazole 500mg by mouth twice daily for 7 days) or the control arm (placebo by mouth twice daily for 7 days). The primary outcome, positive pregnancy test rate (i.e. biochemical pregnancy rate), will then be assessed. Secondary outcomes, such as clinical pregnancy rate, miscarriage rate, and live birth rate will also be examined.
Stanford is currently not accepting patients for this trial. For more information, please contact Jamie Massie, MD, 650-498-7408.
- Independent Studies (5)
- Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss. Fertility and sterility 2015; 104 (4): 927-931
Congenital peribronchial myofibroblastic tumor: case report of an asymptomatic infant with a rapidly enlarging pulmonary mass and review of the literature.
Annals of clinical and laboratory science
2015; 45 (1): 83-89
Congenital peribronchial myofibroblastic tumor (CPMT) is a rare, benign lung tumor of infants, with only 19 reported cases worldwide. It is often diagnosed by prenatal imaging or in the immediate postnatal period due to co-morbidities like polyhydramnios, fetal hydrops, respiratory distress, and heart failure.We report the oldest known infant (8 weeks old) diagnosed with CPMT, and present his clinical course including the relevant radiographic and histopathologic findings.CPMT is a rare tumor that should be considered among other primary lung tumors of infancy (developmental, benign, and malignant) even if not detected prenatally or in the immediate postnatal period.
View details for PubMedID 25696016
Genomic analysis of fibrolamellar hepatocellular carcinoma.
Human molecular genetics
2015; 24 (1): 50-63
Pediatric tumors are relatively infrequent but are often associated with significant lethality and lifelong morbidity. A major goal of pediatric cancer research has been to identify key drivers of tumorigenesis to eventually develop targeted therapies to enhance cure rate and minimize acute and long-term toxic effects. Here we used genomics approaches to identify biomarkers and candidate drivers for fibrolamellar hepatocellular carcinoma (FL-HCC), a very rare subtype of pediatric liver cancer for which limited therapeutic options exist. In-depth genomics analyses of one tumor followed by immunohistochemistry validation on seven other tumors showed expression of neuroendocrine markers in FL-HCC. DNA and RNA sequencing data further showed that common cancer pathways are not visibly altered in FL-HCC but identified two novel structural variants, both resulting in fusion transcripts. The first, a 400kb deletion, results in a DNAJ1-PRKCA fusion transcript, which leads to increased PKA activity in the index tumor case and other FL-HCC cases compared to normal liver. This PKA fusion protein is oncogenic in HCC cells. The second gene fusion event, a translocation between the CLPTML1 and GLIS3 genes, generates a transcript whose product also promotes cancer phenotypes in HCC cell lines. These experiments further highlight the tumorigenic role of gene fusions in the etiology of pediatric solid tumors and identify both candidate biomarkers and possible therapeutic targets for this lethal pediatric disease.
View details for DOI 10.1093/hmg/ddu418
View details for PubMedID 25122662
Features of Gastric and Colonic Mucosa in Congenital Enteropathies A Study in Histology and Immunohistochemistry
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
2014; 38 (12): 1697-1706
View details for Web of Science ID 000345131700015
Evaluation of Intestinal Biopsies for Pediatric Enteropathy A Proposed Immunohistochemical Panel Approach
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
2014; 38 (10): 1387-1395
View details for Web of Science ID 000342001800010
- Successful Treatment with Temozolomide Combined with Chemoradiotherapy and Surgery of a Metastatic Undifferentiated Soft Tissue Sarcoma with Relapse in the Central Nervous System of a Young Adult JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY 2014; 3 (2): 100-103
Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy.
2014; 10 (3): 566-?
A major drawback with current cancer therapy is the prevalence of unrequired dose-limiting toxicity to non-cancerous tissues and organs, which is further compounded by a limited ability to rapidly and easily monitor drug delivery, pharmacodynamics and therapeutic response. In this report, the design and characterization of novel multifunctional "theranostic" nanoparticles (TNPs) is described for enzyme-specific drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery. TNPs are synthesized by conjugation of FDA-approved iron oxide nanoparticles ferumoxytol to an MMP-activatable peptide conjugate of azademethylcolchicine (ICT), creating CLIO-ICTs (TNPs). Significant cell death is observed in TNP-treated MMP-14 positive MMTV-PyMT breast cancer cells in vitro, but not MMP-14 negative fibroblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV-PyMT tumor-bearing mice and subsequent MRI demonstrates significant tumor selective accumulation of the TNP, an observation confirmed by histopathology. Treatment with CLIO-ICTs induces a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death is observed in normal tissues following treatment with CLIO-ICTs, ICT, or ferumoxytol. These findings demonstrate proof of concept for a new nanotemplate that integrates tumor specificity, drug delivery and in vivo imaging into a single TNP entity through attachment of enzyme-activated prodrugs onto magnetic nanoparticles. This novel approach holds the potential to significantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens.
View details for DOI 10.1002/smll.201301456
View details for PubMedID 24038954
Cancer therapy: development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy (small 3/2014).
2014; 10 (3): 417-?
Cancer cells overexpress matrix-type metalloproteinases (MMPs, shown as pacmen). MMPs cleave the peptide linker connecting anticancer prodrug to the dextran coated magnetic nanoparticle. After the cleavage, the drug becomes toxic (active drug shown in purple). As J. Rao, H. E. Daldrup-Link, and co-workers describe on page 566, this tumor specific drug release reduces the side-effects of cancer therapy. The magnetic core of the nanoparticles allows for MRI monitoring of their distribution in the body.
View details for DOI 10.1002/smll.201470016
View details for PubMedID 24497471
Comparison of Latino and Non-Latino Patients With Ewing Sarcoma
PEDIATRIC BLOOD & CANCER
2014; 61 (2): 233-237
Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES.Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing.Latino patients were diagnosed at a younger age (P = 0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (P = 0.001), were less likely to have insurance (P = 0.001), and were more likely to present to the emergency room at onset of symptoms (P = 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% P = 0.37; OS: 77.6% vs. 68.6% P = 0.54).Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients.
View details for DOI 10.1002/pbc.24745
View details for Web of Science ID 000328694300016
View details for PubMedID 23970433
Adequacy of lymph node examination in colorectal surgery: contribution of the hospital versus the surgeon.
2013; 51 (12): 1055-1062
Examination of at least 12 lymph nodes (LNs) in the staging of colon cancer (CC) was recommended by the National Comprehensive Cancer Network in 2000; however, rates of an adequate examination remain low. This study compares the impact of the hospital contextual variance against that of the operating surgeon on delivery of an adequate LN examination.Retrospective analysis of California Cancer Registry data for all CC operations (2001-2006). Hierarchical models predicted the adequacy of LN examination as a function of patient, surgeon, and hospital characteristics. Models were created using penalized quasi-likelihood approximation with second order Taylor linearization as implemented in MLwiN 2.15.A total of 25,606 resections involving 3376 surgeons operating in 346 hospitals were analyzed. Half of cases had an adequate examination. Hierarchical models showed the median odds of an adequate examination associated with the hospital context [(MORhosp 2.05; 95% confidence interval, 1.9-2.2) was much higher than that associated with the surgeon (MORsurg 1.34; 95% confidence interval, 1.2-1.4)]. Hospital characteristics teaching and high volume predicted higher odds of an adequate examination. There was no association with hospital revenue.Approximately half of patients undergoing surgery for CC received an adequate LN examination. Hospital contextual factors had a stronger association with receipt of an adequate examination than surgeon factors. Our results suggest that quality improvement initiatives and incentives should be targeted at the hospital level to achieve the highest impact. Furthermore, we have identified nonteaching and low volume settings as rational targets for these efforts.
View details for DOI 10.1097/MLR.0b013e3182a53d72
View details for PubMedID 23969586
Liver Pathology in Infantile Mitochondrial DNA Depletion Syndrome
PEDIATRIC AND DEVELOPMENTAL PATHOLOGY
2013; 16 (6): 415-424
Mitochondrial DNA (mtDNA) depletion syndrome is a relatively novel cause of hepatic dysfunction in the pediatric population. It is caused by mutations in either mtDNA or nuclear DNA (nDNA) that result in a quantitative reduction in mtDNA and, in turn, dysfunctional oxidative phosphorylation. In infants, it results in the hepatocerebral phenotype, characterized by hyperbilirubinemia, coagulopathy, lactic acidosis, hypoglycemia, lethargy, encephalopathy, developmental delay, and hypotonia. Three infants diagnosed with mtDNA depletion syndrome at The Children's Hospital of Philadelphia were identified, and their clinical presentation, disease course, and histologic and ultrastructural features of liver samples (pre- and postmortem) were characterized. While a different mutant gene was identified in each child, they all showed clinical evidence of metabolic dysfunction soon after birth and expired by 1 year of age. Steatosis, cholestasis, and cytoplasmic crowding by atypical mitochondria were consistent pathologic liver findings. Other findings included hepatocyte hypereosinophilia, fibrosis, and hemosiderosis. This analysis provides insight into the important clinical signs/symptoms and histopathologic and ultrastructural features of mtDNA depletion syndrome in infants and young children. Knowledge of these characteristics will facilitate early recognition and appropriate treatment of this rare disorder. Additionally, ultrastructural evaluation of liver samples by electron microscopy is an important diagnostic component of hepatic dysfunction caused by metabolic abnormalities. This type of analysis should be routinely employed in the setting of unexplained cholestasis, especially when accompanied by steatosis and hepatocyte hypereosinophilia.
View details for DOI 10.2350/12-07-1229-OA.1
View details for Web of Science ID 000328893600003
View details for PubMedID 24050659
Ovarian Surface Epithelial Neoplasms in the Pediatric Population Incidence, Histologic Subtype, and Natural History
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
2013; 37 (4): 548-553
Surface epithelial neoplasms account for a small but significant proportion of pediatric ovarian tumors. The overall incidence, prevalence of histologic subtypes, and natural history of these neoplasms has not been thoroughly evaluated. A retrospective review of the pathology archives of Stanford University School of Medicine yielded 69 surface epithelial ovarian tumors in 64 pediatric patients 18 years of age or younger from 1974 to 2010. Tumors comprised benign (57.8%), borderline/low malignant potential (LMP) (37.5%), and malignant (4.7%) subgroups and exhibited serous, mucinous, and mixed histology; there were no clear cell, pure endometrioid, or transitional (Brenner) tumors. In addition, no high-grade carcinomas were identified. Clinical follow-up data were available in a subset of patients (maximum follow-up, 22 y). Similar numbers of recurrences were found in each of the 3 subgroups. However, overall survival was 100% for benign and borderline/LMP tumors and 50% for carcinomas. The type of surgical management and the use of chemotherapy varied; 2 patients with borderline/LMP tumors were treated by sterilizing procedures and/or chemotherapy. These data suggest that surface epithelial neoplasms comprise a small but significant proportion of ovarian tumors in the pediatric population, and they exhibit a marked preponderance for benign, borderline, and low-grade malignant subgroups. In contrast to their adult counterpart, high-grade serous carcinoma in children is extraordinarily rare and not seen in this series. Given this difference, uniform treatment modalities with consideration for ovarian conservation and fertility preservation should be rigorously adopted in any pediatric patient with a suspected ovarian surface epithelial neoplasm.
View details for DOI 10.1097/PAS.0b013e318273a9ff
View details for Web of Science ID 000316184000009
View details for PubMedID 23388124
A Case of Genitourinary Crohn's Disease
2012; 80 (5): 1132-1134
Scrotal swelling in young boys is a common problem. The differential diagnosis includes testicular torsion, epididymoorchitis, and idiopathic scrotal edema. We report the unusual case of a 17-year-old boy who presented with recurrent episodes of penile and scrotal edema as extraintestinal manifestations of Crohn's disease. Genitourinary complications of Crohn's disease are not uncommon; however, they more typically present in the form of nephrolithiasis, obstructive uropathy, and enterovesical fistulization. Few reports have described Crohn's disease presenting with isolated genital edema in the absence of associated intestinal or systemic symptoms.
View details for DOI 10.1016/j.urology.2012.07.044
View details for Web of Science ID 000310566300047
View details for PubMedID 22999453
Predictors of acute chemotherapy-associated toxicity in patients with Ewing sarcoma
PEDIATRIC BLOOD & CANCER
2012; 59 (4): 611-616
Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue of children and young adults. Patients with ES are treated with intensive chemotherapy regimens. We describe predictors of acute chemotherapy-associated toxicity in this population.In this retrospective cohort study, records of ES patients treated at two academic medical centers between 1980 and 2010 were reviewed. Grade 3 and 4 non-hematologic chemotherapy-associated toxicities during frontline therapy were recorded for each patient, along with potential clinical and demographic predictors of toxicity. Bivariate analyses were performed using the Fisher exact test. Multivariate analysis was performed using logistic regression.The cohort included 142 patients with ES and toxicity data. In bivariate analyses, age <12 years at diagnosis, Latino ethnicity, low family income, and treatment on a clinical trial were associated with higher incidence of toxicity (P < 0.01). Tumor size, site, stage, mode of local control, body mass index, overall chemotherapy exposure and dose-intensity were not associated with toxicity. In multivariate analysis, low income (odds ratio (OR) 4.97, 95% confidence interval (CI) 1.9-13.1), clinical trial enrollment (OR 3.67, 95% CI 1.2-10.9), pelvic tumor site (OR 3.88, 95% CI 1.17-12.88), and age <12 years (OR 2.8, 95% CI 1.0-7.5) were independent predictors of toxicity.ES patients who are younger, of Latino ethnicity, have pelvic tumors or low income have higher rates of toxicity that may require increased supportive care. Treatment on a clinical trial was also associated with higher rates of toxicity, though this finding may reflect better reporting in these patients.
View details for DOI 10.1002/pbc.24031
View details for Web of Science ID 000307386300004
View details for PubMedID 22180320
Congenital Pancreatoblastoma: Report of an Atypical Case and Review of the Literature
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
2012; 34 (4): 310-315
Pancreatoblastoma is a rare malignant tumor of the pancreas mostly diagnosed in childhood. The clinical presentation and outcome of infantile and congenital pancreatoblastoma have not been clearly elucidated. This report describes our recent institutional experience with an unusual case of congenital pancreatoblastoma. Review of the scientific literature identifies approximately 200 cases of pancreatoblastoma. We describe the 9 infantile (aged 3 mo and younger) and 4 congenital cases previously reported and summarize their clinical presentation and outcome. We also define the close association of infantile/congenital pancreatoblastoma and Beckwith-Wiedemann syndrome (50%) versus all affected age groups (4.5%).
View details for DOI 10.1097/MPH.0b013e318239f4f6
View details for Web of Science ID 000303652500029
View details for PubMedID 22278199
- Gorham's disease: diagnostic utility of an autopsy for a rare bone disease. Journal of pediatric health care 2011; 25 (6): 391-398
First Trimester Miscarriage Evaluation
SEMINARS IN REPRODUCTIVE MEDICINE
2011; 29 (6): 463-469
Miscarriage is a relatively common occurrence for otherwise healthy women. Despite its frequency, evaluation for cause is rare. The most common cause of miscarriage is sporadic chromosome errors. Chromosomal analysis of the miscarriage offers an explanation in at least 50% of cases. Conventional cytogenetic evaluation can only be done on fresh tissue, so it is critical that the treating physician consider genetic testing at the time of the miscarriage. Ultrasound can estimate the gestational age at the time of miscarriage and identify major abnormalities in some embryos. A careful pathological examination can add to the evaluation by ruling out rare disorders with the highest recurrence risk. A multidisciplinary approach to miscarriage evaluation is essential to understanding the cause and risk of recurrence. A thorough evaluation of a miscarriage, in combination with emotional support, can often provide the necessary reassurance and confidence as the patient prepares for her next pregnancy.
View details for DOI 10.1055/s-0031-1293200
View details for Web of Science ID 000298281100003
View details for PubMedID 22161459
Tissue microarrays from bone marrow aspirates for high-throughput assessment of immunohistologic markers in pediatric acute leukemia
PEDIATRIC AND DEVELOPMENTAL PATHOLOGY
2008; 11 (4): 283-290
Gene expression profiling studies have been employed to investigate prognostic subgroups in pediatric acute leukemia. Tissue microarrays (TMAs) are useful for high-throughput analysis of protein expression of target genes in acute leukemia samples and for validation of gene microarray analysis. Using cryopreserved samples of pediatric acute leukemia bone marrow aspirates, we constructed TMA from as few as 1 million cells. Bone marrow core biopsies from the same patients were included on the same TMA for comparison. A panel of 15 immunohistochemical markers typically used for diagnosis as well as those targeting recently characterized, prognostically relevant molecules of interest in pediatric acute leukemia was used to evaluate protein expression. Staining results confirm that suspension cells from bone marrow aspirates can be effectively used to derive protein expression data from multiple cases simultaneously with comparable efficacy to that of biopsy tissue. This method allows for new markers of diagnostic, prognostic, or therapeutic importance to be screened on large numbers of study patients. Furthermore, this technique may facilitate the inclusion of small samples, aspirates, and body fluids in large-scale studies of protein expression in clinical trials and protocols in which tissue biopsies are often unavailable.
View details for DOI 10.2350/07-04-0253.1
View details for Web of Science ID 000259353300005
View details for PubMedID 17990919