ZMIZ1::ABL1 Fusion: An Uncommon Molecular Event With Clinical Implications in Pediatric Cancer.

CONTEXT.­: Pediatric B-cell acute lymphoblastic leukemia is genetically and phenotypically heterogeneous, with a genetic landscape including chromosomal translocations that disrupt ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1). OBJECTIVE.­: To characterize an uncommon chromosomal translocation in acute leukemia. DESIGN.­: Genetic testing, including karyotype and fluorescence in situ hybridization (FISH) analysis, was used to determine the underlying genetic aberration driving the disorder and to guide disease classification and risk stratification. More-detailed testing using RNA sequencing was performed, based on the results from these assays. Three-dimensional molecular modeling was used to visualize the impact of aberrant fused transcripts identified by transcriptome profiling. RESULTS.­: Karyotype analysis of the bone marrow demonstrated a complex karyotype with, most notably, a t(9;10)(q34.1;q22) translocation. ABL1 break-apart probe FISH findings supported ABL1 disruption. Bone marrow transcriptome analysis revealed mutant ZMIZ1::ABL1 (ZMIZ1, zinc finger MIZ-type containing 1) fusion transcripts as a consequence of t(9;10)(q34.1;q22). Three-dimensional modeling of the mutant ZMIZ1::ABL1 fusion protein confirmed an altered ABL1 protein structure compared to that of the wild type, suggesting a constitutively active conformation. CONCLUSIONS.­: The t(9;10) translocation resulting in ZMIZ1::ABL1 fusion transcripts is an uncommon form of BCR::ABL1-like (BCR, BCR activator of RhoGEF and GTPase) acute lymphoblastic leukemia. Although the karyotype was complex, identifying the t(9;10)(q34.1;q22) translocation, ABL1 disruption, and ZMIZ1::ABL1 transcript enabled effective ABL1-targeted treatment. Our data support the use of tyrosine kinase inhibitors to treat ZMIZ1::ABL1-derived B-cell acute lymphoblastic leukemia.

Genetic counseling program remediation practices for students underperforming in clinical skills: An exploratory study.

Program-level clinical remediation in genetic counseling training programs aims to help students who are underperforming gain clinical skills to successfully manage clinical counseling sessions with patients. Student remediation often requires intervention, including discussions with program leadership and/or a formal remediation plan through the program. This study surveyed genetic counseling program leaders to explore the remediation landscape by identifying skills in which students underperformed, program remediation activities to improve skills, and remediation outcomes. Thirteen participants indicated their program required at least one student to complete program-level clinical remediation during the last 10 years. Eight of the 13 programs (61.5%) required at least one student to participate in clinical remediation for underperformance in professionalism, seven (53.8%) for underperformance in educating patients, six (46.2%) for underperformance in critical thinking, and two (15.4%) for underperformance in demonstrating empathy. Nineteen students were remediated for underperformance in critical thinking. Of those 19 students, one student (5.2%) was dismissed from the training program, and five students (26.3%) chose to withdraw from their program. One of 13 (7.7%) students remediated for underperformance in educating patients and one of 11 (9.1%) students remediated for underperformance in professionalism chose to withdraw from their programs. All students remediated for underperformance in demonstrating empathy successfully completed program-level clinical remediation and graduated. The most frequently endorsed factor positively associated with remediation success was completion of additional in-person patient encounters. The most frequent barrier was a student's poor mental health. Participants most frequently endorsed identification of resources for specific areas of remediation to improve their programs' efficacy in clinical remediation practices. This exploratory study provides valuable information describing clinical skills that require remediation in genetic counseling graduate training, the remediation practices utilized by training programs, and resources that may increase remediation success.

Improvement of diagnosis in children with Burkitt lymphoma in Kenya: feasibility study for the implementation of fluorescence in situ hybridisation testing for MYC and the MYC/IGH translocation.

Background: Indiana University (IU) initiated fluorescence in situ hybridisation (FISH) methodology for Burkitt Lymphoma (BL) to advance the accuracy and speed of diagnosis in the AMPATH Reference Laboratory at Moi Teaching and Referral Hospital (MTRH) in Eldoret, Kenya. Standard diagnostic testing for BL at MTRH includes morphology of the biopsy specimen or aspirate and limited immunohistochemistry panels. Methods: Tumour specimens from 19 children enrolled from 2016 to 2018 in a prospective study to improve the diagnosis and staging of children with suspected BL were evaluated. Touch preps from biopsy specimens or smears from fine needle aspiration were collected, stained with Giemsa and/or H&E and reviewed by pathologists to render a provisional diagnosis. Unstained slides were stored and later processed for FISH. Duplicate slides were split between two laboratories for analysis. Flow cytometry results were available for all specimens. Results from the newly established FISH laboratory in Eldoret, Kenya were cross-validated in Indianapolis, Indiana. Results: Concordance studies found 18 of 19 (95%) of specimens studied yielded analysable FISH results for one or both probe sets (MYC and MYC/IGH) in both locations. There was 94% (17/18) concordance of results between the two FISH laboratories. FISH results were 100% concordant for the 16 specimens with a histopathological diagnosis of BL and two of three non-BL cases (one case no result in IU FISH lab). FISH was similarly concordant with flow cytometry for specimens with positive flow results with the exception of a nasopharyngeal tumour with positive flow results for CD10 and CD20 but was negative by FISH. The modal turn-around time for FISH testing on retrospective study specimens performed in Kenya ranged between 24 and 72 hours. Conclusion: FISH testing was established, and a pilot study performed, to assess the feasibility of FISH as a diagnostic tool for the determination of BL in a Kenyan paediatric population. This study supports FISH in limited resource settings to improve the accuracy and speed of diagnosis of BL in Africa.

Malignant gastrointestinal neuroectodermal tumour arising in the extrahepatic bile ducts; a rare neoplasm in an unusual anatomic location.

Malignant gastrointestinal neuroectodermal tumour (GNET) is a rare, aggressive neoplasm with fewer than 100 cases reported in the literature. Most cases arise in the tubular gastrointestinal tract. We reported a unique case of GNET arising in the extrahepatic bile ducts and reviewed the literature of GNETs. The patient is a female in her mid-30s who presented with painless jaundice and diarrhoea several months after cholecystectomy for biliary dyskinesia. Workup revealed a tumour arising from the peripheral 4B bile ducts involving the left hepatic duct and bifurcation. Histologic examination of the lesion showed a malignant spindled and epithelioid neoplasm which strongly expressed S100 and SOX-10. Neoplastic cells were negative for various cytokeratins and melanoma markers. FISH testing using EWSR1 break-apart probes showed rearrangement of the EWSR1 gene region. The immunohistochemical and molecular findings are consistent with a diagnosis of GNET arising in the extrahepatic bile ducts.

Fatal melanoma with a novel MYO5A-BRAF fusion and small associated conventional nevus: A case report and review of literature.

Kinase fusions play an important role in the pathogenesis of Spitz neoplasms and occasionally non-Spitz neoplasms. We report a case of a 19-year-old woman with a growing nodule on the scalp, morphologically consistent with a diagnosis of melanoma with epithelioid features arising in association with small nevus. This tumor aggressively metastasized and failed to respond to immunotherapy. Next-generation sequencing of a metastatic focus revealed an MYO5A-BRAF kinase fusion with a low mutational burden and fluorescence in situ hybridization (FISH) of the primary melanoma showed similar results. FISH testing of the associated nevus failed because of technical reasons. MYO5A has rarely been reported as the fusion partner with BRAF-rearranged melanocytic tumors. Moreover, this case raises speculations and contributes to the growing literature on the pathogenesis, nomenclature, and tumorigenic pathways in kinase-fusion melanomas. The patient succumbed to disease, which is in concordance with some literature suggesting aggressive behavior of BRAF fusion melanomas with TERT promoter mutations.

Laboratory and Clinical Implications of Incidental and Secondary Germline Findings During Tumor Testing.

CONTEXT.­: Next-generation sequencing is a powerful clinical tool for cancer management but can produce incidental/secondary findings that require special consideration. OBJECTIVE.­: To discuss clinical and laboratory issues related to incidental or secondary germline findings in the clinical setting of tumor testing and inform future guidelines in this area. DESIGN.­: A College of American Pathologists workgroup including representation from the American Society of Clinical Oncology, the Association for Molecular Pathology, and the American College of Medical Genetics and Genomics created a review of items that should be considered when developing guidelines for incidental or secondary findings when performing clinical tumor testing. RESULTS.­: Testing recommendations should be cognizant of the differences among anticipated incidental, unanticipated incidental, and secondary findings, and whether normal tissue is also tested. In addition to defining which variants will be reported, robust recommendations must also take into account test design and validation, reimbursement, cost, infrastructure, impact on reflex testing, and maintenance of proficiency. Care providers need to consider the potential of a test to uncover incidental or secondary findings, the recommendation of upfront counseling, the need for consent, the timing of testing and counseling, and that the exact significance of a finding may not be clear. CONCLUSIONS.­: As clinical oncology testing panels have become a mainstay of clinical cancer care, guidelines addressing the unique aspects of incidental and secondary findings in oncology testing are needed. This paper highlights clinical and laboratory considerations with regard to incidental/secondary findings and is a clarion call to create recommendations.

Klinefelter's Syndrome with Maternal Uniparental Disomy X, Interstitial Xp22.31 Deletion, X-linked Ichthyosis, and Severe Central Nervous System Regression.

We presented in this article a patient with Klinefelter syndrome (KS) (47,XXY) who had maternal nondisjunction and uniparental disomy of the X chromosome with regions of heterodisomy and isodisomy, an interstitial Xp22.31 deletion of both X chromosomes, and other problems. His mother also possesses the same Xp22.31 deletion. The patient presented with status epilepticus and stroke, followed by severe brain atrophy and developmental regression. His unusual clinical and cytogenetic findings apparently have not been reported with either KS or Xp22.31 deletions. Based on the patient's available genetic and biochemical information, we cannot satisfactorily explain his seizures, strokes, or catastrophic brain regression.

A brother and sister with the same karyotype: Case report of two siblings with partial 3p duplication and partial 9p deletion and sex reversal.

Two siblings with the same male unbalanced karyotype demonstrate sex reversal. The older sib appeared phenotypically female and the younger sib demonstrated a male gender. The female had gonadal dysgenesis with bilateral ovatestes. The male had bilateral testes. The report discusses the phenotypical differences and genes associated with sex reversal.

Positive and negative professionalism experiences of genetic counseling students in the United States and Canada.

Many aspects of genetic counseling training programs have been examined over the years. However, no study has explored professional or unprofessional behaviors genetic counseling graduate students experience during their training, and how these behaviors influence satisfaction with their training. This exploratory study examined students' experiences with program leaders, instructors, supervisors, and other trainees. Specific experiences included actions of favoritism, bias, negativity, abuse of power, and examples of positive role modeling. A survey was sent to all members of the National Society of Genetic Counselors and program directors in order to reach graduates of Accreditation Council for Genetic Counseling (ACGC)-accredited programs from 2015-2019 who were eligible to participate. Responses to questions relating to demographics, satisfaction with graduate education, behaviors experienced or seen during graduate school, and reporting of inappropriate behaviors were collected and analyzed. Results demonstrated that 95% of the genetic counseling graduates were highly satisfied with their graduate education and those who experienced inappropriate behaviors during their training were somewhat less satisfied (p = .04). Individuals who felt more prepared by their graduate education were more satisfied with their graduate education (p < .01). Being publicly embarrassed or humiliated, being made to feel like a burden in clinic, or being subjected to negative or offensive behavior based on their personal beliefs or personal characteristics (excluding areas of gender, race/ethnicity, or sexual orientation) were all negatively associated with satisfaction (all p < .04). We conclude that this survey could serve as a "Genetic Counseling Training Experiences Assessment" which could be incorporated into annual evaluations required by the ACGC. Implementation of this assessment would enhance the current evaluations of genetic counseling training programs and provide important information regarding student experiences during their training.

An Adolescent with a Rare De Novo Distal Trisomy 6p and Distal Monosomy 6q Chromosomal Combination.

We report on a 12-year-old female with both a partial duplication and deletion involving chromosome 6. The duplication involves 6p25.3p24.3 (7.585 Mb) while the deletion includes 6q27q27 (6.244 Mb). This chromosomal abnormality is also described as distal trisomy 6p and distal monosomy 6q. The patient has a Chiari II malformation, hydrocephalus, agenesis of the corpus callosum, microcephaly, bilateral renal duplicated collecting system, scoliosis, and myelomeningocele associated with a neurogenic bladder and bladder reflux. Additional features have included seizures, feeding dysfunction, failure to thrive, sleep apnea, global developmental delay, intellectual disability, and absent speech. To our knowledge, our report is just the sixth case in the literature with concomitant distal 6p duplication and distal 6q deletion. Although a majority of chromosomal duplication-deletion cases have resulted from a parental pericentric inversion, the parents of our case have normal chromosomes. This is the first reported de novo case of distal 6p duplication and distal 6q deletion. Alternate explanations for the origin of the patient's chromosome abnormalities include parental gonadal mosaicism, nonallelic homologous recombination, or potentially intrachromosomal transposition of the telomeres of chromosome 6. Nonpaternity was considered but ruled out by whole exome sequencing analysis.

Two Patients with Complex Rearrangements Suggestive of Germline Chromoanagenesis.

Chromoanagenesis, a phenomenon characterized by complex chromosomal rearrangement and reorganization events localized to a limited number of genomic regions, includes the subcategories chromothripsis, chromoanasynthesis, and chromoplexy. Although definitions of these terms are evolving, constitutional chromoanagenesis events have been reported in a limited number of patients with variable phenotypes. We report on 2 cases with complex genomic events characterized by multiple copy number gains and losses confined to a single chromosome region, which are suggestive of constitutional chromoanagenesis. Case 1 is a 43-year-old male with intellectual disability and recently developed generalized tonic-clonic seizures. Chromosomal microarray analysis identified a complex rearrangement involving chromosome region 14q31.1q32.2, consisting of 16 breakpoints ranging in size from 0.2 to 6.2 Mb, with 5 segments of normal copy number present between these alterations. Interestingly, this case represents the oldest known patient with a complex rearrangement indicative of constitutional chromoanagenesis. Case 2 is a 2-year-old female with developmental delay, speech delay, low muscle tone, and seizures. Chromosomal microarray analysis identified a complex rearrangement consisting of 28 breakpoints localized to 18q21.32q23. The size of the copy number alterations ranged from 0.042 to 5.1 Mb, flanked by 12 small segments of normal copy number. These cases add to a growing body of literature demonstrating complex chromosomal rearrangements as a disease mechanism for congenital anomalies.

Rapid quantification of underivatized alloisoleucine and argininosuccinate using mixed-mode chromatography with tandem mass spectrometry.

Plasma elevations of the amino acids alloisoleucine and argininosuccinic acid (ASA) are pathognomonic for maple syrup urine disease and argininosuccinate lyase deficiency, respectively. Reliable detection of these biomarkers is typically achieved using methods with tedious sample preparations or long chromatographic separations, and many published amino acid assays report poor specificity and/or sensitivity for one or both of these compounds. This report describes a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) method that provides rapid quantification of alloisoleucine and ASA in human plasma. The basis of this method is a mixed-mode solid phase separation that achieves baseline resolution of alloisoleucine from isobaric interferents without the use of derivatization or ion pairing agents. The inject-to-inject time is 6 min including elution, column washing and re-equilibration. Validation studies demonstrate excellent limits of quantification (1 µmol/L), linearity (r = 0.999 from 1 to 250 µmol/L), accuracy (bias = -3.8% and -10.1%), and inter-assay imprecision (CV < 8.06%) for plasma analyses. Data from long-term clinical application confirms chromatographic consistency equivalent to more traditional reversed-phase or HILIC based columns. Additional matrix studies indicate low suppression (<10%) for a wide range of amino acids and compatibility with other matrixes such as blood spot analyses. Finally, analysis of our first 257 clinical specimens demonstrates high analytic specificity and sensitivity, allowing the detection of subtle but clinically relevant elevations of alloisoleucine and ASA that may be missed by other less sensitive methods. In conclusion, the novel LC-MS/MS method reported here overcomes a number of the challenges associated with alloisoleucine and ASA quantification. Combining this approach with published incomplete amino acid quantification methods allows, for the first time, a rapid and comprehensive LC-MS/MS analysis of underivatized amino acids without the use of ion pairing agents.

Preanalytics and Precision Pathology: Pathology Practices to Ensure Molecular Integrity of Cancer Patient Biospecimens for Precision Medicine.

Biospecimens acquired during routine medical practice are the primary sources of molecular information about patients and their diseases that underlies precision medicine and translational research. In cancer care, molecular analysis of biospecimens is especially common because it often determines treatment choices and may be used to monitor therapy in real time. However, patient specimens are collected, handled, and processed according to routine clinical procedures during which they are subjected to factors that may alter their molecular quality and composition. Such artefactual alteration may skew data from molecular analyses, render analysis data uninterpretable, or even preclude analysis altogether if the integrity of a specimen is severely compromised. As a result, patient care and safety may be affected, and medical research dependent on patient samples may be compromised. Despite these issues, there is currently no requirement to control or record preanalytical variables in clinical practice with the single exception of breast cancer tissue handled according to the guideline jointly developed by the American Society of Clinical Oncology and College of American Pathologists (CAP) and enforced through the CAP Laboratory Accreditation Program. Recognizing the importance of molecular data derived from patient specimens, the CAP Personalized Healthcare Committee established the Preanalytics for Precision Medicine Project Team to develop a basic set of evidence-based recommendations for key preanalytics for tissue and blood specimens. If used for biospecimens from patients, these preanalytical recommendations would ensure the fitness of those specimens for molecular analysis and help to assure the quality and reliability of the analysis data.

Pretransplant HLA typing revealed loss of heterozygosity in the major histocompatibility complex in a patient with acute myeloid leukemia.

INTRODUCTION: Chromosomal abnormalities are frequent events in hematological malignancies. The degree of HLA compatibility between donor and recipient in hematopoietic stem cell transplantation is critical. PURPOSE OF THE STUDY: In this report, we describe an acute myeloid leukemia case with loss of heterozygosity (LOH) encompassing the entire HLA. MATERIALS AND METHODS: HLA molecular typing was performed on peripheral blood (PB) and buccal swabs (BS). Chromosomal microarray analysis (CMA) was performed using a whole genome platform. RESULTS: Typing results on PB sample collected during blast crisis demonstrated homozygosity at the -A, -B, -C, -DR, and -DQ loci. A BS sample demonstrated heterozygosity at all loci. A subsequent PB sample drawn after count recovery confirmed heterozygosity. The CMA performed on PB samples collected during and after blast crisis revealed a large terminal region of copy-neutral LOH involving chromosome region 6p25.3p21.31, spanning approximately 35.9 Mb. The results of the CMA assay on sample collected after count recovery did not demonstrate LOH. CONCLUSIONS: LOH at the HLA gene locus may significantly influence the donor search resulting in mistakenly choosing homozygous donors. We recommend confirming the HLA typing of recipients with hematological malignancies when homozygosity is detected at any locus by using BS samples, or alternatively from PB when remission is achieved.

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update.

PURPOSE.­: To update key recommendations of the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline. METHODS.­: Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations. RECOMMENDATIONS.­: Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in >10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended workup for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 ( HER2/chromosome enumeration probe 17 [CEP17] ratio ≥2.0; average HER2 copy number <4.0 signals per cell), ISH group 3 ( HER2/CEP17 ratio <2.0; average HER2 copy number ≥6.0 signals per cell), and ISH group 4 ( HER2/CEP17 ratio <2.0; average HER2 copy number ≥4.0 and <6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results.

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update.

Purpose To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline. Methods Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations. Recommendations Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in > 10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended work-up for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 ( HER2/chromosome enumeration probe 17 [CEP17] ratio ≥ 2.0; average HER2 copy number < 4.0 signals per cell), ISH group 3 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 6.0 signals per cell), and ISH group 4 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 4.0 and < 6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results. Find additional information at www.asco.org/breast-cancer-guidelines .

Novel phenotype of 5p13.3-q11.2 duplication resulting from supernumerary marker chromosome 5: implications for management and genetic counseling.

BACKGROUND: Supernumerary marker chromosomes derived from chromosome 5 (SMC5) and 5p13 duplication syndrome are rare disorders, and phenotypic descriptions of patients are necessary to better define genotype-phenotype correlations for accurate, comprehensive genetic counseling. The purpose of this study is to highlight the unique findings of a patient with a 5p13.3-q11.2 duplication arising from a SMC5 and compare and contrast the phenotype with cases in the literature. CASE PRESENTATION: We report on an adult male with a 22 Mb duplication of chromosome 5p13.3-q11.2 resulting from a small SMC5. The patient has a history of prenatal polyhydramnios, dysmorphic features, respiratory issues, talipes equinovarus, hypotonia, developmental delay, and autistic features. The patient also has novel features of aortic dilation, pectus excavatum, kyphoscoliosis, and skin striae, suggestive of a connective tissue disorder. Despite these features he did not meet clinical diagnostic criteria for a well-characterized connective tissue disorder. Additional molecular genetic testing for syndromic and non-syndromic aortic aneurysms was negative. CONCLUSIONS: Many of the patient's features are consistent with individuals reported with 5p13 duplication syndrome and similar cases of SMC5, including polyhydramnios, macrocephaly, dolichocephaly, pre-auricular pits, arachnodactyly, respiratory problems, and developmental delays. It is unclear if the patient's unique features of aortic dilation, pectus excavatum, kyphoscoliosis, and skin striae could be novel features of the SMC5 given its rarity and the few well-phenotyped adults in the literature. This report reviews the literature and provides additional phenotypic information to define the genotype-phenotype correlation of SMC5 and 5p13 duplication syndrome.

Independent Prognostic Significance of Monosomy 17 and Impact of Karyotype Complexity in Monosomal Karyotype/Complex Karyotype Acute Myeloid Leukemia: Results from Four ECOG-ACRIN Prospective Therapeutic Trials.

The presence of a monosomal karyotype (MK+) and/or a complex karyotype (CK+) identifies subcategories of AML with poor prognosis. The prognostic significance of the most common monosomies (monosomy 5, monosomy 7, and monosomy 17) within MK+/CK+AML is not well defined. We analyzed data from 1,592 AML patients age 17-93 years enrolled on ECOG-ACRIN therapeutic trials. The majority of MK+ patients (182/195; 93%) were MK+/CK+ with 87% (158/182) having ≥5 clonal abnormalities (CK≥5). MK+ patients with karyotype complexity ≤4 had a median overall survival (OS) of 0.4y compared to 1.0y for MK- with complexity ≤4 (p<0.001), whereas no OS difference was seen in MK+vs. MK- patients with CK≥5 (p=0.82). Monosomy 5 (93%; 50/54) typically occurred within a highly complex karyotype and had no impact on OS (0.4y; p=0.95). Monosomy 7 demonstrated no impact on OS in patients with CK≥5 (p=0.39) or CK≤4 (p=0.44). Monosomy 17 appeared in 43% (68/158) of CK≥5 patients and demonstrated statistically significant worse OS (0.4y) compared to CK≥5 patients without monosomy 17 (0.5y; p=0.012). Our data suggest that the prognostic impact of MK+is limited to those with less complex karyotypes and that monosomy 17 may independently predict for worse survival in patients with AML.

Signet-ring cell lymphoma: clinicopathologic, immunohistochemical, and fluorescence in situ hybridization studies of 7 cases.

CONTEXT: Signet-ring cell lymphoma (SRCL) is a rare morphologic variant of non-Hodgkin lymphoma. Although it was initially reported as a rare morphologic variant of follicular lymphoma (FL), SRCL has to date been described in most types of non-Hodgkin lymphoma, mostly as single-case reports. OBJECTIVE: To study SRCL systematically by immunohistochemical stains and fluorescent in situ hybridization analyses. DESIGN: Seven SRCL cases were stained for CD3, CD5, CD20, PAX-5, CD10, CD21, CD23, cyclin D1, BCL2, BCL6, Ki-67, and MUM-1, and were analyzed by fluorescent in situ hybridization for BCL2, BCL6, MYC, and MALT1 rearrangements. Clinical information and patient outcome were reviewed in all patients. RESULTS: The patients were 3 women and 3 men, ranging in age from 31 to 75 years (average 60.3 years). The lesions involved lymph nodes, tonsil, parotid gland, soft tissue, and breast. There were 4 FLs, 1 diffuse large B-cell lymphoma (DLBCL), 1 DLBCL with FL, and 1 DLBCL with marginal zone lymphoma. All cases had typical signet-ring cell morphology. They were positive for CD20 and BCL-2, and had low-to-intermediate Ki-67 proliferation index (10%-40%) except in the parotid DLBCL with FL (70%). BCL-6 was detected in all but 1 FL (6/7). Fluorescent in situ hybridization detected IGH/BCL2 translocation in 1 FL, increased BCL6 copy number in another FL, BCL6 rearrangement, and increased copy number of MYC and MALT1 in the DLBCL with marginal zone lymphoma. CONCLUSIONS: The FL with signet-ring cell morphology (1/5) tends to lack IGH/BCL2 translocation, and an extended immunohistochemical study is recommended for correct diagnosis and classification of SRCL.