Panels Of Combined Markers Help Discriminating Pulmonary Metastatic Breast Carcinoma And Primary Pulmonary Adenocarcinoma

ObjectiveThe aim of this study was to investigate the specificity and sensitivity of combined biomarkers in distinguishing metachronous lung adenocarcinoma in patients with a history of breast cancer, and to clarify the clinicopathological characters of metachronous lung cancer with a history of breast cancer.Methods(1) Case-control study was employed in321patients including41pulmonary metastatic breast carcinomas,33pulmonary metastatic adenocarcinom other than breast origin,52primary pulmonary carcinomas,35primary breast carcinomas and160adenocarcinomas from other organs than breast and pulmonary origin. Tissue microarray was constructed for immunohistochemical detection against Mammoglobin (MGB1), Gross cystic disease fluid protein-15(GCDFP-15), Estrogen receptor (ER), Progesterone receptor (PR), Thyroid transcription factor-1(TTF-1), Surfactant protein A (SP-A), Surfactant protein B (SP-B) and Napsin A.The specificity and sensitivity of different antibodies were then assessed and selected by diagnosis test and ROC analysis for discrimination between primary lung adenocarcinoma and metastatic breast carcinoma in55pulmonary malignancies with a history of breast cancer.(2) QRT-PCR method was employed in detecting other51primary breast and48pulmonary carcinomas than the above321cases for BS106and BU101gene expression, and significance between pulmonary and breast carcinomas was observed by rank-sum test.(3) According to the above immuohistochemical panels, fifty-five metachronous lung cancer with a history of breast cancer were divided into metastatic breast carcinomas and secondary primary pulmonary carcinomas. Clinicopahtoligcal characters were retrospectively analyzed and two special cases were reported separately. Results(1) TTF-1, NapsinA, SP-A and SP-B were positively expressed in84.6%,82.7%,69.2%, and46.2%of lung adenocarcinomas, respectively; and were not detected in non-pulmonary adenocarcinomas and pulmonary metastatic non-mammary adenocarcinomas. MGB1and GCDFP-15were positively expressed in62.9%and42.9%of breast carcinomas, respectively, and were not detected in lung adenocarcinomas. The expression level of ER and PR were significantly higher in breast carcinoma than those in lung adenocarcinoma (88.6%vs.2.6%,71.4%vs.2.6%; respectively). The diagnostic index for pulmonary primary adenocarcinoma is TTF-1>NapsinA>SP-A> SP-B, as for pulmonary metastatic breast carcinoma is ER>MGB1> GCDFP-15>PR.Forty-seven of55pulmonary malignant nodules with a history of breast carcinoma were conversely expressed between TTF-1/NapsinA/SP-A/SP-B and MGB1/GCDFP-15/ER/PR, which was consistent with the grouping of11pulmonary primary and36metastatic cases based on morphological characters. Series-parallel connection diagnostic test was applied among the above markers. We found that the differential efficacy of double markers was higher than that of single marker (p<0.05),and was equivalent with triple or four markers (p>0.05) among the markers of TTF-1/NapsinA/SP-A/SP-B and MGB1/GCDFP-15/ER/PR, respectively. The combination of four makers of MGB1, ER,SP-B, and TTF-1(or NapsinA) was superior to other marker combinations for diagnosis of pulmonary metastatic breast carcinomas, with the sensitivity of91.7%and specificity of81.8%, and an area under the curve(AUC)=0.941, significantly larger than that of the standard normal reference line (AUC=0.5)(p<0.05)。(2) The expression levels of BU101and BS106genes were tested in other51primary breast carcinomas and48primary pulmonary carcinomas by QRT-PCR method. The expression fold change for breast primary carcinomas was found significantly higher than that of primary pulmonary carcinomas (Rank-sum test, p<0.05)).(3) Clicopathological analysis of55pulmonary malignant nodules with a history of breast carcinomas revealed no significance in the length of breast carcinoma history, numbers of nodules, whether or not a radiotherapy history and the pulmonary operative range (Chi-square test,p>0.05). The two special cases revealed specific analysis according to specific situations for individual diagnosis and treatment scheme.Conclusions(1) Four markers combination of MGB1+ER+SP-B+TTF-1(or NapsinA) can be efficiently used in differentional diagnosis for pulmonary metastatic breast carcinomas, thus can provide pathological principal evidence for individualized therapy for pulmonary malignancy patients with a history of breast carcinomas.(2) Genes BS106and BU101may be promsing biomarkers for differential diagnosis of pulmonary metastatic breast carcinomas for their higher level in primary breast carcinomas than that in primary pulmonary carcinomas. Further investigation is needed for the correspondingly protein markers in differential diagnosis of pulmonary metastatic breast carcinomas.(3) The length of breast history, chest radiotherapy history, and the numbers of pulmonary nodules are not independent factors for differential diagnosis of pulmonary metastatic breast carcinomas. We conclude from the clinicopathological analysis of55cases that frozen section and detailed postoperative pathological reports are essential for pTNM staging and personalized treatment for patients with a breast carcinoma history.