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NKX3.1 is a prostate specific homeobox gene (chromosome 8p21), which as an immunohistochemisry IHC marker has shown specificity for prostate epithelium and prostate adenocarcinomas. Normal IHC expression is found in the nucleus of benign and malignant prostate glands. Unfortunately, like most other markers, it is not completely specific. Occasional mucous glands in the lung, testis, and scattered ureteral epithelial cells have shown expression (Brown, et. al.)

Two important points: (1) expression (sensitivity) decreases with hormone refractoriness and advanced stage (metastasis), and (2) expression appears independent of Gleason score (Brown, et al.). In a related article by Mohanty et. al., they showed NKX3.1 to be very sensitive (100%) and specific (100%) in the setting of poorly differentiated prostate adenocarcinomas located in the bladder trigone with the differential diagnosis of urothelial carcinoma.

NKX3.1 may be a potential prognostic marker of progression and hormone refractoriness in low stage patients, but this needs further study (Brown, et. al.). However, due to limited sensitivity in metastatic disease, this marker appears to have limited use in the workup of carcinomas of unknown primary site (CUPS).

Table 1. Expression characteristics of NKX3.1

	Prostate Adenocaricnoma Expression
Brown, et. al. (self-made clone)
– Overall (all grades/stages)	75% (N=176)
– T1 disease	94% (N=109)
– T3/4 disease	78% (N=27)
– Metastasis	23% (N=40)
– Hormone Refractory	66% (N=128)
Mohanty, et. al. (polyclonal, Biocare)
– Poorly differentiated prostate adenocarcinoma, bladder neck	100% (N=20)

Microscopic Images

NKX3.1 - Prostate — NKX3.1 expression in prostate gland tissue.

NKX3.1 expression in prostate gland tissue.

References

Mohanty SK, Smith SC, Chang E, et al. Evaluation of contemporary prostate and urothelial lineage biomarkers in a consecutive cohort of poorly differentiated bladder neck carcinomas. Am J Clin Pathol. 2014;142(2):173–183. doi:10.1309/AJCPK1OV6IMNPFGL.

Bowen C, Bubendorf L, Voeller HJ, et al. Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Res. 2000;60(21):6111–6115.

Napsin A is an aspartic proteinase, and is normally found in lung pneumocytes and alveolar macrophages, pancreatic acini and ducts, and renal tubules. Neoplastic tissue which stains with Napsin A includes: lung adencarcinoma, renal cell carcinoma (clear cell and papillary), thyroid (papillary) carcinoma, and ovarian clear cell carcinoma.

Napsin A is primary used in combination with TTF-1 in identifying lung adencarcinomas (TTF-1 appears to be a little more sensitive in poorly differentiated tumors). While approximately 97% of Napsin A expressing lung adenocarcinomas express TTF-1, up to 13% of TTF-1 negative cases express Napsin A. The more recent description of Napkin A expression in 100% of ovarian clear cell carcinomas by Kandalaft, et al. further emphasizes the importance of using an appropriate panel of IHC stains for a given differential diagnosis to obtain optimal sensitivity and specificity.

In the setting of ovarian tumors (Kandalaft, et al.), Napsin A was 100% sensitive for ovarian clear cell carcinoma. Endometrioid carcinomas of the ovary had focal Napsin A expression in 10% of cases, but no cases of high grade serous carcinoma or serous borderline tumor demonstrated expression.

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