Recently, during rounds at the Fuda Haizhu Campus, we encountered a case of a prostate cancer patient with multiple metastases. The patient, around 60 years old, had a relatively young age for this common geriatric disease. Additionally, it was a rare small cell prostate cancer that had already metastasized outside the prostate during diagnosis.
Small cell cancer is mainly seen in lung cancer. Extrapulmonary small cell carcinoma (EPSCC) is rare, with an incidence of approximately 0.1%-0.4% of all cancers (Intern Med J. 2023;53(9):1556). A 2023 article reviewed 60 cases of EPSCC, with the most common primary sites being the genitourinary system (42%, mainly prostate and bladder) and the gastrointestinal tract (28%, mainly esophagus and colon). Previously, the Haizhu Campus had admitted a 28-year-old woman with small cell ovarian cancer, which is even rarer.
Small cell prostate cancer was first reported in 1975 (Nat Rev Urol. 2014;11(4):213). In 2019, Metzger and colleagues collected literature reports on 657 patients, with a median age of 68 years. Most patients had positive lymph nodes (60.1%) and metastatic disease (70.0%), with a median survival of 12 months (11.1-13.3 months) (Prostate. 2019;79(12):1457). The disease has the following clinical features:
Short or no response to androgen deprivation therapy (ADT);
Significant prostate enlargement or large soft tissue pelvic mass, visceral, or large lymph node involvement;
High prevalence of osteolytic metastases;
Frequent intracranial metastases (more common than conventional prostate adenocarcinoma);
Rapid disease progression (within 6 months);
Low or undetectable serum PSA levels;
Paraneoplastic syndromes related to ectopic hormone production (parathyroid hormone and adrenocorticotropic hormone-like peptides);
Elevated serum LDH (≥2×IULN), malignant hypercalcemia, and elevated serum CEA (≥2×IULN).
Further research found that small cell prostate cancer often arises from "standard" prostate adenocarcinoma. Standard prostate cancer is mostly sensitive to androgen receptor (AR) antagonists. Drugs like abiraterone, enzalutamide, apalutamide, and darolutamide have been used for first-line androgen deprivation therapy (ADT). These effective AR-targeted drugs are increasingly used in the early stages of the disease spectrum to delay disease progression and extend survival. Although these therapies can effectively control androgen-dependent prostate tumors, the prostate tumor cells that survive the powerful treatments may evolve and develop resistance.
Studies indicate that the dual inactivation of TP53 (a gene encoding the p53 protein) and RB1 (a gene encoding the RB protein) is the basis for ADT resistance, pathologically manifesting as the transformation from adenocarcinoma to neuroendocrine/small cell carcinoma. Reports suggest that patients with a history of prostate adenocarcinoma develop small cell carcinoma about 18-25 months after the initial prostate adenocarcinoma diagnosis. Approximately 65% of primary prostate adenocarcinomas and 90% of metastatic prostate adenocarcinomas develop into neuroendocrine prostate cancer (including small cell carcinoma) after ADT (Int J Mol Sci. 2021;22(23):12742). Therefore, in clinical practice, when ADT is ineffective or initially effective but later fails, it should be considered that aggressive prostate cancer variants induced by the treatment may have occurred.
Cancer is a dynamic disease, and any single static treatment method, whether chemotherapy or gene-targeted drugs, often fails. To avoid threats, cancer cells undergo an infinite number of mutation combinations and evolve according to the laws of evolution. Clinically, it is essential to recognize and be vigilant against this therapeutic "evolution" of cancer cells to implement effective prevention and intervention strategies.