Introduction: Small-cell-carcinoma (SCC) accounts for 0.5-1% of prostate cancers. It usually presents with markedly enlarged prostate, lymph node (LN) and bone metastases and low PSA relative to disease-burden. SCC has rapid progression with a median-survival <1-year. 10% are secreting-tumors and present with paraneoplastic-syndrome. We report a patient with prostate SCC with a paraneoplasic SIADH of difficult management.
Clinical findings: A 63yo man presented with a 2 month history of painful left lower limb edema. Doppler-ultrassound excluded deep vein thrombosis and abdomen-pelvic CT and MRI documented a bulky prostatic lesion (61x83x46mm) involving left seminal vesicle, bladder trigone, anterior rectum and obturator muscles; enlarged retrocrural, lateroaortic, bilateral obturator and iliac LN , extending from the emergence of the superior-mesenteric-artery to the deep inguinal-region. Bone-scan excluded bone-metastasis. PSA was 1,2ng/dL.
Diagnosis & Treatment: Prostatic biopsy documented a SCC (AE1/AE3+, CAM5.2+, chromogranin+, synaptophysin+, CD56+, CD20-, CD3-, CD38-, CD138-, PSA-, CK7-, CK20-, CDX2+) with a Ki67=90%. Tumor was staged as cT4N1M1a (IVB) and treated with Cisplatin/Etoposide for 6-cycles. After first-treatment, he was hospitalized with symptomatic hyponatremia (nadir 111mmol/L) attributed to Cisplatin (switched to Carboplatin in second-cycle).The pain and lower extremity improved and CT after 5-cycles of chemotherapy documented a partial response (LN and prostate). For better local control, external beam radiation to prostate and obturator LN (55Gy/20Fr and 46Gy/20Fr) was given. Two-months later, he was hospitalized with painful left lower limb edema with inflammatory signs and functional impotence. Disease progression was documented on CT with new retroperitoneal and axillary LN , as well as LN involvement of the iliac-vein and focally occlusive thrombosis of the distal external-iliac-vein (Figure 1 and 2). Anticoagulation and antibiotics were started and stent was placed in external-iliac-vein, with symptomatic improvement. Second-line chemotherapy was started with Carboplatin/Docetaxel (with Pembrolizumab added on second-cycle); Foundation1® tumor testing did not identify target mutations; PD-L1=0%. Euvolemic hyponatremia (nadir 113mmol/L) due to paraneoplasic SIADH (elevated urinary osmolarity and sodium, with normal ACTH and cortisol) was diagnosed, with partial-response to water restriction, salt-tablets and loop-diuretics. Until now, patient received 4-cycles of chemotherapy with clinical improvement, despite multiple delays due to persistent hyponatremia (not present in last evalution, with can evidences some disease control) (Figure 3).
Conclusion: The case reported is a rare presentation of SCC prostate cancer, diagnosed as metastatic and bulky disease, which is unresponsive to hormonal manipulation. Management of concomitant paraneoplastic syndromes are challenging and dependent on disease control. First-line treatment consists of platinum/etoposide, typically with prompt response and early recurrence. Promising benefit of immunotherapy in prostate-SCC was reported is phase-Ib trial of pembrolizumab + standard-of-care chemotherapy with a response-rate of 43% and 12-monthPFS of 36%.

Global Congress on Prostate Cancer 2022