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

Abstract

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.

Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer

“…Detection of hTERT expression either in plasma [65,112], peripheral blood mononuclear cells [113] or by IHC in primary tumors [114] has been identified as diagnostic for prostate, colon, esophageal cancers, and paragangliomas, respectively. In terms of breast cancer, Chen et al [97] identified hTERC and hTERT mRNA in primary tumors and sera of breast cancer patients presenting with invasive lobular carcinoma and invasive ductal carcinoma.…”

Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma

“…GAPP is composed of six parameters; those parameters have previously been examined for significance for differentiating between benign and malignant pheochromocytomas. Ki67, which is a marker for proliferating cells, has been of particular interest and examined previously (Nagura et al 1999, Elder et al 2003. Ki67 LI range is very wide in PHEO/PGL and it is generally accepted that PHEO/PGL with high Ki67 LI highly metastasize and have malignant course.…”

“…Of these, some molecular biomarkers such as the Ki67 labelling index (LI; Nagura et al 1999, Elder et al 2003, loss of cell adhesion molecules such as CD44 and human telomerase reverse transcriptase expression (van der Harst et al 2000, Elder et al 2003, August et al 2004) have been proposed as useful markers for the detection of high-grade malignancy. However, these markers failed to detect low-and moderate-grade malignant PHEO/PGL.…”

Malignant pheochromocytoma: current status and initiatives for future progress

“…HSP90 is now understood to function as a molecular chaperone that maintains the folding and conformation of proteins crucial in regulating the balance between degradation and synthesis of cell signaling proteins, including many involved in multiple oncogenic pathways. Such proteins include the human telomerase reverse transcriptase, which also shows increased expression in malignant pheochromocytoma (Boltze et al 2003, Elder et al 2003. Should HSP90 be proven to be involved in the transition from a benign to malignant pheochromocytoma phenotype, then new inhibitors of the protein, such as 17-allylamino, 17-demethoxygeldamycin (Sausville et al 2003), may be of value as treatments for the malignancy.…”

“…Hendrik Lehnert presented evidence that molecular markers, such as expression of human telomerase reverse transcriptase and heat shock protein 90 (HSP90) (Boltze et al 2003, Elder et al 2003, might provide alternative methods for distinguishing malignant from benign pheochromocytoma (Table 3). Other possible molecular markers include secretogranin II-derived peptide (Yon et al 2003) and numerous factors associated with angiogenesis (Salmenkivi et al 2001a,b, Favier et al 2002, Khorram-Manesh et al 2002, Zielke et al 2002, Salmenkivi et al 2003.…”