Publications by authors named "Dolores H Lopez-Terrada"

19 Publications

  • Page 1 of 1

Integrated DNA and RNA sequencing reveals targetable alterations in metastatic pediatric papillary thyroid carcinoma.

Pediatr Blood Cancer 2021 Jan 3;68(1):e28741. Epub 2020 Oct 3.

Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.

Background: Pediatric papillary thyroid carcinoma (PTC) is clinically and biologically distinct from adult PTC. We sequenced a cohort of clinically annotated pediatric PTC cases enriched for high-risk tumors to identify genetic alterations of relevance for diagnosis and therapy.

Methods: Tumor DNA and RNA were extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation using a custom 124-gene hybridization capture panel and the 75-gene Archer Oncology Research Panel, respectively. NGS libraries were sequenced on an Illumina MiSeq.

Results: Thirty-six pediatric PTC cases were analyzed. Metastases were frequently observed to cervical lymph nodes (29/36, 81%), with pulmonary metastases less commonly found (10/36, 28%). Relapsed or refractory disease occurred in 18 patients (18/36, 50%). DNA sequencing revealed targetable mutations in 8 of 31 tumors tested (26%), most commonly BRAF p.V600E (n = 6). RNA sequencing identified targetable fusions in 13 of 25 tumors tested (52%): RET (n = 8), NTRK3 (n = 4), and BRAF. Mutually exclusive targetable alterations were discovered in 15 of the 20 tumors (75%) with both DNA and RNA analyzed. Fusion-positive PTC was associated with multifocal disease, higher tumor staging, and higher American Thyroid Association risk levels. Both BRAF V600E mutations and gene fusions were correlated with the presence of cervical metastases.

Conclusions: Targetable alterations were identified in 75% of pediatric PTC cases with both DNA and RNA evaluated. Inclusion of RNA sequencing for detection of fusion genes is critical for evaluation of these tumors. Patients with fusion-positive tumors were more likely to have features of high-risk disease.
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http://dx.doi.org/10.1002/pbc.28741DOI Listing
January 2021

Pediatric myeloid sarcoma: a single institution clinicopathologic and molecular analysis.

Pediatr Hematol Oncol 2020 Feb 4;37(1):76-89. Epub 2019 Nov 4.

Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA.

Myeloid sarcoma (MS) is a neoplastic condition composed of immature myeloid cells involving an extramedullary site. We investigated underlying chromosomal and molecular alterations to assess potential molecular markers of prognosis and outcome in this rare pediatric disease. We conducted a retrospective review of clinicopathologic and cytogenetic data from 33 pediatric patients with MS (ages 1 month-18 years) at our institution over a 32 year period (1984-2016). Tissue-based cancer microarray and targeted next-generation sequencing analysis were performed on six cases. The median age at diagnosis was 2.8 years with a male-to-female ratio of 2.6:1. MS is commonly presented with concomitant marrow involvement ( = 12, 36.4%) or as a recurrence of acute myeloid leukemia (AML;  = 14, 42.4%). The skin ( = 18, 54.5%) and soft tissue ( = 9, 27.3%) were the most common sites of involvement. Twenty-one of 25 samples (84.0%) harbored chromosomal aberrations; alterations ( = 10, 40.0%) or complex cytogenetics ( = 7, 28.0%) were most frequent. Mutations in RAS, tyrosine kinase, cell signaling, and chromatin remodeling genes were detected. When compared to pediatric patients with AML without extramedullary involvement (EMI), inferior overall survival (OS) was observed (18.8 months vs. 89.3 months,  = .008). Pediatric patients with MS with non-favorable cytogenetics [abnormalities other than t(8;21), inv(16)/t(16;16), or t(15;17)] had a significantly lower OS compared to patients with AML with non-favorable cytogenetics and no extramedullary involvement (8.0 months vs. 28.1 months,  < .001). Pediatric MS is a rare disease with diverse clinical presentations. Non-favorable cytogenetics may be a poor prognostic marker for pediatric patients with MS and molecular diagnostics can assist with risk stratification and identify potentially actionable targets.
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http://dx.doi.org/10.1080/08880018.2019.1683107DOI Listing
February 2020

Sustained remission with azacitidine monotherapy and an aberrant precursor B-lymphoblast population in juvenile myelomonocytic leukemia.

Pediatr Blood Cancer 2019 10 28;66(10):e27905. Epub 2019 Jun 28.

Department of Pediatrics, Section of Hematology Oncology, Texas Children's Hospital/Baylor College of Medicine, Houston, Texas.

Juvenile myelomonocytic leukemia (JMML) has a poor prognosis in general, with hematopoietic stem cell transplant (HSCT) remaining the standard of care for cure. The hypomethylating agent, azacitidine, has been used as a bridging therapy to transplant. However, no patients have been treated with azacitidine without an HSCT post azacitidine. We report on an infant with JMML with somatic KRAS G12A mutation and monosomy 7 who achieved sustained remission following azacitidine monotherapy. He also developed an aberrant B-lymphoblast population which declined with similar kinetics as his JMML-associated abnormalities, suggesting that a B-lymphoblast population in JMML does not always progress to acute leukemia.
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http://dx.doi.org/10.1002/pbc.27905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328527PMC
October 2019

Evaluation of the diagnostic biopsy approach for children with hepatoblastoma: A report from the children's oncology group AHEP 0731 liver tumor committee.

J Pediatr Surg 2020 Apr 11;55(4):655-659. Epub 2019 May 11.

Division of Hematology/Oncology, Department of Pediatrics, Nemours Children's Specialty Care/Wolfson Children's Hospital, Jacksonville, FL.

Background: The histopathological assessment of pediatric liver tumors at presentation is critical to establish a diagnosis, guide treatment, and collect appropriate research samples. The purpose of this study was to evaluate complications associated with different approaches to liver biopsy for newly diagnosed hepatoblastoma.

Methods: Children with hepatoblastoma were enrolled on Children's Oncology Group study AHEP0731 (September 2009-March 2012). This analysis evaluated the study cohort of initially unresectable patients who therefore underwent a biopsy procedure at diagnosis. The primary endpoint was clinically significant postbiopsy hemorrhage, defined as requiring red blood cell transfusion.

Results: We identified 121 children who underwent open (n = 76, 63%), laparoscopic (n = 17, 14%), or percutaneous (n = 28, 23%) liver biopsies. All biopsy procedures yielded adequate tissue for diagnosis. Postbiopsy hemorrhage requiring transfusion occurred after 26% (n = 31) of biopsies. Need for blood product transfusion most frequently occurred following open (n = 27/76, 36%) and laparoscopic (n = 4/17, 24%) biopsies, compared with percutaneous (n = 0/28, 0%) biopsies (p < 0.01).

Conclusions: Pretreatment biopsy of pediatric liver tumors via a percutaneous approach yielded the lowest frequency of clinically significant hemorrhage requiring transfusion, without evidence of sacrificing diagnostic accuracy.

Level Of Evidence: Level I.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842675PMC
April 2020

Multimodal molecular analysis of an atypical small cell carcinoma of the ovary, hypercalcemic type.

Cold Spring Harb Mol Case Stud 2018 10 1;4(5). Epub 2018 Oct 1.

Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.

A 12-yr-old normocalcemic female treated for a ruptured ovarian juvenile granulosa cell tumor at an outside hospital presented for exploratory laparotomy and gross surgical debulking of pelvic recurrence. Morphologically, the tumor was composed of sheets and nests of small blue cells forming cysts of various sizes and focal mucinous differentiation. Epithelial membrane antigen (EMA), patchy inhibin, and strong and diffuse p53 immunoreactivity were also observed. A revised diagnosis of mixed sex cord stromal tumor with heterologous elements was favored because of the inhibin immunoreactivity. Targeted next-generation sequencing of the tumor revealed a c.1141C>T, p.Arg381Ter (NM_001128849.1) nonsense mutation and an in-frame 18-bp deletion (c.594_611del18, p.Gly199_Glu204del, NM_001126112.2). Cytogenetic analysis revealed a normal 46,XX karyotype, and OncoScan single-nucleotide polymorphism array analysis demonstrated copy-neutral loss of heterozygosity (CN-LOH) of 19p13.3-19p13.2 and mosaic CN-LOH of 17p13.3-p11.2 encompassing the and loci, respectively. Subsequent germline sequencing confirmed a heterozygous p.Arg381Ter mutation. In lieu of the molecular findings, the diagnosis was amended to small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The patient was treated aggressively with paclitaxel, carboplatin, and bevacizumab. She received an autologous stem cell transplant but died 5 mo after SCCOHT diagnosis secondary to complications of the transplant. This case expands the morphologic, immunophenotypic, and genomic spectrum of SCCOHT and highlights how multimodal molecular analysis can assist with the diagnosis and clinical management of SCCOHT patients.
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http://dx.doi.org/10.1101/mcs.a002956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169825PMC
October 2018

Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular Carcinoma Development in Mice.

Am J Pathol 2018 03 15;188(3):656-671. Epub 2017 Dec 15.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee. Electronic address:

Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics that have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathologic heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis by orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC and displayed a striking acquisition of CC-related pathologic and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathologic evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Finally, liver cancer organoid-generated high-grade tumors exhibited significantly increased extracellular vesicle secretion, suggesting that identifying tumor-specific extracellular vesicle proteins in plasma may be a promising tool for liver cancer detection.
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http://dx.doi.org/10.1016/j.ajpath.2017.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840495PMC
March 2018

USP6 activation in nodular fasciitis by promoter-swapping gene fusions.

Mod Pathol 2017 11 28;30(11):1577-1588. Epub 2017 Jul 28.

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

Nodular fasciitis is a self-limited myofibroblastic lesion that can be misdiagnosed as a sarcoma as a result of its rapid growth, cellularity, and sometimes prominent mitotic activity. A recurrent translocation t(17;22) has been identified in nodular fasciitis, fusing the coding region of USP6 to the promoter region of MYH9, and resulting in increased USP6 expression. A subset of cases show USP6 rearrangement without the typical fusion variants by RT-PCR, or any MYH9 rearrangement by FISH. We sought to further characterize such tumors using molecular diagnostic assays. A novel RT-PCR assay was designed to detect the two known MYH9-USP6 fusion types in formalin-fixed paraffin-embedded and frozen tissue, and a break-apart FISH assay was designed to detect USP6 rearrangement. Twenty-six cases of nodular fasciitis diagnosed between 2002 and 2013 were retrieved from the pathology files of our institutions and were confirmed to be positive by FISH and/or RT-PCR. Seven samples showed USP6 rearrangement by FISH but were negative for MYH9-USP6 fusion by RT-PCR; these cases were subjected to a next-generation sequencing assay utilizing anchored multiplex PCR technology. This assay targets a single partner gene associated with fusions in bone and soft tissue tumors for agnostic detection of gene fusion partners. Novel fusion partners were identified in all seven cases and confirmed by RT-PCR. Structurally, all fusions consisted of the juxtaposition of the entire coding region of USP6 with the promoter of the partner gene, driving increased USP6 expression. This study confirms the neoplastic nature of nodular fasciitis, defines additional pathogenic fusion partners, and adds to the growing body of literature on USP6-associated neoplasia. Given the diagnostic challenges of these tumors, molecular assays can be useful ancillary tools; however, the prevalence of promoter swapping must be recognized when interpreting results.
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http://dx.doi.org/10.1038/modpathol.2017.78DOI Listing
November 2017

The use of BRAF V600E mutation-specific immunohistochemistry in pediatric Langerhans cell histiocytosis.

Hematol Oncol 2018 Feb 20;36(1):307-315. Epub 2017 Feb 20.

Department of Pathology, Texas Children's Hospital, Houston, TX, USA.

BRAF p.V600E mutations are detected in greater than 50% of pediatric Langerhans cell histiocytosis (LCH) lesions. However, the use of mutation-specific BRAF V600E immunohistochemistry (IHC) as a surrogate for molecular testing in pediatric LCH is unknown. We tested the mutation-specific BRAF V600E monoclonal antibody (clone VE1) in formalin-fixed, paraffin-embedded LCH samples from 26 pediatric patients (14 males and 12 females, ages 7 mo-17 y) using allele-specific real-time polymerase chain reaction (PCR) with a limit of detection of 0.5% as the comparative gold standard. BRAF VE1 staining was scored for both intensity (0-3+) and percentage of immunoreactive tumor cells (0%-100%). BRAF VE1 immunoreactivity was determined using both lenient (≥1+, ≥1%) and stringent (≥2+, ≥10%) scoring criteria. Using lenient-scoring criteria, we found that the sensitivity and specificity of IHC compared with allele-specific real-time PCR were 100.0% and 18.2%, respectively. The poor specificity of lenient IHC analysis was attributable to weak, 1+ staining in both BRAF-mutated and wild-type LCH. Using stringent-scoring criteria, we found that specificity improved to 100.0% at the expense of sensitivity that decreased to 80.0%. Stringent scoring generated 3 false-negative results, but in all cases, neoplastic tissue comprised less than 5% of the stained section and/or the specimen was decalcified. In conclusion, highly sensitive molecular assays remain the gold standard for BRAF mutation analysis in LCH paraffin-embedded lesions. To avoid false-positive results, unequivocal VE1 staining of 2+ intensity in greater than or equal to 10% neoplastic histiocytes is required. However, negative VE1 results require additional studies to exclude false-negatives, and stringent-scoring criteria may not be optimal for scant or decalcified specimens.
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http://dx.doi.org/10.1002/hon.2388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886693PMC
February 2018

Cutaneous nodular fasciitis with genetic analysis: a case series.

J Cutan Pathol 2016 Dec;43(12):1143-1149

Department of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Nodular fasciitis is a benign self-limited myofibroblastic neoplasm, which usually involves the upper extremities and trunk of young patients. These tumors have been shown to harbor a translocation involving the MYH9 and USP6 genes, leading to overexpression of the latter. We report seven cases of nodular fasciitis with cutaneous presentations. All cases involved the dermis, with six involving the superficial subcutis, and one auricular tumor extending into cartilage. All cases showed USP6 rearrangement by fluorescence in situ hybridization; in two of three cases, the characteristic MYH9-USP6 fusion was shown by RT-PCR. All patients underwent conservative resection. Nodular fasciitis is an uncommon mesenchymal neoplasm that can occasionally present in superficial locations and is sometimes mistaken for a malignant process. Molecular testing can be useful to distinguish this entity from other cutaneous spindle cell tumors.
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http://dx.doi.org/10.1111/cup.12828DOI Listing
December 2016

Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors.

JAMA Oncol 2016 May;2(5):616-624

Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3The Human Genome Sequencing Center, Baylor College of Medicine, Houston, T.

Importance: Whole-exome sequencing (WES) has the potential to reveal tumor and germline mutations of clinical relevance, but the diagnostic yield for pediatric patients with solid tumors is unknown.

Objective: To characterize the diagnostic yield of combined tumor and germline WES for children with solid tumors.

Design: Unselected children with newly diagnosed and previously untreated central nervous system (CNS) and non-CNS solid tumors were prospectively enrolled in the BASIC3 study at a large academic children's hospital during a 23-month period from August 2012 through June 2014. Blood and tumor samples underwent WES in a certified clinical laboratory with genetic results categorized on the basis of perceived clinical relevance and entered in the electronic health record.

Main Outcomes And Measures: Clinical categorization of somatic mutations; frequencies of deleterious germline mutations related to patient phenotype and incidental medically-actionable mutations.

Results: Of the first 150 participants (80 boys and 70 girls, mean age, 7.4 years), tumor samples adequate for WES were available from 121 patients (81%). Somatic mutations of established clinical utility (category I) were reported in 4 (3%) of 121 patients, with mutations of potential utility (category II) detected in an additional 29 (24%) of 121 patients. CTNNB1 was the gene most frequently mutated, with recurrent mutations in KIT, TSC2, and MAPK pathway genes (BRAF, KRAS, and NRAS) also identified. Mutations in consensus cancer genes (category III) were found in an additional 24 (20%) of 121 tumors. Fewer than half of somatic mutations identified were in genes known to be recurrently mutated in the tumor type tested. Diagnostic germline findings related to patient phenotype were discovered in 15 (10%) of 150 cases: 13 pathogenic or likely pathogenic dominant mutations in adult and pediatric cancer susceptibility genes (including 2 each in TP53, VHL, and BRCA1), 1 recessive liver disorder with hepatocellular carcinoma (TJP2), and 1 renal diagnosis (CLCN5). Incidental findings were reported in 8 (5%) of 150 patients. Most patients harbored germline uncertain variants in cancer genes (98%), pharmacogenetic variants (89%), and recessive carrier mutations (85%).

Conclusions And Relevance: Tumor and germline WES revealed mutations in a broad spectrum of genes previously implicated in both adult and pediatric cancers. Combined reporting of tumor and germline WES identified diagnostic and/or potentially actionable findings in nearly 40% of newly diagnosed pediatric patients with solid tumors.
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http://dx.doi.org/10.1001/jamaoncol.2015.5699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471125PMC
May 2016

Integrating Molecular Testing in the Diagnosis and Management of Children with Thyroid Lesions.

Pediatr Dev Pathol 2016 Mar-Apr;19(2):94-100. Epub 2015 Sep 14.

1 Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.

Thyroid nodules occur in 1-2% of children, and identifying which nodules are malignant is often challenging. Cytologic evaluation facilitates the diagnosis of thyroid lesions (TLs), but in 10-40% of cases the interpretation is indeterminate. Patients with indeterminate diagnoses are often treated with hemithyroidectomy followed by completion thyroidectomy, if cancer is found in the initial specimen. Exposing patients to multiple surgeries increases costs and morbidity. The American Thyroid Association states that a combination of molecular markers is likely to optimize the management of patients with indeterminate cytology. However, few studies have addressed the molecular alterations present in pediatric TL. Twenty-seven thyroid carcinomas from patients 10 to 19 years of age were tested for alterations common in adult TL, including BRAF V600E mutation, RET fusions, and TERT promoter mutations. Mutation-negative cases were subsequently analyzed with a next-generation sequencing (NGS) mutation panel to search for additional targets. Histologic diagnoses included 12 classic papillary thyroid carcinomas (PTCs), 13 follicular variant PTCs, 1 medullary thyroid carcinoma, and 1 follicular carcinoma. Fourteen cases showed lymph node involvement, and 13 cases demonstrated lymphovascular invasion. The BRAF V600E mutation was detected in 10/27 cases, and RET fusions were detected in 6/27 cases. No TERT promoter mutations were identified in any of the cases. The NGS panel revealed additional RET and CTNNB1 pathogenic missense mutations. Our results demonstrate that molecular abnormalities are common in pediatric TLs and suggest that incorporation of molecular testing will be helpful in optimizing patient management.
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http://dx.doi.org/10.2350/15-05-1638-OA.1DOI Listing
June 2016

Mucoepidermoid Carcinoma in Children: A Single Institutional Experience.

Pediatr Blood Cancer 2016 Jan 29;63(1):27-31. Epub 2015 Jul 29.

Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.

Purpose And Objective: To determine the clinicopathologic and molecular features and outcome of children with mucoepidermoid carcinoma (MEC).

Methods: A retrospective analysis of clinical and histopathologic findings was performed in patients with MEC diagnosed at Texas Children's Cancer Center between 2000 and 2014.

Results: Ten female and four male patients with median age 12 years (range 7-19 years) were included in the study. Tumors involved major salivary glands, minor salivary glands of the palate, and the tracheobronchial tree. Nine of 11 patients with salivary MEC underwent more than one surgical resection at the time of initial diagnosis to achieve a gross total resection. Three patients with tracheobronchial tumors underwent pulmonary lobectomy. Three patients received postoperative radiation therapy. No patient was treated with chemotherapy. Histopathologic grades were classified as low (n = 2), intermediate (n = 9), and high (n = 3). All 12 patients with tumor tissue available for testing were positive for MECT1/MAML2 fusion transcripts. There were no deaths, metastases, or recurrences in this series, with a median follow-up of 24 months (range 5-96 months).

Conclusions: Low to intermediate histopathologic grade MECs are more common than high grade MEC in children. In contrast to adults, MECT1/MAML2 fusion transcripts occur with a frequency of 100% in our pediatric MEC series. Complete excision is the treatment of choice and is associated with excellent outcome. The role of radiotherapy is unclear, but may be indicated in patients with high grade tumors with positive surgical margins.
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http://dx.doi.org/10.1002/pbc.25681DOI Listing
January 2016

Cytogenetically cryptic and FISH-negative PML/RARA rearrangement in acute promyelocytic leukemia detected only by PCR: an exceedingly rare phenomenon.

Cancer Genet 2014 Jan-Feb;207(1-2):48-9. Epub 2014 Jan 16.

Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX; Department of Pathology, Texas Children's Hospital, Houston, TX; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX. Electronic address:

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http://dx.doi.org/10.1016/j.cancergen.2014.01.001DOI Listing
May 2014

Molecular testing of solid tumors.

Arch Pathol Lab Med 2011 Jan;135(1):67-82

Molecular Pathology Laboratory, BloodSource, Mather, CA 95655-4128, USA.

Context: Molecular testing of solid tumors is steadily becoming a vital component of the contemporary anatomic pathologist's armamentarium. These sensitive and specific ancillary tools are useful for confirming ambiguous diagnoses suspected by light microscopy and for guiding therapeutic decisions, assessing prognosis, and monitoring patients for residual neoplastic disease after therapy.

Objective: To review current molecular biomarkers and tumor-specific assays most useful in solid tumor testing, specifically of breast, colon, lung, thyroid, and soft tissue tumors, malignant melanoma, and tumors of unknown origin. A few upcoming molecular diagnostic assays that may become standard of care in the near future will also be discussed.

Data Sources: Original research articles, review articles, and the authors' personal practice experience.

Conclusions: Molecular testing in anatomic pathology is firmly established and will continue to gain ground as the need for more specific diagnoses and new targeted therapies evolve. Knowledge of the more common and clinically relevant molecular tests available for solid tumor diagnosis and management, and their indications and limitations, is necessary if anatomic pathologists are to optimally use these tests and act as consultants for fellow clinicians directly involved in patient care.
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http://dx.doi.org/10.1043/2010-0413-RAR.1DOI Listing
January 2011

Detection of myxoid liposarcoma-associated FUS-DDIT3 rearrangement variants including a newly identified breakpoint using an optimized RT-PCR assay.

Mod Pathol 2010 Oct 25;23(10):1307-15. Epub 2010 Jun 25.

Division of Molecular Pathology, Department of Pathology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.

Myxoid/round cell liposarcoma is characterized by the recurrent translocations t(12;16)(q13;p11) and, less commonly, t(12;22)(q13;q12), which fuse FUS or EWSR1, respectively, to DDIT3 on chromosome 12. Although a number of different variant breakpoints have been described, greater than 90% of all cases have one of the three different FUS-DDIT3 fusions, which may have clinical significance. To identify the individual breakpoints, a sequence-specific assay such as reverse transcription-PCR (RT-PCR) is needed. In this study, we optimized primer design to develop an RT-PCR assay for the detection of the most common translocations in formalin-fixed paraffin-embedded tissue specimens. We compared our assay with primers previously published for testing formalin-fixed paraffin-embedded specimens and achieved the most consistent results with our primers. We obtained RNA from 32 MLS cases, of which 27 carried one of the three common FUS-DDIT3 chimeric transcript types. Four of the negative cases were from very small biopsies with very low RNA concentration. One case was consistently negative by RT-PCR, but showed a FUS rearrangement by fluorescent in situ hybridization, suggesting that it may harbor one of the rarer FUS-DDIT3 chimeric types. In addition to the common fusions, our assay also identified a novel FUS-DDIT3 fusion between exon 9 of FUS and exon 3 of DDIT3 in one of the cases.
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http://dx.doi.org/10.1038/modpathol.2010.118DOI Listing
October 2010

Monophasic synovial sarcoma arising in the vulva: a case report and review of the literature.

Arch Pathol Lab Med 2008 Apr;132(4):698-702

Internal Medicine, UT Southwestern Dallas, Dallas, Tex, USA.

Synovial sarcomas most commonly arise in the soft tissue of the extremities. Less commonly, these tumors present in the head and neck, abdominal wall, and other sites. However, synovial sarcoma occurring in the vulvar area is extremely rare. Only 2 previous cases of biphasic synovial sarcoma of the vulva have been reported, but no case of vulvar monophasic synovial sarcoma has been described in the English literature. We report the third case of synovial sarcoma and apparently the first case of monophasic synovial sarcoma arising in soft tissues of the vulva. The patient was a 33-year-old woman who presented for evaluation of a painless vulvar mass. The tumor was located in the deep fibroadipose tissue of the right vulva (6.5 x 4.2 x 3.5 cm). The histology of the lesion was that of a monophasic synovial sarcoma with a hemangiopericytic vascular pattern. A subsequent molecular analysis revealed SYT-SSX2 gene fusion, which confirmed the diagnosis of synovial sarcoma. After an initial wide local excision, the patient developed a recurrence in the right groin and received chemotherapy and additional surgery. The patient is currently disease free, on adjuvant chemotherapy, and being followed up closely.
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http://dx.doi.org/10.1043/1543-2165(2008)132[698:MSSAIT]2.0.CO;2DOI Listing
April 2008

Clear cell sarcoma of soft tissue: diagnostic utility of fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction.

J Cutan Pathol 2008 Apr;35(4):411-7

Department of Pathology, Baylor College of Medicine, Houston, Texas, USA.

A 7-year-old girl presented with pain and progressive swelling on the left plantar surface. Biopsy of a 2.5 cm mass showed nests of large round to oval neoplastic cells with abundant amphophilic to clear cytoplasm, prominent nucleoli and high mitotic activity. Occasional cells showed spindled morphology. Infrequent melanin pigment was present. Melanocytic markers (HMB45, S-100) were diffusely positive. A diagnosis of clear cell sarcoma of soft tissue (CCSS) was made, and the mass was re-excised with negative margins. 28 months later, a 1.0 cm pulmonary nodule was identified and wedge excision showed metastatic CCSS. Cytogenetics showed a complex karyotype (unbalanced translocation der(12;14)(q10;q10), additional chromosome 22 material of unknown origin). Although the CCSS translocation t(12;22)(q13;q12) was not identified, EWSR1 gene rearrangement was detected by fluorescence in situ hybridization (FISH). Reverse transcription polymerase chain reaction (RT-PCR) showed an EWS-ATF1 fusion transcript, confirmed by direct sequencing. CCSS requires differentiation from malignant melanoma, because of overlapping clinical presentations, sites of involvement, histomorphology, immunocytochemical profiles and ultrastructure. In many circumstances, definitive diagnosis is only possible with confirmation of the CCSS-defining translocation.
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http://dx.doi.org/10.1111/j.1600-0560.2007.00821.xDOI Listing
April 2008

Protocol for the examination of specimens from pediatric patients with hepatoblastoma.

Arch Pathol Lab Med 2007 Apr;131(4):520-9

Department of Pathology, Texas Children's Cancer Center at Baylor College, Houston, USA.

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http://dx.doi.org/10.1043/1543-2165(2007)131[520:PFTEOS]2.0.CO;2DOI Listing
April 2007