Clonality as Expression of Distinctive Cell Kinetics Patterns in Nodular Hyperplasias and Adenomas of the Adrenal Cortex

Díaz‐Cano, Salvador; Miguel, Manuel de; Blanes, Alfredo; Tashjian, Robert J.; Galera, H; Wolfe, Hubert J.

doi:10.1016/s0002-9440(10)64732-3

Cited by 53 publications

(90 citation statements)

References 30 publications

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“…Following this primary phenomenon, other genetic events may accumulate over time, as suggested by microarray data [35], that lead to additional proliferation signals and the formation of monoclonal nodules. This mechanism is consistent with the finding of both monoclonal and polyclonal lesions within the same gland [78,111,112,113]. …”

Section: Pathophysiologysupporting

confidence: 92%

Clinical and Subclinical ACTH-Independent Macronodular Adrenal Hyperplasia and Aberrant Hormone Receptors

Christopoulos

Bourdeau

Lacroix³

2005

Horm Res Paediatr

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ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a very rare cause of endogenous Cushing’s syndrome (CS). In this review, the clinical characteristics, the pathophysiology, and the management of AIMAH are described. AIMAH typically presents with overt CS, but subclinical oversecretion of cortisol has been increasingly described. The diagnosis is suspected by adrenal nodular enlargement on conventional imaging following the demonstration of ACTH-independent hypercortisolism. Final diagnosis is established by histological examination of the adrenal tissue. Bilateral adrenalectomy is the treatment of choice but unilateral adrenalectomy has been proposed in selected cases. In patients with subclinical CS, the decision to treat should be individualized. The pathophysiology of this condition has begun to be elucidated in recent years. Diverse aberrant membrane-bound receptors expressed in a non-mutated form in the adrenal gland have been found to be implicated in the regulation of steroidogenesis in AIMAH. When systematically screened, most patients with AIMAH and CS or subclinical CS exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. A protocol designed to screen patients for the presence of these aberrant receptors should be undertaken in all patients with AIMAH. The identification of these receptors provides the potential for novel pharmacological therapies by suppressing the endogenous ligands or blocking the receptor with specific antagonists.

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Section: Pathophysiologysupporting

confidence: 92%

Clinical and Subclinical ACTH-Independent Macronodular Adrenal Hyperplasia and Aberrant Hormone Receptors

Christopoulos

Bourdeau

Lacroix³

2005

Horm Res Paediatr

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“…However, precancerous lesions and early neoplasms (even those with low nuclear grade) can show the genetic and kinetic Kinetic and microsatellites in AMN features of established malignancies (clonal proliferation with accumulation of cooperative genetic abnormalities, and advantageous proliferation/ apoptosis disbalance), along with molecular evidence of progression. 1,6,17,27,28,44,45 This progression would be related to the accumulation of genetic abnormalities and selective segregation of tumor cells with invasive capabilities, which are frequently topographically distributed. 20,23,46 A progressive and significant reduction in marker expression from junctional to deep dermal compartments was a general finding mirrored by the microsatellite profile.…”

Section: Discussionmentioning

confidence: 99%

“…7,18,20,24,27,28 This ratio represents 80% of clonal cells in the sample and hence was used to increase the detection specificity. 7 (b) Additional allele bands present in tumor samples but not in the corresponding controls were considered as evidence of somatic microsatellite abnormalities.…”

Section: Tsg Microsatellite Analysismentioning

confidence: 99%

Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi

et al. 2011

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Atypical (dysplastic) melanocytic nevi are clinically heterogeneous malignant melanoma precursors, for which no topographic analysis of cell kinetic, cell cycle regulators and microsatellite profile is available. We selected low-grade atypical melanocytic nevi (92), high-grade atypical melanocytic nevi (41), melanocytic nevi (18 junctional, 25 compound) and malignant melanomas (16 radial growth phase and 27 vertical growth phase). TP53, CDKN2A, CDKN1A, and CDKN1B microsatellite patterns were topographically studied after microdissection; Ki-67, TP53, CDKN2A, CDKN1A, and CDKN1B expressions and DNA fragmentation by in situ end labeling for apoptosis were topographically scored. Results were statistically analyzed. A decreasing junctional-dermal marker expression gradient was observed, directly correlating with atypical melanocytic nevus grading. High-grade atypical melanocytic nevi revealed coexistent TP53-CDKN2A-CDKN1B microsatellite abnormalities, and significantly higher junctional Ki67-TP53 expression (inversely correlated with CDKN1A-CDKN1B expression and in situ end labeling). Malignant melanomas showed coexistent microsatellite abnormalities (CDKN2A-CDKN1B), no topographic gradient, and significantly decreased expression. Melanocytic nevi and low-grade atypical melanocytic nevi revealed sporadic junctional CDKN2A microsatellite abnormalities and no significant topographic kinetic differences. High-grade atypical melanocytic nevi accumulate junctional TP53-CDKN1A-CDKN1B microsatellite abnormalities, being progression TP53-independent and better assessed in the dermis. Melanocytic nevi and low-grade atypical melanocytic nevi show low incidence of microsatellite abnormalities, and kinetic features that make progression unlikely.

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“…Clonality analysis has helped to resolve this disparity, but the results of any analysis must be interpreted in the appropriate setting of neoplastic transformation and cellular kinetics (tumor cell selection) [15,17,18]. Additionally, the association between clonality and cell kinetics closely correlates with intratumor heterogeneity, depth of invasion, and the molecular pathways [51,52,61].…”

Section: Introductionmentioning

confidence: 99%

Molecular and kinetic features of transitional cell carcinomas of the bladder: biological and clinical implications

et al. 2001

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Molecular and kinetic analyses have contributed to our understanding of the biology of transitional cell carcinomas (TCC) of the bladder. The concordant pattern of X-chromosome inactivation of multiple TCCs appearing at different times and at different sites and concordant genetic abnormalities in a subset of muscle-invasive TCC strongly support a monoclonal origin and a homogeneous tumor cell selection throughout the neoplasm. However, topographic intratumor heterogeneity results from the accumulation of genetic lesions in tumor suppressor genes, predominantly neurofibromatosis (NF)-1-defective in the superficial compartment and tumor protein p53 (TP53)-defective in the deep one, with lower proliferation and down-regulation of apoptosis in the latter. TCCs follow the general concept of multistep carcinogenesis and proceed through two distinct genetic pathways responsible for generating different TCC morphologies. These are the inactivation of cyclin-dependent kinase inhibitors (p15, p16, and p21WAF/CIP1) in low-grade TCC and early TP53-mediated abnormalities in high-grade TCC. TCC progression correlates with genetic instability and accumulation of collaborative genetic lesions mainly involving TP53, retinoblastoma (RB)-1, and growth factors. Distinctive genetic (low incidence of RB-1 and NF-1 abnormalities) and kinetic (slower cell turnover) profiles also correlate with a "single-file" infiltration pattern and poor survival in muscle-invasive TCCs. The underlying molecular changes of carcinoma in situ involve multiple and more extensive deletions (normally TP53-defective) than coexistent invasive TCC, suggesting an independent genetic evolution, while low-grade dysplasia is mainly polyclonal and shows a low rate of gene deletions.

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Clonality as Expression of Distinctive Cell Kinetics Patterns in Nodular Hyperplasias and Adenomas of the Adrenal Cortex

Abstract: Neoplasms result from the progressive and convergent selection of cell populations, but several factors should be considered. On one hand, selection will determine tumor progression and cellular heterogeneity. On the other hand, cellular selection must be related to cell kinetics process.

Cited by 53 publications

References 30 publications

Clinical and Subclinical ACTH-Independent Macronodular Adrenal Hyperplasia and Aberrant Hormone Receptors

Clinical and Subclinical ACTH-Independent Macronodular Adrenal Hyperplasia and Aberrant Hormone Receptors

Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi

Molecular and kinetic features of transitional cell carcinomas of the bladder: biological and clinical implications

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