Overexpression of the drug resistance-associated protein metallothionein does not correlate with response of sarcomas to isolated limb perfusion treatment

J Surg Oncol. 2010 May 1;101(6):465-70. doi: 10.1002/jso.21513.


Background and objectives: Hyperthermic isolated limb perfusion with TNF-alpha and melphalan (HILP-TM) achieves high response rates in sarcomas. Melphalan resistance was previously reported to be associated with overexpression of metallothioneins (MTs). Objective of this study was to investigate the influence of MT expression on tumor responses in HILP-TM-treated soft tissue (STSs) and bone sarcomas (BS).

Methods: In primary biopsies of 41 HILP-TM-treated sarcomas (37 STSs and 4 BS), MT expression was assessed by an immunoreactive score. The pathologic response to HILP-TM was quantified in the corresponding tumor resection specimens. We studied the association of MT-IRS between histological regression (responder >90%, or non-responder <or=90% regression), tumor proliferation, and other clinico-pathological parameters.

Results: MT expression was found in 70.7% (N = 29) of tumors (high 12.2%, moderate 19.5%, and low 39.0%). After HILP-TM, 20 cases (48.8%) were categorized as "responders" and 21 (51.2%) as "non-responders." Six "responders" (14.6%) presented with complete regression. MT expression positively correlated with tumor proliferation but not with HILP-TM.

Conclusions: HILP-TM showed a favorable response in a high rate of sarcomas. Although MT overexpression was observed in this cohort of sarcomas, the immunohistochemical MT status was not predictive of the tumor response after HILP-TM treatment.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / pathology
  • Chemotherapy, Cancer, Regional Perfusion*
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Melphalan / administration & dosage
  • Metallothionein / analysis*
  • Middle Aged
  • Sarcoma / drug therapy*
  • Sarcoma / metabolism*
  • Sarcoma / pathology
  • Soft Tissue Neoplasms / drug therapy*
  • Soft Tissue Neoplasms / metabolism*
  • Soft Tissue Neoplasms / pathology
  • Tumor Necrosis Factor-alpha / administration & dosage


  • Antineoplastic Agents, Alkylating
  • Tumor Necrosis Factor-alpha
  • Metallothionein
  • Melphalan