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We previously hypothesized that cytogenetic abnormalities precede morphological abnormalities in developing malignant conditions. In this context we evaluated additional cases to further confirm that hypothesis. We report on 2 additional cases in which clonal cytogenetic abnormalities were observed in otherwise morphologically normal samples. Case 1 is a bone marrow from a 73 year old male with transformed follicular lymphoma (FL), while case 2 is a lymph node from a 53-year-old with lymphadenopathy, both referred to the cytogenetics laboratory for evaluation. A 73-year-old male presented with an enlarging left inguinal mass surrounding and obliterating the left iliac vein. A tissue core biopsy of the mass revealed recurrent high grade FL with diffuse large B-cell lymphoma (DLBCL). Examination of a random bone marrow biopsy of the adjacent left posterior iliac crest showed only mild hypercellularity (50%) and no evidence of malignancy, and the results were confirmed by flow cytometry. Cytogenetic evaluation revealed an interstitial deletion, del (9)(q13q32). In case 2, morphologically the lymph node showed extensive paracortical hyperplasia with numerous eosinophils and no clear indication of a neoplastic process with no abnormal lymphoid population observed by flow. PCR studies for TCR gamma and IgH gene rearrangements were negative for clonality. Chromosome analysis demonstrated 47,XY,+add(1)(p22),t(3;14)(q27;q11.2)[13]/46,XY[7]. FISH studies showed a BCL6 gene rearrangement but no TCRAD rearrangement. A subsequent inguinal lymph node biopsy showed DLBCL. These cases along with the other cases in the literature provide further evidence of genetic abnormalities preceding morphological abnormalities in developing malignant conditions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Hodgkin and Reed-Sternberg cells are considered to represent the malignant fraction in Hodgkin's disease. Several studies have shown that the Hodgkin and Reed-Sternberg cells are chromosomally abnormal, but genetic data about the morphologically normal cell population in Hodgkin's disease are very limited. This latter cell population has therefore been examined for chromosomal aberrations, using the in situ hybridization (ISH) procedure, making use of DNA probes for chromosomes 1, 7, 8, 9, 11, 12, 15, 17, and 18. Nuclei were isolated from freshly frozen (10 cases) and paraffin-embedded (16 cases) biopsy samples and 1000 nuclei per case were evaluated. The cases of Hodgkin's disease were compared with reactive lymph nodes, which show aberrant chromosome copy numbers in less than 1 per cent of the cells. Using strict scoring criteria, nuclei in the tumour were found to show an abnormal genotype, in the range of 1-12 per cent, with trisomies occurring most frequently. No characteristic numerical chromosome abnormality was observed. ISH on 4 microns thick paraffin sections of six cases of Hodgkin's disease revealed numerical aberrations for chromosome 1 in cells which appeared to be morphologically normal. The genomically abnormal nuclei did not differ in morphology or size from the nuclei of morphologically normal cells, but differed considerably in size when compared with the nuclei of Hodgkin/Reed-Sternberg cells after the ISH procedure. Three of these six cases revealed a population of apparently normal cells with an aberrant copy number which differed notably from the fraction observed in reactive lymph nodes. It is concluded, therefore, that a subset of morphologically normal cells, next to the Hodgkin/Reed-Sternberg cells, are chromosomally aberrant and may participate in the malignant cell fraction of Hodgkin's disease.

We have karyotyped cells from a lymph node of a patient with atypical lymphoid hyperplasia. Among other clonal chromosomal abnormalities, a t(2;19) translocation was observed with breakpoints at 2p11.2 and 19q13. The genes for transforming growth factor alpha and beta have been mapped to 2p11-p13 and 19q13, respectively, but Southern blot analysis did not reveal any alteration in the structure of these genes. Similarly, the kappa immunoglobulin gene, which maps to 2p11-p12 was not rearranged. In addition, Southern blot analysis using immunoglobulin and T-cell receptor genes as probes, did not demonstrate any clonality of either B or T cells. We propose that this patient represents an early, polyclonal stage of atypical hyperplasia. The chromosome changes observed may have been one of the etiologic factors causing this disorder.

Chromosome and pathologic studies were performed on two patients (a 12-year-old boy and a 62-year-old woman) with malignant histiocytosis (MH). Both patients had chromosome abnormalities in their neoplastic cells: the boy's karyotype was 45,Xp+,-Y,9p+,18q-, and the woman's 48,XX,+16, inv(1),mar(5),6p-,10p+,12q+,i(18q),+i(18q). The boy had typical clinical and pathologic findings of MH, and died without achieving remission by chemotherapy. At the initial stage the woman had the clinical and hematologic findings of MH. Chemotherapy was given, but had no beneficial effects. At the terminal stage the bone marrow (BM) biopsy and aspirate, and the autopsy findings, were consistent with those of non-Hodgkin lymphoma, diffuse large cell type, although some histiocytes or abnormal cells in monocyte-macrophage lineage remained in the BM and the autopsied lymph nodes. This study and a review of data on six other cases have failed to establish any specific chromosome changes in MH.

Chromosomal studies have been performed in 2 patients with angio-immunoblastic lymphadenopathy. In both the cases the presence of abnormal cell lines characterized by marker chromosomes has been detected. Application of banding techniques allowed to detect the structural composition of the marker chromosome in 1 of the cases and to show a clonal evolutive pattern of the rearranged chromosomal set; In the same patient a consistent Y loss observed in the major fraction of the investigated metaphases did not appear to be related to any defined rearrangement of the karyotype. Longitudinal chromosomal studies are stressed in order to better correlate th cytogenetic abnormalities and the immunoreactive picture of the lymph nodes along the course of the disease.

Fluid from a pleural effusion in a child with malignant histiocytosis was grafted into nude mice. Cytogenetic studies were performed on the xenografted cells which revealed a diploid karyotype with a translocation t (5;6) and a marker (13q+). This study reports a new rearrangement which has not been described previously in malignant histiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHLH) is an uncommon disorder characterized by multiorgan infiltration with phagocytic histiocytes/macrophages. It may be inherited as an autosomal recessive trait, but specific associated cytogenetic abnormalities have not been documented. The authors describe a 10-week-old white female without prior family history of FHLH, who fulfilled the histologic and clinical criteria for the diagnosis. In addition, cytogenetic abnormalities, including the presence of double minute chromosomes and occasional loss of chromosomes 7 and 12, were documented in unstimulated peripheral blood cells. These karyotypic findings are usually associated with dyserythropoietic and leukemic states, and have not been described previously in the context of FHLH. It may be useful to do chromosome analyses on unstimulated peripheral blood cultures from FHLH patients before treatment to examine the karyotype of proliferating cells, which may represent the infiltrative histiocytes seen in the disorder.

Cytogenetic studies were performed on direct and 24-hour culture preparations of eight lymph node biopsies from seven patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC)-associated lymphadenopathy in whom histological evidence of lymphoma was not detected. Three of these seven had chromosomal abnormalities, including chromosome instability in one and clonal chromosomal abnormalities in two; one of the latter was a t(8;14)(q24;q32). The remaining five showed normal karyotypes. Epstein-Barr virus (EBV) titers were elevated in all three patients that exhibited chromosome abnormalities, two of whom later developed malignant lymphoma. A control group of five patients with reactive lymphadenopathy not associated with AIDS failed to reveal chromosomal aberrations, but elevated EBV titers were present in two. These data are consistent with current views on the role of EBV and chromosome change in the development of lymphoma in immunodeficient states and suggest that karyotypically abnormal AIDS-related lymphadenopathy represents a prelymphomatous proliferation.