Chin-Lee Wu

Synovial sarcoma is a rare malignant mesenchymal neoplasm that typically occurs in soft tissue sites, and the kidney is an uncommon primary location. Previous studies of primary renal synovial sarcoma are limited by small sample sizes, and our understanding remains incomplete. Here, we present the largest multi-institutional case series to date of primary renal synovial sarcoma, with a focus on novel and molecular findings. A total of 70 cases were contributed by multiple institutions. Comprehensive clinical and histopathologic data were collected and analyzed. The mean patient age was 40 years, with a male-to-female ratio of 1.9:1. The most common presenting signs and symptoms were pain and hematuria. The mean tumor size was 11.6 cm (range: 2.3 to 26 cm), with frequent cystic change and necrosis. The mean follow-up was 29 months (range: 2 to 129 mo), and the rates of metastasis, recurrence, and death due to disease were 62.7%, 33.3%, and 50.0%, respectively. Histologically, 56.1% were monophasic synovial sarcoma, 15.1% were biphasic, and 28.8% were poorly differentiated or showed round cell features. Molecularly, SS18::SSX2 fusion was detected in the majority of cases assessed (n=19), followed by SS18::SSX1 fusion (n=6) and a rare SS18::NEDD4 fusion (n=1). Given the morphologic and immunohistochemical overlaps with many other neoplasms, accurate diagnosis with preferably molecular techniques is crucial for appropriate prognostication and treatment of this aggressive tumor.

Both embryonic-type neuroectodermal tumor and nephroblastoma arising as somatic-type malignancies are rare, particularly nephroblastoma. Concurrent embryonic-type neuroectodermal tumor and nephroblastoma have only been reported once in literature, identified in metastatic pelvic lymph nodes in association with a mixed germ cell tumor. Herein, we report the first concurrent embryonic-type neuroectodermal tumor and nephroblastoma within the primary testicular tumor, arising associated with a mixed germ cell tumor. A 36-year-old man presented with a 4.5 cm right testicular mass. He underwent right orchiectomy. Gross examination revealed a well-circumscribed, solid to cystic mass confined to the testis (pT1). Histological examination demonstrated a mixed germ cell tumor composed of teratoma (40% of the tumor mass), seminoma (10%), embryonal carcinoma (2.5%), and yolk sac tumor (2.5%), with associated germ cell neoplasia in situ. Additionally, two somatic-type malignancy components were identified, including embryonic-type neuroectodermal tumor (40%) and nephroblastoma (5%). The embryonic-type neuroectodermal tumor consisted of primitive neural tubules, rosettes, and blastemal cells. The nephroblastoma was composed of tubules, blastemal cells, and stromal cells. Immunohistochemically, the embryonic-type neuroectodermal tumor showed diffuse positivity for SOX11, with focal expression of synaptophysin and CD99, while the nephroblastoma was positive for PAX8 and WT1. The patient developed metastasis to a retroperitoneal lymph node 1 month after the orchiectomy, subsequently received chemotherapy, and is alive without metastatic disease at 13 months of follow-up.

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Purpose:Computational pathology has emerged as an attractive option for improving risk stratification in prostate cancer, but most approaches either lack interpretability or focus solely on tumor morphology. We aimed to identify an interpretable, immune microenvironment–derived computational pathology biomarker for prostate cancer. Experimental Design:We identified two cohorts (discovery and validation) with M0 prostate cancer (n = 490) who were treated with radical prostatectomy, with hematoxylin and eosin–stained whole-slide images (WSI) and data on distant metastasis (DM). We identified a third cohort from The Cancer Genome Atlas with M0 prostate cancer (n = 326) with prostatectomy WSIs and bulk sequencing. Immune cells were identified from WSIs using a deep learning method (CellViT), and spatially dense immune clusters were quantified using density-based spatial clustering of applications with noise (DBSCAN). CIBERSORTx was utilized for immune cell deconvolution and TRUST4 for immune receptor repertoire reconstruction. Results:Median follow-up was 12.6 years (discovery) and 8.1 years (validation). Fourteen percent (n = 37, discovery) and seventeen percent (n = 38, validation) had Gleason 8 to 10 disease. Immune cell abundance was not associated with DM. In discovery, increased immune cluster was associated with decreased risk of DM for Gleason 8 to 10 (adjusted hazard ratio, 0.42; 95% confidence interval, 0.19–0.93) but not Gleason 6 to 7 (1.26, 0.77–2.05; Pint = 0.020), with similar results in validation (Gleason 8–10: 0.60, 0.37–0.98; Gleason 6–7: 1.19, 0.74–1.91; Pint = 0.043). In Gleason 8 to 10 but not 6 to 7, high-cluster samples were enriched for CD8+ T cells, activated memory CD4+ T cells, regulatory T cells (P ≤ 0.037), and clonal T-cell populations (P ≤ 0.039). Conclusions:These findings propose immune spatial clustering as a novel, interpretable computational pathology biomarker and provide insight into the unique immune features of high-grade prostate cancer.

Undifferentiated/dedifferentiated melanomas typically lack all conventional melanocytic biomarkers and closely mimic non-melanocytic malignancies, risking misclassification and missed melanoma-directed therapy. We report four metastatic undifferentiated/dedifferentiated melanomas from 3 women and 1 man (median age 67 years) to genitourinary (GU) sites, involving the adrenal gland (n = 2), kidney (n = 1), and perirenal soft tissue (n = 1). Resected tumors (n = 3; median 5.4 cm) and one biopsy specimen showed high-grade epithelioid and/or spindle-cell morphology with brisk mitotic figures. All four tumors were S100/SOX10/MelanA/HMB45 negative. PAX8 was also negative. In contrast, pan-keratin/CAM5.2/cytokeratin AE1/AE3 and/or p63 showed focal/multifocal staining in all resected tumors. Additional pitfalls included focal weak TFE3 and scattered cathepsin K expression. PD-L1 was diffusely positive (70%-100% of tumor cells) in 2 tested tumors. Targeted next-generation sequencing showed a MAPK-pathway driver in all tumors: BRAF class-3 (D594N, G466R) in 2/4 tumors, NRAS Q61R in 1 tumor, and NF1 truncation (R440*) in 1 tumor, with frequent co-events ( TERT promoter mutations; CDKN2A loss; TP53 mutation). UV mutational signatures and high tumor mutational burden supported cutaneous origin. One patient showed clonal continuity between a prior liver metastasis and the subsequent adrenal gland lesion. All patients received PD-1-based immunotherapy (pembrolizumab n = 3; nivolumab n = 1). Three patients achieved complete responses and remain alive and disease-free (median follow-up 28 months; range, 1.8 months-10.5 years), while one patient was lost to follow-up at 2 months with progressive disease. Accurate recognition of these metastatic tumors enables effective therapy. To our knowledge, this is the first dedicated series of GU-site specific undifferentiated/dedifferentiated melanoma and provides a framework for work-up and management.

Purpose: Computational pathology has emerged as an attractive option for improving risk stratification in prostate cancer, but most approaches either lack interpretability or focus solely on tumor morphology. We aimed to identify an interpretable, immune microenvironment–derived computational pathology biomarker for prostate cancer. Experimental Design: We identified two cohorts (discovery and validation) with M0 prostate cancer (n = 490) who were treated with radical prostatectomy, with hematoxylin and eosin–stained whole-slide images (WSI) and data on distant metastasis (DM). We identified a third cohort from The Cancer Genome Atlas with M0 prostate cancer (n = 326) with prostatectomy WSIs and bulk sequencing. Immune cells were identified from WSIs using a deep learning method (CellViT), and spatially dense immune clusters were quantified using density-based spatial clustering of applications with noise (DBSCAN). CIBERSORTx was utilized for immune cell deconvolution and TRUST4 for immune receptor repertoire reconstruction. Results: Median follow-up was 12.6 years (discovery) and 8.1 years (validation). Fourteen percent (n = 37, discovery) and seventeen percent (n = 38, validation) had Gleason 8 to 10 disease. Immune cell abundance was not associated with DM. In discovery, increased immune cluster was associated with decreased risk of DM for Gleason 8 to 10 (adjusted hazard ratio, 0.42; 95% confidence interval, 0.19–0.93) but not Gleason 6 to 7 (1.26, 0.77–2.05; Pint = 0.020), with similar results in validation (Gleason 8–10: 0.60, 0.37–0.98; Gleason 6–7: 1.19, 0.74–1.91; Pint = 0.043). In Gleason 8 to 10 but not 6 to 7, high-cluster samples were enriched for CD8+ T cells, activated memory CD4+ T cells, regulatory T cells (P ≤ 0.037), and clonal T-cell populations (P ≤ 0.039). Conclusions: These findings propose immune spatial clustering as a novel, interpretable computational pathology biomarker and provide insight into the unique immune features of high-grade prostate cancer.

Background In the absence of primary or secondary pattern 5, Gleason pattern 4 encompasses Gleason scores 3 + 4, 4 + 3, and 4 + 4 at radical prostatectomy (RP). The associated adverse pathological features, including Gleason pattern 4% (%GP4), cribriform/intraductal carcinoma (Crib/IDC), and tertiary pattern 5 (TP5), have become particularly important factors for improving postoperative risk stratification. However, few studies have simultaneously evaluated the prognostic significance of %GP4, Crib/IDC, and TP5 specifically within Gleason pattern 4 disease. Objective To investigate the prognostic significance of %GP4, Crib/IDC and TP5 for biochemical recurrence (BCR) and metastasis in RP patients with Gleason pattern 4 disease. Methods A retrospective cohort of RP patients with Gleason pattern 4 disease was identified from 2008 to 2014 at Massachusetts General Hospital. Pathological variables included %GP4, Crib/IDC, and TP5. Patients were stratified by these features to assess their prognostic impact. Cox proportional hazards models were applied to evaluate their prognostic associations with BCR and metastasis. Results Among 559 RP patients with Gleason pattern 4 disease, 55.1% had %GP4 ≥ 50%, 49.0% were Crib/IDC-positive, and 12.3% exhibited TP5, with these three variables exhibiting clear interrelationships. All three adverse morphological features were associated with significantly worse BCR-free survival and metastasis-free survival (log-rank P < 0.001). In multivariable Cox regression, Crib/IDC demonstrated the strongest prognostic association, independently predicting an 80% increased risk of BCR (HR 1.80, 95% CI 1.35–2.40) and 90% increased risk of metastasis (HR 1.90, 95% CI 1.19–3.03). %GP4 remained a significant continuous predictor of both endpoints (HR 1.009 per 1% increase for BCR; HR 1.016 for metastasis), whereas TP5 retained significance as a predictor only for BCR (HR 1.47, 95% CI 1.04–2.06) but not for metastasis (HR 1.31, P = 0.298). Conclusion %GP4, Crib/IDC, and TP5 were correlated and adverse features in RP patients with Gleason pattern 4 disease and were associated with worse oncologic outcomes. Crib/IDC demonstrated the strongest prognostic relevance, supporting consideration of standardized reporting beyond Gleason score alone.