The three-tier immunophenotype (desert, excluded, and inflamed) and the four-tier immunophenotype (cold, immunosuppressed, excluded, and hot) have been linked to prognosis and immunotherapy response. This study aims to evaluate whether immunophenotypes of clear cell renal cell carcinoma, identified on hematoxylin and eosin-stained slides, correlate with gene expression signatures related to cancer immunity, and clinical outcomes. We evaluated tumor-associated immune cells (TAICs) status using three methodologies: three-tier immunophenotype based on the location of TAICs, four-tier immunophenotype considering both the location and degree of TAICs and inflammation score focusing only on the degree of TAICs, using a localized clear cell renal cell carcinoma cohort (n = 436) and The Cancer Genome Atlas (TCGA)-KIRC cohort (n = 162). We evaluated the association of the TAICs status assessed by three methodologies with CD8 and PD-L1 immunohistochemistry and immune gene expression signatures by TCGA RNA-sequencing data. All three methodologies correlated with immunohistochemical and immune gene expression signatures. The inflammation score and the four-tier immunophenotype showed similarly higher accuracy in predicting recurrence-free survival and overall survival compared to the three-tier immunophenotype. In conclusion, a simple histologic assessment of TIACs may predict clinical outcomes and immunotherapy responses.

Prostate-specific antigen (PSA) is a cornerstone of screening for prostate cancer (PC); however, serum PSA levels may remain deceptively low in certain high-grade, aggressive subtypes. Aggressive-variant prostate cancer (AVPC) is a clinical entity characterized by rapid progression, bulky lymphadenopathy, and visceral metastases despite low or non-correlative PSA levels, often requiring treatment approaches beyond conventional therapies. Here, we report the case of a 69-year-old Japanese man with multiple comorbidities, including diabetes, hyperlipidemia, hypertension, angina pectoris, and lower limb occlusive arteriosclerosis, who presented to our center with lower back pain and gait disturbance. Diagnostic imaging demonstrated extensive pelvic bone metastases, seminal vesicle invasion, and pelvic and para-aortic lymphadenopathy. Laboratory evaluation showed a normal PSA level of 2.95 ng/mL and an elevated alkaline phosphatase (ALP) of 669 U/L. A prostate biopsy revealed acinar adenocarcinoma with a Gleason score of 8 (4+4) and intraductal features. Immunohistochemical tests showed positive results for NKX3.1 and androgen receptor but negative results for PSA, synaptophysin, and chromogranin A. Given these findings, the patient was diagnosed with AVPC (cT3bN1M1b) and underwent androgen deprivation therapy combined with etoposide and cisplatin (EP) chemotherapy, achieving a partial response with marked improvements in his symptoms and lymph node lesions. Subsequent radium-223 therapy further reduced bone metastases and normalized ALP levels, leading to substantial functional recovery. This case underscores the necessity of maintaining a high index of suspicion for AVPC when clinical findings contradict low PSA values. Furthermore, the favorable response to EP highlights the potential role of platinum-based chemotherapy in managing low-PSA, high-grade PC. Additional cases are needed to refine the clinical characterization of AVPC and establish evidence-based treatment guidelines.