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PubMed2002

Distinct cytogenetic pathways of advanced-stage neuroblastoma tumors, detected by spectral karyotyping.

Molecular studies of advanced-stage neuroblastoma (NBL) have revealed a marked genetic heterogeneity. In addition to MYCN amplification and chromosome 1 short-arm deletions/translocations detected by conventional cytogenetics, application of fluorescence in situ hybridization has disclosed a high prevalence of 17q gain, whereas allelotyping and comparative genomic hybridization techniques also have revealed loss of 11q and of other chromosomal material. Using the recently developed technique of spectral karyotyping (SKY), we sought to refine the cytogenetic information, identify hidden recurrent structural chromosomal abnormalities, and compare them to the molecular findings. Thirteen samples of metaphase spreads from 11 patients with advanced-stage NBL were analyzed by SKY. Most of them were found to have complex karyotypes (more than three changes per metaphase) and complex unbalanced rearrangements. Recurrent aberrations leading to 17q gain, deletion of 1p, MYCN amplification, and loss of 11q appeared in 7, 4, 4, and 5 patients, respectively, in simple and complex karyotypes. Chromosome 3 changes and gain of 1q and 7q appeared in 6, 5, and 4 patients, respectively, in complex karyotypes only, reflecting later changes. A strikingly high prevalence of the unbalanced translocation der(11)t(11;17), leading to concomitant 11q loss and 17q gain in 4 patients, delineated a distinct cytogenetic group, none having 1p deletion and/or MYCN amplification. der(11)t(11;17) was associated with complex karyotypes with changes in chromosomes 3 and 7q. The 17q translocations with partners other than 11q were associated with 1p deletion and/or MYCN amplification. The distinct cytogenetic subgroups identified by SKY confirm and extend the recent molecular observations, and suggest that different genes may interact in the der(11)t(11;17) pathway of NBL development and progression.

Adolescent↗
PubMed1997

Highly complex chromosomal aberrations in bone marrow of a patient with metastatic prostate neoplasm.

Prostate cancer is the single most common malignancy among men in North America. Nevertheless, cytogenetic evaluation of bone marrow in patients with metastatic prostate neoplasm has been rare and, to date, only five such patients have been reported. We report an additional case where chromosomal abnormalities of a bizarre nature were found in the bone marrow. Though cytogenetic findings in prostate cancer are heterogeneously complex, the chromosome regions involved include 1p, 1q, 7q, 8p, 10q, 12p, and 17q and are considered hot spots. What is the significance of these so-called hot spots in metastasis of prostatic cancer to the bone marrow? At present, no meaningful conclusion can be drawn, as data are limited, but accumulation of such cases may provide valuable information concerning the role of chromosomal abnormalities in patients--specifically with metastatic stage--and may help urologists during therapeutic decision making, particularly if a genetic marker for aggressiveness can be determined.

Adenocarcinoma↗
PubMed2003

Evaluating the volume ratio of bone marrow affected by fibrosis: a parameter crucial for the prognostic significance of marrow fibrosis in chronic myeloid leukemia.

Marrow fibrosis (MF) is a complication of bone marrow neoplasms that usually impairs quality of life and shortens survival time. Proof and exact quantification of MF is not yet standardized, thus impeding the comparability of results and the evaluation of its prognostic impact. In this study on 360 bone marrow biopsy specimens from 135 patients with either chronic idiopathic myelofibrosis (CIMF) (evaluation group) or chronic myeloid leukemia (CML) (test group), marked differences were detected between six different approaches systematically compared with respect to proof and quantification of MF. A new volumetric approach quantifying the marrow volume affected by fibrosis turned out to be superior to all of the other morphometric methods considering practicability and specificity of results, and superior to a semiquantitative procedure considering sensitivity, precision, and reproducibility (P < 0.00005). The assessment of the marrow volume with fibrosis was the only feature of MF independently influencing the survival time of patients (test group with CML; multivariate analysis, P = 0.0008). We conclude that an approach estimating the marrow volume affected by fibrosis is the method of choice to exactly quantify and prove MF. The loss of marrow volume due to fibrosis appears to be crucial with respect to the prognostic significance of MF in CML. Hum Pathol 34:391-401.

Adult↗
PubMed1981

Monoclonal antibody to ganglioside GQ discriminates between haemopoietic cells and infiltrating neuroblastoma tumour cells in bone marrow.

An immunological approach has been sought for the identification of minimal metastatic spread of neuroblastoma to bone marrow. Here we describe the reactivity of the monoclonal antibody A2B5 to human neuroblastoma cell lines and fresh tumour tissue. This reagent, raised against chick retinal cells, reacts with all human neuroblastoma lines assayed although quantitative differences in antigenic expression exist between cultures. Analysis of tumour cells in heavily infiltrated bone marrow aspirates indicates that only 70% of the samples reacted with A2B5, suggesting that the heterogeneity seen in the expression of antigen on cell lines is paralleled in fresh tumour material. A2B5 showed no reactivity to either a panel of human leukaemic cell lines or normal human bone marrow, although reactivity to an occasional leukaemic marrow aspirate was detected. We suggest that A2B5 could form part of a panel of monoclonal reagents necessary for detecting metastatic spread of all neuroblastoma cells to bone marrow. Such a group of reagents may be useful therapeutically in a programmed of autologous bone marrow transplantation for the removal of tumour cells prior to reinfusion of haemopoietic cells to patients receiving high-dose chemotherapy.

Antibodies, Monoclonal↗
PubMed1990

[Detection of bone marrow involvement in breast cancer and malignant lymphoma using immunoscintigraphy of the hematopoietic bone marrow].

Radioimmunoimaging of bone marrow was performed for non-invasive detection of skeletal involvement in 15 patients with carcinoma of the breast and 17 patients with malignant lymphomas. Bone marrow scans were performed by means of a monoclonal 99mTc-labelled antibody, directed against NCA-95 and CEA. The presence and extent of skeletal involvement were controlled by skeletal scintigraphy, plain radiographs and CT; bone marrow biopsies were obtained in 19 patients as well. 20 subjects without suspected malignant disease served as controls. Haematopoietic bone marrow was imaged homogeneously and with high contrast in all controls. 15/15 patients with carcinoma of the breast and 10/17 patients with malignant lymphomas had multifocal bone marrow defects due to skeletal metastases. Bone marrow scans revealed significantly more lesions than skeletal scintigraphy both in carcinoma of the breast (p = 0.027) and malignant lymphomas (p = 0.015). Thus, radioimmunoscintigraphy of bone marrow may provide a new, sensitive approach for non-invasive detection of metastatic spread to the skeletal system.

Adult↗
PubMed1991

Expression of 'small cell carcinoma antigens' in primary small cell lung cancer and metastases: an immunohistochemical study.

The presence of 'small cell lung cancer antigens' was evaluated in pretreatment biopsies of primary SCLC, liver metastases, and/or bone marrow metastases from 46 patients. The antigen expression was detected immunohistochemically by applying monoclonal antibodies to routinely formalin-fixed and paraffin embedded tissue. The antibodies applied were second workshop codes: 3(CAM 5.2), 45 (MOV15), 54 (NCCST433), 75 (PE35), 81 (HMFG-1), 95 (LCA1/L38) and HMFG-2 123C3, F4 and MOC-21. High expression was observed for WS 3, 45, 75, 81 and HMFG-2, both in the primaries and metastases. A good correlation was observed between the presence of antigens in primary biopsies and metastases, but there was a general tendency toward a lower proportion of positive tumour cells in the metastases compared to the primaries. For WS 45, 54, 75 and 95 the difference between primaries and bone marrow was statistically significant, and this was also true for WS 45 and 81 in the liver. The clinical relevance is discussed.

Antibodies, Monoclonal↗
PubMed1994

Bone marrow immunoscintigraphy versus conventional bone scintigraphy in the diagnosis of skeletal metastases in urogenital malignancies.

Bone marrow immunoscintigraphy using a 99mTc-labelled anti-NCA-95 monoclonal antibody and conventional bone scintigraphy with 99mTc-methylene-diphosphonate were compared in the diagnosis of skeletal metastases in 58 patients with urogenital tumours. In 13 patients with metastatic disease, bone marrow immunoscintigraphy proved to be superior to bone scintigraphy, detecting 431 metastatic lesions on immunoscans as compared to 261 lesions on bone scans. However, on a patient-by-patient basis bone marrow immunoscintigraphy did not demonstrate a clinical advantage over conventional bone scanning, as in this study no patient was identified with metastatic disease still confined to the marrow space, with bone scintigraphy and bone X-ray being normal.

Adult↗
PubMed1995

Technetium-99m-labeled antigranulocyte antibody bone marrow scintigraphy.

UNLABELLED: Although bone scintigraphy is a sensitive method for detecting skeletal metastases, it is often equivocal for metastases due to poor specificity. This study evaluates 99mTc-antigranulocyte antibody (AGA) bone marrow scintigraphy in differentiating malignant from benign lesions, in 42 patients with skeletal tumors who had equivocal bone scans. METHODS: AGA scans performed approximately 1 wk after 99mTc-MDP bone imaging were visually assessed for the presence of concordant marrow defects. Final diagnoses were made from radiological results, follow-up bone scans or clinical evaluation for 12 mo or longer. RESULTS: The final diagnoses were: skeletal metastasis (19 patients), no metastasis (20 patients) and unconfirmed (3 patients). AGA scans could not determine the presence of a concordant defect in three patients because of overlying liver activity or previous irradiation of the region. Seventeen patients had bone marrow defects concordant with bone scan lesions, whereas 15/19 patients without metastasis had normal AGA scans. The sensitivity and specificity of AGA for detecting skeletal metastases were 100% and 79%, respectively. CONCLUSION: AGA scans had a low incidence of skeletal metastases in patients who had equivocal bone scans. Although a concordant marrow defect increases the possibility of metastasis, further radiological investigation to exclude benign disease is warranted.

Antibodies, Monoclonal↗
PubMed1989

Cytogenetically unrelated clones in hematological neoplasms.

We have reviewed literature data on 6,306 cases of hematological neoplasia--acute and chronic lymphatic and myeloid leukemias (CML excepted), myelodysplastic and chronic lymphoproliferative and myeloproliferative disorders, and malignant lymphomas--with the goal of quantitatively ascertaining how often cytogenetically unrelated clones occur in these diseases. Unexpectedly wide variations were found: in ANLL, unrelated clones were present in 1.1% of the 2,506 known cases with chromosome abnormalities characterized with banding technique; in the various myelodysplastic (MDS) and chronic myeloproliferative (CMD) disorders (total number of cases 1,299) the frequency was 4.3% and in lymphatic malignancies 1.3% (total case number 2,501). In the latter group the proportions varied between 0.4% and 0.6% in ALL and malignant lymphoma (ML) to as much as 6.2% in CLD and 7.3% in CLL. Some karyotypic abnormalities were encountered more often than would be expected from their general frequency in the various diseases. This discrepancy was particularly evident in MDS and CMD, where 5q- was found in slightly less and +8 in somewhat more than half of the 56 cases. Furthermore, these two aberrations were found as the only changes in the two coexisting clones in one-fourth of the material. Although if viewed in isolation these data would undoubtedly be best explained by assuming a multicellular origin of the neoplasm, it is entirely possible that what are cytogenetically perceived as unrelated clones could be subclones with some invisible aberration in common. If so, this interpretation indicates that changes like +8 and 5q-, both of which are common rearrangements in bone marrow neoplasms, are actually secondary changes that develop during tumor progression.

Chromosome Aberrations↗
PubMed2003

Infiltration of Helicobacter pylori in the gastric mucosa.

It is our hypothesis that if Helicobacter pylori could be demonstrated conclusively to have transgressed the mucosal surface into the lamina propria, this would help explain how H pylori recruits inflammatory cells. We report our immunohistochemical and electron microscopic findings that demonstrate that H pylori can be detected in the lamina propria of the stomach, offering evidence of its invasive potential. We stained 67 endoscopic gastric biopsy specimens with Warthin-Starry silver and immunoperoxidase stains for H pylori. In addition, transmission electron microscopy was performed on 1 case. The presence of surface H pylori was associated significantly with active (P < .0001) and chronic (P < .0001) inflammation. H pylori could not be identified in the lamina propria using the Warthin-Starry silver stain alone. Immunoreactivity for H pylori in the lamina propria was detected in 20 (30%) of 67 gastric biopsy specimens. Transmission electron microscopy confirmed the immunohistochemical findings. H pylori can infiltrate the lamina propria of the gastric mucosa, thereby proving morphologic evidence of its invasive capability.

Acute Disease↗
PubMed1985

Metastatic neuroblastoma in an infant: translocation (1;11), deletion (2) and double minute chromosomes.

An extensive chromosomal analysis was performed in cells of primary tumour and bone marrow metastases from an 8-month-old girl with disseminated neuroblastoma prior to therapy. A modal chromosome number of 46 was found. Consistent abnormalities in the karyotype were seen: in particular, a translocation (1;11), a deletion (2)(p21) and a chromosome 7p+. Furthermore, double minute chromosomes of two distinct sizes were found in 50%-80% of metaphases in the cell populations examined. These extra chromosomal double minutes might be the cytogenetic form of amplified cellular oncogene-DNA.

Adrenal Gland Neoplasms↗
PubMed1997

Lesions of the bones of the hands and feet.

Neoplasms and their simulators in the bones of the hands and feet include the majority of those found in other skeletal sites, and a disproportionate number of some. We examined the clinical, radiologic, and pathologic features of 240 lesions of the hand and foot bones. Benign tumors and lesions including reactive and reparative conditions comprised 203 cases. The largest single category of neoplasms was that with cartilaginous differentiation, with enchondromas (29 cases) and chondrosarcomas (15 cases) the most common. Noncartilaginous malignant tumors were infrequent and displayed typical radiologic and pathologic features. Florid reactive periostitis, bizarre parosteal osteochondromatous proliferations, and giant cell reparative granulomas made up a larger percentage of lesions in these locations than in other skeletal sites. Lesions of the bones of the hands and feet may frequently be biopsied or treated at hospitals without large orthopedic tumor services. Thus, it is important for the surgical pathologist to be aware of the frequency and characteristics of lesions which may present in these sites.

Adult↗
PubMed2001

Hepatosplenic gamma/delta T-cell lymphoma in bone marrow. A sinusoidal neoplasm with blastic cytologic features.

We report 8 cases of hepatosplenic T-cell lymphoma (HSTCL) involving bone marrow and correlate histologic findings with disease progression. Immunophenotypic analysis demonstrated mature, aberrant gamma/delta T-cell immunophenotypes. Isochromosome 7q was identified in 4 cases; 1 case showed the t(7;14)(q34;q13). Seven of 7 cases tested had monoclonal TCR gamma gene rearrangements. The initial diagnostic bone marrow biopsy specimens were hypercellular with a frequently subtle, predominantly sinusoidal infiltrate of atypical small to medium-sized lymphoid cells. In all cases, aspirate smears at diagnosis and in subsequent specimens contained malignant cells that resembled blasts, some with fine cytoplasmic granules. With progression, the pattern of HSTCL in bone marrow biopsy specimens became increasingly interstitial, and the neoplastic cells became larger. In aspirate smears, the proportion of blasts increased. Seven patients died; 1 was lost to follow-up. Autopsy performed on 1 patient demonstrated malignant cells within vascular channels in all organs sampled, with relatively little tumor formation, resembling intravascular lymphoma at these sites. HSTCL often can be recognized in bone marrow by its unique combination of a sinusoidal pattern in core biopsy specimens and blastic cytology in aspirate smears.

Adolescent↗
PubMed1994

1;17 translocations and other chromosome 17 rearrangements in human primary neuroblastoma tumors and cell lines.

We report on the finding of a t(1;17) in two primary neuroblastomas. Subsequent fluorescence in situ hybridization (FISH) analysis revealed the presence of 1;17 translocations in four out of nine neuroblastoma cell lines. The chromosome 1 short arm breakpoints were determined using region-specific probes. FISH screening also demonstrated or confirmed the presence of 11;17 translocations in three cell lines and other chromosome 17 rearrangements in those cell lines that did not carry a t(1;17) or t(11;17). Our data extend previous cytogenetic findings and suggest that, in addition to the known involvement of chromosome 1, one or more genes on chromosome 17 also play a role in neuroblastoma development.

Adrenal Gland Neoplasms↗
PubMed1996

Histopathologic analysis of bone marrow and bone metastasis in murine neuroblastoma.

To elucidate the development of bone metastasis in human neuroblastoma, bone marrow and bone metastases were analysed histologically in a hematogeneous metastasis model of murine neuroblastoma. The bone marrow metastasis occurred initially in the bone marrow sinusoid where tumor cells adhered and extravasated to bone marrow parenchyma, resulting in the formation of nodular lesions in the medullary cavity. The nodular lesions eventually progressed to diffuse lesions segmentally occupying the medullary cavity. During the establishment of the diffuse lesions, tumor cells invaded cancellous bone and/or bone cortex, resulting in bone metastasis. Such nodular or diffuse bone marrow metastatic lesions occurred sporadically in a variety of bones. To improve the results of treatment for neuroblastoma, the characteristics of the bone marrow and the bone metastases demonstrated in this study should be considered in the diagnosis and treatment of this disease.

Animals↗
PubMed1999

Stem cell transplantation for metastatic breast cancer: analysis of tumor contamination.

The purpose of this study was to determine the efficacy, engraftment kinetics, effect of bone marrow tumor contamination, and safety of high-dose therapy and granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood progenitor cell (PBPC) support for patients with responding metastatic breast cancer. Forty two patients underwent G-CSF (10 microg/kg) stimulated PBPC harvest. PBPC and bone marrow aspirates were analyzed by histologic and immunocytochemical methods for tumor contamination. Thirty-seven patients received high-dose therapy consisting of cyclophosphamide 6 g/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 (CTCb) given as an infusion over 4 d followed by PBPC reinfusion and G-CSF (5 microg/kg) support. No transplant related deaths or grade 4 toxicity was recorded. CD34+ cells/kg infused was predictive of neutrophil and platelet recovery. With a median follow-up of 38 months, three year survival was 44% with relapse-free survival of 19%. Histological bone marrow involvement, found in 10 patients, was a negative prognostic factor and was associated with a median relapse-free survival of 3.5 months. Tumor contamination of PBPC by immunohistochemical staining was present in 22.5% of patients and found not to be correlated with decreased survival. G-CSF stimulated PBPC collection followed by a single course of high dose chemotherapy and stem cell infusion with G-CSF stimulated marrow recovery leads to rapid, reliable engraftment with low toxicity and promising outcome in women with responding metastatic breast cancer.

Adult↗
PubMed1999

Testicular lymphoma with bone/bone marrow metastases illustrated by scrotal sonography, spinal MRI, and total body Tc-99m HMDP and Tc-99m MIBI images.

An 83-year-old man with testicular lymphoma demonstrated progressive scrotal enlargement with non-homogeneity sonographically and abnormally increased uptake in the scrotum of Tc-99m HMDP and Tc-99m MIBI scintigraphically. Extensive bone/bone marrow metastases were exhibited by Tc-99m MIBI and Tc-99m HMDP scintigraphies and MRI of the spine. In addition, focal/tubular activity of the femoral bone marrow on Tc-99m MIBI imaging was consistent with skeletal scintigraphic findings. It is emphasized that Tc-99m MIBI total body imaging enabled the demonstration of testicular lymphoma as increased uptake and the illustration of skeletal/bone marrow metastases as diffuse and/or focal increased uptake, especially focal/tubular MIBI activity of the femoral marrow.

Aged↗
PubMed1999

Sub-super bone scan caused by bone marrow involvement of prostate cancer.

A 67-year-old man presented with malaise and marked anemia. A diagnostic workup revealed severe pancytopenia on a complete blood count and diffuse sclerotic change in the axial skeleton on a plain abdominal radiograph. Bone metastases being suspected from these findings, bone scintigraphy was performed. The bone scan demonstrated uniformly increased skeletal activity with faint soft-tissue activity. The findings of the bone scan, however, appeared atypical of the super scan caused by diffuse bone metastases, without any decrease in radioactivities of the appendicular skeleton and kidneys. Bone marrow scintigraphy with In-111 chloride demonstrated central marrow failure and peripheral expansion, which indicated the possibility of myelophthisis. The patient underwent bone marrow biopsy, which revealed replacement of the bone marrow by metastatic adenocarcinoma. Further examinations detected the primary lesion in the prostate. In this case, the findings of the bone scan were insufficient for the super scan, and might be categorized as a sub-super scan. It would be important to recognize this incomplete form of super scan as a rare scintigraphic pattern of diffuse bone marrow metastases.

Adenocarcinoma↗