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Results for “clonal evolution”

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PubMed1990

Clues from natural history and results of treatment supporting the monoclonal origin of germ cell tumours.

Recent observations have suggested that a major factor in the development of germ cell tumours may be excessive mitogenic stimulus developed because of failure of feedback suppression of the normal pituitary drive due to atrophic damage to germinal epithelium. With this observation and the increasing recognition that there is a common in situ stage which precedes both seminoma and malignant teratoma/non-seminoma there has been a polarisation of views regarding the relationship between seminoma and malignant teratoma/non-seminoma, with some authors viewing these two entities as separate unrelated transformational events while others hypothesise that seminoma is an interim stage of clonal evolution associated with increased malignant potential towards malignant teratoma/non-seminoma. This chapter reviews the clinical evidence supporting the concept of clonal evolution which arises from the observation that the modal DNA content of seminoma (3.6N) is intermediate between that of in situ carcinoma (4.2N) and malignant teratoma/non-seminoma (2.8N). These observations, taken with the observation that the median age of patients with mixed tumours containing both seminoma and non-seminoma elements (30 years) is intermediate between the slower growing seminoma (35 years) and faster growing malignant teratoma/non-seminoma (25 years), as well as studies of spontaneous regression, tumours in AIDS patients chemo/radio sensitivity and post mortem histology, provide the most convincing evidence supporting clonal evolution. However, these observations cannot explain the fact that some patients have more than one focus of tumour (which can be of different histological type) in a single testis with normal tubules in between, even if they have in situ carcinoma. An extreme manifestation is seen in patients who are treated and cured from metastases arising from one testicle who then die from metastases from a completely different histological type arising from a second transformation event of a germ cell in the contralateral testis. The conclusion from these observations is that it is indeed possible for polyclonal development of tumours to occur, as is seen for bladder and bowel tumours, but they do not detract from the concept that seminoma is an intermediate event in the evolution from in situ carcinoma to malignant teratoma/non-seminoma.

Adult↗

PubMed1987

Nonrandom chromosomal aberrations and clonal chromosomal evolution in acute leukemia associated with Down's syndrome.

Nine Down's syndrome (DS) children, four with acute leukemia, one with acute leukemia as well as rhabdomyosarcoma, and four with other hematologic disorders, were analyzed for constitutional and acquired chromosomal aberrations. Acquired clonal chromosomal aberrations were identified only in the acute leukemia cases, and four of the five acute leukemia demonstrated numerical and/or structural aberrations involving chromosomes #8, #19, and #21. Of the 11 aneuploid stem cell lines identified in the five acute leukemia cases, trisomy 21, trisomy 8, trisomy 19, and tetrasomy or pentasomy 21 was found in 11, seven, four, and two lines, respectively. The frequent appearance of multiple stem cell lines with common and/or overlapping chromosomal aberrations in acute leukemia cases demonstrates the existence of genomic instability and heterogeneity of the neoplastic cell population, which results from clonal chromosomal evolution. Furthermore, trisomy 19 was identified only with the concurrent presence of trisomy 8, suggesting that the nondisjunction of chromosome #19 probably occurred after that of #8. Trisomy 21 was observed in every aneuploid stem cell line and, in one case, trisomy 21 was maintained in the bone marrow leukemic cells but not in the orbital rhabdomyosarcoma cells, indicating that this constitutional chromosomal aberration is probably crucial for and predisposed to the development of acute leukemia in DS patients. The association of acquired clonal chromosomal aberrations, especially those involving chromosomes #8, #19, and #21, with DS acute leukemia strongly suggests the clinical implication of cytogenetic analysis in the diagnosis of acute leukemia development in DS patients.

Acute Disease↗

PubMed1991

Biclonal analysis of busulfan-induced sister chromatid exchange in blast crisis of Philadelphia chromosome-positive chronic myeloid leukemia.

The frequency of induced sister chromatid exchange (SCE) as a sensitive parameter for chemotherapy resistance was studied after in vitro treatment with busulfan in four cases of myeloid blast crisis of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Prerequisite was a chromosomally biclonal condition with cells characterized by numerical and/or structural clonal evolution [e.g., +8, +17, +19, or i(17q)] and those only Ph+, which allowed a direct comparison of both clones. We found almost identical mean SCE frequencies in cells with and without clonal evolution after in vitro treatment with 1, 3, and 5 micrograms busulfan. The distribution of the SCE frequency within chromosome groups also remained similar in all cases. Because the SCE assay has proven a very sensitive tool for detection of resistance to chemotherapy with alkylating agents, we conclude that the clonal evolution of CML blast crisis is not associated with a significant degree of chemotherapy resistance. Other aspects, e.g., the lack of normal bone marrow cells necessary for reconstitution of hematopoiesis, may play a more important role in the poor results of chemotherapy in myeloid CML blast crisis.

Blast Crisis↗

PubMed1992

Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine.

PURPOSE: To evaluate the efficacy of interferon-alpha (IFN-A) and low-dose cytarabine (ara-C) combination chemotherapy in patients with chronic myelogenous leukemia (CML). PATIENTS AND METHODS: Sixty patients with advanced phases of Philadelphia chromosome (Ph)-positive CML received combination therapy with IFN-A 5 x 10(6) U/m2 daily, and low-dose ara-C 15 mg/m2 daily for 2 weeks every 4 weeks until remission, then for 1 week every month as maintenance. Forty patients were in late chronic-phase CML, and 20 were in accelerated-phase CML (16 with clonal evolution only, four with other criteria). Their outcome was compared with 58 patients (39 late chronic-phase CML and 19 accelerated-phase CML) who had been previously treated with IFN-A alone in the same dose schedule. RESULTS: In late chronic-phase CML, patients receiving IFN-A plus ara-C had a better complete hematologic response (CHR) rate compared with those treated with IFN-A alone (55% v 28%; P = .02), a trend for better Ph suppression (15% v 5%; P = .13), and a longer survival (3-year survival rate 75% v 48%; P less than .01). These differences do not seem to be caused by imbalances in prognostic factors between the two treatment groups. In accelerated-phase CML, the addition of ara-C to IFN-A did not improve the response rate of treated patients, and the difference in survival was accounted for by different patient characteristics. Suppression of clonal evolution was observed in five patients (25%). Patients with clonal evolution as the only criterion for disease acceleration had a longer survival than those with other or additional accelerated-phase criteria (3-year survival rate 67% v 22%; P less than .01). CONCLUSION: The results with the combination of IFN-A plus ara-C in late chronic-phase CML are encouraging, and suggest the need for its evaluation in early chronic-phase CML.

Adult↗

PubMed1985

Cytogenetics and cell surface marker analysis in CML--1. Prediction of phenotype of acute phase transformation.

Thirty-nine patients with Philadelphia chromosome-positive (Ph1) chronic myelocytic leukemia (CML) were monitored using cytofluorometry and cytogenetics. During chronic phase, abnormal populations could be detected using commercially available monoclonal antibodies. Most of these abnormal populations had either an HLA.DR+ or an OKM1+ HLA.DR- phenotype. Thirteen patients progressed to acute phase disease. Five patients with HLA-DR+ abnormal cells during chronic phase showed no clonal evolution detectable using standard cytogenetic techniques and underwent lymphoid transformation. Seven patients with OKM1+-HLA.DR- abnormal cells exhibited chromosomal abnormalities in addition to the Ph1 and progressed to a myeloblastic acute phase. One patient with HLA.DR+ OKM1+ 63D3+ abnormal cells in chronic phase showed clonal evolution and progressed to a myelomonocytic acute phase. These results suggest that cell surface markers on chronic phase cells can be used in conjunction with cytogenetic monitoring to predict the phenotype of cells involved in the acute transformation of CML. B cells (6, 13), but not T cells (18), bearing the Ph1 have been isolated from chronic phase CML patients. Thus cells other than those of myeloid lineage may be involved. Periodic cytogenetic monitoring has been shown to detect clonal evolution (i.e. genetic changes in addition to the PH1) in as many as 75% of patients prior to the acute phase (14, 37). However, neither cytogenetic changes nor morphologic analysis appear to predict the lymphoblastic type of transformation (14). Since fluorescence analysis of cell surface markers has shown reduced numbers of normal cells (28), the identity of the 'abnormal' cells was probed with antibodies recognizing a variety of markers on immature and mature lymphoid and myeloid cells. Not only were significant numbers of abnormal cells detected in the peripheral blood of chronic phase patients, but the phenotype of the abnormal population, in combination with cytogenetic analyses, predicted the type of blasts involved in acute phase disease.

Adult↗

PubMed1989

Cytogenetic studies of 21 patients with acute lymphoblastic leukemia in relapse.

Karyotypes of 21 patients, originally entered into the Third International Workshop on Chromosomes in Leukemia (3IWCL), were investigated in first, second and/or subsequent relapses. Karyotypes at diagnosis were related to the relapses in the following ways: normal to normal (N-N) (five cases); abnormal to normal (A-N) (two cases); abnormal to abnormal with no change (A-A) (five cases); abnormal to abnormal with clonal evolution (A-A+) (eight cases); and normal to abnormal (N-A) (one case). The A-A group comprised two each of t(4;11) and t(9;22) cases and one pseudodiploid case; included in this group were the only two patients who did not receive intensive treatment. Both A-N cases had been pseudodiploid at diagnosis. Clonal evolution A-A+ occurred in patients who had had 47-49 chromosomes or pseudodiploidy at diagnosis and was mainly due to the addition of structural change. The additional abnormalities were different in each case. The only de novo appearance of a clone (N-A) was in host cells in relapse following bone marrow transplantation. Clonal evolution occurred in patients who had been intensively treated and who relapsed late; the median time from diagnosis to relapse studied for the A-A group was 6 months and for the A-A+ group was 24 months. Survival following relapse was shorter for patients who had had a clonal abnormality at any time (median 10 months) than for those with no abnormality at diagnosis or in relapse (median 26 months).

Adolescent↗

PubMed1987

Cytogenetics and cell surface marker analysis in chronic myelocytic leukemia. II. Implications for patient management.

Chronic myelocytic leukemia (CML) is a model system for the study of many aspects of malignant disease. One aspect that correlates with decreasing therapeutic response is tumor progression. This progression is often accompanied by clonal evolution. In those cases where aggressive therapy does not prevent this evolution, the clinical response to therapy usually proves to be poor and of short duration. Investigators are concentrating their efforts in three primary, but not mutually exclusive, areas with respect to the clinical management of CML. These include: an attempt to distinguish patients at risk for early transformation from those who will have a prolonged chronic phase; the cryopreservation of autologous bone marrow or buffy coat early in chronic phase for subsequent use in the accelerated phase and; endeavors to identify early markers for disease progression allowing intervention before an irreversible blast crisis occurs. This report deals with two types of potential prognostic markers of transformation: chromosomal and cell surface characteristics. The appearance of nonrandom abnormal chromosomal patterns has been correlated with myeloblastic transformation by many investigators. However, there has always been a subset of CML patients who do not undergo clonal evolution. Additionally, the type(s) of transformation in CML may vary depending on the cell lineages involved. Unlike myeloblastic transformants, many of our patients who do not exhibit clonal evolution as a concomitance of disease progression develop a lymphoblastic transformation. Cytofluorometric analysis can distinguish small populations of abnormal cells with lymphoblastic characteristics (HLA DR+). Initial data suggests that patients expressing the HLA DR+ in their "normal" peripheral blood cells are at risk of undergoing lymphoblastic transformation. The combined use of clinical, cytogenetic, and cytofluorometric data to predict an impending transformation and to discriminate between myeloblastic and lymphoblastic populations allows clinicians to manage their patients more effectively.

Adolescent↗

PubMed1991

[Large cell anaplastic lymphomas in the immunocompromised host].

Large cell anaplastic (LCA) lymphomas are a newly defined tumor entity, which has recently been integrated in the updated Kiel classification. The occurrence of CD30+ LCA lymphoma in the setting of renal transplant patients has so far been reported only once. This report describes two LCA lymphomas of B-cell phenotype in renal transplant patients. The clonal evolution and possible etiologic role of Epstein-Barr Virus (EBV) in LCA lymphoma was studied. Our findings give further evidence that clonal evolution of B-cell populations is a second event in lymphomagenesis and is, at least in the cases studied, preceeded by either reactivated latent or primary EBV-infection with clonal EBV proliferation.

Antigens, CD↗

PubMed1992

Clonal remission in aplastic anemia after treatment with antithymocyte globulin.

Aplastic anemia includes a group of disorders characterized by peripheral blood pancytopenia and marrow hypocellularity. The current report describes a patient who is an apparent constitutional mosaic and presented with marrow aplasia. Using cytogenetic analysis of bone marrow, skin, and peripheral T lymphocytes, we demonstrated the clonal nature of this patient's aplastic marrow, and, in addition, identify clonal evolution. The patient was treated with antithymocyte globulin (ATG) and achieved a complete remission, with disappearance of an abnormal evolved clone. This case illustrates that clonal cytogenetic abnormalities do not preclude a response to ATG and that aplastic anemia may be a nonmalignant clonal disorder with clonal evolution.

Aged↗

PubMed1992

Frequent clonal abnormalities of chromosome band 13q14 in B-cell chronic lymphocytic leukemia: multiple clones, subclones, and nonclonal alterations in 82 midwestern patients.

We performed cytogenetic analyses of peripheral blood lymphocytes from 82 Midwestern B-cell chronic lymphocytic leukemia (B-CLL) patients. The cells were cultured with mitogens for 3-4 days. At least 15 metaphase cells were analyzed in 79 (96%) cases. Fifty (63%) of the 79 patients had clonal chromosomal alterations. Structural modifications of the long arm of chromosome 13 at or near band 13q14 were the most frequent abnormalities, identified in 23 (46%) of the patients with clonal abnormalities. In several patients, the abnormality involving band 13q14 was the sole chromosomal alteration. There was a high incidence of complex karyotypes. Nine patients had multiple subclones that appeared to result from clonal evolution; seven patients had cytogenetically unrelated clones; three patients had both subclones and cytogenetically unrelated clones. Nonclonal abnormalities were also prominent. Our study confirms the high incidence of clonal abnormalities involving chromosome arm 13q and documents the clustering of abnormalities at band 13q14 in B-CLL. The evidence for clonal evolution and the presence of multiple unrelated clones in these patients suggest that B-CLL may not be a karyotypically stable disease.

Aged↗

PubMed1991

Translocations t(14;18) and t(8;14) with rearranged bcl-2 and c-myc in a case presenting as B-ALL (L3).

Follicular lymphoma is a low grade malignancy characterized by the translocation t(14;18), which involves the putative oncogene bcl-2. We describe a 73-year-old patient presenting with Burkitt acute lymphoblastic leukemia (B-ALL) L3 (Burkitt type), whose cells had the following immunophenotype: CD19+, CD22+, HLA-DR+, CD10+, TdT-, Cyt IgM-, CD34-. Analysis of 25 peripheral blood metaphases showed the presence of t(14;18) (q32;q21), and t(8;14) (q24;q32) in 24 cells and t(14;18) only in one cell, suggesting that the latter translocation came first during clonal evolution. Both bcl-2 and c-myc were rearranged in addition to the immunoglobulin heavy and light chain genes. The presence of small lymphoid cells in paratrabecular areas on the bone marrow biopsy, together with evidence of cytogenetic clonal evolution, was indicative of a transformation from a low grade follicular lymphoma to a more aggressive Burkitt type malignancy.

Aged↗

PubMed1988

Cytogenetics of chronic myelogenous leukemia.

The fundamental pathogenetic significance of the Ph chromosome abnormality in CML has been clarified by molecular studies. However, this balanced reciprocal t(9;22) is probably not the primary event in the pathogenesis of this disease, at least at a cytogenetic level. The cause of Ph variants in +/- 5% of patients is still unknown. Improvements in cytogenetic techniques and molecular studies in a limited number of cases indicate that simple variants do not exist: Region 9q34 appears to be involved in all types of Ph variants. There is tentative evidence that these variants may in fact represent a clonal evolution from a standard t(9;22). The types of additional secondary abnormalities found in Ph variants are the same as those commonly found in standard cases. Ph negative CML represents a heterogeneous group of myeloproliferative/myelodysplastic disorders. The various mechanisms that could lead to Ph negativity are discussed. Some karyotypically normal cases and those showing a chromosome abnormality other than the Ph during the chronic phase have shown the same molecular changes as found in Ph positive CML. The types of clonal changes accompanying transformation to an acute phase are similar to those seen in myeloid disorders as a whole. The prognostic karyotypic factors in predicting imminent metamorphosis to the acute stage and during the acute phase are discussed. The extent of clonal evolution, the type of secondary abnormalities, and their relationship to the hematopoietic lineage of blast cells should be assessed. The nonrandom clonal changes found in 80% of cases are +Ph, +8, i(17q), +19, and loss of the Y. The significance of +Ph is possibly related to amplification of the bcr/abl fusion gene product, but the reason for the other persistent nonrandom changes is still speculative. Recent cytogenetic data indicate that the specific changes observed in various types of ANLL may be seen in corresponding types of MT, such as t(15;17) in promyelocytic transformations and abnormalities of 3q21-3q26 in megakaryoblastic transformations. Patients with LT usually have an early precursor B phenotype associated with a better prognosis. They tend to have either normal or hypodiploid karyotypes. An i(17q) is never seen and +8 and +19 are absent in most series. Duplication of the Ph and loss of the Y are common to both MT and LT. Data relating 14q+ abnormalities to LT are presently ambiguous.(ABSTRACT TRUNCATED AT 400 WORDS)

Chromosome Aberrations↗

PubMed1992

Natural history of intraepithelial neoplasia in humans with implications for cancer chemoprevention strategy.

Intraepithelial neoplasia is of critical importance to the cancer chemoprevention field because it is a target condition for which drugs must be sought that will prevent its development or stop its progression. The term "dysplasia" refers to the morphological alterations that characterize intraepithelial neoplasia and according to many authors consists of seven basic morphological changes that occur in the majority of human epithelia, as well as in the epithelium of mouse skin papillomas induced by 7,12-dimethylbenz(a)anthracene and 12-O-tetradecanoylphorbol-13-acetate: increased nuclear size; altered nuclear shape; increased nuclear stain uptake; nuclear pleomorphism (increased variation in nuclear size, shape, and stain uptake); increased mitoses; abnormal mitoses; and disordered or absent maturation. Clonal evolution appears to begin early in the neoplastic process during intraepithelial neoplasia. Aneuploidy has been found during intraepithelial neoplasia in many human epithelia, and, in association with other forms of genetic instability, may provide the increase in genetically variant cells required for clonal evolution to occur. It is postulated that two major factors affecting the rate of progression of intraepithelial neoplasia are the cellular mutation rate, which is enhanced by environmental carcinogens, and the cellular proliferation rate, which is enhanced by agents that include sex hormones, inducers of chronic inflammation, and irritant chemicals which stimulate reactive hyperproliferation. A preferred chemoprevention strategy should consist of the development of drugs and drug combinations which will block mutagenic carcinogens or prevent epithelial hyperproliferation or its causes. Two examples of the induction of regression of intraepithelial neoplasia by chemopreventive drugs are the regression of oral leukoplakia produced by beta-carotene and the regression of colorectal polyps in patients with familial polyposis produced by sulindac. It is evident that there is a strong need for more research on the induction of regression of intraepithelial neoplasia with chemopreventive agents. There is also a critical need to identify and develop biomarkers that correlate with the appearance and regression of intraepithelial neoplasia.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1987

Morphologic and phenotypic heterogeneity of two cases of translocation t(4;11) acute leukemia.

The morphological, ultrastructural, and immunological characteristics of two cases of acute leukemia with t(4;11) (q21;q23) were studied. The blasts from both cases were initially classified as L1 lymphoblasts. Ultrastructural examination indicated a heterogenous blast population in both cases, with some regular lymphoblast-like cells, and others exhibiting nuclear irregularity, small bundles of microfilaments, or large inclusions. In one case at diagnosis, fresh cells expressed B-associated and a myeloid antigen (B4 and 1G10). At the second relapse, the cells from this patient expressed another myeloid-associated antigen, LFA1 molecule, recognized by the monoclonal antibody M232 (CD18). At the end of clinical evolution, a further myeloid antigen was expressed (OKM1), while 8% peroxidase were noted. The other case was studied at diagnosis only and did not express any myeloid marker but expressed the B-associated B4 antigen. Furthermore, the case that exhibited a phenotypic transformation, was noted to show a chromosomal clonal evolution not described so far in other reported cases of t(4;11) acute leukemia. A dual lymphoid-myeloid nature of t(4;11) acute leukemia has been widely discussed. One of the cases reported here supports this hypothesis while the other does not. We would like to underline the possibility of heterogeneity of a case at presentation and transformation to a myeloid phenotype through clonal evolution.

Acute Disease↗

PubMed1978

Down's syndrome and leukemia: mechanism of additional chromosomal abnormalities.

There is an increased incidence of acute leukemia in patients with Down's syndrome patients have a trisomy-21 chromosomal pattern, and chromosomal abnormalities can be seen in acute leukemia. It is possible that the increased incidence of acute leukemia in Down's syndrome persons may be due in part to their chromosomal abnormalities. Such abnormalities, some appearing in a stepwise clonal evolution, were found in five Down's syndrome patients, four with acute leukemia and one with abnormal regulation of leukopoiesis. Morphological abnormal chromosomes were also found in three patients. These chromosomal abnormalities are similar to those seen in non-Down's syndrome leukemic patients. There is suggestive evidence for clonal evolution hypothesis of luekemogenesis in non-Down's syndrome patients. The abnormal chromosomal pattern reported in our Down's syndrome patients could be the result of nondisjunction in mitosis, and leukemia may be the phenotypical expression of this nondisjunction.

Acute Disease↗

PubMed1986

Chromosomal aberrations in lymphocyte and fibroblast cultures of patients with the sporadic type of Kaposi sarcoma.

Numerical and structural chromosomal aberrations were found in metaphases from lymphocyte cultures from Sardinian patients with the sporadic type of Kaposi sarcoma, and also in fibroblasts derived from cultured biopsies of the tumoral lesions. In several cases there was evidence of clonal evolution of some of the chromosomal aberrations. The chromosomes most frequently involved in numerical aberrations were 10, 13, 15, 22 and the X and Y chromosomes, and those most frequently involved in translocations and deletions were 7, 13, 15, 22 and the X chromosomes. The hypothesis is made that in Kaposi sarcoma the chromosomal instability and clonal evolution in vivo could be modulated by the immunologic situation peculiar to the condition.

Aged↗

PubMed2025

Genomic characteristics and prognostic correlations in Chinese multiple myeloma patients.

BACKGROUND: Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of abnormal clonal plasma cells in the bone marrow. The heterogeneity in Chinese MM populations remains underexplored. METHODS: We conducted whole-exome sequencing (WES) on 241 tumor samples, complemented by RNA sequencing (RNA-seq) on 131 samples from 212 Chinese MM patients. RESULTS: We identified a novel mutational signature and analyzed molecular differences between newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients. NFKBIA mutations were notably more frequent in NDMM patients compared to the MMRF-COMMPASS cohort (4/50 vs 22/937, p = 0.048), with additional recurrent mutations in several genes like TTN, IGLL5 and SYNE1. In RRMM patients, UBR5 mutations were more prevalent (4/24 vs 0/50, p = 0.01), alongside frequent mutations in OBSCN, CACNA1H, and HSPG2. Clonal evolution was assessed through multiple time points and locations, identifying genes potentially linked to circulating plasma cell formation. Cox regression analysis revealed that age and mutations in OBSCN and RB1 were significant predictors of progression-free survival (PFS) in NDMM patients. Additionally, albumin, β2-microglobulin, and RB1 mutations were correlated with overall survival (OS). CONCLUSIONS: In summary, we characterized the genomic landscape of MM in diverse Chinese populations, confirmed clonal evolution, and identified prognostic genes.

Adult↗

PubMed1988

Clinical transformation of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is usually stable over months to years however a small proportion of cases may transform to more aggressive forms. These transformations include diffuse lymphoma (Richter syndrome), prolymphocytic transformation, acute lymphoblastic leukemia and multiple myeloma. There are a variety of techniques to determine whether the transformation represents a clonal evolution of the original CLL or an independent disease. These include cytogenetic analysis, immunoglobulin gene rearrangement by Southern blot analysis, and anti-idiotypic antibodies. While identity can be determined by gene rearrangement and anti-idiotypic antibodies, lack of identity can occur because of somatic mutation within a single clone. Thus, even with optimal techniques it is difficult to definitively exclude lack of identity in some instances. In most cases where transformation has taken place, definitive studies were not performed. In instances where detailed data are available, most do not suggest clonal evolution. Further studies are needed to allow definite conclusions.

Cell Transformation, Neoplastic↗