title: NKX3.1 as a marker of prostatic origin in metastatic tumors.
abstract: NKX3.1 is a prostatic tumor suppressor gene located on chromosome 8p. Although most studies have shown that staining for NKX3.1 protein is positive in the majority of primary prostatic adenocarcinomas, it has been shown to be downregulated in many high-grade prostate cancers, and completely lost in the majority of metastatic prostate cancers (eg, in 65% to 78% of lesions). A recent study showed that NKX3.1 staining with a novel antibody was highly sensitive and specific for high-grade prostatic adenocarcinoma when compared with high-grade urothelial carcinoma. This raised the question that this antibody may perform better than earlier used antibodies in metastatic prostate tumors. However, the sensitivity and specificity for prostate carcinomas for this antibody in metastatic lesions was not determined. Although prostate-specific antigen (PSA) and prostatic-specific acid phosphatase (PSAP) are excellent tissue markers of prostate cancer, at times they may be expressed at low levels, focally, or not at all in poorly differentiated primary and metastatic prostatic adenocarcinomas. The purpose of this study was to determine the performance of NKX3.1 as a marker of metastatic adenocarcinoma of prostatic origin. Immunohistochemical staining against NKX3.1, PSA, and PSAP was carried out on a tissue microarray (TMA) (0.6-mm tissue cores) of hormone naïve metastatic prostate adenocarcinoma specimens from lymph nodes, bone, and soft tissue. To determine the specificity of NKX3.1 for prostatic adenocarcinoma, we used TMAs that contained cancers from various sites including the urinary bladder, breast, colon, salivary gland, stomach, pancreas, thyroid, and central nervous system, and standard paraffin sections of cancers from other sites including the adrenal cortex, kidney, liver, lung, and testis. Overall 349 nonprostatic tumors were evaluated. Any nuclear staining for NKX3.1 was considered positive and the percentage of cells with nuclear staining and their mean intensity level were assessed visually. Sensitivity was calculated by considering a case positive if any TMA core was positive. The sensitivity for identifying metastatic prostatic adenocarcinomas overall was 98.6% (68/69 cases positive) for NKX3.1, 94.2% (65/69 cores positive) for PSA, and 98.6% (68/69 cores positive) for PSAP. The specificity of NKX3.1 was 99.7% (1/349 nonprostatic tumors positive). The sole positive nonprostatic cancer case was an invasive lobular carcinoma of the breast. NKX3.1 seems to be a highly sensitive and specific tissue marker of metastatic prostatic adenocarcinoma. In the appropriate clinical setting, the addition of IHC staining for NKX3.1, along with other prostate-restricted markers, may prove to be a valuable adjunct to definitively determine prostatic origin in poorly differentiated metastatic carcinomas.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Bora
authors.initials: B
authors.lastname: Gurel
authors.forename: Tehmina Z
authors.initials: TZ
authors.lastname: Ali
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Montgomery
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Begum
authors.forename: Jessica
authors.initials: J
authors.lastname: Hicks
authors.forename: Michael
authors.initials: M
authors.lastname: Goggins
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Clark
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Bieberich
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Epstein
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
mesh_terms: D000135:Acid Phosphatase; D000230:Adenocarcinoma / Q000737:chemistry* / Q000556:secondary; D000918:Antibody Specificity; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000276:immunology; D001859:Bone Neoplasms / Q000737:chemistry* / Q000556:secondary; D002454:Cell Differentiation; D018398:Homeodomain Proteins / Q000032:analysis* / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D008198:Lymph Nodes / Q000737:chemistry* / Q000473:pathology; D008297:Male; D009382:Neoplasms, Unknown Primary / Q000737:chemistry* / Q000473:pathology; D011237:Predictive Value of Tests; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000032:analysis; D012680:Sensitivity and Specificity; D012983:Soft Tissue Neoplasms / Q000737:chemistry* / Q000556:secondary; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000032:analysis* / Q000276:immunology
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D014157:Transcription Factors; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases; D017430:Prostate-Specific Antigen