Rizwan Naeem | Albert Einstein College of Medicine - Yeshiva University (original) (raw)

Papers by Rizwan Naeem

Journal of Cutaneous Pathology, 2015

The histopathologic diagnosis of mycosis fungoides (MF) has classically relied on the presence of... more The histopathologic diagnosis of mycosis fungoides (MF) has classically relied on the presence of atypical epidermotropic T-lymphocytes predominating over spongiosis. However, in some cases of MF, prominent epidermal mucinosis in a spongiosis-like pattern mimics a spongiotic dermatitis. To our knowledge, only one series in the literature has thus far recognized the presence of epidermal mucinosis in MF. We evaluated 30 skin biopsies from 18 patients with the clinical diagnosis of MF, which fulfilled all histopathologic criteria for patch- or plaque-stage MF, but also showed epidermal mucinosis in a spongiosis-like pattern. A total of 15 specimens were studied by immunohistochemistry, and seven were tested for T-cell receptor (TCR) gene rearrangements. Twenty biopsies of spongiotic dermatitides were included as controls. We confirmed the presence of epidermal mucinosis in all 30 cases of MF with a spongiosis-like pattern based on histopathologic criteria and the colloidal iron stain for mucin. Immunohistochemistry in 15 specimens showed significant loss of pan-T-cell antigens CD5 (10/15) and CD7 (14/15); and TCR clonality was detected in 7 specimens from 6 patients, supporting the diagnosis of MF. We report helpful histopathologic criteria for distinguishing MF with epidermal mucinosis in a spongiosis-like pattern from spongiotic dermatitis.

Human Pathology, 2001

The HER-2/neu oncogene encodes a transmembrane receptor with intrinsic tyrosine kinase activity. ... more The HER-2/neu oncogene encodes a transmembrane receptor with intrinsic tyrosine kinase activity. A pilot study was performed to investigate downstream effects of HER-2/neu (or related growth factor receptor) activation by identifying phosphorylated tyrosine. Fifty-four breast carcinomas were evaluated for HER-2/neu overexpression by the HercepTest (Dako, Carpinteria, CA) and the monoclonal CB11 antibody (Ventana, Tucson, AZ). Phosphotyrosine (an indication of tyrosine kinase activity) was detected by an antiphosphotyrosine mouse monoclonal antibody (Upstate Biotechnology, Lake Placid, NY). The gene amplification status was evaluated in 50 of the 54 cases by fluorescence in situ hybridization (FISH) using the Ventana gene probe. The HER-2/neu oncogene amplification was detected in 28% (14 of 50) of cases. Of the 14 cases showing oncogene amplification, tyrosine kinase activity was detected in 9 (64.2%) cases. There was moderate agreement between HER-2/neu gene amplification and tyrosine kinase activity (kappa = 0.43). Immunohistochemical staining of 3+ (with both HercepTest and CB11) showed better agreement with HER-2/neu oncogene amplification and increased tyrosine kinase activity than 2+ immunohistochemical staining. Overall, oncogene amplification and overexpression correlated with increased tyrosine kinase activity, supporting the mechanism of tyrosine kinase activation by HER-2/neu amplification and overexpression. However, 7 cases showing increased tyrosine kinase activity did not show gene amplification or 3+ receptor expression (by either HercepTest or CB11), raising the possibility of other growth factor receptors operating via the tyrosine kinase pathway. There was no apparent correlation between tyrosine kinase activity and hormone receptor status (estrogen or progesterone). Increased tyrosine kinase activity is more commonly associated with higher-grade tumors and thus may correlate with aggressive biologic behavior in breast carcinoma. The results of this pilot study suggest that a larger-scale investigation into downstream activation of tyrosine kinase and correlation to clinical outcome or response to Herceptin therapy may identify subsets of patients whose clinical response or outcome may be predicted by tyrosine kinase activation.

Pediatric Blood & Cancer, 2008

Accurate detection of recurrent chromosomal abnormalities is critical to assign patients to risk-... more Accurate detection of recurrent chromosomal abnormalities is critical to assign patients to risk-based therapeutic regimens for pediatric acute lymphoblastic leukemia (ALL). We investigated the utility of array comparative genomic hybridization (aCGH) for detection of chromosomal abnormalities compared to standard clinical evaluation with karyotype and fluorescent in situ hybridization (FISH). Fifty pediatric ALL diagnostic bone marrows were analyzed by bacterial artificial chromosome (BAC) array and findings compared to standard clinical evaluation. Sensitivity of aCGH was 79% to detect karyotypic findings other than balanced translocations, which cannot be detected by aCGH because they involve no copy number change. aCGH also missed abnormalities occurring in subclones constituting less than 25% of cells. aCGH detected 44 additional abnormalities undetected or misidentified by karyotype with 21 subsequently validated by FISH, including abnormalities in 4 of 10 cases with uninformative cytogenetics. aCGH detected concurrent terminal deletions of both 9p and 20q in three cases, in two of which the 20q deletion was undetected by karyotype. A narrow region of loss at 7p21 was detected in two cases. aCGH detects the majority of karyotypic findings other than balanced translocations, and may provide key prognostic information in the approximately 35% of cases with uninformative cytogenetics.

Journal of Pediatric Hematology/Oncology, 2009

The 8p11 myeloproliferative syndrome is a rare hematologic malignancy derived from a pluripotent ... more The 8p11 myeloproliferative syndrome is a rare hematologic malignancy derived from a pluripotent hematopoietic stem cell associated with rearrangements involving the fibroblast growth factor receptor 1 (FGFR1) gene located on chromosome 8p11. The most common translocation, t(8;13) (p11;q13), results in a ZNF198-FGFR1 fusion gene and constitutively active FGFR1 tyrosine kinase activity. Typical pathologic findings include myeloid hyperplasia, lymphadenopathy, precursor T-lymphoblastic lymphoma, and eosinophilia. The disease is usually associated with an aggressive course and progression to acute myeloid leukemia is frequent. We report here the first case of 8p11 myeloproliferative syndrome in an infant and demonstrate the value of molecular testing in the diagnosis and minimal disease monitoring of this rare disease.

JNCI Journal of the National Cancer Institute, 2008

Journal of Cutaneous Pathology, 2008

A 7-year-old girl presented with pain and progressive swelling on the left plantar surface. Biops... more 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.

Journal of Cutaneous Pathology, 2013

Patients with hypopigmented mycosis fungoides (HMF) present at a younger age than those with clas... more Patients with hypopigmented mycosis fungoides (HMF) present at a younger age than those with classic MF. Our goal was to describe the clinical presentation, histopathologic features and long-term outcome in patients who developed HMF before the age of 21. It was observed that among 69 pediatric patients diagnosed with MF between 1992 and 2010, 50 had HMF. Thirty-five patients had clinical follow-up. There were 37 males and 32 females with a mean age of 13.6 years. Most patients were African American or Hispanic and presented with multiple hypopigmented patches. All biopsies showed epidermotropism of T-lymphocytes, whereas fibroplasia and lichenoid infiltrate were variable. All specimens tested were CD8+. Treatment modalities included topical steroids, narrow band ultraviolet B and psoralen and ultraviolet A. HMF patients were followed for &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1-12 years. Most children responded to treatment, but recurrence rates were high. One patient progressed to plaque/tumor stage. Others did not progress; however, many were lost to follow-up. We present a large cohort of children with HMF and report on the features of disease and progression. A major difference in histology of HMF was lack of fibroplasia and lichenoid infiltrate, probably because of presentation in the early patch stage. Most patients have a waxing-and-waning course and relapse after discontinuation of therapy, requiring repetitive treatment.

Cancer is a genetic disease that could develop either from a predisposing mutation followed by ac... more Cancer is a genetic disease that could develop either from a predisposing mutation followed by acquired somatic mutations or from an accumulation of somatic mutations that develop into a cancer phenotype. Many different types of DNA alteration have been reported in cancer, with some of the recognized forms being as follows: • Subtle DNA or RNA alterations • DNA methylation • Changes in chromosome number (aneuploidy) • Loss of heterozygosity • Chromosome translocations in somatic cells rather than in germ cells • Gene amplification • Incorporation of exogenous sequences

Genes, Chromosomes and Cancer, 2009

We report a novel translocation t(17;19)(q22;q13.32) found in 100% of blast cells from a pediatri... more We report a novel translocation t(17;19)(q22;q13.32) found in 100% of blast cells from a pediatric acute myeloid leukemia (AML) patient. Fluorescence in situ hybridization and vectorette polymerase chain reaction were used to precisely map the chromosomal breakpoint located on the derivative chromosome 17 at 352 bp 5′ of MPO, encoding myeloperoxidase a highly expressed protein in myeloid cells, and 2,085 bp 5′ of ZNF342 on 19q, encoding a transcription factor expressed in human stem cells and previously implicated in mouse models of leukemia. Analysis of RNA levels from the patient sample revealed significant overexpression of ZNF342, potentially contributing to AML formation. This is the first report of a translocation in myeloid leukemia occurring only in the promoter/enhancer regions of the two genes involved, similar to translocations commonly found in lymphoid malignancies. Analysis of ZNF342 protein levels in a large dataset of leukemia samples by reverse phase protein array showed that higher levels of ZNF342 expression in acute lymphoblastic leukemia was associated with poorer outcome (P = 0.033). In the myeloid leukemia samples with the highest ZNF342 expression, there was overrepresentation of FLT3 internal tandem duplication (P = 0.0016) and AML subtype M7 (P = 0.0002). Thus, overexpression of ZNF342 by translocation or other mechanisms contributes to leukemia biology in multiple hematopoietic compartments.

Genes, Chromosomes and Cancer, 2007

Studying the molecular basis of familial renal cell carcinoma (RCC) has allowed identification of... more Studying the molecular basis of familial renal cell carcinoma (RCC) has allowed identification of novel RCC genes involved in the pathogenesis of both inherited and sporadic RCC. We describe a constitutional balanced t(3;8)(p14;q24.1) translocation found in a brother and sister with bilateral clear cell RCC (CC-RCC) diagnosed in their forties. Consistent with a prior report, we demonstrated by RT-PCR of RNA from lymphoblastoid cells fusion mRNAs derived from the fragile histidine triad (FHIT) at 3p14 and TRC8 at 8q24.1 in both affected siblings. Cytogenetic analysis of a CC-RCC tumor from the affected sister from short-term tumor cell culture showed both diploid and pseudotetraploid populations containing the translocation and normal appearing chromosomes 3 and 8. Fluorescent in situ hybridization using bacterial artificial chromosomes containing sequences from the FHIT and TRC8 genes demonstrated normal FHIT signals and TRC8 signals on nontranslocated chromosomes in the constitutional blood sample, but the TRC8 signal was absent in a subset of diploid and pseudotetraploid cells from the tumor. The tumor also contained a heterozygous VHL frameshift somatic mutation. These results confirm that balanced translocations disrupting the TRC8 and FHIT genes result in an increased genetic susceptibility for bilateral CC-RCC. The presence of diploid and tetraploid tumor cells with and without TRC8 deletions on the nontranslocated chromosome suggest that loss of the remaining normal allele of TRC8 may contribute to tumor development at later stages.

Genes, Chromosomes and Cancer, 1995

An unusual hematologic neoplasia has been described recently in which the predominant clinical fe... more An unusual hematologic neoplasia has been described recently in which the predominant clinical features include T-cell lymphoma, myeloid hyperplasia, and eosinophilia. The multilineage involvement in this disorder suggests transformation of a primitive stem cell. Abnormal karyotypes have been described in three such cases, including one case with t(8;13)(p11.2;q12) and a second case with t(8;13)(p23;q14). We report translocation of chromosomes 8 and 13 in lymph node karyotypes from two patients with this syndrome. Fluorescence in situ hybridization confirmed an identical translocation, t(8;13)(p11;q11-12), in lymphoma cells from each patient. The translocation breakpoints are of particular interest because the FLT3 receptor tyrosine kinase gene has been mapped 13q12. FLT3 is expressed highly in hematopoietic progenitor cells and in myeloid and lymphoid acute leukemias.

Cell, 2005

Fibroblasts often constitute the majority of the stromal cells within a breast carcinoma, yet the... more Fibroblasts often constitute the majority of the stromal cells within a breast carcinoma, yet the functional contributions of these cells to tumorigenesis are poorly understood. Using a coimplantation tumor xenograft model, we demonstrate that carcinoma-associated fibroblasts (CAFs) extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammary fibroblasts derived from the same patients. The CAFs, which exhibit the traits of myofibroblasts, play a central role in promoting the growth of tumor cells through their ability to secrete stromal cell-derived factor 1 (SDF-1); CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1.

Cancer Research, 2004

Loss of heterozygosity (LOH) occurs commonly in cancers causing disruption of tumor suppressor ge... more Loss of heterozygosity (LOH) occurs commonly in cancers causing disruption of tumor suppressor genes and promoting tumor progression. BALB/c-Trp53 ؉/؊ mice are a model of Li-Fraumeni syndrome, exhibiting a high frequency of mammary tumors and other tumor types seen in patients. However, the frequency of mammary tumors and LOH differs among strains of Trp53 ؉/؊ mice, with mammary tumors occurring only on a BALB/c genetic background and showing a high frequency of LOH, whereas Trp53 ؉/؊ mice on a 129/Sv or (C57BL/6 ؋ 129/Sv) mixed background have a very low frequency of mammary tumors and show LOH for Trp53 in only ϳ50% of tumors. We have performed studies on tumors from Trp53 ؉/؊ mice of several genetic backgrounds to examine the mechanism of LOH in BALB/c-Trp53 ؉/؊ mammary tumors. By Southern blotting, 96% (24 of 25) of BALB/c-Trp53 ؉/؊ mammary tumors displayed LOH for Trp53. Karyotype analysis indicated that cells lacking one copy of chromosome 11 were present in all five mammary tumors analyzed but were not always the dominant population. Comparative genomic hybridization analysis of these five tumors indicated either loss or retention of the entire chromosome 11. Thus chromosome loss or deletions within chromosome 11 do not account for the LOH observed by Southern blotting. Simple sequence length polymorphism analysis of (C57BL/ 6 ؋ BALB/c) F1-Trp53 ؉/؊ mammary tumors showed that LOH occurred over multiple loci and that a combination of maternal and paternal alleles were retained, indicating that mitotic recombination is the most likely mechanism of LOH. Nonmammary tumors of BALB/c mice also showed a high frequency of LOH (22 of 26, 85%) indicating it was not a mammary tumor specific phenomenon but rather a feature of the BALB/c strain. In (C57BL/6 ؋ BALB/c) F1-Trp53 ؉/؊ mice LOH was observed in 93% (13 of 14) of tumors, indicating that the high frequency of LOH was a dominant genetic trait. Thus the high frequency of LOH for Trp53 in BALB/c-Trp53 ؉/؊ mammary tumors occurs via mitotic recombination and is a dominant genetic trait that associates with the occurrence of mammary tumors in (C57BL/6 ؋ BALB/c) F1-Trp53 ؉/؊ mice. These results further implicate double-strand DNA break repair machinery as important contributors to mammary tumorigenesis.

Cancer Research, 2007

Proper chromosome segregation in eukaryotes is driven by a complex superstructure called the mito... more Proper chromosome segregation in eukaryotes is driven by a complex superstructure called the mitotic spindle. Assembly, maintenance, and function of the spindle depend on centrosome migration, organization of microtubule arrays, and force generation by microtubule motors. Spindle pole migration and elongation are controlled by the unique balance of forces generated by antagonistic molecular motors that act upon microtubules of the mitotic spindle. Defects in components of this complex structure have been shown to lead to chromosome missegregation and genomic instability. Here, we show that overexpression of Eg5, a member of the Bim-C class of kinesin-related proteins, leads to disruption of normal spindle development, as we observe both monopolar and multipolar spindles in Eg5 transgenic mice. Our findings show that perturbation of the mitotic spindle leads to chromosomal missegregation and the accumulation of tetraploid cells. Aging of these mice revealed a higher incidence of tumor formation with a mixed array of tumor types appearing in mice ages 3 to 30 months with the mean age of 20 months. Analysis of the tumors revealed widespread aneuploidy and genetic instability, both hallmarks of nearly all solid tumors. Together with previous findings, our results indicate that Eg5 overexpression disrupts the unique balance of forces associated with normal spindle assembly and function, and thereby leads to the development of spindle defects, genetic instability, and tumors.

Cancer Genetics and Cytogenetics, 1995

Cytogenetic analyses of short-term cultures revealed clonal chromosome aberrations in 6 of 13 des... more Cytogenetic analyses of short-term cultures revealed clonal chromosome aberrations in 6 of 13 desmoid tumors. These aberrations included two consistent events, trisomy 8 (n = 4) and trisomy 20 (n = 3), which have not been reported previously in desmoid tumors. Because trisomy 8 was found in two recurrent desmoid tumors, we used fluorescent in situ hybridization (FISH) methodology to evaluate chromosome 8 in 25 paraffin-embedded and frozen desmoid specimens. The FISH studies demonstrated that both patients with cytogenetic trisomy 8 at the time of recurrence also had had trisomy 8 in primary tumors 4 years earlier. The proportion of trisomy 8 cells in these cases did not change substantially between original diagnosis and recurrence. The FISH studies also revealed trisomy 8 in one recurrent desmoid tumor which had been cytogenetically unremarkable and revealed trisomy 8 in one recurrent desmoid that had not been karyotyped. Four of six patients with trisomy 8 had been followed for more than 1 year, and the desmoid tumors in each of these 4 patients recurred. By contrast, recurrence was noted in only 2 of 17 patients whose desmoid tumors lacked trisomy 8. Our findings demonstrate that trisomy 8 and trisomy 20 are nonrandom aberrations in desmoid tumors. Trisomy 8 appears to be associated with an increased risk of recurrence. From the Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School (J. A. E, R. N., S. X., J. P. C.): and the Divisions of Pediatric Ontology, Dana-Farber Cancer Institute (J. A. I':), and Hematolagy-Oncology,

Cancer Genetics and Cytogenetics, 2007

Translocations involving the mixed-lineage leukemia gene (MLL) confer a poor prognosis in acute l... more Translocations involving the mixed-lineage leukemia gene (MLL) confer a poor prognosis in acute leukemias. In t(1;11)(q21;q23), MLL is fused reciprocally with AF1q. Here we describe a t(1;11) (q21;q23) with a secondary event involving insertion of the telomeric portion of MLL into the p arm of chromosome 11 (11p11). We show that this latter event interrupts the CUG triplet repeat binding protein-1 (CUGBP1) gene, a translational enhancer of C/EBPβ. We then showed that these cells have reduced expression of CUGBP1 and C/EBPβ when compared to other AML blasts. This is the first report to describe insertional disruption of the CUGBP1 gene and to suggest a role for the CUGBP1-C/EBPβ pathway in leukemogenesis.

Biology of Blood and Marrow Transplantation, 2007

Several chromosomal abnormalities detected by conventional cytogenetic analysis have an adverse i... more Several chromosomal abnormalities detected by conventional cytogenetic analysis have an adverse impact on the outcome in myeloma patients. A wide spectrum of abnormalities involving chromosomes 1, 13, 14, and 17 has been described. We analyzed the outcome of 83 patients with clonal cytogenetic abnormalities, who underwent high-dose therapy and autologous stem cell transplantation for multiple myeloma at our institution. Clonal abnormalities were detected at diagnosis by conventional cytogenetic analysis in 83 patients. Patients underwent a single autologous transplant between April 2000 and May 2005. Preparative regimen was high-dose melphalan alone (73), or a combination of topotecan, melphalan, and cyclophosphamide (TMC ‫؍‬ 10). The most commonly observed chromosomal abnormalities were deletion of chromosome 13 (32%), hyperdiploidy (21%), deletion of chromosome 1p (18%), and t (11; 14) in 7% patients. Median follow-up among surviving patients was 25.5 months. Median interval from diagnosis to autotransplant was 7.7 months (range: 2.5-52). Median progression-free survival (PFS) for the entire group was 19 months and the median overall survival (OS) was 52 months. On univariate analysis, both PFS and OS were significantly shorter in patients with deletion 1p (P ‫؍‬ .001 and <.0001, respectively). Thirty-two patients whose cytogenetic abnormalities returned to normal prior to autotransplant had longer PFS and OS than patients with persistent abnormalities (P ‫؍‬ .02 and .08, respectively). Deletion 1p is associated with a significantly shorter remission and survival in patients undergoing high-dose therapy and a single autologous transplant for myeloma.

American Journal of Reproductive Immunology, 2004

Cytogenetic evaluation of product of conception (POC) is essential to determine the cause of preg... more Cytogenetic evaluation of product of conception (POC) is essential to determine the cause of pregnancy loss and aid the prenatal diagnosis of subsequent pregnancies. The purpose of this study is twofold. (1) To profile cytogenetic abnormalities, their relationship with maternal and gestational age and analyze sex ratios in our case series of 2052 consecutive samples of POC referred to the Baystate Medical Center, Laboratory Genetics between January 1992 and January 1999. (2) To present a comprehensive review of such data published in the last 15 years, in order to study temporal differences in the above parameters and make this information readily available for cytogeneticists and genetic counselors. Data was entered and analyzed in Epi Info version 6.0 using the Z-test, chi-square test of significance and linear correlation coefficient. The profile of cytogenetic abnormalities detected in POC has not changes significantly over time. The mean maternal age in our study (overall and for trisomies) was higher than that reported previously, which is consistent with the noted trend of increasing age at pregnancy in recent years. Our study provides evidence that abnormal karyotypes are aborted earlier and that tetraploidies have the least survival amongst all abnormalities. The higher mean gestational age for trisomic abortions in our study, as compared with previously reported figures, can be attributed to the increasing practice of active maternal screening with subsequent therapeutic abortions. Analysis of sex ratios may reaffirm a female specific developmental disadvantage in early stages of pregnancy.

American Journal of Medical Genetics Part A, 2005