[Tumor cell originates from normal cell--can this process be reversed? (author's transl)].
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Animals↗
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Multiple visceral and cutaneous granular cell tumors. Ultrastructural and immunocytochemical evidence of Schwann cell origin.
Granular cell tumor of the stomach is rare and may occur in association with similar tumors in the skin. Two such tumors were found in association with cutaneous granular cell tumors in two black females. Infiltrating carcinoma of the stomach was suspected at surgery in one case. All of the lesions were typical granular cell tumors on light microscopic examination. Ultrastructural examination showed clusters of tumor cells that were surrounded by basal laminae and axonal structures were present among the tumor cells. S-100 protein immunoreactivity was also demonstrated in the tumor cells. These findings suggest a Schwannian origin for visceral granular cell tumors.
Adult↗
Immunohistochemical expression of CD10 and t(14;18) chromosomal translocation may be indicators of follicle centre cell origin in nodal diffuse large B-cell lymphoma.
AIMS: Although diffuse large B-cell lymphoma is categorized as a distinct entity in the REAL classification of lymphomas, it represents a heterogeneous group of neoplasms. A subgroup is probably of follicle centre cell origin and may evolve from a pre-existing follicular lymphoma. The t(14;18) chromosomal translocation can be demonstrated in the majority of follicular lymphomas and the aim of this study was to investigate the prevalence of t(14;18) translocation in a series of de novo nodal diffuse large B-cell lymphomas. We correlated this with the immunohistochemical expression of CD10, bcl2 and bcl6, markers which are usually expressed by the neoplastic cells in follicular lymphomas. We also correlated these parameters with the presence or absence of p53 protein expression by the neoplastic cells. METHODS AND RESULTS: Nodal diffuse large B-cell lymphomas (n=34) were stained immunohistochemically with monoclonal antibodies to CD10, bcl2, bcl6 and p53 (D07). Polymerase chain reaction (PCR) for the t(14;18) translocation was also performed. Fourteen, 24 and 29 (41%, 71%, 85%) cases exhibited positivity for CD10, bcl2 and bcl6, respectively. In 12 cases there was positivity with D07 (35%). By PCR, the t(14;18) translocation was identified in five cases (15%), four of which were positive for CD10 and bcl2 and all of which were positive for bcl6. One of five cases positive for the chromosomal translocation exhibited positivity with D07. CONCLUSIONS: In this study the t(14;18) translocation was identified in 15% of diffuse large B-cell lymphomas, all but one of which exhibited positivity for CD10, bcl2 and bcl6. These may represent cases of follicle centre cell origin which may or may not have evolved from a pre-existing follicular lymphoma. It is possible that positivity for CD10 especially may identify cases which are of follicle centre cell origin and that the absence of t(14;18) translocation in some of these cases may reflect the fact that the translocation cannot normally be demonstrated in all follicular lymphomas. Whether the presence or absence of the translocation and the immunophenotype are prognostically important should be investigated further.
Biomarkers, Tumor↗
p63 expression in solid cell nests of the thyroid: further evidence for a stem cell origin.
Solid cell nests of the thyroid are embryonic remnants of endodermal origin that may be difficult to distinguish from squamous metaplasia, metastatic squamous carcinoma, papillary microcarcinoma, medullary carcinoma, and C-cell hyperplasia. These embryonic structures are composed of main cells and C-cells; cystic structures and mixed follicles are sometimes observed intermingled with solid cell nests. Recently, p63, a p53 homologue that is consistently expressed in basal/stem cells of stratified epithelia and plays a major role in triggering the differentiation of some specific cell lineages, has been characterized. We evaluated the immunohistochemical expression of p63, cytokeratins (CAM 5.2, AE1/AE3, 34betaE12, 7, and 20), carcinoembryonic antigen, thyroid transcription factor 1 (TTF-1), thyroglobulin, and calcitonin using the streptavidin-biotin-peroxidase complex technique in 6 bona fide solid cell nests. We observed that main cells of solid cell nests are strongly decorated by p63, while C-cells and all other thyroid structures were consistently negative. Moreover, main cells expressed carcinoembryonic antigen and all cytokeratins but cytokeratin 20 and lacked TTF-1, thyroglobulin and calcitonin. In contrast to this, C-cells of solid cell nests were immunoreactive for calcitonin, CAM 5.2, AE1/AE3, and cytokeratin 7; focal immunoreactivity for TTF-1 was also observed in some C-cells. We conclude that main cells of the solid cell nests display a basal/stem cell phenotype (p63 and basal cytokeratin positivity), whereas C-cells show features of parafollicular differentiation. We conclude, furthermore, that p63 antibodies may help in distinguishing solid cell nests from their mimics.
Adenoma↗
Frequent expression of the B-cell-specific activator protein in Reed-Sternberg cells of classical Hodgkin's disease provides further evidence for its B-cell origin.
The neoplastic cells of classical Hodgkin's disease (cHD), ie, Hodgkin and Reed-Sternberg cells (HRS cells), contain clonally rearranged Ig genes, but are dissimilar to normal B cells in that they mostly do not display B-cell antigens such as CD20 or CD19. The transcription factor B-cell-specific activator protein (BSAP) influences numerous B-cell functions such as B-cell antigen expression, Ig expression, and class switch. We analyzed the expression of BSAP in cHD and control tissues by isotopic in situ hybridization and immunohistochemistry to determine whether BSAP is expressed in HRS cells and, if so, whether it may be involved in the genesis of the abnormal phenotype of these cells. Both in normal lymphoid tissue and non-Hodgkin lymphomas, BSAP transcripts and protein were almost exclusively found in B cells and B-cell lymphomas (40 cases), but were absent from the tumor cells of T-cell neoplasms (41 cases), including 19 cases of anaplastic large cell lymphoma of T- and null-cell type. Among cHD, variable numbers of HRS cells exhibited BSAP transcripts (22 of 25 cases) and protein (28 of 31 cases). Our findings show that BSAP is sufficiently specific to serve as B-cell marker. BSAP expression in HRS cells provides further strong evidence for a frequent B-cell origin of cHD and helps distinguish this disease from anaplastic large cell lymphoma of T- and null-cell type. Because BSAP is much more frequently expressed in HRS cells than the conventional B-cell antigens, the abnormal immunophenotype of HRS cells with frequent absence of B-cell antigens does not appear to be due to absent BSAP expression.
B-Lymphocytes↗
Clear cell carcinoma of the pancreas: an adenocarcinoma with unusual phenotype of duct cell origin.
Although clear cell carcinoma has been found in various organs, only six cases have been reported in the pancreas. Moreover, the histogenesis of clear cell carcinoma of the pancreas remains controversial. We report a case of clear cell carcinoma of the pancreas in a 61-year-old woman, with an unusual pheno- or genotype detected by histochemical, immunohistochemical, and K- ras oncogene analyses. Histologically, the pancreatic tumor was predominantly composed of clear cell nests with scanty fibrous stroma and scattered duct-like structures. Neither clear cell nor duct-like components of the tumor showed mucin production. Immunohistochemical analysis of neoplastic cells showed a positive reaction to antibodies against cytokeratins 8 and 19, carbohydrate antigen 19-9, and alpha-1-antitrypsin, and showed no reaction to antibodies against carcinoembryonic antigen, neuroendocrine markers, trypsin, amylase, and HMB45. K- ras analysis revealed no mutation at codon 12 in either clear cell or duct-like components. The patient has had no recurrence as yet. The pancreatic carcinoma in our patient may be of duct cell origin, but the results of histochemical, immunohistochemical, and gene analyses and patient's outcome were unusual compared with those of previous cases.
Adenocarcinoma, Clear Cell↗
Establishment of a highly differentiated thyroid cancer cell line of Hürthle cell origin.
Hürthle cell carcinomas (HCC) of the thyroid are a variant of follicular thyroid tumors. In contrast to follicular thyroid carcinoma, HCC rarely take up radioiodine and frequently metastasize to the lymph nodes. Histologically they are indistinguishable from Hürthle cell adenomas except for evidence of invasion and metastasis. How these carcinomas develop and why they behave differently than other follicular tumors is not known. Although some differentiated thyroid cancer cell lines exist, none are from Hürthle cell tumors. We have established a well-differentiated thyroid cancer cell line from a metastasis of a HCC, designated XTC.UC1. In vitro, XTC cells display epitheloid morphology, grow with a population doubling time of 4.3 +/- 0.3 days, migrate, and invade through reconstituted basement membranes. The cells are immunoreactive for and release thyroglobulin, respond to thyrotropin (TSH) with increase of intracellular cyclic adenosine monophosphate (cAMP), proliferation, and invasion of reconstituted basement membrane, thus exhibiting characteristics of well-differentiated thyroid carcinoma. In vivo, xenografted XTC cells grow with a doubling time of 9.8 +/- 0.8 days. Tumors spontaneously metastasize to the lymph nodes and less frequently to the lungs and the liver. The cells retained their differentiated function in vivo as assessed by human thyroglobulin (hTG) secretion and immunohistochemistry. This is a first report of the establishment of a unique, highly differentiated thyroid carcinoma cell line derived from an HCC. Based on the ability to invade through reconstituted basement membrane in vitro and the potential to metastasize in vivo, this cell line may provide a unique model to study invasion and metastazation of well-differentiated thyroid cancer.
Adenocarcinoma↗
Use of stimulating capacity of mixed lymphocyte reaction (MLR-S) as a possible marker for the cell-origin of null-cell acute lymphoblastic leukaemia.
The recent introduction of surface marker analysis indicates that the T-cell ALL represents 15--25%, the B-cell ALL represents less than 5% and the null-cell ALL represents more than 70% of cases. The origin of leukaemic null-cells is at present not clear. The present study shows that fresh leukaemic cells from five patients with null-cell ALL exerted a strong stimulating effect while the leukaemic cells from three patients with null-cell ALL failed to stimulate in 'one-way' MLR. Cultured leukaemic cells from three null-cell lines (NALM-16, NALL-1 and MOLT-10) consistently exerted a strong stimulation while leukaemic cells from one null-cell line (REH) exerted little or no stimulation on allogeneic lymphocytes. Leukaemic null-cells from the NALM-,6 line exhibited a lesser but significant stimulation in 'one-way' MLR. These observations lead us to speculate that leukaemic null-cells which possess a stimulating capacity may represent less differentiated leukaemic B lymphoid cells (early B-cell precursors) and leukaemic null-cells which possess no stimulating capacity may represent less differentiated leukaemic T lymphoid cells (early T-cell precursor).
Adult↗
Single cell origin of bigenotypic and biphenotypic B cell proliferations in human follicular lymphomas.
To investigate the possible relatedness of the subpopulations that make up so-called biclonal lymphomas, we examined five bigenotypic and biphenotypic follicular lymphomas using DNA probes specific for the t(14;18) chromosomal translocation, which is a characteristic feature of these neoplasms. On Southern blot analysis, both subpopulations from four of five lymphomas contained comigrating t(14;18) DNA rearrangements, confirming the single cell origins for these neoplasms. No comigrating t(14;18) DNA rearrangements were observed in the fifth lymphoma, but nucleotide sequence analysis of cloned, breakpoint DNA showed identical t(14;18) crossovers in the two subpopulations. The migration differences of both the Ig and chromosome 18 DNA rearrangements were shown to result from somatically acquired mutations of the Ig genes from the fifth lymphoma. These studies indicate that Ig gene rearrangements and idiotope expression are not consistently stable clonal markers since they are subject to variability as a result of somatic mutation. Although translocated chromosome 18 DNA rearrangements are more reliable, they may also vary among cells of some tumors since somatic mutation can affect, as well, DNA of translocated alleles in follicular lymphomas.
B-Lymphocytes↗
Cytogenetic and immunohistochemical evidence for the germ cell origin of a subset of acute leukemias associated with mediastinal germ cell tumors.
Most acute leukemias occurring in patients with mediastinal germ cell tumors (MGCTs) appear to be primary rather than therapy-related; however, no data have been obtained to date to confirm the hypothesized germ cell origin of the leukemias in this syndrome. We identified six male patients with this syndrome treated at Memorial Sloan-Kettering Cancer Center: in all six, the leukemia was studied immunohistochemically for various hematologic and germ cell antigens; in four, the karyotype of the leukemia was available; in one, the MGCT had also been karyotyped. In three patients, we found evidence of a germ cell origin of the acute leukemias. A 19-year-old male developed an acute myeloblastic leukemia 11 months after presenting with an MGCT; karyotypes of the two tumors showed them to be clonally related, both showing an i(12p), a cytogenetic marker of germ cell tumors. A 16-year-old male with probable Klinefelter's syndrome presented simultaneously with acute monocytic leukemia and an MGCT; although the MGCT was not karyotyped, the leukemia showed an i(12p). A 23-year-old male developed concurrently an MGCT and acute myelomonocytic leukemia; the leukemia cells coexpressed myelomonocytic antigens (HAM56, My4, My9) and cytokeratin, suggesting dual differentiation, myeloid and germ cell. Evidence for a germ cell origin of the acute leukemias in the three other patients was not obtained, although in all three the MGCT and the leukemia occurred simultaneously, supporting an etiologic relationship. Hence, these leukemias may represent another form of non-germ cell malignancy developing in germ cell tumors. All patients died of the leukemia, with a median survival of less than 2 months. This syndrome may be a useful pathologic model for the study of germ cell differentiation and hematopoietic ontogeny.
Adolescent↗
Primordial germ cells originate from the endodermal strand cells in the ascidian Ciona intestinalis.
The origin of germ cells in the ascidian is still unknown. Previously, we cloned a vasa homologue (CiVH) of Ciona intestinalis from the cDNA library of ovarian tissue by polymerase chain reaction and showed that its expression was specific to germ cells in adult and juvenile gonads. In the present study, we prepared a monoclonal antibody against CiVH protein and traced the staining for this antibody from the middle tailbud stage to young adulthood. Results showed that positive cells are present in the endodermal strand in middle tailbud embryos and larvae. When the larval tail was absorbed into the trunk during metamorphosis, the CiVH-positive cells migrated from the debris of the tail into the developing gonad rudiment, and appeared to give rise to a primordial germ cell (PGC) in the young juvenile. The testis rudiment separated from the gonad rudiment, the remainder of which differentiated into the ovary. PGCs of the testis rudiment and the ovary rudiment differentiated into spermatogenic and oogenic cells, respectively. When the larval tail containing the antibody-positive cells was removed, the juveniles did not contain any CiVH-positive cells after metamorphosis, indicating that the PGCs in the juvenile originated from part of the larval tail. However, even in such juveniles, positive cells newly appeared in the gonad rudiment at a later stage. This observation suggests that a compensatory mechanism regulates germline formation in C. intestinalis.
Animals↗
[Autoradiography of neurogenesis and morphogenesis of the regio cingularis of the rat. IV. Quantitative studies on the times of cell origins in the cortical lamina].
In 171 embryonic and neonatal rats has been investigated the time of origin of cells in the cortical laminae by means of autoradiographs, after injection of tritiated thymidine. It was made a comparison between the Regio cingularis mesoneocorticalis, Regio cingularis mesoarchicorticalis, Area praecentralis agranularis and Area postcentralis by the laminar differential labeling index. The time of origin indicates for each layer a principal day and three secondary days. In all regions the time of origin of cells is identically for the hylogenetic old layers VI and V, differences exist in the supragranular layers: the cells are generated earlier in the phylogenetic old areas than in the young areas.
Age Factors↗
Evidence for a B-cell origin of the proliferating cells.
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B-Lymphocytes↗
Direct evidence for the single cell origin of mouse liver cell tumours.
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Animals↗
A germ cell origin of embryonic stem cells?
Because embryonic stem (ES) cells are generally derived by the culture of inner cell mass (ICM) cells, they are often assumed to be the equivalent of ICM cells. However, various evidence indicates that ICM cells transition to a different cell type during ES-cell derivation. Historically, ES cells have been believed to most closely resemble pluripotent primitive ectoderm cells derived directly from the ICM. However, differences between ES cells and primitive ectoderm cells have caused developmental biologists to question whether ES cells really have an in vivo equivalent, or whether their properties merely reflect their tissue culture environment. Here, we review recent evidence that the closest in vivo equivalent of an ES cell is an early germ cell.
Animals↗
Common germinal-center B-cell origin of the malignant cells in two composite lymphomas, involving classical Hodgkin's disease and either follicular lymphoma or B-CLL.
BACKGROUND: Classical Hodgkin's disease (HD) and B-cell non-Hodgkin lymphoma (NHL) occasionally occur in the same patient. Such composite lymphomas represent interesting models to study the pathogenesis of B-cell lymphomas and the relationship between HD and B-cell NHL. MATERIALS AND METHODS: We analyzed two composite lymphomas (a combination of classical HD with follicular lymphoma [FL] and a combination of classical HD with B-cell chronic lymphocytic leukemia [B-CLL]) by micromanipulation of single cells from tissue sections and amplification of immunoglobulin V region genes for the clonal relationship of the tumor cells. RESULTS: In both cases, clonally related variable (V) genes with both shared as well as distinct somatic mutations were obtained from the two lymphomas, showing that in each of the cases the distinct tumor cells were members of a common germinal center (GC) B-cell clone. FL cells from two different lymph nodes of patient 1 showed a similar mutation pattern, suggesting that infiltration of these lymph nodes by tumor cells was not restricted to a particular FL cell or subclone. In the FL, a single cell was identified with a mutation signature indicating that premalignant cells can persist in the tissue. CONCLUSIONS: The cases presented here further underline the close relationship between HD and B-cell NHL and the role of the GC in lymphomagenesis. Whereas the latter was already suggested for FL and HD, the present study indicates that also in the B-CLL subset characterized by mutated Ig genes, important steps in malignant transformation happen in the GC, and that HRS cells can derive from CD5-positive B cells.
Aged↗
Primary squamous-cell carcinoma of the thyroid gland: new evidence in support of follicular epithelial cell origin.
Primary squamous-cell carcinoma (SCC) of the thyroid gland is extremely rare. We had an opportunity to treat two such cases recently. Two elderly females presented with left lobe thyroid swelling that had a history of long-standing goiter. Fine-needle aspiration (FNA) of the thyroid nodule was done in both cases. FNA cytology showed an thyroid abscess in the first, and a Hürthle-cell neoplasm in the second case. Histopathologic diagnosis was a well-differentiated squamous-cell carcinoma with an adjacent area of lymphocytic thyroiditis in the first case, and a moderately differentiated squamous-cell carcinoma in association with a Hürthle-cell adenoma in the second case. Serial sections of the excised gland ruled out any other associated thyroid malignancy. Immunostaining for pan-cytokeratin, thyroglobulin, and calcitonin were performed. The tumor, comprising polygonal and spindle cells, showed positive staining for cytokeratin and thyroglobulin; however, calcitonin did not stain any structures. Exhaustive clinical, endoscopic, and radiological examinations, i.e., X-ray of the chest, contrast-enhanced computer tomography (CECT) of the neck and chest, and ENT checkup in both cases did not reveal any primary site of squamous-cell carcinoma as the likely source of the metastases, or any contiguous spread from neighboring structures. Both patients had ipsilateral nodal metastases, and both succumbed to the disease within 6 mo of histological diagnosis. The interesting observation in both cases was thyroglobulin positivity, indicating a follicular epithelial cell origin of the SCC.
Adult↗
[A new serological diagnostic method for malignant ovarian tumors of germ cell origin. Detection of antibodies to large glycopeptides isolated from F9 cells].
Whether the presence of antibodies in patients sera to large glycopeptides (LGP) isolated from a murine teratocarcinoma cell line (F9) can be useful in diagnosing malignant ovarian tumors of germ cell origin was examined by Farr's assay. We measured the binding ability to LGP by Farr's assay of human sera from 188 patients with various ovarian tumors and 110 normal volunteers. All of the 9 patients with dysgerminoma showed negative results (less than 200 cpm). Except the cases with dysgerminoma, 9 (64%) of the 14 patients with malignant ovarian tumors of germ cell origin were found positive (more than 200 cpm). Of these 9 positive cases, 4 cases with endodermal sinus tumor (EST), 2 cases with immature teratoma, one each with immature teratoma plus EST, choriocarcinoma, and mature solid teratoma were included. In contrast, all of the sera from benign ovarian tumors (111 cases), other malignant ovarian tumors (54 cases) and normal nonpregnant women (110 cases) were found negative. These result indicated that Farr's assay of anti-LGP antibodies in sera is useful in diagnosing ovarian germ cell tumors.
Adolescent↗