Stains & CD markers
Prostate specific membrane antigen (PSMA)

Editorial Board Member: Maria Tretiakova, M.D., Ph.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Sven Perner, M.D., Ph.D.
Lars Tharun, M.D.

Last author update: 17 August 2020
Last staff update: 18 June 2021

Copyright: 2002-2024,, Inc.

PubMed Search: PSMA pathology [TIAB]

Sven Perner, M.D., Ph.D.
Lars Tharun, M.D.
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Cite this page: Sven P, Lars T. Prostate specific membrane antigen (PSMA). website. Accessed June 16th, 2024.
Definition / general
  • Type II transmembrane glycoprotein with folate hydrolase and NAALAD (N acetylated alpha linked acidic peptidase) activity, encoded by the FOLH1 (folate hydrolase 1) gene
  • Upregulated with androgen deprivation (EJNMMI Res 2015;5:66)
  • Oncogenic in prostate carcinoma via PI3K and Akt pathways (J Exp Med 2018;215:159)
  • Can be effectively targeted for both diagnostic and therapeutic purposes in the management of prostate carcinoma
Essential features
  • Membranous and cytoplasmic marker of prostate adenocarcinoma, less sensitive and specific than NKX3.1
  • Upregulated with androgen deprivation
  • Correlates with higher Gleason grade
  • Less frequently found in various other tumors
  • Synonymous names outside pathology:
    • Glutamate carboxypeptidase II (GCPII)
    • N acetyl L aspartyl L glutamate peptidase I (NAALADase I)
    • NAAG peptidase
  • In prostate carcinoma: PSMA's carboxypeptidase activity releases glutamate from vitamin B9 and other glutamated substrates, which activate metabotropic glutamate receptor (mGluR I); activated mGluR I then induces activation of phosphoinositide 3 kinase (PI3K) through phosphorylation of p110β (J Exp Med 2018;215:159)
  • In brain: catalyzes hydrolysis of N acetylaspartylglutamate (NAAG) to glutamate and N acetylaspartate (NAA), thus indirect inhibitory effect of NAAG on GABA with consequent regulation of glutamate neutrotransmitter level (J Biol Chem 1987;262:14498)
  • In gut: assists in folate uptake (Clin Cancer Res 1996;2:1445)
Clinical features
  • Clinical use in prostate cancer imaging by gallium 68 PSMA PET scan
  • PSMA PET is also positive in salivary glands (J Nucl Med 2019;60:1270)
  • Radioligand therapy using Lu 177 labelled PSMA ligands for metastatic prostate cancer
  • Membranous and cytoplasmic
Uses by pathologists
  • Sensitive identification of metastatic prostate adenocarcinoma, especially if NKX3.1 antibody is unavailable (Int J Mol Sci 2017;18:1151)
    • PSMA positive in 84.3% of metastatic prostate carcinoma compared with 100% positivity for NKX3.1
  • Sensitive and specific for prostate carcinoma versus urothelial carcinoma (J Pathol Transl Med 2016;50:345)
    • PSMA positive in only 0.7% of urothelial carcinoma; PSMA is less specific than NKX3.1, though (0% positive in urothelial carcinoma)
  • Staining intensity increases with Gleason grade (Sci Rep 2018;8:4254)
Prognostic factors
  • High expression of PSMA on biopsy is associated with higher risk of disease recurrence (Front Oncol 2018;8:623)
Microscopic (histologic) images

Contributed by Lars Tharun, M.D.
Bone metastasis

Bone metastasis

Low PSMA expression

Low PSMA expression

Moderate PSMA expression

Moderate PSMA expression

Strong PSMA expression Strong PSMA expression Strong PSMA expression

Strong PSMA expression

Positive staining - normal
  • Prostate epithelial cells
  • Adrenal gland, bladder, breast, esophagus, fallopian tube, kidney, large intestine, liver (canalicular membranes), ovary, small intestine, spinal cord, stomach, testis
Positive staining - disease
Negative staining
Board review style question #1

A 60 year old patient presents with backache. Bone biopsy shows confluent tubular aggregates in between bony spicules. PSMA immunohistochemistry reveals membranously accentuated reactivity in all tumor cells. Which is correct regarding PSMA?

  1. Expressed in most cases of metastatic prostate carcinoma
  2. Expression is lost with grade progression
  3. NKX3.1 is less specific in detecting prostate carcinoma
  4. NKX3.1 is less sensitive in detecting prostate carcinoma
Board review style answer #1
A. Expressed in most cases of metastatic prostate carcinoma

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Reference: Prostate specific membrane antigen (PSMA)
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