To Investigate The Value Of CEA,EMA,CK7,CK20,TTF-1and Napsin A In The Diagnosis And Identification Of Primary Site Of Meningeal Carcinomatosis

Objective:Carcinomatous meningitis (CM), or leptomeningealmetastases is a term that defines leptomeningeal metastases arising as a resultof metastases from systemic solid or hematological cancer. It is associatedwith insidious onset,complex clinical manifestations, rapid progression, poorprognosis and high mortality. Neither gadolinium-enhanced MRI nor CSFcytology is adequately sensitive to diagnose.The incidence of LMD mayincrease with better treatments and the overall longer survival of patients withcancer in general. In our country,the most common source of systemic cancermetastatic to the leptomeninges is lung cancer, followed by gastric cancer,breast cancer, with adenocarcinoma being the most frequent histological type.Without therapy, the median survival is4to6weeks, which can be extendedto6months to7months with treatment in selected patients. Therefore,well-understanding of MC, early diagnosis and treatment do contribute toprolong survival time, relieve symptoms and improve the quality of life.Our study makes MC of our major object，and is based on CSF.We applyimmunocytochemical staining on examining the expression of CEA, EMA,CK7, CK20,TTF-1and Napsin A in the cancer cells．The aim of this study isto compare the usefulness of CEA, EMA, CK7, CK20,TTF-1and Napsin Afor diagnosing and distinguishing primary tumor of carcinomatousmeningitis,and evaluate the clinic value of single method and consociation ofseveral methods．Methods:The60cases of MC were all diagnosed in the neurologicaldepartment of the second hospital of HeBei medical university, fromMarch,2010to February,2013.There were29cases who arising from lungcancer, among them,10cases from lung primary adenocarcinoma. There were 11cases of MC from gastric cancer,2cases from breast cancer,2cases fromovarian cancer, and16cases from unknown primary site.There were also30cases as control,including10cases of viral encephalitis,5cases of purulentmeningitis,5cases of tuberculous meningitis,5cases of cryptococcalmeningitis and5cases of Guillain-Barre syndromes. All patients werecollected6ml of cerebrospinal fluid and processed within2hours after lumbarpuncture.1All cases were collected7pieces of monolayer cerebrospinal fluid cellsslides each, dried and stained by MGG,CEA,EMA,CK7and CK20.2We performed a battery of immunocytochemistry for cytokeratin7(CK7), cytokeratin20(CK20), Thyroid transcription factor1(TTF-1) andnapsin-A in10cases from ADCs,11cases from gastric cancer,2cases frombreast cancer and2cases from ovarian cancer.3Evaluate the expression of six kinds of tumor marker expression inMC.The data was analyzed with SPSS13.0software.Results:1CSF cytologyAll the60cases were found cancer cells by CSF cytology. The positiverate of the first MGG stain was86.7%(52/60). The others were found positivein a second try.2Immunocytochemical staining2.1The evaluation of CEA,EMA and CK7in the diagnosis of MC.2.1.1Expression of CEA,EMA and CK7：The sensitivity of CEA,EMA and CK7were53.3%,81.7%,61.7%,and thespecificity was all100%.2.1.2Comparison of CEA,EMA and CK7:The sensitivity of EMA was higher than that of CEA andCK7(P<0.05).The sensitivity of CK7was higher than that of CEA(P>0.05).The sensitivity, specificity,positive and negative predictive values were86.7%(52/60),100%,100%,78.9%in combined detection of CEA/EMA andwere91.7%(55/60),100%,100%,85.7%in combined detection of CK7/EMA and were93.3%(56/60),100%,100%,88.2%in combined detection of threekinds of tumor markers.2.2The usefulness of CEA, EMA, CK7, CK20, Napsin A,and TTF-1inlooking for the primary tumor of MC.2.2.1Comparison of the sensitivity of CEA in MCs from lung cancer(55.2%)versus gastric cancer(63.6%) showed no significant difference (P>0.05).2.2.2Comparison of the sensitivity of EMA in MCs from lung cancer(82.8%)versus gastric cancer(90.9%) showed no significant difference (P>0.05).2.2.3Comparison of the sensitivity of CK7in MCs from lung cancer(72.4%)versus gastric cancer(27.3%) showed a significant difference (P<0.05).2.2.4Comparison of the sensitivity of CK20in MCs from lung cancer(0%)versus gastric cancer(27.3%) showed a significant difference (P<0.05).2.2.5Comparison of the sensitivity of TTF-1in MCs from primary pulmonaryadenocarcinoma(70%)versus all other tumors(0%) showed a significantdifference (P<0.05).The specificity and sensitivity of TTF-1were70%and100%.2.2.6Comparison of the sensitivity of Napsin A in MCs from primarypulmonary adenocarcinoma (80%)versus all other tumors(0%) showed asignificant difference (P<0.05).The specificity and sensitivity of Napsin Awere80%and100%.2.2.7Comparison of CK7,CK20,TTF-1and Napsin A:2.2.7.1Combined detection of CK7,CK20:Comparison of the sensitivity ofCK7+CK20-panel in MCs from lung cancer(72.4%) versus gastric cancer(18.2%)showed a significant difference(P<0.05).CK7+CK20+:lung can(0%)versus gastric cancer(9.1%) shows a significant difference (P<0.05).CK7-CK20+: lung cancer(0%) versus gastric cancer(18.2%) showed asignificant difference (P<0.05).CK7-CK20-:lung cancer(27.6%) versus gastriccancer(54.5%) showed no significant difference (P>0.05).2.2.7.2Comparison of the sensitivity of TTF-1(70%) versus Napsin A(80%) inMCs from primary pulmonary adenocarcinoma showed no significantdifference (P<0.05).TTF-1and Napsin A both failed expression in MCs from all other tumors.The specificity of TTF-1and Napsin A were both100%.Taking TTF-1and NapsinA both positive as the diagnostic criteria, thesensitivity, specificity, PPV and NPV were60%(6/10),100%,100%and78.9%,respectively; TTF-1positive only, those were70%(7/10),100%,100%and83.3%; Napsin A positive only,those were80%(8/10),100%,100%and88.2%; TTF-1positive or Napsin A positive, those were90%(9/10),100%,100%and93.8%.2.2.7.3Expression of CK7, CK20, TTF-1and Napsin A.In MCs from primary pulmonary adenocarcinoma, the sensitivity of CK7,CK20, TTF-1and Napsin A were80%,0%,70%and80%, respectively. Therewas no statistically significant difference between any two immunomarkersamong CK7,TTF-1and Napsin A(P>0.05). In the combined detection of thefour,the rate of CK7+CK20-TTF-1+Napsin A+,CK7+CK20-TTF-1-Nap-A+,CK7-CK20-TTF-1+NapsinA-and CK7-CK20-TTF-1-Napsin A-were60%,20%,10%and10%,respectively, without other combination modes.2cases ofMCs from breast cancer are both CK7+CK20-TTF-1-Napsin A-;In2cases ofMCs from pelvic cancer, one was CK7+CK20-TTF-1-Napsin A-1and onewas CK7+CK20-TTF-1-Napsin A-; All cases from gastric cancer wasTTF-1-Napsin A-, and CK7/CK20phenotype saw2.2.7.Conclusions:1EMA has the highest sensitivity.2The combined detection of CEA/EMA,CK7/EMA,CEA/EMA/CK7canimprove the sensitivity of diagnosis.3CEA, EMA has no clinical value in finding primary tumor of MC.4A combination of CK7,CK20,Nap-A and TTF-1would be expected to beuseful in looking for the primary site of MC.4.1CK7+CK20-suggests that the primary site is lung cancer, breast canceror ovarian cancer;4.2CK20+suggests that the primary site is gastrointestinal cancer;4.3CK7+CK20-TTF-1+suggests that the primary site is lung adenocarcinomaor small cell lung cancer; 4.4CK7+CK20-Nap-A+suggests that the primary site is pulmonaryadenocarcinoma;4.5CK7+CK20-TTF-1-or CK7+CK20-Nap-A-suggests that the primary siteis breast cancer.4.6The combined detection of TTF-1+or Napsin A+has the highestsensitivity,specificity,PPV and NPV.