Prognostic Value of Immunohistochemical Expression of Topoisomerase Alpha II, MIB-1, p53, E-Cadherin, Retinoblastoma Gene Protein Product, and HER-2/neu in Adrenal and Extra-adrenal Pheochromocytomas

Gupta, Dilip; Shidham, Vinod B.; Holden, Joseph A.; Layfield, Lester J.

doi:10.1097/00022744-200012000-00003

Cited by 33 publications

(26 citation statements)

References 29 publications

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“…Conflicting results have been reported for DNA flow cytometry (13,31,32), overexpression of the proto-oncogene products c-erb B-2 and bcl-2 (a marker of apoptosis; 16,33,34), mutations in the tumor suppressor gene p53 and its product (14,33,35), elevated plasma neuropeptide Y levels (36, 37), elevated urinary dopamine levels reflecting an immature secretion pattern (27), and absence of S-100 sustentacular cells (16,17). Immunohistochemical staining for the cell adhesion molecule E-cadherin (14), the oncogene product of HER-2/neu (14), PCNA (a marker of proliferative activity; 13), somatic mutations in the RET proto-oncogene (17), and angiogenesis assessed by high microvascular count (15) seem to have no potential diagnostic utility in this tumor type. On the other hand, topoisomerase alpha II, a cell cycle-related protein that correlates with Ki-67 expression (14), and loss of inhibin/activin betaB-subunit expression may prove to be of diagnostic value but need further evaluation (38).…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemical staining for the cell adhesion molecule E-cadherin (14), the oncogene product of HER-2/neu (14), PCNA (a marker of proliferative activity; 13), somatic mutations in the RET proto-oncogene (17), and angiogenesis assessed by high microvascular count (15) seem to have no potential diagnostic utility in this tumor type. On the other hand, topoisomerase alpha II, a cell cycle-related protein that correlates with Ki-67 expression (14), and loss of inhibin/activin betaB-subunit expression may prove to be of diagnostic value but need further evaluation (38).…”

Section: Discussionmentioning

confidence: 99%

“…Ki-67 expression can be detected with the monoclonal antibody MIB-1 and is used as a marker of proliferative activity. It has been suggested as a predictor of malignancy in many cancer types, including pheochromocytoma (13)(14)(15)(16)(17).…”

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KI-67 AND hTERT Expression Can Aid in the Distinction between Malignant and Benign Pheochromocytoma and Paraganglioma

et al. 2003

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The clinical and histopathological distinction between benign and malignant pheochromocytomas and paragangliomas is difficult, and reliable diagnostic markers are lacking. Here we have evaluated the prognostic value of human telomerase reverse transcriptase (hTERT) gene expression detected by reverse transcription PCR (RT-PCR); telomerase activity (TA) measured by TRAP (telomeric repeat amplification protocol) assay; immunohistochemical staining for Ki-67/MIB-1; and the mRNA expression of matrix metalloproteinase (MMP)-2 and EMMPRIN (extracellular matrix metalloproteinase inducer) analyzed by in situ hybridization in 32 primary pheochromocytomas or abdominal paragangliomas. hTERT was expressed in 7/11 malignant tumors (defined as presence of metastasis and/or extensive local invasion) as compared with in 2/21 benign tumors. All of the benign tumors showed <1% proliferative activity, as measured by Ki-67/MIB-1 staining. In all three patients with malignant tumors who developed metastases and/or invasive local recurrence during follow-up, the tumors were positive for either hTERT expression or Ki-67/MIB-1 immunoreactivity. TA was not a significant discriminator between benign and malignant tumors, and the value of EMMPRIN and MMP-2 as predictive markers was limited. In conclusion, the findings imply that the combined use of Ki-67/ MIB-1 and hTERT, in addition to histopathology, provides a highly specific tool to identify benign pheochromocytoma and abdominal paraganglioma cases that are not at risk of developing recurrent or metastatic disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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KI-67 AND hTERT Expression Can Aid in the Distinction between Malignant and Benign Pheochromocytoma and Paraganglioma

et al. 2003

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“…[10][11][12] Five studies, including one from our own group, exclusively described the results of immunohistochemical staining. [13][14][15][16][17] Other studies, examining p53 mutations with or without concomitant protein expression, included only benign or very few malignant pheochromocytomas, and generally did not show p53 gene mutations. [18][19][20] In contrast, Yoshimoto et al 21 described a relatively high frequency of singlestrand conformation polymorphism (SSCP) analysis abnormalities and p53 gene mutations in multiple and malignant pheochromocytomas from an Asian population.…”

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Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

et al. 2008

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Genetic changes in the tumorigenesis of sporadic pheochromocytomas are poorly understood, and there are no good markers to discriminate benign from malignant pheochromocytomas. p53 is a tumor suppressor gene and aberrations in this gene are frequently found in many tumor types. The role of p53 in pheochromocytoma tumorigenesis is unclear, with some studies suggesting that p53 mutations can be used to discriminate benign from malignant pheochromocytomas while other studies do not find such an association. Because most of these investigations were hampered by small series of tumors and the use of varying methods, we have performed a comprehensive analysis of p53 aberrations in a large series of pheochromocytomas. Comparative genomic hybridization analysis of 31 benign and 20 malignant tumors showed loss of the p53 locus at chromosome 17p13.1 in 23/51 (45%) cases, and most of these results were confirmed by fluorescence in situ hybridization. Forty-three tumors, including the malignant tumors and the tumors with loss of the p53 locus, were analyzed for p53 mutations in exons 5-8, but none were found. Furthermore, p53 immunohistochemistry on 35 cases revealed strong nuclear p53 expression in only two pheochromocytoma metastases, all other tumors being negative. We conclude that, although there is frequent loss of the p53 locus on 17p, the p53 gene does not appear to play a major role in pheochromocytoma tumorigenesis.

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“…[5][6][7][8] Moreover, the biological behavior of PCC has been analyzed in various immunohistochemical studies. [9][10][11][12] Unlike the mitotic count, which was found to be useless for predicting the malignant behavior of PCC, 13 the expression of Ki-67 is of prognostic significance. 14,15 The expression of membrane-bound surface glycoprotein CD 44 in both the standard (S) form or its isoforms seems to be associated with invasive growth and development of metastases.…”

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CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas

August¹,

August²,

Schroeder³

et al. 2004

Modern Pathology

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The natural course of pheochromocytomas (PCC) cannot be predicted for certain on the basis of primary histology, their malignant character can only be confirmed by the occurrence of metastases during follow-up. Based on the recently proposed PASS score for evaluation we examined 37 adrenal (36 sporadic and one familial) and six sporadic extra-adrenal paragangliomas (all designated as pheochromocytomas) with a 'malignant histology' to find additional predictive factors. Drawing upon the follow-up (18 months to 12 years, mean 5.8 years) metastasized (n ¼ 20) and nonmetastasized (n ¼ 23) courses could be distinguished. Metastasized PCC revealed significantly (P ¼ 0.03) more copy number changes on comparative genomic hybridization (CGH) (mean 8.3) than nonmetastasized tumors (mean: 4.3). The most frequent chromosomal alterations were losses on 1p (75.6%) and 3q (44%). Both were detected with identical frequency in metastasized and nonmetastasized PCC. A gain on 17q (P ¼ 0.025) was significantly predominant in malignant courses and suggests similarities in the genetic origin and progression of PCC and neuroblastomas. The proliferative activity (MIB-1 score) of metastasized PCC (n ¼ 20) was found to be significantly higher in metastasized tumors (mean 12.8% vs mean 3.5%). In contrast, the semiquantitatively scored membrane-bound staining of CD 44-S was stronger in tumors without metastases (mean 2.1 vs mean: 0.25) during the follow-up period (Po0.01). Although the results correspond to the established weight differences the tumor weight does not appear to be an independent prognostic factor. Our study suggests that CD 44-S and MIB-1 immunostaining as well as the CGH results might complement the PASS score in predicting a metastasized course of PCC. Regardless of tumor weight, tumors with a 'malignant histology' are highly prone to metastasize when more than 5% of MIB1-positive nuclei are present or CD44-S immunostaining is negative, or both. PCC with 10 or more copy number changes on CGH must be referred to as malignant tumors. The safe distinction between benign and malignant pheochromocytomas (PCC) is an unresolved dilemma beleaguering diagnostic pathology to the present day. In most cases the decision is therefore based on the occurrence of metastases as the only proof of malignancy. Recently, Thompson 1 proposed an adrenal gland scoring scale (PASS) capable of determining malignancy solely on the grounds of conventional histological criteria. Within the framework of this scoring scale, less prognostic importance is attributed to vascular and capsular invasion (with a score of 1 point each) than to growth pattern, necroses and characteristics of proliferative behavior (high cellularity, cellular monotony, more than three mitoses/10 HPF and the occurrence of atypical mitoses). These characteristics each have a score of two points).In recent reports on adrenal and extra-adrenal PCC a number of chromosomal aberrations were discussed with a view to their possible involvement

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Prognostic Value of Immunohistochemical Expression of Topoisomerase Alpha II, MIB-1, p53, E-Cadherin, Retinoblastoma Gene Protein Product, and HER-2/neu in Adrenal and Extra-adrenal Pheochromocytomas

Cited by 33 publications

References 29 publications

KI-67 AND hTERT Expression Can Aid in the Distinction between Malignant and Benign Pheochromocytoma and Paraganglioma

KI-67 AND hTERT Expression Can Aid in the Distinction between Malignant and Benign Pheochromocytoma and Paraganglioma

Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas

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