Clinicopathologic Analysis of HER-2/neu Immunoexpression among Various Histologic Subtypes and Grades of Osteosarcoma

Abstract

Overexpression of the HER-2/neu oncogene appears to have prognostic significance in breast cancer. Recently, some have reported a relationship between increased immunohistochemical expression in osteosarcoma and poor clinical outcome. Despite limited data, a pilot trial of Herceptin, which targets the oncogene product, has been initiated for the therapy of some metastatic osteosarcomas (CCG-P9852). Archival formalin-fixed, paraffin-embedded tissue obtained from 41 patients diagnosed with osteosarcoma was examined immunohistochemically by 2 antibodies against the HER-2/neu oncogene product: CB-11 (monoclonal, 1/100) and Oncor (polyclonal, 1/200). All but one tumor (case of recurrent dedifferentiated parosteal osteosarcoma) represented primary tumor samples; when applicable, only prechemotherapy biopsies were analyzed. The study sample included the full spectrum of histologic subtypes and grades of osteosarcoma (25 conventional high grade; 3 telangiectatic; 1 small cell; 6 parosteal; 1 periosteal; and 5 lowgrade intramedullary). A case of metastatic breast cancer with known overexpression of the HER-2/neu oncogene served as the positive control. Complete membranous positivity, considered prognostically significant in breast cancer, was not seen in any of our osteosarcoma cases. At least focal cytoplasmic positivity was documented in 40 (98%) tumors using the CB11 antibody and in 34 (83%) using the Oncor antibody. The intensity of the cytoplasmic staining (0, 1-3؉) did not correlate with histologic subtype/grade, response to chemotherapy (<90% versus >90% necrosis), metastasis, or survival. Immunohistochemical overexpression of the HER-2/neu oncogene, defined as complete membranous positivity, is not present in our series of osteosarcomas. Cytoplasmic positivity is observed in most osteosarcomas, irrespective of histologic subtype/grade, and is not associated with response to preoperative chemotherapy or disease progression.

Evaluation of the predictive value of Her-2/neu gene expression on osteosarcoma therapy in laser-microdissected paraffin-embedded tissue

“…[17][18][19]23 In contrast, other studies observed Her-2/neu expression irrespective of histologic subtype and grade that was not associated with response to preoperative chemotherapy and clinical outcome. 22 Further reports did not observe Her-2/neu overexpression or even reported complete absence of Her-2/neu Figure 5 RNA was extracted from the indicated numbers of lasermicrodissected cells obtained from a decalcified, paraffinembedded and formalin-fixed osteosarcoma section and converted to cDNA. A measure of 1 ml of each cDNA was used to amplify Her-2/neu target sequence followed by a nested PCR.…”

“…In these studies, observation of cytoplasmic positivity was independent of histologic subtype and grade and not associated with response to preoperative chemotherapy or disease progression. 21,22 On the other hand, a correlation of cytoplasmic Her-2/neu positivity with a shorter overall metastasis-free survival has recently been reported. 23 These discrepancies have extensively been discussed in the literature and attributed mainly to technical issues including the type of tissue, fixation method, storage conditions, sensitivity and reliability of the antibodies used, the scoring system and the interpretation of the results.…”

“…23 These discrepancies have extensively been discussed in the literature and attributed mainly to technical issues including the type of tissue, fixation method, storage conditions, sensitivity and reliability of the antibodies used, the scoring system and the interpretation of the results. 24,22 Owing to the methodical problems concerning immunohistochemical analysis of Her-2/neu, we focused on the evaluation of the prognostic significance of Her-2/neu gene expression on the outcome of osteosarcoma therapy. However, a major disadvantage in the analysis of normal or neoplastic tissues using conventional techniques is the cellular heterogeneity of most tissue samples.…”

The clinical value of CXCR4, HER2 and CD44 in human osteosarcoma: A pilot study

“…Of 12 metastatic samples, all 12 were HER2-positive. In bone tumors, several studies on HER2 have been performed for osteosarcoma and Ewing's sarcoma, the two most common types of neoplasms of the skeleton, but the findings reported thus far are contradictory (13)(14)(15)(16)(17). Particularly for osteosarcoma, the data reported are paradoxical, ranging from studies in which HER2-increased expression was detected in 63% of patients (14) to other studies in which it was uncommon or even absent (13,15,17).…”

“…In bone tumors, several studies on HER2 have been performed for osteosarcoma and Ewing's sarcoma, the two most common types of neoplasms of the skeleton, but the findings reported thus far are contradictory (13)(14)(15)(16)(17). Particularly for osteosarcoma, the data reported are paradoxical, ranging from studies in which HER2-increased expression was detected in 63% of patients (14) to other studies in which it was uncommon or even absent (13,15,17). Moreover, as extensively discussed by Anninga and colleagues (17), inconsistent findings have also been reported with regards to HER2 status and its prognostic significance.…”