Predicting metastasis of pheochromocytomas using DNA flow cytometry and immunohistochemical markers of cell proliferation: A positive correlation between MIB-1 staining and malignant tumor behavior

Cancer. 1999 Oct 15;86(8):1583-9.


Background: In the absence of metastases, there are no reliable microscopic features that distinguish malignant from benign pheochromocytomas. Because a common feature of malignancy is the loss of cell cycle regulation and normal growth arrest, the authors hypothesized that analysis of the cell cycle could be used to aid in the diagnosis of malignant pheochromocytoma.

Methods: Cell cycle analysis of archival samples of 51 pheochromocytomas (40 sporadic, 11 familial) from 45 patients, including 6 malignant and 45 benign tumors, was conducted. Flow cytometry data and immunohistochemistry for markers of cell proliferation (proliferating cell nuclear antigen [PCNA] and MIB-1 [Ki-67]) were correlated with the authors' clinical data base records, with a mean follow-up of 66 months.

Results: No correlation of DNA ploidy, S-phase fraction by flow cytometry, or PCNA with malignancy was observed. Staining for the MIB-1 nuclear proliferation marker was positive in 3 of 6 (50%) of the malignant pheochromocytomas and negative in all 45 benign tumors (P< 0.01).

Conclusions: Contrary to some previous reports, a diploid DNA pattern does not necessarily predict benign behavior of pheochromocytoma. In this study, cell cycle analysis and, in particular, assessment of the MIB-1 nuclear proliferation marker was useful in the histologic evaluation of pheochromocytoma, as MIB-1 was expressed only in malignant tumors.

MeSH terms

  • Adolescent
  • Adrenal Gland Neoplasms / genetics
  • Adrenal Gland Neoplasms / metabolism
  • Adrenal Gland Neoplasms / pathology*
  • Adult
  • Aged
  • Biomarkers / analysis*
  • Cell Division
  • Child
  • DNA, Neoplasm / analysis*
  • DNA, Neoplasm / genetics
  • Female
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen / analysis
  • Male
  • Middle Aged
  • Neoplasm Metastasis*
  • Pheochromocytoma / genetics
  • Pheochromocytoma / metabolism
  • Pheochromocytoma / pathology*
  • Ploidies
  • Prognosis
  • Proliferating Cell Nuclear Antigen / analysis


  • Biomarkers
  • DNA, Neoplasm
  • Ki-67 Antigen
  • Proliferating Cell Nuclear Antigen