Glandular Neoplasms of the Prostate
2026-10-07 Yunshin Albert Yeh, MD, PhD, MD , Paola Dal Cin, PhD, PhD , Andres M. Acosta, MD, MD Affiliation1.Overton Brooks VA Medical Center and Louisiana State University Health Shreveport, LA
2.Brigham and Women's Hospital, Harvard Medical School, Boston , MA
3.Department of Pathology, Indiana University, Indianapolis, IN
Keywords
Glandular neoplasms,prostateClassification
Definition
Glandular neoplasms of the prostate are epithelial tumors derived from the prostatic secretory (luminal) glandular epithelium that show glandular differentiation. 1,2 These neoplasms comprise a spectrum of benign, precursor, and malignant lesions, with acinar adenocarcinoma representing the predominant malignant subtype. 1,2
| Glandular neoplasms of the prostate | Genetic event(s) |
|---|---|
| Prostatic cystadenoma | No genetic markers have been so far identified. |
| High-grade prostatic intraepithelial neoplasia (HGPIN) | HGPIN shares several molecular alterations with invasive prostatic acinar adenocarcinoma, supporting its role as a precursor lesion. Recurrent TMPRSS2::ERG gene fusions and TMPRSS2 fusions with other members of the ETS transcription factor family are detected in approximately 20–30% of cases. 1-4 In ETS fusion–negative lesions, SPOP mutations represent an alternative molecular driver. 3,4 Additional alterations include MYC overexpression, 4 PTEN loss in approximately 23% of cases, 3,4 epigenetic silencing of GSTP1 through promoter hypermethylation, 5 and progressive telomere shortening, 5 all of which are implicated in the early stages of prostate carcinogenesis. |
| Intraductal carcinoma of the prostate (IDC-P) | IDC-P is characterized by a distinctive molecular profile associated with genomic instability and aggressive clinical behavior. TMPRSS2::ERG rearrangements are identified in approximately 50–75% of cases. 6-8 Concurrent loss of TP53 and RB1 occurs in approximately 52% of tumors, while loss of PTEN cytoplasmic expression is observed in approximately 69% of cases. 6-8 TP53 and PTEN mutations are also common molecular events. 6,7,9 Additional genomic alterations include RB1 deletions, MYC amplification, FOXA1 mutations, SPOP mutations, and CDK12 alterations. 6-9 Germline mutations in DNA damage repair genes, including BRCA2, ATM, CHEK2, and BRCA1, have been reported in patients with IDC-P, and somatic BRCA2 loss has also been described. 6,8,9 Furthermore, overexpression of the long noncoding RNA SChLAP1 has been detected and is associated with aggressive disease biology. 6,8 |
| Prostatic acinar adenocarcinoma | |
| Prostate adenocarcinoma is characterized by diverse molecular alterations, most prominently TMPRSS2::ERG and other ETS-family fusions involving ERG, ETV1, ETV4, ETV5, and FLI1, which occur in approximately 50% of cases. 9-12 SPOP mutations are identified in 5–15% of tumors, while PTEN deletions or mutations and CHD1 deletions represent other recurrent alterations. 9-12 Additional genomic alterations include AR amplification, point mutations, and splice variants; TP53 mutations or deletions; FLI1 alterations; ATM mutations; MYC amplification; and NKX3-1 deletion. 10-12 Mismatch repair (MMR) deficiency, involving MSH2, MSH6, MLH1, or PMS2, occurs in <3% of primary and approximately 10% of metastatic prostate cancers. 10-12 Germline DNA-repair gene mutations are identified in approximately 12% of patients, with BRCA2 being particularly enriched in metastatic disease, along with alterations in ATM, CHEK2, BRCA1, and ATR. 10-12 Other molecular abnormalities include PIK3CA alterations (~25%), WNT/β-catenin pathway alterations (~10%) associated with adverse histopathological features, and mutations involving FOXA1, CUL3, IDH1, MED12, NCOR1, NCOR2, and CDK12. 10,12 SPINK1 overexpression occurs in approximately 10% of ETS-negative tumors. 13 SChLAP1 is associated with metastatic progression, while PCA3 overexpression occurs in >90% of tumors; EZH2 overexpression and GSTP1 hypermethylation are also characteristic molecular and epigenetic abnormalities. 10-12,14,15 Loss of CDKN1B has additionally been reported. 16 | |
| Hereditary prostate cancer is associated with germline pathogenic variants in DNA damage-repair genes, most notably BRCA2, CHEK2, ATM, BRCA1, PALB2, BRIP1, and NBN. 10,12 Germline alterations in DNA mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2, are also implicated in hereditary prostate cancer susceptibility. 17 In addition, germline HOXB13 variants, particularly the G84E variant, are a well-established genetic risk factor for hereditary prostate cancer. 10-12 | |
| Prostatic ductal adenocarcinoma (PDA) | Molecular alterations in PDA are heterogeneous and include recurrent gene fusions, mutations, and alterations in DNA repair pathways. TMPRSS2::ERG fusion is a characteristic molecular alteration, particularly in ETS fusion-positive tumors. 10,18,19 In ETS fusion-negative tumors, SPINK1 overexpression and SPOP mutations are recurrent molecular events. 15,18,19 Alterations in at least one DNA damage repair gene, including BRCA2, ATM, CHEK2, and BRCA1, are reported in approximately 50% of cases. 18,19 Additional recurrent genomic alterations involve CDK12, PTEN, PIK3CA, BRAF, KRAS, MAP2K1, FOXA1, ERCC2, CTNNB1, and APC. 18,19 |
| Treatment-related neuroendocrine prostatic carcinoma (t-NEPC) | The molecular profile of t-NEPC is characterized by alterations associated with neuroendocrine differentiation, lineage plasticity, and aggressive tumor behavior. Frequent genomic alterations include MYCN amplification and AURKA amplification, along with concurrent loss of TP53 and RB1.9,20 TP53 mutations and PTEN loss are also commonly observed. 9 Suppression of AR signaling is a characteristic feature of t-NEPC and contributes to the transition from androgen-dependent luminal prostate cancer to an AR-independent neuroendocrine phenotype. 9,20 ETS-family gene rearrangements may also be present. 9 In addition, epigenomic alterations, including aberrant DNA methylation and overexpression of the histone methyltransferase EZH2, contribute to transcriptional reprogramming and lineage plasticity during neuroendocrine differentiation. 20 |
Article Bibliography
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Citation
Yunshin Albert Yeh, MD, PhD, MD ; Paola Dal Cin, PhD, PhD ; Andres M. Acosta, MD, MD
Glandular Neoplasms of the Prostate
Atlas Genet Cytogenet Oncol Haematol. 2026-10-07
Online version: http://atlasgeneticsoncology.org/solid-tumor/209389
