Table 1:
Clinical and molecular features of androgen independent prostate cancer variants.
| Small Cell Prostate Cancer | Castration-Resistant/Treatment-Emergent NEPC | PRAD with NE Differentiation | Aggressive Variant Prostate Cancer | Double Negative Prostate Cancer | |
|---|---|---|---|---|---|
| Clinical context | Localized (40%) or metastatic (60%) (20) | Metastatic | Localized or metastatic | Locally advanced or metastatic | Metastatic |
| Typical Presentation | De novo or following treatment with ADT and/or ARSI | Following treatment with ADT and/or ARSI | De novo or following treatment with ADT and/or ARSI | De novo or following treatment with ADT and/or ARSI | Following treatment with ADT and/or ARSI |
| Method of Diagnosis | Histology | Histology and IHC | Histology and IHC | Histology, IHC, imaging, and clinical data | IHC |
| Clinical features | Exclusive visceral metastases; Radiographically evident lytic bone metastases; Bulky lymphadenopathy (≥5 cm) or bulky high-grade mass (≥5 cm, Gleason ≥8) in the prostate or pelvis; Short interval (≤6 months) to castration (104), (17), (14) | No differences compared to non-small cell tumors (7) | No differences compared to PRAD | Exclusive visceral metastases; Radiographically evident lytic bone metastases; Bulky lymphadenopathy (≥5 cm) or bulky high-grade mass (≥5 cm, Gleason ≥8) in the prostate or pelvis; Short interval (≤6 months) to castration (10) | |
| Histology | Small cell | Small cell; adenocarcinoma plus >/= 50% IHC staining for NE markers (36) | Adenocarcinoma with NE differentiation | Small cell; Poorly differentiated carcinoma with or without NE markers; PRAD with or without NE markers | Adenocarcinoma; squamous differentiation (rare) (105) |
| IHC | Expresses CGA, SYP, CD56, NSE; Absence of AR, PSA, PSAP, PSMA | Expresses CGA, SYP, NSE; Absence of AR, PSA, PSAP, PSMA (not required) |
Expresses CGA, SYP, NSE | Combined defects in at least two of the following: TP53, RB1, PTEN (55) | Absence of AR, PSA, and SCPC markers |
| Median PSA (range) | 0.14 (0.05–0.96) (21) | 0.38 (0–29.9) (36); 64.8 (0.4–1500) (7) | 8.7 (0–924.7) (10) | ||
| Serum markers | Elevated CGA, CEA, LDH (21), (17) | Elevated NSE and CGA (36), (7) | Low PSA (≤10 ng/mL) at initial presentation or at the time of symptomatic progression of castrate resistant disease; Elevated CEA and/or LDH (10) |
||
| Molecular features | Likely similar to CR-NEPC | Loss of TP53 and RB1 (49), (89), (7); Expression of proneural TFs (eg MYCN, FOXA2, ASCL1,INSM1); Upregulation of EZH2 (36); Global DNA methylation reprogramming (36); Upregulation of stem cell and EMT markers (eg SOX2) (49) |
Upregulation proneural TFs (eg INSM1, ASCL1, POU3F2, NKX2–1); Low expression of AR and AR regulated genes; Loss of REST; Upregulation of EMT genes (105) |
Combined defects in at least two of the following: TP53, RB1, and PTEN (55) | Increased PRC1 activity (47); Increased FGF and MAPK activity (11); Immunosuppressive and proangiogenic microenvironment (47); Upregulation of EMT genes (105) |
| Reported % of advanced prostate cancer * | 7% (89) | 8% (36); 17% (7) | 10% (11) | 21% (11) | |
| Prognosis | Median survival 13–17 months (20), (21) | Median survival 37 months (7) | Little to no difference compared to PRAD (1) | Median survival 16 months (10) |
*
There is overlap between these variants, so proportions may not be cumulative.
Abbreviations: NEPC, neuroendocrine prostate cancer; PRAD, prostate adenocarcinoma; AR, androgen receptor; NE, neuroendocrine; ADT, androgen deprivation therapy; ARSI, androgen receptor signaling inhibitor; IHC, immunohistochemistry; PSA, prostate specific antigen; CGA, chromogranin A; SYP, synaptophysin; NSE, neuron specific enolase; LDH, lactate dehydrogenase; TF, transcription factor; EMT, epithelial-mesenchymal transition