Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity?

Post-transplant lymphoproliferative disorders (PTLDs) are usually but not invariably associated with Epstein-Barr virus (EBV). The reported incidence, however, of EBV-negative PTLDs varies widely, and it is uncertain whether they should be considered analogous to EBV-positive PTLDs and whether they have any distinctive features. Therefore, the EBV status of 133 PTLDs from 80 patients was determined using EBV-encoded small ribonucleic acid (EBER) in situ hybridization stains with or without Southern blot EBV terminal repeat analysis. The morphologic, immunophenotypic, genotypic, and clinical features of the EBV-negative PTLDs were reviewed, and selected features were compared with EBV-positive cases. Twenty-one percent of patients had at least one EBV-negative PTLD (14% of biopsies). The initial EBV-negative PTLDs occurred a median of 50 months post-transplantation compared with 10 months for EBV-positive cases. Although only 2% of PTLDs from before 1991 were EBV negative, 23% of subsequent PTLDs were EBV negative (p <0.001). Of the EBV-negative PTLDs, 67% were of monomorphic type (M-PTLD) compared with 42% of EBV-positive cases (p <0.05). The other EBV-negative PTLDs were of infectious mononucleosis-like, plasma cell-rich (n = 2), small B-cell lymphoid neoplasm, large granular lymphocyte disorder (n = 4) and polymorphic (P) types. B-cell clonality was established in 14 specimens and T-cell clonality was established in three (two patients). None of the remaining specimens were studied with Southern blot analysis and some had no ancillary studies. Rearrangement of c-MYC was identified in two M-PTLDs with small noncleaved-like features, and rearrangement of BCL-2 was found in one large noncleaved-like M-PTLD. Ten patients were alive at 3 to 63 months (only three patients received chemotherapy). Seven patients, all with M-PTLDs, are dead at 0.3 to 6 months. Therefore, EBV-negative PTLDs have distinct features, but some do respond to decreased immunosuppression, similar to EBV-positive cases, suggesting that EBV positivity should not be an absolute criterion for the diagnosis of a PTLD.     

A recent decrease in the time to development of monomorphous and polymorphous posttransplant lymphoproliferative disorder.

We have noted a decrease in the time to development of posttransplant lymphoproliferative disorder (PTLD) over the last two and one-half years in our multiorgan transplant program. From February 1965 until December 1990, 1622 transplants were performed including 1489 kidneys (KTxp), 87 livers (LTxp), and 46 pancreata. Between February 1965 and July 1988 (group 1), there were 1260 transplants performed and nine cases of either monomorphous PTLD (M-PTLD, n = 8) or polymorphous PTLD (P-PTLD, n = 1) were diagnosed. The mean time to development of PTLD was 163 +/- 128 weeks, all after KTxp. Five of these nine patients received haploidentical living-related grafts. All patients had presented with advanced disease, none had transplant nephrectomy, and all died of their disease. Between July 1988 and December 1990 (group 2), 362 transplants were performed, and four cases of M-PTLD and three cases of P-PTLD were recognized. Of the seven cases of PTLD in group 2, six developed within 90 days posttransplant (early PTLD). The mean time to development of PTLD was 11 +/- 16 weeks. This was significantly earlier than group 1 (P less than .01). Four of the five cases after KTxp had a 1 or 2 DR-matched donor. Five of these seven patients had serological evidence of recent Epstein-Barr Virus infection, and four of these five had received OKT3 and then developed early PTLD. In group 2, three patients are alive 7-15 months after KTxp nephrectomy, the remaining four have died. We hypothesize that risk factors for the development of PTLD may include heavy immunosuppression, including the use of OKT3, good DR matching, and active EBV infection. Treatment should include graft removal, if applicable, and reduction or cessation of immuno-suppression.     

Molecular cytogenetic analysis of head and neck squamous cell carcinoma: By comparative genomic hybridization,spectral karyotyping,and expression array analysis

BACKGROUND: A combination of molecular cytogenetic and expression array analysis has been performed on head and neck squamous cell carcinoma (HNSCC) of the oral cavity and supraglottis. These studies were performed to identify consensus regions of chromosomal imbalance and structural rearrangement to determine whether genes located in these genomic regions are subject to alterations in gene expression. Such combinatorial studies may help to identify recurrent patterns of altered gene expression in the context of specific chromosomal changes. METHODS: Comparative genomic hybridization (CGH) was used to identify net genomic imbalances and spectral karyotyping (SKY) to visualize the numerical and structural chromosomal changes in metaphase preparations. Expression microarray analysis of HNSCC cell lines and primary tongue tumors was also performed to identify genes that were commonly overexpressed or underexpressed compared with adjacent normal tissue. RESULTS: CGH detected gains at 3q (64%), 8q (45%) and 6q22-qter (45%) and losses at 18q22-qter (27%). SKY analysis of seven cell lines identified frequent structural rearrangement of the following chromosomal regions: 3q, 5p13-q11.2, 5q32-q34, 7p12-q11.2, 8p12-q12, 9p, 10p, 13p13-q12, 14q11.1-q11.2, 15p13-q11.2, 16p11.1-q11.1, 18q22-q23, and 22p13-q11.2. Consistent deregulation of interleukin 8, integrin alpha-6, c-MYC, epithelial discoidin domain receptor 1, and sterol regulatory element binding protein were apparent by expression analysis. Interestingly, some of these genes map to regions of genomic imbalance and chromosomal rearrangement as determined by our molecular cytogenetic analysis. CONCLUSIONS: In this small study, a combinatorial analysis using SKY, CGH, and microarray provides a model linking the changes in gene expression to changes in chromosomal dosage and structure. This approach has identified a subset of genetic changes that provide new opportunities for investigating the genetic basis of tumorigenesis in HNSCC.     

Chromosomal changes in incidental prostatic carcinomas detected by comparative genomic hybridization

OBJECTIVES: The genetic changes underlying the development and progression of prostate cancer are poorly understood. To identify chromosomal regions in incidental prostatic carcinoma (T1a and T1b) was the primary aim of this study. MATERIALS AND METHODS: We used comparative genomic hybridization (CGH) to search for DNA sequence copy number changes on a series of 48 T1 prostate cancer diagnosed by transurethral resection (TURP) and by adenomectomy. Incidental prostatic carcinomas have not been studied by CGH previously. RESULTS: CGH analysis indicated that 14 cases (29.2%) of incidental prostatic carcinoma showed chromosome alterations. The most frequent alterations were chromosomal losses of 8p (10.4%), 13q (6.3%), 5q (4.2%) and 18q (4.2%), and gains of 17p (10.4%), 17q (10.4%), 9q (6.3%) and 7q (4.2%). Minimal overlapping chromosomal regions of loss, indicative for the presence of tumor suppressor genes (TSGs), were mapped to 8p22 and 13q14.1-q21.3, and minimal overlapping regions of gain, indicative for the presence of oncogenes, were found at 9q34.2-qter, 17p12 and 17q24-qter. The statistical analysis displayed a significant association between chromosomal aberration detected by CGH and high Gleason score (P < 0.005) as well as between tumor categories T1a and T1b and chromosomal imbalance (P = 0.041). CONCLUSIONS: Studies directed at incidental prostatic carcinomas allow discovery of chromosomal changes in small and highly malignant tumors. Our results suggest that loss or gain of DNA in these regions are important in prostate cancer. This is the first study, which documents the spectrum of chromosomal changes in incidental prostatic carcinomas.     

Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific immunosuppressive drug or by the transplantation per se?

BACKGROUND: An association between posttransplant lymphoproliferative disorder (PTLD) and cyclosporine A (CsA) and OKT3 has often been postulated on the basis of retrospective studies, although a randomized study with PTLD as the endpoint will probably never be performed. Because focus on PTLD coincided with the use of these drugs, a bias could be suspected. METHODS: In a retrospective, nonrandomized study, we reevaluated all lymphoma-like lesions arising in kidney-transplant patients grafted at our center during 1969 to 1998 and observed up to 2002. Case pathology was reviewed, and an association with Epstein-Barr virus (EBV) infection (and latency pattern) was assessed. RESULTS: We did not find any significant difference in the incidence of PTLDs when comparing the prednisolone/azathioprine, and CsA eras (P=0.89), the periods before or after OKT3 (P=0.61), and those before or after antilymphocyte globulin (ALG) (P=0.22). Occurrence time was shorter in the CsA (P=0.059), OKT3 (P=0.007), and ALG (P=0.007) eras. In the OKT3 era, 182 patients received, and 224 did not receive, OKT3; after the same observation time, there had been eight and five PTLDs, respectively (P=0.34). The use of mycophenolate mofetil (MMF) was associated with a reduction in the number of PTLDs (P=0.01). EBV was detected in 16 of 21 (76%) cases. CONCLUSIONS: We found no evidence to implicate any one drug regime preferentially in the development of PTLDs. The risk of developing PTLD seems to be a result of the whole transplantation process, which includes the antigenicity of the foreign graft, the immunosuppression resulting in inadequate cytotoxic T-cell activity, and the result of EBV infection. An important minority of cases are EBV negative.     

Genetic abnormalities associated with nodal metastasis in head and neck cancer

BACKGROUND: Lymphatic metastasis represents the single most important clinical prognostic factor in head and neck squamous cell carcinoma (HNSCC), but underlying genetic mechanisms remain ill defined. Genetic differences between primary carcinomas and their corresponding metastases might form a key to understanding the metastatic phenotype. In this study we aimed to characterize such differences using a genome-wide screening measure. METHODS: Four human cell lines (MDA-686tu, MDA-686Ln, MDA-1386tu, MDA-1386Ln) derived from primary tumor and synchronous lymph node metastasis of two cases of metastatic HNSCC were subjected to comparative genomic hybridization (CGH) by differentially labeling DNA from tumor tissue and normal tissue with fluorescent agents. The labeled DNAs were simultaneously hybridized onto normal metaphase chromosomes. In addition, modified CGH was performed by directly hybridizing labeled primary tumor DNA against differentially labeled metastatic tumor DNA, allowing the direct detection of copy number differences in individual pairs. Image analysis for fluorescence intensity along the entire length of each metaphase chromosome allowed generation of a color ratio, which was used to detect copy number changes. RESULTS: In both cases, significant overlap was found between chromosomal aberrations present in the primary tumor and the corresponding nodal metastasis. However, several abnormalities differentiated primary tumors from their metastases. Modified CGH identified several genetic aberrations that were not detectable with the conventional CGH analysis. Gains at chromosomes 10p11-12 and 11p and deletions at chromosomes 4q22-31, 9p13-24, and 14q differentiated nodal metastases from the corresponding primary tumors in both cases. CONCLUSIONS: The combination of conventional and modified CGH analyses facilitates the identification of DNA copy number changes that might be involved in the development of a metastatic phenotype. Future research should aim at the identification of the genes involved at the identified sites of chromosomal aberration.     

Discovery of new DNA amplification loci in prostate cancer by comparative genomic hybridization

BACKGROUND: DNA sequence amplifications are involved in the progression of many tumor types, and have also been found in advanced prostate cancer. The aim of this study was to detect new loci of DNA amplifications in prostate cancer. METHODS: Comparative genomic hybridization (CGH) was used for whole genome screening of DNA sequence copy number alterations in 27 advanced prostate cancers. RESULTS: The most prevalent changes were losses of 8p, 13q (52%, each), 6q (48%), 18q (37%), 5q (30%), 2q, 4q and 16q (26%, each), and gains of 8q (48%), Xq (40%), and Xp (26%). In addition, 16 high-level amplifications were found. These included Xq12 (five), 8q24 (two), and 11q13 (one) with known putative target genes (androgen receptor, MYC and Cyclin D1), and 1q21-25 (three), 10q22 (two), 17q23-24 (two), and 8q21 (one) where the target genes remain unknown. CONCLUSIONS: High-level amplifications at different chromosomal sites occur in advanced prostate cancer. The detection of amplified chromosomal regions may serve as a starting point to discover novel oncogenes involved in prostate cancer progression.     

Genetic changes in pT2 and pT3 prostate cancer detected by comparative genomic hybridization

Prostate-specific antigen (PSA) screening has led to a remarkable increase in prostate cancer cases undergoing operative therapy. Over half of patients with locally advanced cancer (>or=pT3) develop rising PSA levels (biochemical failure) within 10 years. It is very difficult to predict which patients will progress rapidly to advanced disease following biochemical failure (BF). Therefore, a more useful prognostic factor is needed to suggest the most appropriate therapies for each patient. To determine chromosomal aberrations, we examined 30 patients with stage pT2 or pT3 primary prostate adenocarcinomas and no metastases (pN0M0) by comparative genomic hybridization (CGH). Laser capture microdissection (LCM) was used to gather cancer cells from frozen prostate specimens. Common chromosomal alterations included losses on 2q23-24, 4q26-28, 6q14-22, 8p12-22 and 13q21-31, as well as gains on 1p32-36, 6p21 and 17q21-22. Losses at 8p12-22 and 13q21-31 were observed more frequently in pT3 than pT2 tumors (P<0.05 and P<0.01, respectively). Losses at 8p12-22 were more frequent in tumors with BF (P<0.05), and those at 13q12-21 were more frequent in tumors with Gleason score (GS) 7 or more than lower GS (P<0.05). These findings suggest that losses of 8p12-22 and 13q21-31 are important determinants of prostate cancer progression.     

Screening for genetic aberrations in papillary thyroid cancer by using comparative genomic hybridization

BACKGROUND: Determination of the genetic composition of papillary thyroid cancers may help explain differences in observed clinical behavior. Comparative genomic hybridization (CGH) is a novel molecular cytogenetic assay that allows simultaneous detection of gains, losses, and amplification of genetic information, making it an ideal screening tool. The aim of this study was to identify genetic aberrations occurring in papillary thyroid cancers by using CGH analysis. METHODS: CGH analysis was performed on 21 individual cases of papillary thyroid cancers. Nonparametric statistical comparisons were performed with the Fisher exact test. RESULTS: Genetic abnormalities were identified by CGH in 10 of 21 cases (48%). A recurrent pattern of aberrations was seen in cases where genetic changes were detected, involving losses at chromosome arms 1p and 9q and chromosomes 17, 19, and 22, and gains at chromosome 4 and chromosome arms 5q, 6q, 9q, and 13q. The loss of chromosome 22 was unique to younger patients (P =.05) and was associated with a higher rate of regional lymphatic metastasis (19% vs 80%, P =.02). CONCLUSIONS: Two genetically unique groups of patients were identified by using CGH analysis. One group had no detectable aberrations; the other had a recurrent pattern of aberrations, localizing to the identical chromosomal loci. This pattern of aberrations suggests that the involved loci may contain genes important in thyroid carcinogenesis. The clinical significance of the presence of copy number changes detected by CGH needs to be determined. In addition, molecular cloning of involved genes in each of the aberrations is warranted.     

T-cell posttransplant lymphoproliferative disorder occurring in a pediatric solid-organ transplant patient

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication seen in transplant patients as a consequence of immunosuppressant therapy. Most cases are of B-cell origin and are commonly associated with Epstein-Barr virus (EBV) infection. T-cell PTLDs are rare and only 13 pediatric T-cell PTLDs with clinicopathologic correlation have been reported previously. We present the histologic, immunophenotypic, and molecular features of a monomorphic PTLD (T-cell lymphoma) identified in a pediatric patient following orthotopic liver transplantation. The lymphoma was identified in the ileum, rectum, and mesenteric lymph nodes. In situ hybridization revealed numerous EBER-1-positive tumor cells. A current review of the literature is also discussed. Of the 14 cases of pediatric T-cell PTLD reported in the literature, only 3 (21.4%) are described as being EBV positive. Most of the reported PTLDs are monoclonal, with 9 of 11 cases (82%) showing a clonal T-cell population by gene rearrangement studies. T-cell PTLD cases appear to have a poor prognosis (11 of 14 patients died of the disease), although patients with involvement of specific anatomic sites may have a better outcome.     

Molecular cytogenetic aberrations in autosomal dominant polycystic kidney disease tissue

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder characterized by focal cyst formation from any part of the nephron. The molecular bases include germinal mutation of either PKD1 or PKD2 genes, enhanced expression of several protooncogenes, alteration of the TGF-alpha/EGF/EGF receptor (EGFR) axis, and disturbed regulation of proliferative/apoptosis pathways. To identify new locations of ADPKD related oncogenes and/or tumor suppressor genes (TSG), comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses were performed for a series of individual cysts (n = 24) from eight polycystic kidneys. By CGH, imbalances were detected predominantly on chromosomes 1p, 9q, 16p, 19, and 22q in all tissues. DNA copy number gain was seen on chromosomes 3q and 4q in five samples. The CGH data were supplemented by LOH analysis using 83 polymorphic microsatellite markers distributed along chromosomes 1, 9, 16, 19, and 22. The highest frequency of LOH was found on the 1p35-36 and 16p13.3 segments in cysts from seven samples. Allelic losses on 9q were detected in six, whereas deletions at 19p13 and 22q11 bands were observed in three polycystic kidneys. These results indicate that the deleted chromosomal regions may contain genes important in ADPKD initiation and progression.     

Associations between EBV serostatus and organ transplant type in PTLD risk: an analysis of the SRTR National Registry Data in the United States

In a prior multiorgan transplant database study, recipient Epstein-Barr virus (EBV) seronegativity was not associated with increased risk for posttransplant lymphoproliferative disorders (PTLD) in liver transplants (LTX), at variance with prior single center reports and with data from kidney and heart transplants (KTX and HTX). The Scientific Registry of Transplant Recipients (SRTR) in the United States is the only other registry with data on the required variables for comparison.Our study set comprised 112 756 KTX (580 PTLDs; 0.51%), 13 937 HTX (140 PTLDs; 1.0%) and 40 437 LTX (383 PTLDs; 0.95%) performed January 2003 onward. The unadjusted hazard ratio (HR) for PTLD if recipient EBV seronegative was 5.005 for KTX, 6.528 for HTX and 2.615 for LTX (p < 0.001 for all). In models adjusted for multiple covariates, the adjusted HR was 3.583 (p < 0.001) for KTX, 4.037 (p < 0.001) for HTX, 1.479 (p = 0.03) for LTX. Interaction models using EBV seropositive KTX as reference group showed significantly higher risk for all other EBV seronegative organ transplant groups and also for EBV seropositive LTX (AHR 2.053, p < 0.0001).Recipient EBV seronegativity is still significantly associated with risk for PTLD in LTX, though less so because of higher baseline risk in the EBV seropositive LTX group.     

Post‐transplant lymphoproliferative disorder following kidney transplantation: a population‐based cohort study

Post‐transplant lymphoproliferative disorder (PTLD) incidence is difficult to determine, mainly because both early and other lesions may go unrecognized and unregistered. Few studies have included systematic pathology review to maximize case identification and decide more accurately PTLD frequency after long‐term post‐transplantation follow‐up. A retrospective population‐based cohort study including all kidney transplant recipients at two Danish centres (1990–2011; population covered 3.1 million; 2175 transplantations in 1906 patients). Pathology reports were reviewed for all patient biopsies to identify possible PTLDs. Candidate PTLDs underwent histopathological review and classification. Seventy PTLD cases were identified in 2175 transplantations (3.2%). The incidence rate (IR) after first transplantation was 5.4 cases per 1000 patient‐years (95% CI: 4.0–7.3). Most PTLDs were monomorphic (58.5%), or early lesions (21.5%). Excluding early lesions and patients <18 years, IR was 3.7 (95% CI: 2.9–5.5). Ten patients with PTLD were retransplanted, 2 developing further PTLDs. Post‐transplant patient survival was inferior in patients with PTLD, while death‐censored graft survival was not. Using registry data together with extensive pathological review and long follow‐up, a rather high incidence of PTLD was found.     

Chromosomal imbalances in primary oligodendroglial tumors and their recurrences: clues about malignant progression detected using comparative genomic hybridization

OBJECT: Despite the rapid increase in knowledge concerning the genetic basis of malignant progression in astrocytic tumors, progression of oligodendroglial tumors (including both pure oligodendrogliomas and mixed oligoastrocytomas) is still poorly understood. The aim of the present study is the elucidation of chromosomal imbalances involved in the progression of oligodendroglial tumors toward malignancy. METHODS: Using comparative genomic hybridization (CGH) on snap-frozen tumor tissue, the tumor genomes of five primary oligodendroglial tumors and associated recurrent tumors were screened for chromosomal imbalances. This information was correlated with clinical data (including follow-up data) and histopathological malignancy grade. In all cases an increase in chromosomal imbalances was detected in the recurrent tumor, indicating genetic progression. In three of the five cases this correlated with malignant progression detected at the histopathological level. The results indicate that, similar to what occurs in astrocytic tumors, chromosomal imbalances harboring genes involved in the cell proliferation control mechanism at the G1-S border are involved in the progression of oligodendroglial tumors. Additionally, although gains of genetic material on chromosome 7 and losses on chromosome 10 are most frequently detected in the course of malignant progression of astrocytic tumors, either or both of these can also occur during malignant progression of typical oligodendroglial tumors that contain losses involving chromosome 1p and/or chromosome 19q. CONCLUSIONS: When performed on optimally preserved material from a small set of primary oligodendroglial tumors and associated recurrent tumors, CGH detects chromosomal aberrations that potentially play a mechanistic role in the malignant progression of these tumors.     

Plasmacytoma-like posttransplant lymphoproliferative disorder following orthotopic liver transplantation: a case report

Posttransplant lymphoproliferative disorders (PTLDs) are among the most serious and potentially fatal complications of both stem-cell and solid-organ transplantation. Most monomorphic PTLDs are of B-cell origin and frequently associated with Epstein-Barr virus (EBV) infection in the setting of pharmacological immunosuppression posttransplantation. The majority of monomorphic PTLDs commonly resemble diffuse large B-cell or Burkitt's lymphoma; plasmacytoma-like PTLDs are very rare. We report a case of plasmacytoma-like PTLD arising in the allograft in a 66-year-old male diagnosed 2 months following an orthotopic liver transplant for alcohol-related end-stage liver disease. The liver biopsy revealed marked infiltration of atypical plasma cells with lambda light chain restriction and positivity for EBV by in situ hybridization confirming the diagnosis. Also noted was a remarkable increase of tissue eosinophils. Reduction of immunosuppression led to improvement in his clinical condition, and also resolution of the hepatic lesions and abdominal lymphadenopathy noted on imaging studies. While a few cases of plasmacytoma-like PTLDs have been described in literature, to our knowledge, this is the first reported case of early onset plasmacytoma-like PTLD in a liver transplant recipient occurring in the allograft with associated lymphadenopathy having distinct histopathologic features including tissue eosinophilia. Timely recognition of such an entity is critical in order to initiate early and appropriate intervention.     

Comparative genomic hybridization reveals DNA copy number gains to frequently occur in human prostate cancer

BACKGROUND: Despite intensive studies over many years, there is only limited knowledge on the genetic changes underlying the development and progression of prostate cancer. No specific prostate carcinoma-related genetic event has yet been identified. METHODS: In order to gain an overall view of regional chromosome gains and losses, comparative genomic hybridization (CGH) was used on a series of 16 prostate adenocarcinomas. Five benign prostate hyperplasia (BPH) samples were also evaluated. RESULTS: Using CGH, chromosome alterations were observed in 81% of the prostate carcinomas analyzed. Gains of DNA copy numbers were found as the predominant imbalance, with chromosomes 3q (56%), 12q (56%), 8q (50%), Xq (50%), 4 (44%), 6q (44%), 5 (38%), 7q (38%), 9p (38%), and 13q (31%) being most frequently involved. Whereas DNA copy number gains comprised the whole chromosome or almost a whole arm of chromosomes 4, 5, 6, 9, and 13, the minimal overlapping regions on the other chromosomes were mapped to 3q25-q26, 8q21-q22, 12q13-q21, 7q31, and Xq22-q25. High-level amplifications were not found. Other chromosomes with nonrandom gains or losses of DNA sequences were discovered. The five BPH samples were found to be normal. CONCLUSIONS: Amplification events at different chromosomal sites seem important in prostate cancer development. A new chromosome region with DNA copy number gains was identified on 12q, while other regions on 3q, 7q, 8q, and Xq were confirmed or narrowed down, indicating a possible role of known or putative protooncogenes in these regions for prostate cancer growth. Our low detection rate of DNA losses may to some part be explained by CGH immanent technical limitations.     

Myoid differentiation in mesoblastic nephroma: clinicopathologic and cytogenetic findings of a rare case

The authors report the case of a benign renal mesenchymal tumor in a baby boy detected by ultrasound scanning during prenatal diagnosis. Histologically, the tumor was diagnosed as a congenital mesoblastic nephroma (CMN) with myoid differentiation. The tumor normally is characterized by a fascicular proliferation of bland, spindle-shaped cells. CMN is the most common renal tumor in the neonatal period and presumedly results from a neoplastic transformation affecting the pluripotent mesodermal nephric blastema. In embryonic life, tumorigenic influences acting on the nephric blastema might result in selective overgrowth of its mesoblastic derivates. CMN must be differentiated from other spindle-shaped tumors, like Wilms' tumor, rhabdoid tumor of the kidney, clear cell sarcoma, nephrogenic adenofibroma, fibroma and fibrosarcoma, leiomyoma, metanephric stromal tumor, and, in this case especially, from tumors with myoid differentiation like infantile myofibromatosis. Numerical molecular abnormalities are observed frequently in renal mesenchymal tumors, especially in chromosome 11. Cytogenetic findings in our tumor after comparative genomic hybridization (CGH) showed full trisomies of chromosomes 20 and 22q, partial trisomies for the distal part of 11q and 1p, and an approximately full monosomy of chromosome 4 (4qter-4p15). The chromosomal imbalances of the tumor can be described as: rev ish enh(1p31pter,11q23qter,20,22), dim(4)(p15qter). J Pediatr Surg 37:E22.     

Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation

Posttransplantation lymphoproliferative disorder (PTLD) is a well-recognized complication of conventional bone marrow/stem cell and solid organ transplantation. However, not much is known about PTLD following the more recently introduced nonmyeloablative allogeneic stem cell transplantation (NMST). This study reports the findings from two cases of PTLD following NMST and compares them to the one previously reported case. The donor origin of the PTLD was determined using short tandem repeat analysis, and B- and T-cell clonalities were evaluated by polymerase chain reaction. Two cases of PTLD evolved in a total of 70 patients who have undergone NMST at our institution from 1999 to 2003. Both patients received conditioning with Fludarabine/Cytoxan/Campath 1H (alemtuzumab, anti-CD52 antibody) and T-cell-depleted donor cells with Campath-1H. Both PTLDs were EBV positive (by immunohistochemistry and in situ hybridization) with diffuse large B-cell lymphoma morphology. Our findings indicate the incidence of PTLD following NMST is 3% (2 of 70 patients from our institution and 1 of 30 from the previously reported case). All three PTLDs arose 6 to 7 months after NMST and were rapidly fatal. The pathology of the PTLD in all cases was donor origin, EBV positive, diffuse large B-cell lymphoma.     

Genetic changes in stage pT2N0 prostate cancer studied by comparative genomic hybridization

OBJECTIVE: To identify chromosomal regions important for progression in clinically organ-confined prostate cancer, as the genetic changes underlying the development and progression of prostate cancer are poorly understood. MATERIALS AND METHODS: Comparative genomic hybridization (CGH) was used to search for DNA sequence copy-number changes in a series of 50 primary organ-confined prostate adenocarcinomas (pT2N0) removed by radical prostatectomy. RESULTS: CGH analysis indicated that 23 (46%) of the primary prostate adenocarcinomas showed chromosome alterations. The percentage of tumours with losses (38%) was higher than with gains (28%). Losses of 13q (24%), 8p (18%), 6q (10%), 16q (8%), 18q (6%) and 5q (6%) and gains of 17q (12%), 20q (12%), 9q (10%), 17p (8%) and 8q (6%) were the most frequent alterations. Amplifications were found at 8q24-qter. Minimal overlapping regions of loss, indicative of the presence of tumour-suppressor genes, were mapped to 13q21.1-q21.3 and 8p21.2, and minimal overlapping regions of gain, indicative of the presence of oncogenes, were found at 9q34.4-qter, 17q25-qter and 20q13.3-qter. There was a significant association between Gleason score and losses and gains (P = 0.003), and an association between chromosomal imbalance and high histological grade (P = 0.008). CONCLUSION: These results suggest that losses or gains of DNA in these regions are important for prostate cancer progression, and document the spectrum of chromosomal alterations in stage pT2N0 of clinically organ-confined prostate cancer.     

肝癌转移机制的分子细胞遗传学研究

目的 探索肝癌转移的分子细胞遗传学机制。方法 应用比较基因组杂交技术（com-parative genomic hybridization,CGH)技术分析10对肝细胞癌原发癌及其转移癌灶的染色体变化。结果（1）肝癌中常见的染色体扩增包括1q(10/10)、8q(6/10)及5q(3/10),4例肝癌原发癌及6例转移灶中发现1q12-q22狭小区域的明显扩增。（2）常见的染色体缺失为4q(7/10)、1q(6/10)（且多局限于lpter-p35)、17q(5/10)、19q(4/10)、16q(4/10)及8p(3/10)。（3）转移癌灶中各染色体异常的比例略高于原发癌,但最有意义的发现是8例转移癌灶（8/10,80%）中存在8p的缺失,而原发癌中仅3例（3/10.30%）存在8p缺失（P=0.03),5例肝细胞癌在其获得转移表型时存在8p的缺失。（4）加一重要发现是在所有10对肝癌的原发癌及其转移癌灶中均存在1q的扩增,并在部分癌灶中发现小区域的明显扩增。结论 染色体8q的缺失可能与肝癌的转移特性有关,8q可能存在抑制肝癌转移的基因,1q12-q22可能存在与肝癌发生发展有关的癌基因。